Definium Therapeutics Stock

Hello and welcome to the Definium Therapeutics Phase III PANORAMA Top Line Results Call. Today's call is being recorded. [Operator Instructions] I would now like to pass the call over to Rob Barrow, Chief Executive Officer. Please proceed.

Hello, everyone, and thank you for joining us this morning. I'm joined today by our Chief Medical Officer, Dr. Dan Karlin; our Chief Financial Officer, Brandi Roberts; and our Chief Commercial Officer, Matt Wiley. We cannot be more excited to be here with you this morning to share the topline results from PANORAMA, our third pivotal study of DT120 ODT 100 micrograms and our second Phase III study in generalized anxiety disorder, or GAD. Before we get started, please note that on today's call, we will be making certain forward-looking statements. We encourage you to review our SEC filings for a discussion of the risks and uncertainties associated with these statements, including the risks described in our most recent annual and quarterly reports.

Today's results mark an important milestone for Definium and our DT120 program as we have now replicated the unprecedented results reported last month from VOYAGE, our first pivotal study of DT120 in GAD. Having delivered 3 positive Phase III studies across GAD and MDD over the past 12 weeks, our confidence in the transformational potential of DT120 has never been higher. We believe DT120 represents a highly differentiated profile with the potential to redefine standards of care and become a best-in-class therapy across 2 of the largest and most impactful indications in psychiatry. I'd like to thank our study participants, investigators, partners and the incredible Definium team for making all of this possible.

We are deeply appreciative and humbled by the commitment, trust and belief in our shared vision. Only together could we have arrived at this remarkable moment. At Definium, we have an ambitious vision and believe profound change in psychiatry is truly possible. We set a high standard for DT120 to demonstrate that a single supervised dose can deliver rapid, robust and durable efficacy and offer new hope to the tens of millions of people living with anxiety, depression and other mental health disorders.

The burden that GAD places on patients, families and society is enormous, impairing daily function, productivity and quality of life, and that burden continues to grow. The prevalence has more than tripled since the early 2000s, and GAD is now estimated to be experienced by 10% of the U.S. adult population. Promisingly, we've entered a new era of far greater awareness and openness around anxiety and its impact on people's lives. Despite this need and awareness, there hasn't been a new drug approved for GAD since 2007. And that's not because of a lack of effort.

Over that period, roughly a dozen drug candidates spanning numerous mechanisms have advanced into late-stage development. Nearly all have failed, none have been approved and most have been unable to demonstrate meaningful improvement over placebo. That long period without success has also left the field without a modern benchmark for what truly compelling efficacy in GAD looks like. We believe the PANORAMA results we're sharing today continue to change that picture. They represent the promise of real progress for patients with GAD and further reinforce the potential of DT120 to help usher in a new era of psychiatric care.

PANORAMA marks our third pivotal readout for DT120 this year and our second pivotal readout in GAD. As with our EMERGE and VOYAGE readouts, PANORAMA met its primary and all key secondary endpoints with a high degree of statistical significance. Consistent positive outcomes across 3 complementary studies further strengthens our confidence in DT120's potential and the broader opportunity ahead. In PANORAMA, DT120 ODT 100 micrograms showed a 5.1-point placebo-adjusted improvement over placebo at the week 12 primary endpoint with a p-value of less than 0.0001.

This efficacy was rapid with a 5.3-point placebo-adjusted improvement on the HAM-A at week 1 and a 0.8-point placebo-adjusted improvement on the CGI-S at day 2, both with p-values also less than 0.0001. DT120 was well tolerated with no new safety signals identified, including no suicidality signal. We continue to observe efficient and predictable treatment session dynamics with an average time to clearance on the structured end of session checklist of 6.2 hours and 94% of participants clearing by hour 8. PANORAMA included a DT120 ODT 50-microgram arm, which served as a functional control but was not powered for or assessed in prespecified statistical comparisons. The 50 microgram dose produced a 3.6-point improvement over placebo at weeks 4 and 12, approximately 50% and 29% less than the 100 microgram dose.

The results from both VOYAGE and PANORAMA are closely aligned with the dose-response model generated from our Phase IIb study. It's also worth noting that as in Phase II, at both the 50 and 100 microgram doses of DT120, over 90% of participants correctly guessed their assignment of drug, supporting the conclusion that the dose-response observed is a real treatment effect and is not attributable to functional unblinding. To further emphasize this point, across studies, the 100-microgram dose has consistently exceeded our efficacy target of a placebo-adjusted improvement of at least 4 points on the HAM-A.

The 50-microgram dose has not. At the same time, the adverse event profile was similar across the 50-and 100-microgram doses and the median time to end of session clearance was 6 hours for both. In our view, these results decisively settle the question of dose selection and clearly support the advancement of DT120 ODT 100 micrograms. To put these results in perspective, we have now consistently shown that DT120 100 micrograms delivers a large effect that stands out against the current standard of care in GAD at both week 12 and at earlier time points.

In summary, in a disorder with high prevalence, high burden, high unmet need and no innovation in decades, a single dose of DT120 has consistently shown a rapid and durable effect with a magnitude that is considerably larger than the drugs approved today. We cannot be more excited about what this can mean for patients and the potential to redefine what they can expect from psychiatric care. With that, I'll turn the call over to Dan to walk through the results in greater detail.

Thanks, Rob. Today is another important milestone for DT120 and for patients living with GAD. As a psychiatrist, I have seen firsthand the profound impact that chronic anxiety can have on every aspect of a person's life. While existing treatments can help some patients, many continue to struggle with persistent symptoms or wait weeks or months to experience meaningful relief. The positive VOYAGE results we reported in August marked a major step forward. And today, PANORAMA provides further confirmation of DT120's potential in GAD.

Consistent findings across 2 Phase III trials are especially meaningful because they reinforce the reproducibility of the efficacy signal and the strength of the overall clinical profile. Let me begin with the study design. PANORAMA is comprised of 2 parts: Part A, a 12-week randomized double-blind period and Part B, a 40-week extension period with opportunities for open-label treatment. As in our prior studies, participants were tapered off background antidepressant and anxiolytic medications prior to enrollment.

Notably, as with our entire development program, we did not provide any psychotherapeutic intervention as a part of the study. In Part A, 245 participants were randomized in a 2:1:2 ratio to receive a single dose of DT120 ODT 100 micrograms, DT120 ODT 50 micrograms as a control or placebo. The primary endpoint was the change from baseline in HAM-A total score at week 12 assessed by independent central raters blinded to treatment assignment and visit number. In Part B, participants continue to be followed for an additional 40 weeks and complete regular efficacy assessments. Participants who meet the prespecified treatment threshold of HAM-A score of 16 or greater become eligible to receive an open-label dose of DT120 for up to 4 open-label treatments over the course of the study.

The treatment threshold of a HAM-A score of 16 corresponds to the cutoff for moderate illness and reflects an increase in symptom burden such that participants are experiencing functional impairments. As in VOYAGE, we selected this threshold prospectively as a clinically meaningful marker for when additional treatment may be warranted. We randomized 245 participants, 96 to DT120 ODT 100 micrograms, 52 to the DT120 ODT 50-microgram control and 97 to placebo. All randomized participants were included in the intention-to-treat population.

Approximately 90% of participants completed Part A. Participants entered the study with high disease severity as reflected by baseline HAM-A and CGI-S scores of 28 and 4.7 across treatment groups. These values place participants firmly within the severe range of anxiety. Demographics and baseline disease characteristics were generally balanced across treatment groups. We observed prior psychedelic use consistent with what might be expected in a broad GAD population with 14% of participants reporting any previous psychedelic use and only 7% reporting prior LSD use.

Importantly, these characteristics were balanced across treatment arms, supporting the comparability of the study groups at baseline. Despite a limited number of available treatment options, this population had substantial prior treatment experience and a high disease burden. Half of participants reported receiving 2 or more prior treatments for GAD and 3/4 of participants had severe anxiety at baseline. On average, participants had been diagnosed with GAD for approximately 9 years and reported experiencing anxiety symptoms for nearly 18 years prior to enrollment.

On the HAM-A, which was the study's primary outcome measure, DT120 100 micrograms demonstrated a rapid, robust and durable efficacy. At every measured time point, DT120 100 micrograms statistically and clinically exceeded placebo on the HAM-A with a p-value of less than 0.0001. At week 4, participants receiving DT120 100 micrograms demonstrated a mean improvement of 12.3 points from baseline, corresponding to a placebo-adjusted difference of 7 points. At week 12, the primary endpoint, DT120, achieved a mean improvement of 9.8 points and a placebo-adjusted difference of 5.1 points.

Rapid relief is particularly important for patients in distress. By week 1, the first efficacy assessment following treatment, participants receiving DT120 100 micrograms showed a mean improvement of 9.8 points from baseline, corresponding to a placebo-adjusted difference of 5.3 points. Taken together, these results demonstrate a treatment profile characterized by rapid onset, robust magnitude of improvement and durable efficacy through the primary endpoint after a single administration of DT120 100 micrograms.

A secondary measure of disease severity is the CGI-S. And here, we see that CGI-S tells essentially the same story as the HAM-A. Key secondary endpoints shown here are change from baseline in CGI-S score at week 12 and early improvement measured at day 2. Notably, these instruments use different mechanisms to assess the underlying illness and are conducted by different raters. HAM-A is assessed by independent centralized raters, while CGI-S is a local, site-based clinician-rated measure. The consistency across these independent measures gives us tremendous confidence that the treatment effect represents real meaningful clinical improvement in study participants.

Categorical outcomes provide another way to understand the clinical relevance of the effect. At week 12, 32% of participants receiving DT120 100 micrograms met the response criteria of at least 50% HAM-A improvement compared with 14% on placebo. 35% achieved mild or better status compared with 17% on placebo. Remission was achieved by 15% on DT120 100 micrograms and 4% on placebo. Across each threshold, more DT120 treated participants achieved a clinically meaningful outcome after a single administration.

The week 12 HAM-A treatment effect was maintained across each subgroup we analyzed. Importantly, the effect was maintained in participants who had received 2 or more prior GAD medications, a population with substantial unmet need and fewer remaining treatment options. The consistency of the results across these subgroups strengthens our confidence that the benefit observed in PANORAMA are broadly applicable across the GAD population and are not being driven by any single patient group.

Turning to safety. The adverse event profile was consistent with our DT -- with our prior DT120 experience. Adverse events were largely mild to moderate in severity and most treatment-emergent adverse events occurred and resolved on dosing day. There were no study drug-related serious adverse events, no suicidal or self-injurious behavior and no indication of increased drug-related suicide risk. Overall, these findings continue to support a favorable and predictable tolerability profile.

Treatment-emergent adverse events were reported in 95% of participants receiving 100 micrograms, 96% receiving 50-micrograms and 63% receiving placebo. Two treatment-emergent serious adverse events occurred in the 100-microgram arm, 1 in the 50-microgram arm and 1 in the placebo arm. None of these were study drug related. No treatment-emergent adverse events led to discontinuation or death. Adverse events were collected under FDA guidance for psychedelic drug development, which includes expected effects characterized as positive, favorable or neutral. Among treatment-emergent adverse events occurring in at least 10% of participants, the most frequently reported events were the expected transient perceptual, affective, cognitive, and behavioral effects associated with DT120 administration.

These events occurred primarily on dosing day, were generally mild to moderate in severity and resolved during the supervised treatment session. Rob mentioned this earlier, and we believe treatment session dynamics remain one of the most important aspects of DT120's overall profile. The DT120 session is well matched to the needs of GAD patients with a combination of session duration and depth of experience that continues to produce efficacy outcomes like the ones we've shared with you today.

We use a structured end-of-session checklist to assess readiness to leave the treatment setting safely. The average time to clear the checklist was 6.2 hours with more than half of participants clearing at hour 6 and 92% clearing by [ hour 8 ]. Across all known Phase III DT120 dosing sessions, we see a remarkably predictable duration with the vast majority lasting between 5 and 8 hours. We believe this translates cleanly into clinical practice where the end of session checklist can be easily implemented to inform medical decision-making by the clinical staff supervising sessions.

Now we turn to Part B, the 40-week extension phase. As a reminder, participants are eligible to receive up to 4 open-label treatments with DT120 for moderate or worse disease severity as assessed by the centrally rated HAM-A. This phase aims to better understand long-term durability from Part A, subsequent treatment patterns, response to retreatment and durability over the full year of observation and dosing opportunities. At the time of this analysis, 86 participants originally assigned to DT120 100 micrograms, 42 assigned to the 50-microgram control and 76 assigned to placebo had entered Part B. Today's discussion focuses on data through week 28, where enough participants have been evaluated to provide a meaningful analysis. The demographics and baseline characteristics of participants entering Part B were generally consistent with the broader Part A population.

As anticipated, multiple treatment trajectories emerge with the participants receiving intermittent open-label treatment based on symptom recurrence and retreatment eligibility. The data show a distribution of participants receiving 0 to 3 open-label treatments through week 28. These early patterns provide an encouraging first look at how DT120 may be used in a real-world treatment setting. Longitudinal HAM-A results showed durability from the initial active dose and additional improvement after open-label treatment. Their convergence toward the original active group provides early supportive evidence that subsequent administration can produce additional benefit.

Notably, about 1/4 of patients in the active arm remain mild or better for roughly 6 months without needing any additional dose. As with Part A, we can look at response and remission over time in Part B. Across each of these measures, patients continue to benefit with subsequent treatment administrations. Response and remission rates improved through week 28, demonstrating sustained disease control. The consistency of these findings across multiple clinically meaningful endpoints gives us strong confidence in DT120's potential to safely deliver durable efficacy with intermittent symptom-triggered retreatment. And with that, I'll turn the call back over to Rob.

Thanks, Dan. As I said at the outset, our goal at Definium is to enable a new treatment paradigm that can fundamentally reshape clinical practice in psychiatry. We believe the landmark results shared today represent another important step toward that goal. Across 4 studies with various designs, populations and indications, DT120 has demonstrated a large durable effect. While the complementary study designs have yielded differences in symptom presentation and the variance of study outcomes, the magnitude of effect and high degree of statistical significance has remained remarkably consistent.

We are nearing completion of our registrational development program for DT120, which has always been grounded in precise science. This includes 4 positive Phase II and III studies with complementary designs, a comprehensive clinical pharmacology, nonclinical and CMC program, all of which have benefited from close regulatory engagement under the Breakthrough therapy Designation Program. We've also gone to great lengths to address the key considerations for the development of psychedelics and believe the consistent efficacy and safety data generated to date support a compelling argument for the safety and effectiveness of DT120 ODT 100 micrograms.

We're excited to hold our pre-NDA meeting in the fourth quarter, and we anticipate NDA filing for DT120 in the first half of 2027. We believe there is a significant opportunity to bring a differentiated treatment to the patients who continue to need better solutions. Today, an estimated 50 million adults in the U.S. are affected by GAD or MDD with approximately 26 million diagnosed, 13 million receiving pharmacotherapy and more than 4 million having been failed by 2 or more treatments. We view this initial scale as the starting point rather than the ceiling with a long-term opportunity that can meaningfully expand as we continue to generate evidence, broaden access and reach additional patients across these large and underserved markets.

With such a major need, even modest uptake has the potential to deliver impact for a sizable portion of the population. The large and growing ecosystem of interventional psychiatric clinics provides a springboard for exactly this sort of adoption. With around 8,000 such sites today, if only half of them were to treat 2 patients per month, this could represent over 100,000 patients in a year. Based on our market research, this is well within the excess capacity that exists today, and we continue to see a high degree of enthusiasm for adoption among these providers.

We're making great progress in preparing for commercial execution and the launch of DT120. We've continued to solidify our commercial team with the addition of key leadership over the course of 2026, bringing immense experience and importantly, a shared philosophy that has driven our success to date. Core of this philosophy is a commitment to delivering the best patient and provider experience possible. We are highly focused and heavily invested in optimizing patient support, provider enablement and site readiness to help remove barriers and create a seamless treatment experience for all those involved in the process. We continue to make progress on 2 distinct value drivers, our continued commitment to excellence in clinical and regulatory execution and setting the standard for commercial impact and execution to bring this clinical promise to the patients as impactfully as possible.

We're working tirelessly to build Definium into a psychiatry powerhouse that can reset expectations for what patients and providers can expect from care. Today's positive PANORAMA results further strengthen the DT120 story and build on the positive Phase III results from EMERGE and VOYAGE, which our team delivered in the past 12 weeks. With approximately $1.1 billion in cash and investments, we are well positioned to advance toward our planned NDA filing, prepare for commercialization and continue investing in our broader pipeline.

We believe the opportunity ahead is significant, and we look forward to delivering on the many milestones still to come. Before we go to Q&A, I want to say a special thanks again to our incredible team at Definium. We've built an organization of exceptional people who are deeply passionate about our mission and the patients we serve. To deliver consistent landmark results in such a rapid succession is truly extraordinary and a testament to the amazing people we have at Definium. With that, we'll open up the call for Q&A.

[Operator Instructions]

Our first question comes from Paul Matteis from Stifel.

Can you guys hear me?

We can.

Okay. Great. Awesome. Congratulations on the data. I wanted to just ask maybe a 2-part regulatory question here. So one, going to this pre-NDA meeting, what are the key questions? And what's your level of confidence that you have enough data to also file for MDD? And then second, can you remind us your agreement with the FDA as it relates to how much redosing data you need? And is it about like a certain number of patients getting a certain number of doses? Or is this not as kind of quantitatively defined?

Yes. Thanks so much for the questions, Paul. Taking each of those one by one. I mean, our overall confidence going into the NDA meeting is extraordinarily high. We've had a very constructive relationship with FDA and continue to have a continuous dialogue there. And of course, with the data we've been able to generate, we think they're unequivocal and really answer the questions that need answering. In terms of alignment on MDD filing, that is exactly the purpose of our pre-NDA meeting is to talk about the filing strategy for GAD and for MDD.

Of course, with the recent breakthrough therapy designation that we received for MDD, we're very excited about the promise that program holds and the high degree of alignment to efficiently bring that product forward. So we'll be eager to get to that pre-NDA meeting and come out of that, hopefully, with clarity we can offer to everyone about the filing strategy across both the indications.

In terms of your second part of your question and redosing, obviously, we all have historically lived under the framework of ICH E1 and the requirement to dose patients -- 1,500 independent patients. That's for chronic daily treatments, though. And in this case, both the lexicon and the realities of how DT120 and other drugs in the category are being used are not at all like a daily drug. We're talking about a few intermittent administrations over the course of a year.

And given the long history and high degree of characterization we have for this program and just in the Phase III studies alone, the over 1,000 treatment sessions that we've now delivered and have data for, we feel quite confident about where we are positioned today and the data we have available to us, which is why we feel comfortable that we'll be in a position to go forward with the filing in the first half of next year.

Our next question comes from Andrew Tsai with Jefferies.

Congratulations on another hugely successful readout. So in the -- I guess, the eventual label for GAD and MDD, I'd be curious how you would envision the front page label claim to read because we noticed that the FDA's NEJM paper suggests how the FDA is permitting dosing intervals to be established in a post-marketing setting. So it feels like the front page label claim could be quite broad for you guys. So I'd be curious what your thinking is, what you plan to propose to the FDA at the end of the day.

Thanks so much, Andrew. Yes. In terms of our development program, our intent has always been to have front page label that indicates that these -- that the DT120 is indicated for the treatment of generalized anxiety disorder and for the treatment of major depressive disorder. Of course, there are other sections of the label where the dose and regimen and administration are described thoroughly and certainly, over time, the historical standard even for daily antidepressants has been 2 acute studies and post-marketing studies then that establish a maintenance regimen.

Those maintenance regimen studies are often complex and for many drugs that are already approved, have not succeeded even. So we haven't ever seen that be a barrier in a commercial setting to adoption. But based on our dialogue and based on our understanding and the data we've been able to generate to date, we're going to be pursuing a broad GAD and MDD label that isn't restricted in terms of the exact interval or redosing dynamics because that aligns with what we've been able to demonstrate in the development program.

Our next question comes from Gavin Clark-Gartner with Evercore ISI.

This is Yesha for Gavin. Just a quick one from us. In theory, could the FDA potentially ask you to file the 50 [ mcg ] in addition to the 100 given what the dose-response curve showed?

Yes. Thanks so much for the question Yesha. We certainly feel that any questions about 50 micrograms or functional unblinding have been settled by our development program. We have gone to the greatest length of anyone in the field to thoroughly interrogate this and now establish in 2 studies that in order to derive the kind of efficacy that we are targeting here, the 100-microgram dose is necessary. We would not feel comfortable with pursuing a 50-microgram dose and do not believe that the benefit risk assessment of these 2 doses would in any way support moving forward with that dose. So while we're going to be having those discussions, of course, at pre-NDA and thereafter, we feel quite clear. And obviously, the data stand up behind that to decisively land on the 100-microgram dose and to really close the chapter on questions about 50 micrograms or functional unblinding or things of this nature.

Our next question comes from Marc Goodman with Leerink.

Just to come back to this new FDA guidance, any general thoughts on anything there? Was there anything surprising there? I'm specifically focused on just commercialization and standardization and the monitoring and the dosing and just this end of session checklist and how you think that's going to play into what their commentary is there? And is there going to be a -- you've got 94% at 8 hours. So you think the FDA says, well, are we 100% at 9 hours. So this is a 9-hour session, and you think they're just going to leave it open to interpretation by each clinic. I'm just curious how much you think there's standardization there.

Yes. I mean it's a really good question and obviously, some place that we've been extremely focused and I think a reasonable place for all of us to focus. As you correctly identified, we had a 94% ready at hour 8 rate, which I might have misspoken previously. But the ultimate -- what we're trying to enable here, we're collecting all of these data on end of session checklist. We're trying to standardize in the trials. We -- we examine in a very structured way what actually happens in the treatment room, what treatment session support really consists of.

All of that is in service of being able to go to the agency with evidence-based arguments for what the minimum conditions for safety and efficacy are. We've noted throughout this program that by stripping away psychotherapy, conducting the trial, by reducing the role of the treatment session support folks in the room, all of that's in service of establishing these minimum conditions for safety and efficacy because at the end of the day, clinical experience and clinical expertise ought to guide the delivery of this treatment in ways that exceed that minimum standard.

So our best bet here is to go to the agency, show the curves, show when people are ready. I think there's a pretty strong argument to say that keeping 95% of people in who could be ready to leave because 5% might not be isn't absolutely the best move. So that at the end of the day, it's a balance between safety and access and deference to clinical expertise and community standards that will emerge as we gain experience with this drug in the real world, if approved. One thing that we highlighted here was that we've now had more than 1,000 sessions with DT120 ODT 100 micrograms. And of those, 97% are ready to leave by hour 8. I think that's a pretty strong argument for a shorter absolute minimum time so long as there are standards for what constitutes readiness, and that's what we've established with the checklist now.

Our next question comes from David Amsellem with Piper Sandler.

Maybe a question on commercial dynamics. We know GAD is a pretty expansive indication. But I guess in practice, how do you think step-throughs and prior treatments on average are going to shake out before patients can get access to 120. Do you think ultimately, this is going to profile as more of the, for lack of a better term, treatment resistant population who've been through multiple reuptake inhibitors and even ex chronic (sic) [ extensive ] exposure to benzodiazepine. Just wanted to get a flavor for how you're thinking about that in practice. I realize that, that also is -- leans into a discussion on payer dynamics, but would love to get your thoughts.

Yes. I'll go ahead and turn that over to Dan initially and certainly can have Matt weigh in, too.

Yes. I mean I have a 2-part answer, I think, to this one, which is that, yes, at launch, we fully expect that we will be a step 3 therapy. That's been the case for every new antidepressant and anxiolytic for quite some time. That hasn't been a substantial barrier to success, however, by the time a GAD or an MDD patient reaches psychiatry and the sorts of providers who are likely to be our prescribers and provide our treatment session support, they, in many cases, have already had an opportunity to try and been failed by multiple SRIs. I think a benzodiazepine requirement is pretty unlikely given the emerging evidence over the past decade about the effects of benzodiazepines.

So yes, step 3 therapy, but don't really see that as a substantial obstacle given where patients will be in their treatment journey by the time they reach the opportunity to be prescribed. There's another argument that I'll make very briefly here that certainly we'll hit on more over time, which is that in the prior treatment landscape, where subsequent drugs where the new branded drugs were effectively the same as the prior drugs, step 3 seems not unreasonable, right? A drug that has about the same efficacy, about the same mechanism but costs a lot more. Well, okay, that makes sense to make folks try something that's very similar but much less expensive.

What we see with the data we've been able to present over these past 10 weeks with 3 positive Phase III readouts is a drug that works completely differently. DT120 offers a really different profile for how it can help people's disorder and their experience of their life change. And so what starts to come out of that is an argument for the step system that previously existed, not necessarily making sense, not making people wait and suffer when something that is more likely to help them more conclusively is waiting out there for them. So while we'll launch into a step 3 environment, we think that ultimately, there's an argument waiting to be made for some change in the way that the dynamics of treatment courses work.

This is Matt. Just to dovetail on Dan's comments, we've spent a lot of time talking to payers over the years and everything that Dan said is consistent with what they've told us. The management of DT120 may be similar to that of [ esketamine ] -- prior authorization with a 2x drug failure rate is likely, and that's our plan and operating assumption going to market.

Our next question comes from Brian Abrahams of RBC Capital Markets.

Maybe just a follow-up on the payer side. Just wondering if you could characterize kind of your latest payer discussions just in light of the consistency of efficacy that you're seeing the robust effects, particularly in these more refractory patients. Any kind of changes or evolution in your view on the potential pricing power here? And congrats again on the data.

Yes. Thanks so much, Brian. I'll comment briefly and turn it over to Matt. We certainly -- we continue to sort of use a benchmark that's out there in the world today, and we're not in a position today certainly to announce pricing until much later on a drug like DT120, which typically happens after approval and interim final rule is issued. But absolutely, what you said is correct, which is that we see quite stark efficacy, something that really hasn't been seen before. And in this indication, it hasn't been seen in a very long time. And so that certainly gives us a lot of negotiating power and positioning when we think about pricing. But I'll turn it over to Matt to talk a little bit more detail.

Again, we've spent quite some time with payers and both in research and in advisory roles. And they've been impressed with the data to date. Obviously, with the data over the summer and the data presented today, I think that strengthens our argument with them. And the broad indication set that we're pursuing is also of great interest. So there may be additional value there as we think about the price point, but there's a lot of work to do between now and launch.

Our next question comes from Ben Burnett with Wells Fargo.

I'll add my congrats. I wanted to ask just one point of clarification real quick, and that's just on the CGI data, which I believe is Slide 17. It just looks like the table is showing a drug effect of minus 1.1, but the chart or the plot looks more like a minus 1.0. Just curious if maybe one of those is a modeled estimate. But then my question is just around the discontinuations. So great to see no discontinuations due to adverse events. By our estimate, it looks like that maybe sort of 5 patients or so dropped off in each arm by week 12. Just curious if you had any color on the dropouts.

Yes. Thanks so much, Ben. I'll turn that over to Dan to talk about the dropouts.

Yes. So no single predominant reason for dropouts. We always see sort of a smattering of different reasons and sometimes it's just protocol noncompliance or lost to follow-up. One interesting phenomenon though, that we've seen in these studies that I have not really seen before is people leaving because they're doing extraordinarily well. And in any other drug study where you're giving someone daily drug, your folks who sustain the greatest efficacy from getting that daily study drug are unlikely to leave because they only get the drug by staying in the study, whereas with our study, where we have this 12-week randomized double-blind period with a single treatment session at the beginning, there are certainly people who have a tremendous response right out of the gate there -- and as a result, don't really see a reason to continue to participate in a GAD or MDD study.

So that dynamic is a little bit different. And of course, when someone does extraordinarily well, the modeling that we do to fill in for missing data is going to modulate that to some extent and bring them a bit back toward the median performance. But beyond that, nothing stands out as being unusual or different from what we would ordinarily see just in the course of a fairly long clinical study.

Our next question comes from François Brisebois from LifeSci Capital.

Congrats on the data. I was just wondering in terms of the breakdown, if you talked about clinics, I think about 4,000, I believe that was by taking about half of them. I was just wondering if there's any more work done in terms of how the distribution is amongst the clinics? Is it -- would it be 2 patients a month or something? Or are there clinics where there's just so much more volume? And if so, what is the reason that you would expect some clinics to have way more volume than other clinics?

Yes. Thanks so much, Frank. There absolutely is a distribution that is -- when we look out in the world today, at least in terms of things like [ esketamine ] that are delivered, there's a high degree of concentration in a number of centers. And in that context, there's certainly a dynamic that could be at play that's driving certain centers to adopt a much higher volume framing and business for -- and it kind of makes sense for a drug that you have to administer up to 56 times a year, doing it a lot and getting in a pattern of retreatment for that drug in particular, that requires rapid return by patients and rapid turnover -- in this instance, we obviously don't know yet what the real-world distribution is exactly going to look like, but we feel that there's some really great opportunity here for those sites that maybe don't set themselves up to deliver esketamine or ketamine on a recurrent basis and make that the entirety of their business, but want to offer more treatment options to their patients perhaps on a regular basis, but not every single day.

So we certainly expect there will be higher concentrations of prescribers that there will be some centers that treat a lot more patients than others. But the dynamics here, really what we've been after and what we're seeing is that it opens up a possibility for an even broader set of sites of care and providers that could be involved in the eventual delivery of 120. That's what gets us excited because that footprint out in the world today is quite large. And our point is that even modest adoption at a modest treatment rate really leads to some incredible opportunities to help many, many patients and for us as a huge opportunity for value generation. So our focus is going to be going as broad and as impactfully as possible as we get out into that setting.

Great. And then if I could just lastly here, in terms of the -- I know the 50 and 100 weren't like powered to be compared to each other. But I was just wondering what you make of the AEs being similar between the 50 and the 100 and also the time, I think it was 6 hours to leave the clinic. I'm just wondering if -- what we should make of that? And also in the real world, do we expect the time once people feel more comfortable, could actually come down for people to be ready to leave the clinic?

Yes, I'll turn that one over to Dan.

You're noticing exactly the reason that we picked 50 micrograms, which is to service -- to serve as this functional control, right, not an arm of analytic interest, but there to confound the beliefs of folks who got either placebo or 100 and more to confound 100, quite frankly, because of that adverse event profile. So what we know is that across the arms that included DT120, both 100 micrograms and 50 micrograms, people detected drug. They knew they got drug, yet we saw this remarkably more effective clinical activity out of 100 micrograms. So again, that the AE profile is consistent with the ability to guess one zone allocation, and it means we got the right functional control.

Same for the time, really not seeing a markedly different time with the 50-microgram time to readiness. And yes, the end of session checklist is something that's evolved somewhat over the course of these studies. We've had a chance now to evaluate its sort of psychometric properties as it were across more than 1,000 sessions, which has allowed us to refine language and make sure it's clear and easy to use. And we think that, that will tighten up curves a bit and lead to fewer outliers and really make it an effective and efficient clinical instrument that people will get increasingly comfortable with and increasingly comfortable with what the end of these sessions look like.

[Operator Instructions] Our next question comes from Jay Olson with Oppenheimer.

Maybe just to follow up on an earlier question about step therapy. From a longer-term perspective, now that you have multiple studies with consistent overwhelmingly positive results. And meanwhile, the older existing GAD therapies have much smaller effect sizes and less consistent outcomes compared to DT120. Could you just comment on the potential for DT120 to eventually become the new standard of care for GAD and what that could look like?

Yes. Thanks so much, Jay. I think I'll just take a step back, which is I think you articulated it quite well. And for -- in the context of most psychiatry programs in the history of drug development in this field, we do not -- it is quite unusual for this many studies in this broad set of indications and different study designs to repeatedly deliver such profound activity, such profound efficacy across all of those studies. And that is just remarkable. We feel an enormous sense of responsibility and excitement around about that reality. As we said, there's obviously a process and there is an evolution over time in terms of where new drugs reside in terms of market access, patient access and those dynamics with payers. But I'll turn it over to Dan to maybe comment if a patient walked in the door in a practice and you had the option of going down one road that likely led to treatment failures and another that led to the outcomes we're seeing, how he might frame that as psychiatrists.

It feels like a little bit of a setup there. Look, the reality is that we want to give patients the best treatment that's most likely to work for them as efficiently as possible. And so the idea that people can get better from a single or a few doses with a relatively constrained session dynamic and experience that most folks experience as at least positive. That, I think, does have the potential to move into a standard of care. And of course, there's -- there's always going to be folks for whom one drug or another or one experience or another, one path to recovery is better for them or their choice and providers will always have preferences as well.

But our goal moving forward from here is to continue to build the best body of evidence for the use of DT120 to ensure that for the people who want to pick this path and are able to and have a provider who wants to work down this path with them, they can get to it as soon as they can in the course of their illness. We saw this incredibly across our -- both of our GAD studies, we saw this really prolonged course of illness that I think has been under focused on people suffering for 20 years being in some form of diagnosis and in many cases, treatment for 10 years and still being severely ill, that is probably not something that we, as a professional or really as a society should expect or tolerate. So our argument will always be the same and will always be evidence-based as best as we're able to say that the point of all of this is to reduce suffering where we're able.

Thank you. Congrats on these results.

Our next question comes from [ Tazeen Ahmad ] from Bank of America.

And congrats on the additional positive data. As we think about a continuous comparison, let's say, with SPRAVATO and ramping of the launches, can you talk to us about how we should think about the ramp here for frankly either indication if you get both approved? It did take a while to set up all of the infrastructure and educate physicians about the benefits of their drug. And given what additional benefits your treatment would have these, is it right to think about this as having a steeper initial uptake curve? And if not, what would be needed in order for that curve to start off steeper relative to what SPRAVATO pick up?

Yes. Thanks so much, [ Tazeen ]. I'll turn it over to Matt to comment a little bit about the ramp and Dan certainly have to add anything. Matt, do you want to go ahead?

Sure. Yes. Thank you. Thanks for the question. A couple of things to consider here. There is no real surrogate for what we're about to do. And so in thinking about the ramp and the launch curve of the drug, we have a clear understanding of where our administration sites will be. We know where the concentration of patients are in the referring sites as well. And we also understand every dynamic that can impact this market, I think, much more clearly than other surrogates may have in the past.

So even without having a specific playbook for this type of intervention, we do have a clear understanding of every component that is needed to be successful. So we have the capabilities, we have the experience, we have the team that this market requires, and we expect to help as many patients as we can as early in the process when we launch if approved.

I'll just add one thing on that, which is to say that we absolutely understand the reality is that for any drug such as this, it's going to take some time. But we are -- to the greatest extent we can, engaging with sites of care today and engaging with providers. Our MSL team is out in the world to really share this information and understand every single friction point. We need -- the goal here is to maximize the footprint when we get this out in the world and to have every last detail understood to the greatest degree of precision so that we can solve for them so that we can ease that friction and make it so that we can reach as many patients as Matt was saying. Again, we recognize it's going to take some time, but we hold ourselves to a different standard than anything that's been out there in the past and any ramp, regardless of which organization is coming from, we're going to seek to do better than better across the board and certainly are eager to get there and show the world what's possible.

Our next question comes from Sumant Kulkarni from Canaccord Genuity.

Can you hear me?

We can.

Great. So great to see these data, I guess, coincidentally on the day of the public hearing that the FDA is holding on this class of products. How do you see the retreatment paradigm evolving beyond 40 weeks in the real world? And from the highly consistent data you've generated and your interactions with payers so far, are there any nuances that could make either indication, GAD or MDD relatively easier or more difficult to obtain reimbursement for.

Yes. Thanks. I had a little trouble with audio, but I think the first question was around research (sic) [ retreatment ] beyond 40 weeks. I'll turn that one over to Dan.

Yes. I mean it's something we're incredibly interested in. And quite frankly, it goes beyond the data we will have coming out of these studies. We'll know a great deal about what we do in the first year of treatment, and that will allow us to provide substantial guidance in the form of publications on all of the patterns that we're able to observe in that 40-week extension period. We do continue to monitor participants for an additional year. And actually, as long as people want to keep giving us data in a remote form, we will keep collecting data from folks who want to.

So we'll have more than that additional year worth of efficacy from the end of the availability of open-label treatment. So we'll be able to integrate across that to look out beyond a year. But what we won't have are data for treatment beyond a year. The guidance for treaters will be based on that first year. And in essence, as we've said over and over again, it will be based on triggered retreatment that if folks have symptoms, they ought to get drug and that as is usually the case with that kind of triggered label, it will be optimized treatment to maintain optimal patient response sort of language. And so we expect that will continue.

What we do know from some things outside of our research, from some other research and from compassionate use programs outside of the U.S. is that over time, people tend to require less drug so that whatever amount of drug helps people get into mild or better in the first year, it will take less in the second. And then -- and what we've seen out in the world is that in many cases, people don't continue to require drug and are better functionally. We haven't really had an opportunity to do a thing like that in psychiatry before. And so we will set up structures and systems so that we can look at real-world use, if approved and be sure that we're capturing all of the data that we need to inform long-term treatment in addition to that early phase of treatment.

But this is -- that's our goal is to learn as much as we can about that as we move forward.

Yes. And I'll just say on the payer side, we feel really comfortable with where we are for both these indications. Obviously, it's going to be subject to additional engagement and discussions and finalization, but regardless of what's on the label when both of these are highly impactful high-burden disorders that cost payers quite a bit of money. And we look at examples out in the world of where predictable, rapid, durable efficacy can be had. And that makes a difference not only for patients' lives, but makes a difference for payer budgets. And we're obviously very much aware of that as we think about everything from here.

Our next question comes from Pete Stavropoulos with Cantor.

Rob, Dan and team, congrats on another robust data set. How should we be thinking about DT120 monotherapy versus adjunctive therapy for both GAD and MDD in the real-world setting? Patients staying on their background anxiolytic or antidepressant therapy. Is it something you may try to address via small clinical study or just it will get sorted out in clinical practice? What are your expectations? And what's the feedback from consultants and KOLs on this?

Yes. Thanks so much, Pete. I'll turn that one over to Dan as well.

Yes. It's a great question, something, again, that we've thought about quite a bit. And so as everyone listening will know, for the conduct of our Phase III studies, we took background medications off prior to treatment. And that's largely for the interpretability of the research to try to control another condition that we could control so to reduce variability. We don't think that will be necessary in the real world. Psychiatry has gotten very comfortable with perhaps too comfortable with polypharmacy. And so while the vast majority of drugs that are ultimately labeled as monotherapies were tested as monotherapies in almost all cases, those are used as a component of polypharmacy.

So we don't think that the provider base based on the conversations we're out there having with them are going to be reluctant to make individualized patient decisions to try to do whatever is best for a patient. So if a patient is sustaining some benefit from background med, treat them DT120 first and then take off the background med once they're feeling better, if they're feeling better. We are doing exactly as you say, some additional research to ensure that we've got the ability to go out and detail on that and publish on it to establish that the transient effects of DT120 aren't mediated by background anxiolytic or antidepressant medications. So doing the work, but absolutely expect that, that will be an individualized clinical decision that's made at the point of care.

Congrats on the data again.

Our next question comes from Chris Chen with Baird.

Congrats on the data again. Just a quick one on dose responses. I did notice at week 1, the 50-microgram arm did show a slightly greater improvement on the HAM-A than the 100-microgram arm and then the curves invert afterwards. But I think this phenomenon did happen in the Phase IIb between the 200 microgram and 100 microgram dose, but not between the 50 and 100 micrograms. So just curious what you think is explaining that.

Yes. Thanks so much, Chris. I mean I think really what you're describing is kind of exact confirmation of what we're seeing here, which is that 50, as you would expect with any drug, a lower dose of dose is about half has some initial activity. And especially here, we see the drug has some action, right? In some patients, it's quite large. But when we do studies and we think about the conclusions and the means, we use means because we're trying to establish evidence for the broad population out in the world, right? The transition here is not purely academic or scientific interest. It's how do we find the drug and establish and confirm the efficacy and the tolerability and safety so that it can be used by clinicians and by patients out in the world.

And so what we see is reliably that 50 does not have the activity that drives durable or large enough change for what we are desiring here, right? So we see that initial reaction. And in this context, you could see some of those patients who have an initial reaction, but beyond a week that pretty rapidly fades. That's not the profile of the drug we're developing here. And so the reason why we established 12-week durable or 12-week primary endpoint in the study is because we're so focused on the durability of action here and the ability to drive that large change simply requires 100 micrograms.

So the other trade-off we see is that there's no sort of reduction in tolerability profile, at least in the studies we have to date, right? So if there's no added benefit to going to 50 as we've seen, there certainly is no worsening of safety or difference in tolerability profile between 50 and 100, there just isn't a rationale for why you wouldn't use a more efficacious dose that we've now seen repeatedly be 100 micrograms. So seen in that initial response is actually quite interesting to us as well, but -- looking at the curves and looking at the data overall in the context of the full development program, again, we feel remarkably clear on the data and the fact that 100-microgram dose was and is the right dose to bring forward.

Our next question comes from Ami Fadia with Needham.

Congrats on the really strong data. My question was about the patients that did not need retreatment for up to 6 months. Did you look at any correlation between either baseline characteristics or whether or not the patient achieved remission and see if there was any sort of way to predict which would be the patients that can go longest without requiring retreatment. And if you can comment on any experience from any of the other Phase III trials as well, that would be helpful.

Thanks so much, Ami. We're, of course, going to continue to interrogate that and try to really find an answer. If we could identify exactly the people who are going to respond, that would be a remarkable finding, not only for our program, but for the entire field of psychiatry. We've yet to see anything that is a sort of decidedly clear marker on who going into the first treatment is going to be a responder. I think the really interesting thing here, though, and it's something that is really important and I think often overlooked is that what we do see is that early response is quite predictive of more durable response. And that shouldn't be a terrible surprise in the context of what we're seeing, but it isn't always the case for drugs and particularly the drugs that are out there today, right?

Patients start on drugs and often go weeks or months without knowing whether it's actually going to sustain efficacy. Even when there is an initial response that can often wane over time. And so here, what we're seeing is that within a few days. I mean, as early as we measure it, the earliest measure of response is quite useful in determining whether a patient is going to respond and that response is going to be durable. And so with those kind of dynamics, of course, for a provider and for a patient and for payers, if you can find out very quickly whether it's the right drug for patients or not, that will be a great outcome and has some really nice characteristics for all the stakeholders. So what we're seeing is really exciting, but we're going to keep digging and keep trying to identify if there's anything, of course, that could prospectively be able to define the likeliness of treatment response to be really cool if there is.

Our last question comes from Rudy Li with Wolfe.

Congrats on the strong data. Can you maybe provide additional color on the economics of DT120 treatment session for the centers? And based on current CPT code, what do you think will be the key differences versus SPRAVATO buy-and-bill model? And any key learnings for you from today's public hearing for that day?

Yes. Thanks so much, Rudy. Just at a high level, I think we're obviously a detailed understanding of site economics and the economics that we're anticipating for DT120. A little premature to say decisively what they are going to be. But an important thing for everyone to understand is that, while there are opportunities for unique codes and while drug-specific J-codes are something that we're very focused on, by and large, the infrastructure and the administrative aspects of coding and billing exists. And we don't need to recreate the billing system in order to have a direct path to adoption. So we feel like it's something that probably helped the world is not fully understood, and it's a very specific conversation and it requires a level of detail both in this context and for sites of care.

But this is exactly what our commercial team is focused on and what we're going to be solving for over the years come as we get ready and get out in the market. In terms of hearing, we're excited to have the public conversation continue and continue to hear from a number of stakeholders. We have -- we've always said, we have an extraordinary opportunity to really look out into the future. And with sort of evidence we've generated to date, sit down and have these conversations about how to design a framework for these products to be safely adopted in the world and also get them out to patients at a remarkable scale. That's been the goal all along. So the more voices we hear in that process, the better and the better hopefully, we can collectively design a system that balances access and the need.

Thank you. That concludes the allotted time for the Q&A session. I will now hand back to Rob Barrow for closing remarks.

Thanks again, everyone, for joining today. It's been an absolutely incredible summer to have 3 pivotal studies read out in such quick succession. It's quite unique and something that we're really proud of and certainly could not be more grateful to our team and to everyone who's been a part of this in the process. We are going from one sprint to another. We are so excited to take the next steps here to move forward, have a pre-NDA meeting and to get ourselves ready for an NDA application on -- the NDA filing and to get ready for a launch of a product if we're able to get it approved.

We have such a remarkable opportunity ahead of us, and we are fully, fully committed to doing everything possible to recognize that. So thank you again to everyone who's been here today, thanks everyone who's been involved in the process from the beginning, and we look forward to sharing in that continued path forward and the continued success in the years to come.

This concludes conference call. You may now disconnect.

All right. Awesome. Thanks so much, everybody. Always a pleasure to be moderating a discussion for Rob Barrow, CEO of Definium. I'm sure people who are dialing in here mostly know the story, but maybe Rob can give us sort of a quick snapshot of where you guys are at. Maybe talk about some of the data you generated this year with 120, the upcoming readout that we're going to dig into pretty deeply and some of the nuances there. So Rob, thanks again. Always good to see you, and yes, take it away.

Yes. Likewise, thanks so much for having us. It's been an incredibly exciting summer. So our lead program, DT120 is an ODT form of LSD we're developing in generalized anxiety disorder, major depressive disorder. 2024, we had landmark results. First study readout for this molecule in this program in generalized anxiety disorder where we saw an incredibly large effect size 12 weeks after a single treatment effect size of 0.81, a demonstrated dose response and then we kicked off a Phase III program.

And based on those data, we kicked off the program in GAD and in MDD. First data we had this summer in June were from Emerge, MDD Pivotal study, where we saw an effect size of 0.81 and 8.1 on the MADRS separation about 6 or 8 weeks later in August, we had a second Phase III readout, our first GAD readout in Phase III VOYAGE where we saw an effect size of 0.81. And now we're here in September. And by the end of this month, we anticipate having our third Phase III readout this summer.

So our team has been quite busy. We've got breakthrough therapy designation for the GAD program and then working feverishly over the last several years, but over -- especially over the course of this year to get ready for hopefully an NDA filing if we have another positive study here.

Cool. I'm old enough to remember when I said to you in March that you shouldn't set a bar for the MDD study. It turns out that bar was a total sandbag. So congrats. So yes, maybe let's talk about PANORAMA. I guess, how are you thinking about the bar for success for that study? And we'll talk about this more, but maybe help frame for people the context around having the 100 dose and also the 50 dose and what different clinical outcomes for the 50 dose could or could not have in terms of implications for 120 in the program overall?

Yes. I mean at this point, of course, when we talk about bars for outcomes, I think there's sort of the fundamental truth and reality. And then there's, of course, the outside looking in perspective of what people want to see. We're talking about -- to just take a brief step back, we're talking about in market in generalized anxiety disorder where the last approval was in 2007. Eli Lilly had Cymbalta approved initially for depression and then moved into GAD. There hasn't been anything new since then.

The prevalence over that time has tripled. So we have 10% of U.S. adults that is not for lack of trying it in a dozen programs that have tried and failed in late-stage development in GAD over that time. It is a very difficult indication, a very difficult scale to show any sort of separation for. And so fundamentally, at this stage, we have 2 positive studies.

We need a second pivotal study in GAD and that will provide the evidence of typical pivotal studies to support an NDA for a new product. And so if the study is positive and what we saw from the interim sample reestimation in Panorama is that the implied separation needed to demonstrate statistical significance is quite small or a little over 2 points that we would expect the study to be positive based on all those assumptions.

And so fundamentally, what we need is a positive study. Now if we just had a 2.5 point separation, but it was positive, would people be excited? Probably not as much. We've continually set a very high bar just because of the data we've been able to generate to date. We powered the study to have 90% power to detect a 5-point difference, assuming a 10-unit standard deviation.

So about 0.5 effect size. And what we've consistent we can show a separation of 4 points or greater it's among the largest effect ever seen in the GAD. So not only we have a new drug, first new drug in 20 years, but with the most significant efficacy, the largest efficacy to be seen in pivotal studies. So all of those dynamics, we feel like anything that is positive, but certainly 4 points or greater separation is remarkably strong and sets us up very well.

As you mentioned, that study is almost exact replica of the VOYAGE study that you read out a few weeks ago. The difference being that it also includes a lower dose of 50microgram of control. Everyone talks about functional blinding, which is dose arm is there to try to address in some capacity. And really what it's trying to do is lower the configuration value of patients feeling something.

So patients take a dose of 120. And whether it's 50 or 100 micrograms in our Phase II study, we showed that folks can reliably tell that they're on a dose of drug. It shouldn't be surprising to anyone. This is how psych drugs work, but a lot of attention and a lot of inks filled around this topic in our field. And so basically what we're trying to say is if you feel the effects of drug, you can't assume it's the real dose of drug. It might be a dose of drug that previously we showed had no clinical separation or statistical separation from placebo.

And it's trying to sort of build a robustness argument. It's really not a study-specific argument. It's one that's programmatic. So we had a 5-arm study where we showed an effect size of 0.81. We had a 2-arm study where we showed effect size of 0.81. If we have a third study with a different design and we're consistently seeing statistically significant large magnitude efficacy, that's going to give us a ton of confidence that there is a real drug effect that's happening. And that's the point of FDA asking for these complementary designs across the program.

When you say -- it's super interesting. So when you say it's about influencing patient expectation bias, like is this -- like is this framed to patients in the way you just described to us? Like I know you're speaking in a more kind of like conversational way, like, hey, you might feel something it may or may not be efficacious. But like how operational is that kind of framing to patients on what arm they could be randomized and what can.

I mean it's part of the informed consent process. And you're right. I don't think it's quite as casually described as say here for you or for those who are listening in. But it is exactly what I described is that there are 2 doses of drug in the study and to provide the context of what those doses could be. It's a similar thing that we did in Phase II, where the informed consent in Phase II described placebo or 1 of 4 doses of drug.

And patients are typically told the probability of getting the drug, and they're also told at the different dose levels, what might be the effects of those drugs so that they have appropriate level of information to consent to the study. So yes, it is absolutely a part of the education process and something that we can -- in some ways, not overly so, but sort of lean into because if it's there to try to sort of sever the ties between expectancy and some biased reporting of outcomes, do you want people to be aware of it. If we just sort of hit it, it wouldn't have any purpose at all.

Right, right. Okay. And I guess the only sort of subquestion that I've gotten from some investors about this is sort of what if 50 actually does a lot better than you expected? What if it's as good or what if it's better than 100 nominally? Like does that -- is there any risk that, that opens a can of worms where the FDA says, now we want you to do another study looking at lower doses. And it gets back to this whole sort of lowest effective dose question, which I think has actually been a murky question in general for neuropsych, but maybe like entertain that hypothetical scenario for us, Rob. What does that mean?

Every regulatory decision necessarily is one of benefit and risk, right? It's for a drug that was highly toxic where we had -- if we were talking about a narrow therapeutic index and butting up against the top of that, then that argument might have a little bit more traction. Here, we're talking about intermittent sparsely intermittent dosing where patients are in a controlled clinical environment and the tolerability, the safety profile has been quite benign so far in all that we've seen.

And so in that context, one would have to argue that you either really truly expect superior efficacy or that you'd be mitigating some risk that somehow the risk would be unacceptable at 100 micrograms and acceptable at 50. Part of the challenge with drawing any conclusions from this is that the study was not powered around a 50-microgram dose in any way. It is not being tested differentially in any way. And so there's really no statistical conclusion. And again, we look at things nominally and we see the scores and we see the numbers are different or higher or lower.

But fundamentally, to prove something, you have to establish a hypothesis and power the study to be confident in the conclusion and then test it. And when you're testing multiple endpoints, you have to control for multiplicity. So you'd have to have somewhere in a statistically multiplicity controlled way, establish that the thing is happening. We're not even attempting to do that. We're not -- nowhere in our statistical analysis, are we comparing 100 to 50 or 50 to placebo. It is there as an operational control.

Another thing is sort of as you think about the sort of regulatory precedents, the thing that's quite fascinating to look at, I think folks can easily jump over history. One of the very few approved drugs in generalized anxiety disorder is effector. And there, in a dose response study, they saw a linear dose response. And then in a Phase III study where they tested doses of 75 and 150 milligrams, the 75 outperformed the 150.

You don't see psychiatrists concerned about both of those doses were approved. They were both controlled, and it was a study that was designed to assess both of those doses. But just because of lower or a different dose of a drug, works or doesn't work, tells you nothing about the dose of interest. And so the entire point, the entire design of these studies has been to establish that beyond a statistical degree of confidence, right, that 100 is superior to placebo. That's what we're trying to establish through these studies. And the last point I'd make is that in the absence of the study we did in Phase II, this might be more appropriately elevated as a concern. But uniquely in this field, we -- going into Phase II, we didn't know the answer.

We didn't know what the right dose of drug was. So we designed a study to actually address that question. And we established statistically and clinically a dose response. We established that to get clinically meaningful and durable efficacy, you need the 100-microgram dose. And so if there are questions about what dose is the right dose, each study can provide different point estimates of something. But when you have a body of evidence supporting the efficacy of 100 micrograms and you've statistically and clinically shown that you have a dose response and the 100 is the right dose, I'm not sure what we're really still asking anymore about what 50 could do or not do.

Right, right. Okay. Fair enough. Maybe one other question on PANORAMA, and that's just maybe talk about the population you've enrolled. There's you ran a really interesting experiment with VOYAGE where you tried to really isolate GAD symptoms. What did you learn from the VOYAGE results? And is that read through? And is it the same expectation with how Panaroma could play out?

Yes, absolutely. There's historically been a lot of conversation and this could -- we could take up the rest of the hour probably with this history. But the sort of pendulum for a long time swung towards MDD as a sort of central focal point of psychiatry. Like all the new drugs were for MDD and even in the DSM GAD took a sort of backseat to MDD so that if you had MDD, you couldn't even then arrive at the GAD diagnosis, which is, of course, not a reflection of any fundamental reality or any kind of broader history. sort of where the sort of structural elements of the world went.

We're seeing that go entirely the other direction now, it seems. But through that process, there was this concern about pseudospecificity, particularly in the context of SRIs that all started as antidepressants and we're trying to expand the labels into GAD. So the concern was given the high degree of overlap between MDD and GAD and particularly between the scales between the MADRS and the HAM-A, the concern was that if you have someone with both GAD and MDD who has elevated depression and mood scores that you could be having an antidepressant effect and it's showing up as an anxiolytic effect, right, that you're not really treating the anxiety, you're just treating depression and making anxiety better. has a little bit of a face validity problem.

Why does FDA even care at the end of the day, why something is working if it's working?

For regulatory purposes, we have to isolate variables. It's like good science, right? You have to isolate a variable, try to establish that variable. So presumably, if your FDA say, well, if you've already got an MDD label, why am I going to give you a new label for a different set of symptoms if you've already proven that it works for that set of symptoms. And you end up with this sort of highly overlapping Venn diagram, when we go for GAD approvals, we have to isolate the GAD without MDD. And so we pay a lot of attention to that in pivotal studies. And one of the most interesting kind of things that we've now learned from our development program and just looking epidemiology and disease impact is some of the most focus of clinical care are those with anxious depression or elevated anxiety and elevated depression.

Drugs we have work more against the mood symptoms and less good against the anxiety symptoms. So in VOYAGE, I guess you think of it this way, while we -- in all of our GAD studies did not include patients who are in a depressive episode, and we went to greater lengths, both procedurally and with minor additions to entry criteria in the Phase III studies to really isolate the GAD symptoms. So HAM-A scores elevated without the commensurate increase in MADRS scores.

In Phase II, we saw baseline MADRS scores in the mid- to upper 20s across the arms. That's just right sort of at the threshold for what it would require to get into an MDD study on the MADRS. In Phase III, in VOYAGE, we saw a baseline MADRS score of 14, around 14 -- the end result of that is that you not only are isolating appropriately again for regulatory purposes, but isolating GAD population, you do 2 other things. One, you limit the dynamic range of what you can change on the HAM-A. So item 6 in the HAM is depressed mood. Each of the items on the HAM-A, most of them can also map on to the MADRS and the depression symptoms.

So if you take away the depression symptoms, you artificially, in some ways, depress the starting point and on an item level, you sort of take away the ability to move things, right? You can only move things as much as they're there to be moved in the first place. The other thing you do is you -- because the HAM-A has 2 subcomponents, one is physiological and one is psychological. Sort of biased the phenotype towards a more physiological manifestation. It turns out that's a lot harder to move. It's one of the really difficult things about JD is that you get symptoms that are captured in the hand like cardiovascular and genitourinary and things that aren't just how are you feeling right now.

And so the end result of all of this is we ended up with the right population for regulatory purposes. But it's a little bit different in terms of how it's going to show out from a measurement standpoint. If you have a less of a dynamic range on the scale, you have lower item level starting point, you're going to get less nominal change in scores, you get less nominal variance in the data as a result. It's using a ruler instead of a yardstick, right? It's just that level of difference.

And so exactly what we saw in VOYAGE, same study design, same dynamics at play with Panaroma. -- we'd expect a similar sort of dynamic where what we saw in our blinded sample reestimation was a lower-than-anticipated variance in the data, reflective of all the things I've been describing. And then the nominal sort of starting point of baseline HAM-A scores were a couple of points lower than in Phase II. I think we would expect something quite similar in Panaroma as we saw in VOYAGE.

Yes. Okay. Rob, people can't resist but to just hammer me with 50-microgram questions. So I'm going to throw out a few of them, if that's cool. Okay. One, did FDA clear the second GAD Phase III trial with the 50-microgram dose to be sufficient in addressing functional unblinding? Maybe talk about how explicitly this was discussed with FDA.

Every one of our studies has been discussed explicitly starting for Phase III in the Phase II meeting, including many rounds of detailed protocol review and advice letters and information requests throughout the development program. So we've had a -- the FDA has been incredibly collaborative throughout the development program and has been very close to the study designs and the conduct of these studies with us over the course of the last several years.

Thing that's so interesting is that I want to -- as a point maybe worth clarifying and I may be nitpicking on the wording, but functional blinding happens with psych drugs period. It just does, right? I mean Xanax is a great example of this, another anxiety drug. People who take 2 milligrams of Xanax know they're on drug regardless if they're a randomized study or not.

The thing we're trying to do is not eliminate functional blinding because that's not possible. What we're trying to do is add an element to the study design that increases confidence in the reliability of the outcomes we're drawing from the development program. That's why 50 is there. And so that's the purpose it serves, and that's what we've been discussing in that context with FDA.

Yes. Yes. Okay. Makes sense. And then I guess -- do you expect 50 to perform the same way as it did in Phase II? Like I asked another way, do you think that's a real signal in Phase II where there's like this modest effect, but it's clearly less than $100.

I think Yes. Based on what we've been able to model from a dose response standpoint, we think that there is probably a sort of threshold effect where the activity of the drug is more reliably achieved at 100 micrograms, and is it 50?

And that while some people will take 50 and we tell us these sort of PDMS-endpoints trying to measure how an effect the drug is having put a lot of credence in those endpoints because they're a little bit fuzzy.

But some people are going to take 50 micrograms and have the most profound experience they've ever had but we're not worried about individual patients, we're looking at averages here. And so when we look at the dose response modeling, we assumed it was going to be monotonic, we assumed that higher doses are going to have higher effect or at least not less than the lower dose. And that's what we saw really is that sort of this plateau at 100 micrograms, it doesn't increase further at 200. But at 50, we see a much lower effect.

So regardless of what we see from the -- I'm ballparking here, but the roughly 50 patients in the study who will have received 50 micrograms, that one study's point estimate of what the effect is, we feel highly confident in the dose response that we've chosen the right one and 100 micrograms and that it could show up sort of anywhere between 0 separation from placebo and very similar to 100, and it won't have any impact on the actual results of the study.

Yes. Okay. All right. I'm going to hit you with one more 50 question that I got, and I promise we can move on. Did FDA suggest you include the 50 dose? Or did you suggest it? And why? Well, you kind of already said sort of the context, but.

Yes. FDA has suggested that all sponsors include effectively intermediate dose control our argumentation and I think the sound logic here is that if you're going to use a control for this purpose, it needs to be a dose that is reliably functional, right, that it is reliably detectable, otherwise, it's unclear what purpose it would serve.

So we chose the dose based on data we had generated in Phase II that we don't believe is clinically efficacious based on the evidence we have, but that is reliably detectable sort of the best dose one could choose, but as sort of codified FDA's guidance, they're asking sponsors to do this.

And really, again, what they've said is use complementary designs between your Phase II and III program to support the robustness of the conclusions. And that's exactly what we've done. So at this stage, we've got 2 of 3 studies that are positive and serve that purpose.

We feel that there's a quite low relevance to what happens in one single study for one very small arm to construct the ultimate argument, which is that 100 micrograms is with an effective dose to treat GAD symptoms.

Yes. One other -- maybe a couple of other regulatory questions. What did you make of this FDA guidelines that just came out? And how do you make sense of the seemingly confusing comment around 1-year blinded data as like not an explicit requirement, but like a sort of like would be the best way to -- I mean, look, obviously, like a study of 100,000 people would be the best way to characterize efficacy. But look, the FDA is a contentional to some degree of what they put in these things. So maybe speak about that, too.

Yes. FDA has been very collaborative with us, and I'm sure with other sponsors and nothing in the guidance was a surprise, I think, to any of us in the field, right? I think those who are sort of direct interactions with FDA's viewpoints is when guidelines like that are published. Obviously, the draft guidance was 3 years before that and get an updated view 3 years later. But over the course of those 3 years, we've had dozens of interactions with FDA.

And I'd say that the final guidance that was issued is aligned with our program and is aligned with the arguments that we and others have been making and the sort of dialogue we've had with FDA since the inception of our development program. So there's nothing particularly surprising. I think that is -- there were some refinements between the draft guidance and the final guidance, one of which was an explicit statement that for an initial application, you need 12 weeks of data.

So like -- I mean, studies in a post-approval setting, if you look at most antidepressants that have been approved, they're approved on 2 acute studies. And then post marketing, people do randomized withdrawal studies. Now there's some complexity with this category of drugs and how you might do that here a randomized withdrawal study. But yes, the longer and the larger the study is, the more informative value it had.

Ideal studies would be huge and forever. It's just sort of impractical. I think the most important thing here is that what is clearly stated there and again, a reflection of the need and the opportunity here is that you establish acute efficacy, and that's what you need. You want FDA and the guidance is what you need to establish for initial application. Subsequent research can be done that could be informative. But even what's in that guidance, our -- you've heard me say this, but people talk about double-blinded studies. They're quadrupling-blinded studies.

And in our studies, at all points throughout the duration of the study, they're at least single blinded. So the guidance says most informative study design would be a blinded 1-year follow-up with effectively triggered pretreatment -- exactly what we're doing. The outcome assessors are blinded no matter what, no matter when we are in the study, whether we've unblinded, whether patients take an open-label drug, they don't know that no matter what.

Now a different -- once a patient takes open-label drug from that point forward, of course, they are unblinded and the treating physicians unblinded. Once we unblind Part A, we, of course, are unblinded to the treatment assignment. But throughout the duration, at least 1 of those 4 legs of the stool remains blinded. And so our interpretation is that even interpreting that as some sort of direct relevant to the studies that are ongoing, it is very much in line with what we've done. I guess the last reflection there too would be FDA is really thoughtful.

And I think they've been really -- again, I can only speculate for other programs, but seemingly, there's been the same degree of constructive dialogue for this field, which is why they came out with guidance. It would be pretty shocking if they had given out several breakthrough therapy designations had meetings with us to align on the program and with others in the field thinking of psilocybin programs and DMT programs each time there is agreement on the study design for the Phase IIIs, which included exactly the study design we're doing and somehow guidance would be issued that is directly in contrast with that, that will be a little bit odd.

So I think even in that context, I understand that these things have a lot of nuance to them, but we just don't see that as anything other than aligned with what we're doing.

Yes. Okay. Makes sense. When you guys -- can you -- again, more questions coming on the regulatory side. Can you talk about just like when you firmed up your regulatory alignment on the designs of the MDD and GAD studies? Was this before like this guidance was kind of crystallized? And like does the timing of that matter at all?

The guidance was issued a couple of months ago. So it was quite a bit before.

I know -- obviously, I know that this was before the couple of months ago, but there was like a draft guidance and stuff like that. Like I guess maybe just like as this guidance has evolved, like you firmed up your program like a number of years ago, like is there anything that's kind of changed with the FDA on the guidance side that isn't aligned with your program, Rob?

No. I think what we saw is that our conversations with FDA were crystallized in the finalized guidance and that FDA's thinking continued to evolve. Again, I'm sure based on dialogue with us and others in the field and engaging with the field broadly. And so while that guidance was sort of put out there for the world to see a few months ago, it is a reflection of the iterative and very granular discussion we've been having with them over the past 5 years, definitely from the point of having our Phase II data in early 2024 and the design of the Phase III program. So there's just not a thing there that we were surprised or that is misaligned with the discussions we've been having with FDA.

Right. Makes sense. So assuming the PANORAMA study is positive, I guess a 2-part question, one, do you plan on holding a pre-NDA meeting? And two, what's your degree of confidence going into a meeting like that, that you have enough data not just to file GAD, but also even MDD with it?

Absolutely going to have pre-NDA meeting, that's exactly we're going to have that discussion and come away with hopefully clarity on filing pathway for both of these indications, all the things we were describing before about the overlapping symptomatology and epidemiology in these indications is exactly why the law was updated in 1996 to allow for one study approvals in highly adjacent indications with really compelling evidence.

So I think there's a sound rationale for at least having that discussion. Now practically, either these scenarios, we feel like we're in great shape, right? If we were to file GAD first, go through the review cycle and immediately file an sNDA, we don't think it's going to have any sort of adverse downstream effect in terms of launching the drug, updating the label and so forth. But there's a huge degree of urgency in both of these calculations. And given the overlap, the comorbidity, there's a reasonably sound argument to say prescribers, patients would benefit from being informed about the utility in both the indications. That's the argument that we'll be constructing as we come away from a pre-NDA meeting, we'll be able to offer more clarity on exactly what the plan is there.

This whole set of pseudo-specificity thing that you had to do in GAD. Could they make you do the inverse of that in MDD?

This is -- we're getting to the strange constructs of psychiatric diagnosis. That has never been a concern. So someone who's in a depressive episode who also has anxiety -- there's never been a concern that you need to prove that it's...

It seems so arbitrary. I think I can get this issue with schizophrenia and cognition, but with depression and anxiety, like kind of makes no sense. My words not yours, you probably can't say that.

Look, there's not -- it's not just an FDA thing. And again, I think there's been annually thoughtful and evolving conversation around this. Part of this was a reflection. So much of these fields is a reflection of the availability of drugs for a long time. And a new anxiety drug in 20 years and over that time, we've had many new antidepressants. So when you end up in a world where for the PHQ-9 in primary care, which was effective way of screening patients and getting them diagnosed so that they can get SRIs, they get referred off.

When you think of the introduction and the evolution of the diagnostic framework, it largely reflected the in-vogue theories of the time that we were just bags of serotonin that needed more serotonin, everyone would be happy, which didn't work, at least entirely, and the sort of structural elements to pay for drugs and then to diagnose people said they could get the new drug started to reflect that.

So you end up with this sort of hierarchical framing of depression anxiety with a DSM -IV that has since been rolled back. There's since some recognition that, no, in fact, both can exist and they're not ones not contingent on the other. You can be anxious and have depression and if you have anxiety and depression, it's not just depression causing anxiety that makes no sense. So a lot of this is an artifact of times pass, but it's things that we just pay attention to make sure that no matter what we can send up with the highest degree of sound reasoning and data to justify that forward.

Yes. Okay. Have we hammered the regulatory stuff to death or anything else to add before we move on to the commercial side?

Again, I think FDA has been a great partner in this. We feel really confident in the studies we have designed and really building a strong body of evidence to support a path forward here. So there's always anything that isn't just a me too for the tenth time is going to have its own complexity and nuance.

But given the degree of attention and focus and regular we've put in this, we feel really good about regulatory framing and have an incredible regulatory team that has helped us navigate it to this point and will help us navigate the path ahead.

Okay. Cool. Maybe let's talk about the commercial side. And I like to start because I know there's a lot of angles we can talk about. Can you talk about like what we understand right now and what still is, I guess, yet to be elucidated related to what the economics could look like for DT120 at practices. And if you can, maybe sort of compare that to how that runs today with Spravato.

Yes. I mean I think the structural pieces that need to be in place to pay for medicine and to pay for drugs are going to be intact, right? I mean that's just a sort of fundamental reality.

There's 3 components to this. there's prescribing. There's monitoring and then for the 2 different models for buy-and-bill sites, there's a potential to make money on the drug. And each of those have current frameworks for reimbursement and they have frameworks that will need to continue emerging, that's having on different time scales. There's been a lot -- there's a discussion about CPT 3 codes and the adoption of those and transitioning those over time.

E&M codes are used for evaluation and prescribing of a drug, nothing will change there, right? No matter whether a patient is assessed and prescribed Spravato or DT120 or any other sort of complex treatment, we would expect the NM codes to be consistent. Monitoring codes paid on an hourly rate, hourly plus add-ons. Those codes exist.

Time is a thing that is a little bit different is that you're effectively collapsing visits so that instead of paying for, say, 6 hours of monitoring over the course of 3 Spravato visits, you'd be coding that over 1 visit. Why that would be a problem when you say potentially saving 70%, 80% or more of the monitoring time versus this Spravato over the course of the year, we've yet to have a payer tell us that they rather pay more as long as you have it over more visits.

It just hasn't happened. And then there's -- again, for buy-and-bill sites, which are not -- it's not 100% by any means, Spravato volume buying those sites, you make a markup on wait the outside and an ASP over time.

And so that's going to be something that is going to emerge, buying the economics are generally unleashed with obtaining a permanent J-code for a drug, and so we also provide. And once you get a permit J-code, folks feel that they can reliably get the drug reimbursed and they're willing to take on that spread if you don't know whether you're going to get drug paid for now, it's going to be a little bit harder to take on that risk and what we're going to get paid for it.

So all of those dynamics are pieces that over time would ideally be in place, on the monitoring side, there are advantages, we think, for something like DT120 where the efficiency of not having to turn over rooms and the ability to potentially treat multiple patients at the same time, although these rooms amount of work and the nature of work that's necessary to watch a few patients receiving a drug like a psychodelic versus having to turn over multiple rooms at the same time and have that sort of high throughput model is we think advantageous is something that could really lead to broader adoption.

I think there's also this sort of -- diverging a little bit from the plumbing of the system, the coding and the payments. There's thing that can't be overlooked here, which is that everyone sort of focuses on to Spravato because it exists today.

But these drugs aren't ketamine or esketamine. They work differently. They have a very different profile clinically for that reason. And so when we have these conversations with sites of care and with providers and payers even , we really don't hear a lot of -- oh, if only this was just like on that would be exactly what we'd like.

These sites and these providers see the data, they assume the opportunity and they understand in large part the differences and what it's going to look like, we think there will be a path for there to be favorable economics or there'd be a favorable sort of effort to profitability and payment structure at sites of care and that at the end of the day.

If we can enable sites to have a meaningfully better clinical outcome for similar patients and be profitable in the process, and that tends to be a good recipe for a pretty widespread adoption.

Yes. Yes. Makes sense. So maybe just taking a step back, like we talked about -- and we talked to this a little bit like at our dinner like last week, but like this whole interventional psychiatry model for people that are kind of like newer to the space and doing work on it, can you -- can you give sort of a little bit of a review of how that model has evolved over the past 5 to 10 years?

Like someone else in this industry told me that 10 years ago, there were a single-digit number of these clinics. I don't know if that's correct, but what is like the context there, one? And then two, like from a system capacity like do you guys, as you strategically plan for a launch, do you think this capacity is still growing? Like do we think the number of these clinics is going to go up another 50% to 100% over the next 5 years? Like how do you sort of think about that piece of it?

Yes. So I won't be able to put numbers on how many there were 10 years ago. But the framework, the model, the interventional psych care did not exist and there's a great -- it's easiest as really awful psychiatrists in San Diego area who is at UCSD, treating patients some you know quite well.

And it does a lot of Spravato mean today and as in all of our conversations signaled a real intent to adopt these drugs if they're approved and available, was it UCSD saw the opportunity to treat patients with ketamine, she used to require anesthesiologists to be the ones administering kind of members anesthetic hasn't been in psychiatry all that long.

And through that process and through store rigidity of not being able to actually get patients access to the drug ended up leaving that role in setting up an interventional psychiatry clinic. And now doing a ton of treatment and sees a huge opportunity at that site.

And so when we look at those sites, that's exactly the sort of phenotype of what's emerged is that folks that are treating patients and see the need and see something new coming for the first time in a very long time, are willing to set up their practices in many cases, to do exactly this.

And so if you wind back the clock to when the Spravato program was taking shape and so starting, none of this existed and at least based on what we've learned, we think part of the label indication selection and the sort of approach for that program was also aimed at the world that didn't exist, which is the patients we're getting ketamine in hospitals.

Now you fast forward 5 or 6 years, and we've got thousands of these clinics around the country, still growing. And this is for drug that has some really challenging dynamics of having to treat patients many times up to 56 times a year. 2 hours a session, there's a lot of burden on both providers and on patients.

And so in many ways, that -- we talk about these in shorthand, again, sort of Spravato sites, it's not what they are. There's sites treating patients who have registered under a REMS so that they can deliver Spravato. That's all it is.

When we engage with that are some of the most enthusiastic adopters -- not the only enthusiastic doctors, there's many outside of those treatment sites that say, oh, I see this coming, and I absolutely want to be a part of it and tend to treat patients in my practice as well. there's a lot of dynamics that are challenging for some of those broader settings to actually adopt Spravato, right?

It's our you have to have a patient coming in twice a week for a month and then weekly thereafter or biweekly thereafter. By the time you get to a dozen or so patients, your life is now just doing that. And that's a fine choice, but not everyone wants to do that. So some of the dynamics with our folks, we think, open up an even broader opportunity.

All that said, based on any of the projections that we have seen for the first many years of adoption, even just with the capacity that exists today, the rooms and the people and the sites of care, that are available that wouldn't have to displace Spravato event, it was more than enough capacity for us and for several others to be out successfully in the world and achieve those sort of numbers.

Over time, if this drug and this category continues to evolve in the way it has and continues to show the incredible promise it has. It's hard to not get excited about continued growth and those other providers who aren't and all involved in from a ketamine today becoming involved and growing that capacity dramatically over time.

And for us as an organization, we really look at this problem as for the sort of enormity of what it is and for the rate it's growing. And if we're not aiming and actually having adoption and uptake in capacity done very, very responsibly.

But if we're not aiming to actually treat a lot of patients, we're not going to make a difference. We're not actually going to change the problem we have with things a depression in our country.

So the goal is to continue to grow that to lean into it. And we find ourselves in a really fortunate position to be able to go out and establish ourselves out in that setting in a way that we think will enable that over time.

Makes sense. What do you think the REMS will look like for 120? And is this Spravato REMS a good analog outside of the maybe difference in recommended monitoring time?

Yes. I think the main structural elements are pretty prescriptive in REMS, right? There's sort of core elements of what REMS typically entails. It would be obviously subject to review and discussion with the FDA through the NDA review.

But I think from what we know today from what we see, I think an easy enough in a log, although not exactly the same and easy enough analog or the elements and the sort of components that they anticipate with Spravato could be applicable here as well that needs to be in an appropriate setting.

Administration needs to be under -- under the supervision of a health care provider and that you need to have REM's goals for diversion and misuse to trying to make sure this drug doesn't end up in the wrong hands.

Yes. Yes. Okay. Makes sense. Do you think FDA will have prescriptive language around. Redosing or like a -- maybe not monitoring, but like following up with patients like I covered Sage from the IPO until the end. And like I was always going to be fascinated how the FDA was going to handle redosing for zuranolone and MDD and then we never got to find out. But this, I guess, Compass will maybe be the first of like a PRN antidepressant. But what's your sort of perspective?

I think even as we see sort of the language in the guidance, right? There is informative value for what prescribers could expect over time, we think, having some information on the label about what was seen in trials at least, would be useful.

Now where you get sort of in the weeds of where things go on labels and what you're saying? And is it -- what we don't think is going to be the case is being able to make do inferential stats and making placebo contrast claims and saying, Oh, this was so much -- this was better than the design of any of the studies in Phase III to do that. But what we've done, and again, the language about informative study designs following patients for a year with triggered retreatment is exactly what we're doing.

When symptoms return at a level that you see functional impairments and moderate or worse symptoms in our studies, patients get treated with open-label drug. So at the end of these, even now, we have estimates of what the typical use patterns are, how often on average takes until patients need a second dose and how many over the course of 6 or 12 months, how many doses that they need.

And so that sort of information. Again, too early to say exactly, but you can see a world in which that sort of information makes it into descriptions of what was observed in the clinical trials in Section 14 of the label. And have very, very good utility there and not go too far to try to make claims.

And again, I think that that's kind of the case that this isn't typically done, but look at things like Xanax and very fair old approval, but approved on 4 weeks of data. how it's used out in the world.

Typically, I mean FDA doesn't regulate the practice of medicine. They need to set the conditions of use to prove out the safety and effectiveness of drugs. And so labeling and reds are intended to accomplish that. clinical practice is first going to iterate over time and have a lot of learnings as clinicians actually treat patients in the real world.

Yes. Yes. Okay. But at the end of the day, you don't think a label will be overly prescriptive on how to redose.

Based on what we know today, no, I don't think that that's like the...

Okay. Fair enough. I'm not trying to box you in a corner. Makes sense.

Say what we know and then we iterate with new information, that's all I can do, right?

Fair enough. . One thing on the GAD market opportunity. So I talked to you about this before. I was covering Definium. One thing I've been trying to figure out since the beginning is like on the one at is like this an overwhelmingly big market. On the other hand, like you talked to a psychiatrist from GuidePoint, right?

And they actually don't really treat that many patients that like just have GAD. It's usually this overlap with MDD. And maybe we're splitting hairs here because, right, we're talking about millions of people anyways. But like how do we think about GAD is like a distinct market? And maybe what did you learn from enrolling the Voyage and panorama studies, right?

You basically have people -- like, were you enrolling those patients? Were they already in like specialist care? Like maybe talk about that and the implications for the commercial model.

Yes, I think it is a bit splitting hairs because when we think of real-world use, we're not talking about treating patients who just have GAD and don't have elevated depression scores, that would be absurd.

There is kind of going back to what we talked about, there's some interesting operational aspects to psychiatric diagnoses, right, which is that over the last 20 years, if you wanted to offer a patient in specialty care, the new drug that's available, they would need an MDD diagnosis to get it paid for.

When you have no new drugs for anxiety, why code people's anxiety specially when you have 2 options, one of which will be the drugs and 1 of which there's nothing new for.

And so I think it's one of these -- it just isn't a reflection of any reality that we see -- whether we look at GAD and where patients are cared for or whether we look at the places that we engage with, where psychiatric care is delivered and what their populations look like.

No matter how you sort of attack that, there is a lot of anxiety burden broadly in psychiatry. It is present at the same time as MDD when depression symptoms are improved, the thing that is often residually not treated well are anxiety symptoms.

I mean we had an Investor Day we had earlier this year is [indiscernible] Psychiatrist in South Carolina was talking about treat a lot of patients with Spravato and the comment she made was the thing it does the least good is help with anxiety symptoms.

And so much that the case you said, so had a patient but it's unfortunately lost to suicide because of the residual anxiety that was unable to be treated. I think there's just -- there's a complete lack of familiarity with anxiety from the outside looking in because there has been focused elsewhere for the last 20 years, that is, again, operational, not a reflection of any sort of fundamental reality.

So when we look at numbers anyway, I think that the realities are that the patients who are showing up in the care environments where we expect this drug to be delivered, there is a high prevalence and incidence of anxiety and depression, and both of those are going to be overlapping and there's going to be an opportunity that is quite extensive about these indications?

Yes. Okay. Well, I want to be sensitive to time. One other question I got, Rob, from the audience here is just what are you expecting? Or what do you think FDA wants to discuss in this public year and then schools coming up in a couple of weeks.

Yes. I think continued dialogue about the field. And I think kind of what's coming in the future, right, the considerations beyond just approving a drug. At the end of the day, while we all talk about a lot of the complexities from a development standpoint, I think FDA is now codified in guidance. I think it's an issue drug class specific guidance all that often.

The degree of thought and consideration that's already gone in from the office of neuroscience and from the Division of Psychiatry is reflective in the fact that we now have that written down in a final guidance document. So I think what we can anticipate is a broader discussion, perhaps more forward-looking about some of the public health considerations here.

We're not strangers to the reality that these drugs have a past history and that they need to be rolled out responsibly and I think that's part of the dialogue. So we don't know exactly all the topics that will be covered, I think it's likely to be Something was trying to sort of set the context for how do we -- it's really incredible.

I mean, rarely in medicine, do you have a chance to sit down, look into the future and say, we have a chance to make a real difference. How do we do that well? A lot of times things are just reactive and iterative when we end up in a world that we didn't intend to design. No one would design the U.S. health care system perspective given whiteboard and design the best health care system, you probably wouldn't end up with what we have.

And so here, we have an opportunity to really engage a bunch of stakeholders and sit down and try to design that future. And so hopefully, it's a constructive dialogue there that informs thinking beyond just whether drug should be approved or not.

Yes, yes. Okay. Well, good. Well, anything else we have like a minute left. Anything else you want to add or get across that you didn't have the chance to?

No. I think I appreciate all the always thoughtful questions and for having us here. Again, it's great to have a summer like this. We have 3 readouts coming this close together.

This last one we're incredibly excited about and really eager to the other side and assuming we could do a positive outcome to charge forward from there and continue pushing the bounds of the field. We think there's an incredible opportunity and last to the read out of the year come in expected by the end of the month.

Okay. By the end of the month, would you like to share the date?

We've been told Wednesday, Thursdays and Fridays are no longer allowable.

So it's not by Tuesday. Everyone's going to panic.

It's 100 days a year now, but that's okay. It's great. We're excited. The team has been incredibly busy, but it's all for a great reason and now look forward to share in the state of here soon.

Okay. Great. All right. Thanks, Rob, and thanks for everyone listening and Yes, feel free to follow up if you want to chat more. Appreciate it.

Thank you.

Hello, and welcome to the Definium Therapeutics Phase III Voyage Topline Results Call. [Operator Instructions] As a reminder, this conference is being recorded today. If you have any objections, please disconnect at this time. I would now like to pass the call over to Rob Barrow, Chief Executive Officer. Please proceed.

Thank you, operator. Hello, everyone, and thank you for joining us this morning. I'm Rob Barrow, Chief Executive Officer of Definium Therapeutics, and I'm joined today by our Chief Medical Officer, Dr. Dan Karlin; and our Chief Financial Officer, Brandi Roberts. We could not be more excited to be here with you this morning to share the unprecedented topline results from Voyage, our first pivotal study of DT120 ODT in generalized anxiety disorder or GAD.

Before we get started, please note that on today's call, we'll be making certain forward-looking statements. We encourage you to review our SEC filings for a discussion of the risks and uncertainties associated with these statements, including the risks described in our most recent annual and quarterly reports.

When we presented our Emerge results in June, I noted how rare it is to have an opportunity to share truly transformational data. That is even more true today when we have the privilege of sharing such findings for a second time in a row. As with our MDD results, we believe the findings being presented today have the potential to redefine what patients can expect from the treatment of GAD and position DT120 as a potentially best-in-class product across 2 of the biggest and most impactful indications in psychiatry.

I'd also like to take a moment to thank our study participants, investigators, partners and our incredible team at Definium for making all of this possible. We are deeply appreciative and humbled by your commitment, your trust and your belief in our vision. Your efforts have brought us to this remarkable moment and most importantly, have brought us one step closer to making our dream a reality.

We have an ambitious vision at Definium and a belief that profound change in psychiatry is truly possible. We set a high standard for DT120 to demonstrate that a single supervised dose can deliver rapid, robust and durable efficacy and offer new hope to the tens of millions of people living with depression, anxiety and other mental health disorders.

We've always believed there's a particular need for innovation in anxiety, and we remain steadfast in prioritizing GAD as a lead indication for DT120. GAD places an enormous burden on patients, families and society, impairing daily function, productivity and quality of life, and that burden has grown dramatically. Prevalence has increased from roughly 3% in the early 2000s to approximately 10% today.

At the same time, we've entered an era of far greater awareness and openness around anxiety and its impact on people's lives. But our ability to treat it simply hasn't kept pace. There hasn't been a new drug approved for GAD since 2007, and that's not for lack of trying. Over that period, roughly a dozen drug candidates spanning numerous mechanisms have advanced into late-stage development. Nearly all have failed with most unable to demonstrate any meaningful improvement over placebo.

That long period without success has also left the field without a modern benchmark for what truly compelling efficacy in GAD looks like. We believe the unprecedented Voyage results we're sharing today change that. They represent the promise of real progress for patients with GAD and further reinforce the potential of DT120 to help usher in a new era of psychiatric care. Voyage marked our second pivotal readout for DT120 this year and our first pivotal readout in GAD.

As with our Emerge readout, Voyage met the primary and all key secondary endpoints with a high degree of statistical significance. Seeing consistent positive outcomes across 2 large Phase III studies in 2 adjacent comorbid and highly prevalent psychiatric disorders further strengthens our confidence in the potential of DT120 and the broader opportunity ahead of us.

To briefly summarize some of the key points, the primary endpoint demonstrated a 5.4 point placebo-adjusted improvement on the HAM-A at week 12, corresponding with an effect size of 0.81 and a p-value of less than 0.0001. To our knowledge, this is both the largest nominal change and largest standardized effect size ever observed in a pivotal study in GAD. This efficacy was also rapid with a 7.7 point placebo-adjusted improvement on the HAM-A at week 1 and a 0.8 point placebo-adjusted improvement on the CGI-S at day 2.

DT120 was well tolerated with no new safety signals identified, including no suicidality signal. We continue to observe an efficient and predictable dynamic of treatment sessions with an average time to clearing the structured end-of-session checklist of 6.4 hours and over 90% of participants clearing by hour 8. The strength of the DT120 program as a whole is anchored in consistency. DT120 has demonstrated a large and consistent effect size with a Cohen's d over 0.8 in each study.

Using the standardized effect size is especially useful in looking across studies as changes in study design, population, baseline characteristics and other study dynamics can impact nominal scores and make comparisons of nominal scores difficult. The fact that this extraordinary effect size has now been shown across 3 studies in 2 indications gives us a high degree of confidence in the robustness of the efficacy and continues to build the case for a potential multi-indication practice-changing profile.

And finally, to put all of this in context of the broader treatment landscape, DT120 has now shown in 2 studies in GAD, an effect size of 0.81, and that is more than double the standard of care. To reiterate that, in a disorder with high prevalence, high burden, high unmet need, and no innovation in decades, a single dose of DT120 has shown a rapid and durable effect with a magnitude that is more than twice as large as the drugs approved today. With that, I'll turn the call over to Dan, who will walk through the study results in greater detail.

Thanks, Rob. Today is a special day. As a psychiatrist who has treated many patients with GAD, I have seen firsthand how difficult it is to help these folks find relief from the complex interplay among the emotional, cognitive and somatic experiences of the illness. In our studies, these are measured using standardized assessments like the HAM-A, but in people's lives, they produce a nearly constant onslaught of distressing internal experiences.

Medications available today may tamp down one aspect of someone's experience of anxiety, but often leave the others untouched. What we've seen in Phase II and now in Voyage is that DT120 provides a different kind of relief in those who benefit from it, a relief that isn't bound to one domain of the illness. I'm excited to share further specifics of the Voyage results with you. As Rob highlighted, the study demonstrated rapid, robust and durable improvements in anxiety along with a favorable tolerability profile and efficient treatment session dynamics.

Let me begin with the study design. Voyage is comprised of 2 parts: Part A, which is a 12-week randomized, double-blind, placebo-controlled period; and Part B, which is a 40-week extension period with opportunities for open-label treatment. Participants were tapered off background antidepressant and anxiolytic medications prior to enrollment, and no psychotherapeutic intervention was provided as a part of the study.

In Part A, participants received a single dose of DT120 100 micrograms or placebo and were followed for 12 weeks. The primary endpoint in the study was change from baseline in HAM-A total score at week 12 assessed by independent central raters who are blinded to treatment assignment and visit number. In Part B, participants continue to be followed for an additional 40 weeks and completed regular blinded, centrally rated efficacy assessments for a total of 52 weeks of blinded efficacy assessments.

Each time a participant meets the study's prespecified criteria for retreatment, they become eligible for an open-label dose of DT120 for a total of up to 4 open-label doses. The retreatment threshold in Part B is a HAM-A total score of 16 or greater, which corresponds to the cutoff for moderate illness and is characterized by a meaningful increase in disease burden, functional impairment and disability.

From the outset, we picked this cutoff as the target for treatment because we thought it was both achievable and meaningful to patients. A total of 214 participants were randomized in the study with 107 participants in each arm. Approximately 90% of randomized participants completed Part A. The demographics of participants enrolled in Voyage were generally balanced between treatment groups and representative of GAD patients commonly encountered in clinical practice.

Participants entered the study with a high degree of disease severity as reflected by baseline HAM-A and CGI-S scores of 27.9 and 4.6 across the groups. These values place participants firmly within the severe range of anxiety. We also observed past psychedelic exposure consistent with the background range of use in the population we would expect based on epidemiological estimates with 21% reporting any prior psychedelic use and 9% reporting prior LSD use.

Another way to understand the enrolled population is to look at the distribution of disease characteristics at baseline. 3/4 of participants were characterized as severe on the HAM-A with a score of 24 or higher and the remaining 1/4 categorized as moderate with a HAM-A of 20, the minimum for study enrollment to 23. Despite a limited number of treatment options, we observed a population with characteristic prior treatment experience. 36% of participants reported receiving 2 or more prior GAD pharmacotherapies.

One particularly notable aspect of the experience of GAD for these participants is the time since diagnosis and time since symptom onset. On average, participants in the study reported experiencing GAD symptoms for approximately 24 years at the time of enrollment and on average, received their GAD diagnosis about 12 years prior to enrollment. This speaks to both the long delays in diagnosing GAD and the reality that GAD is a chronic lifelong condition that leads the folks who suffer from it to do so without diagnosis or explanation for many years and in cases like our enrolled population to continue to not find relief even long after diagnosis.

Between our MDD program and our GAD program, we have endeavored to recruit populations that are maximally representative so that we can make reliable and reproducible assessments of DT120's ability to treat the disease of interest, both with and without comorbidity. On the HAM-A, which was the study's primary outcome measure, DT120 demonstrated rapid, robust and durable efficacy. At every measured time point, DT120 statistically and clinically exceeded placebo on the HAM-A total score, demonstrating a consistent treatment effect throughout the study. In fact, at each time point, the p-value was less than 0.0001.

There are several dimensions we consider when evaluating a treatment profile. First is robustness. At the primary endpoint measured at week 12, DT120 demonstrated a mean improvement of 11.6 points and a placebo-adjusted change of 5.4 points. Rapidity is particularly important for patients with GAD. By week 1, the first HAM-A efficacy assessment after treatment, patients receiving DT120 showed a mean improvement of 11.9 points from baseline, corresponding to a placebo-adjusted change of 7.7 points. This early separation from placebo was maintained across subsequent assessments.

Taken together, the rapid onset of action, robust magnitude of improvement and durable benefit observed over 12 weeks provide strong evidence of a meaningful and sustained treatment effect after a single administration of DT120 in patients with GAD. A secondary measure of disease severity is the CGI-S. And here, we see that the CGI-S tells essentially the same story as the HAM-A. Key secondary endpoints shown here are change from baseline in CGI-S score at week 12 and early improvement measured at day 2. Notably, these instruments, the CGI-S and the HAM-A use different mechanisms to assess the underlying illness and are conducted by different raters.

The HAM-A is assessed by independent centralized rater, while the CGI-S is a local site-based clinician-rated measure. The consistency across these independent measures gives us tremendous confidence that the treatment effect that we are able to measure represents real meaningful clinical improvement in the study participants.

Another way of looking at the HAM-A data is based on fixed thresholds, remission and mild. We can also look at relative response rates. At week 12, 14% of participants receiving DT120 were in clinical remission compared with only 4% of those receiving placebo with a p-value of less than 0.05. 51% of participants in the DT120 group reached mild or better status compared with just 23% of those receiving placebo with a p-value of less than 0.0001 and 43% of participants receiving DT120 met the response criteria compared with 16% of those receiving placebo with a p-value of less than 0.0001. These response and remission outcomes further support the clinical relevance and robustness of the treatment effect observed with DT120.

We also conducted subgroup analyses to better understand whether the treatment effect was consistent across different patient populations and baseline characteristics. We evaluated factors such as time since diagnosis, prior GAD medication exposure and sex, along with a number of other baseline measures. Across each of these analyses, the treatment effect was reliably similar. Importantly, this included patients who have been failed by 2 or more prior GAD treatments, a population with substantial unmet need and often more limited treatment options. The consistency of these results across the subgroups strengthens our confidence that the benefits observed in VOYAGE are broadly applicable across the GAD population and are not being driven by any single patient group.

Turning to safety. DT120 was generally well tolerated, and the adverse event profile was consistent with the known pharmacology of DT120 and with prior clinical experience. DT120 showed a favorable tolerability profile with all adverse events mild to moderate in severity and most treatment-emergent adverse events occurring and resolving on dosing day. There were no serious adverse events in the DT120 arm, no suicidal or self-injurious behavior, and no indication of drug-related suicide signal or suicide-related risk based on C-SSRS assessments.

In the DT120 arm, 61% of AEs were mild and 38% were moderate. One severe AE of diverticulitis was reported in the placebo arm. There were 3 treatment-emergent serious adverse events in the placebo arm, 1 adverse event leading to discontinuation in the drug arm and no adverse events leading to death. The discontinuation was related to a new-onset depressive episode approximately 6 weeks after dosing in a patient with comorbid recurrent MDD.

Taking a look at the most common treatment-emergent adverse events, those with an incidence of at least 10%. The most frequently reported events were the expected transient perceptual, affective, cognitive and behavioral changes occurring primarily on dosing day. These events were mild to moderate, occurred on dosing day and resolved by the conclusion of the dosing session.

Rob mentioned this earlier, and we believe the treatment session dynamics remain one of the most important aspects of the overall profile of DT120, and the DT120 session is well matched to the needs of GAD patients with a combination of session duration and depth of experience that continues to produce efficacy outcomes like the ones we've been able to share with you today.

We use a structured end-of-session checklist to assess readiness to safely leave the treatment setting. The average time for clearance on the checklist was 6.4 hours with more than half of participants clearing at hour 6 and 92% clearing by hour 8. When we look at all of the known Phase III DT120 dosing sessions, we see a remarkably predictable duration with the vast majority lasting between 5 and 8 hours. We believe this translates very cleanly into clinical practice where the end of session checklist can be easily implemented to inform medical decision-making and the clinical staff involved in supervising sessions.

Now we turn to Part B, the 40-week extension phase. As a reminder, participants are eligible to receive up to 4 open-label treatments with DT120 based on disease severity of moderate or worse as assessed by the centrally rated HAM-A. The purpose of this phase is to better understand long-term durability from Part A, subsequent treatment patterns, response to retreatment and their durability over the full year of observation and dosing opportunities.

At the time of the interim analysis, 87 participants assigned to DT120 and 90 participants assigned to placebo had entered Part B. Today's discussion focuses on data through week 28, where enough participants have been evaluated to provide a meaningful analysis. The demographics and baseline characteristics of participants entering Part B were generally consistent with the broader Part A population. As expected, symptom severity of Part B entry reflected the treatment effects observed during Part A.

As anticipated, multiple treatment trajectories emerged with participants receiving intermittent open-label treatment based on symptom recurrence and retreatment eligibility. The data show a distribution of participants receiving 0 to 3 open-label treatments through week 28. These early patterns provide an encouraging first look at how DT120 may be used in a real-world treatment setting.

Longitudinal HAM-A scores moving from Part A into Part B continue to show both the ongoing durability from the initial dose of DT120 in the active arm and the incremental benefit from open-label treatments. Participants originally assigned to placebo begin to converge toward those who received DT120 in Part A after receiving open-label treatment. These results increase our confidence in the durability and retreatment paradigm for DT120 and provide early support for how intermittent dosing could sustain improvement over time.

As with Part A, we can look at response and remission over time in Part B. What we see is that across each of these measures, patients continue to benefit with subsequent treatment administrations. Response and remission rates improved through week 28, demonstrating sustained disease control over time. The consistency of these findings across multiple clinically meaningful endpoints and safety measures gives us enormous confidence in the potential for DT120 to safely deliver durable efficacy with intermittent symptom triggered retreatment in a variety of real-world clinical settings. And with that, I'll turn the call back over to Rob.

Thanks much, Dan. As I said at the outset, our goal at Definium is to enable a new treatment paradigm that can profoundly reshape clinical practice in psychiatry. We believe the landmark results shared today are another important step in pursuit of that goal. With the unprecedented results we have delivered in MDD and GAD, we continue to believe -- to build what we believe is one of the strongest clinical data packages in psychiatry.

We are moving with a high degree of urgency to pursue a potential NDA submission for DT120 ODT, and we approach our final pivotal readout of 2026 with more momentum than ever. Looking ahead, we anticipate the topline readout from Panorama next month. We continue to advance Ascend in MDD toward a topline readout in 2027, and we are progressing plans to initiate Haven in PTSD in 2027.

The need across GAD and MDD remains enormous. Today, an estimated 50 million adults in the United States are affected by GAD or MDD with approximately 26 million diagnosed, 13 million receiving pharmacotherapy and more than 4 million having been failed by 2 or more treatments. We believe this represents a significant opportunity to bring a differentiated treatment to patients who continue to need better solutions.

Even modest uptake in the addressable population that has the potential to impact tens of thousands of patients and create substantial value. Importantly, we view the initial scale as the starting point rather than the ceiling with a long-term opportunity that could meaningfully expand as we continue to generate evidence, broaden access and reach additional patients across these large and underserved markets.

We see 2 distinct value drivers ahead of us. Our continued commitment to excellence in clinical and regulatory execution and setting the standard for commercial impact and execution to bring this clinical promise to patients as impactfully as possible. We're working tirelessly to build Definium into a psychiatric powerhouse that can reset expectations for what patients and providers can expect from care.

Before we go to Q&A, I want to say a special thanks again to our incredible team at Definium. We've built an organization of exceptional people who are deeply passionate about our mission and the patients we serve. None of this would be possible without your unwavering dedication and tireless effort. It is an honor and a privilege to work alongside each and every one of you every day, and I cannot wait to see what the future holds for all of us. With that, we will open up for Q&A. Thank you.

[Operator Instructions] Our first question comes from Andrew Tsai of Jefferies.

Congratulations again on another robust data set. So my question is basically around now that you have 3 profound game-changing Phase II/III data sets in MDD, GAD, can you maybe talk briefly about what your FDA interactions actually have been like after the MDD data set in June, whether there is any inclination the agency might be supportive to a combined filing in MDD and GAD actually?

And then secondly, for MDD, could we expect you to seek a breakthrough designation? You already have one in GAD. I figure maybe a breakthrough can help the MDD time lines as well because I think you're waiting for the base case MDD second Phase III to read out in 2027.

Yes. Thanks so much for the question, Andrew, for being here this morning. Yes, we've had an incredible dialogue. And I think it's worth taking a minute to just acknowledge the division of psychiatry at FDA. These drugs that we are working on and the entire field is working on, have been sitting on the shelf for 60 years almost -- 50 years.

The willingness to look at science objectively and lean in and understand the complexities and navigate those complexities with us is something that isn't required of any agency, and FDA has really stepped up to meet that mark. It's really encouraging, I think, for all of us and for the field of what lies ahead. In terms of interactions, we regularly are having formal and ongoing dialogue with FDA on a number of fronts on everything that goes to what's going to inform our NDA filing strategy.

As we approach the Emerge data in MDD, we obviously were very much focused on that potential, and we've been working very hard over the course of this year to prepare ourselves for an NDA filing and draft a lot of the NDA, which we made incredible progress towards. With 3 data sets in Phase III, if Panorama is positive, we certainly believe there is a compelling opportunity and a compelling reason to consider filing and consider a path to getting both of these indications on the label. The effect sizes we have now consistently shown across 3 studies are outstripping everything that is approved today and really from what we've seen, everything that's in development.

And that puts us in a position where we can think broadly about the patient population that's in need here. And with the strength of those results, we're still conducting a second study in MDD, but the added value of additional research, we already have a high, high degree of statistical significance and a belief in the effects across both of these indications.

So we continue to dialogue with FDA. We're going to continue having those meetings, we've had meetings since the EMERGE results, we'll continue to have meetings in the months ahead as we approach and get closer to filing our potential filing for 120 in these indications. And as far as a breakthrough therapy designation goes, we have had, again, a great dialogue and a great opportunity to really interact with the agency frequently under the GAD program, we're always exploring every opportunity to bolster that alignment, that collaboration with FDA and to seek every way to expedite development and path to market. So we're going to continue exploring all those options. And certainly, as any of that unfolds, we'll continue to share updates for that one.

Our next question comes from Marc Goodman with Leerink.

I was just wondering if you could share some detail on what exactly is included in the end of session checklist and if the FDA has given any feedback on how it may be used in clinical practice. Also, if it's evolved over time since it was used in the Phase II study?

I'll turn that one over to Dan here to comment, thanks.

Yes. Thanks. It's an excellent question, and we obviously focus on this because we think it's incredibly important to provide tools to clinicians so that they can make informed medical decisions in the use of a product if approved. The Phase II study used a different instrument that we devised because we hadn't had clinical experience using 120 in treatment of people with GAD at that time. So in Phase II, we looked at the entirety of the DSM-defined symptoms of hallucinogen intoxication to just try to understand what it looked like for folks between hours 8 and 12 after treatment. We also used a 200-microgram dose in Phase II. So we just really wanted to understand and characterize what the end of that experience looked like.

Beginning in Phase III and in our safety studies after the transition to the ODT product, we created the end of session checklist, which effectively looks at the domains required for capacity for decision-making. It looks at people's alertness and orientation. It looks at the resolution of perceptual symptoms. It looks at their ability to safely navigate their environment and things like this. It's an 8-item scale. And throughout our use of it, it's been submitted alongside protocols for FDA review. So we've gotten extensive FDA feedback. We've had back and forth with them on even the details down to the item level and the phrasing of those items as we've moved along.

Because we used the checklist in our trials, despite having an 8-hour minimum, the requirement for end of session in the studies is 8 hours plus checklist completion. What we take this to mean is that the checklist is adequate for determining people's ability to safely end their sessions. And so while we have no reason to think that an 8-hour minimum persists in the real world because that's a trial artifact, right? We need to have long enough sessions to ensure that we're not letting half of patients in Part A leave at whatever that minimum is and the others have to stay longer because they're not quite ready to leave, that would provide another source of unblinding and confounding in the study. But based on the checklist results that are showing the sorts of numbers we're seeing at 5 and 6 hours ready to leave, we fully expect that it will translate very cleanly into real-world clinical practice.

Our next question comes from Gavin Clark-Gartner with Evercore ISI.

Great to see this data. Just for the second GAD Phase III study, could you remind us what your expectations or maybe lack of expectations are for the 50-microgram control arm that's included there?

Yes. Thanks so much, Gavin, and thanks for the question. I think this is one of those things. When we look at the field and research methodologies in the field, the historically have been a lot of different ideas out there, and a lot of those have fallen by the wayside. The concept of adding on additional controls in studies is a reasonable one depending on the motivations for it. With the inclusion of an intermediate or a lower dose of drug, particularly here and what it's intended to do is trying to mitigate the connective tissue, let's say, between potential expectancy and biasing outcomes after the drug is administered.

We continue to see that patients who are administered 100 micrograms of DT120 can reliably guess that they receive the active drug. I think it's just somewhat common sense here that people taking a high dose of -- any psychiatric drug, but a high dose of certainly a profoundly -- a drug that profoundly alters affect and perception and things of that is going to be detectable.

And so what we try to do is include the 50-microgram dose so that in the consent process, we can inform patients that just because they feel something on the day of dosing, they can't be sure that it's the active dose of drug. And we've also seen in our Phase II study that 50 micrograms, while it produced no clinical separation, clinical activity over placebo, it was also very reliably detectable by the patients. So the logic is just because we feel something, don't assume it's the real thing.

The important part is that it doesn't have any impact on how we're assessing, analyzing or interpreting the results of the study. I always probably too much rely on analogy of eyeglasses. If we were to do a study of patients with eyeglasses who gave some people half the prescription that they would see well with, and we gave other folks placebo and we gave other folks the correct prescription, it wouldn't negate anything if we found that people who get half the prescriptions can see a little bit better. The reality is that a drug that works, works regardless of what other doses of that drug do.

And so we're not at all focused on that retrospectively as a sort of analytical outcome. It is purely an operational control and something that is designed to have prospective futility in the study.

Our next question comes from Paul Matteis of Stifel.

This is Emily on for Paul. Congratulations on the data. We were just wanting to think like as we look ahead to the commercial opportunity in GAD, what is the profile of these early adopters? And given that many of these patients are currently treated in primary care, what are kind of like the levers you guys can rely on to try and change referral patterns to get patients into these more interventional centers?

Yes. Thanks so much, Emily. I think that as part of our belief in the opportunity to have a profound impact for these patients is a recognition that -- if we go all the way back, psychiatry really started focused on anxiety symptoms. I mean that is structurally where the focus was. It's where early pharmacotherapies were really focused in neurotic illness. We had barbiturates, benzodiazepines. And over time, the entire system shifted away from that, perhaps in part because it's so difficult to actually show any improvement on.

And so when we look at that reality and we think of what's possible, we don't look at the fact that a lot of anxiety patients are given SRIs in primary care and say, oh, it inaccessible to us. It's just an artifact of reality that that's kind of all we have today. Without long-term benzodiazepine use, the class of drug that is really used are SRIs, and there's only a few of them approved in anxiety disorders.

And so when we -- certainly on a personal level, when we talk to anyone with anxiety, we don't hear them saying, well, I'd rather stay in primary care on the drugs that I've been taking if they haven't been working for them. There's a real eagerness to have better options. And I think even for those patients who aren't currently in treatment, the availability of something that is really actively effective for them could drive further seeking of care, right?

If a patient doesn't have hope that they can get better by getting treatment, why go get treatment in the first place. And so that's really, I think, an opportunity initially to focus on those that are easily identifiable, they're already showing up, to have comorbidities that obviously, one of the things that's really cool of what we've seen so far in the data is that we seem to have an even more pronounced effect when looking at anxious depression or depressed anxious populations. I mean either of these studies, either direction we look. And so there's an enormous initial opportunity with millions of patients. But over time, we think that it grows even further. Turn over to Dan, maybe comment a little bit further too, just on patient profile.

Yes, for sure. And so I absolutely agree. I mean what we've observed repeatedly in the epidemiology that exists and in the epidemiological work that we've done is that there is this huge population of folks who are either undiagnosed or undertreated. And as you know, that absolutely happens in primary care settings.

Our early patient profiles most likely to get the drug soon after launch are folks who aren't exactly that population. Well, as Rob says, we will work on the levers that allow folks to advance through the care system such that they ultimately have access to the drug, but early on, the folks most likely to get our drug are people who have had these multiple drug trials, each of which has been in some way unsatisfactory, either inefficacious or excess side effect burden. And usually, it's a combination of the two, right? The side effect burden exceeds the benefit, and it's not worth it to stay on the drug for the patient or they stay on it despite that because it offers some little relief.

By the time folks have had these drug trials, they're almost always in the care of a psychiatric professional, either an advanced practice nurse or a psychiatrist because working with these late-line drugs is something that the primary care just generally doesn't do. So it's those patients, in particular, the ones with severe illness who progressed through the system, who have ended up in the care of psychiatrists and APRNs and where those prescribers are the very same people we talk to who say that they don't have the tools in their toolbox to be able to adequately address the suffering of those patients.

So at every level, those patients who are out in the world, have never been diagnosed, the patients in primary care who have been and the patients who've been traveling through the system and are in late-stage use of drugs that may be prescribed off label, we think we have the ability to access each of them at various stages after we launch if approved.

Our next question comes from David Amsellem with Piper Sandler.

So I have another question about commercial -- sorry, clinical practice. So how do you think treatment in practice is going to shake out between monotherapy of DT120 versus adjunctive therapy? In other words, patients staying on their background antidepressant or anxiolytic therapy. And this is bearing in mind, of course, as you know, it's not easy to taper off of reuptake inhibitors, particularly dual reuptake inhibitors. So how are you thinking about that? And do you expect that practitioners will lean more into keeping their patients on their background medications and just layering in DT120? Or do you see a paradigm where tapering is going to be more of the norm?

Yes. Thanks so much, David. I'll turn that one over to Dan to answer.

It's an excellent question, David, and it's something we talk about a lot ourselves and with the clinical experts that we engage with on a near daily basis. And there's a larger structure to how we've done things through our development program, which is to say that we've designed our trials to attempt to demonstrate the minimum conditions necessary for safe and effective use. That is not to push into specific practice patterns to the extent we're able.

So consistent with the history of drugs that have been developed and successfully developed for anxiety and depression, we tested the drug as a monotherapy without associated psychotherapy, right? We stripped everything back and tried to show to the extent we were able drug-only effect. It's not because we think that's the absolute most efficacious way or it's a perfectly safe way to use the drug, but we didn't necessarily push for the most efficacious thing we can do with combination therapies because of that desire to show the minimum necessary conditions for safe and effective use that included taking people off background medication.

In the real world, we expect that clinical practice will evolve over time and that individual clinical practice will dominate the day. So while there will absolutely be clinicians and patients who decide together that they want to take whatever meds are in the background because they're not working adequately and stop them prior to treatment, we also intend to and continue to provide information that will allow clinicians to also make the choice with their patients to keep background meds in the picture until relief is sustained from DT120. So that aspect of clinical practice is something which we'll be very interested in. We'll continue to design studies that inform clinical practice, but we wouldn't consider our role to say whether an individual patient and provider dyad make one choice or the other.

Our next question comes from Brian Abrahams with RBC Capital Markets.

Congratulations on the data. So with these data in hand, like what do you think you need to show in Panorama to support filing and approval? Do you think you need to hit statistical significance at 100 micrograms? And then I'm curious if you could just remind us the alignment you have with the FDA, specifically on their recent guidance and if you're maintaining some blind here for the full 12 months, at least for investigators and patients to fulfill that?

Yes. Thanks so much for the question, Brian. I mean, I think especially given the results today and the consistency of this large effect size that we've seen, we feel quite confident going into these Panorama data in September. Obviously, as always, we're going to be in a dialogue with FDA with more data is going to inform those discussions. And so we feel very good about the path forward. But we feel that we've demonstrated time and again some profound efficacy that has rarely been seen in these indications. And so we feel like there's a clear path forward for this drug.

In terms of guidance and alignment, I mean, we've -- over the course of the development program in the last little under 5 years, we've had an incredible dialogue with FDA and that dialogue has moved towards alignment, we think, in terms of the overall program, the methodologies we use in our trials and all of that. And it culminates in sort of public-facing documents like the guidance, but that guidance is reflective of an ongoing discussion that we've had over that entire development program.

In terms of the specific commentary about a year of blinded assessment, it's exactly what we have in the study. Patients -- the rating of symptoms in the study is blinded at all times. The central raters who are unaware of treatment assignment or visit numbers. They don't know if it's a screening visit or someone who's at week 52 after receiving several doses of DT120.

Obviously, with a year-long study and with the sort of urgency that we have to move this program forward, at different times in the studies, we now have locked Part A of the study and unblinded Voyage and -- excuse me, Voyage and Emerge. And the reality there is that of the 4 arms of the quadruple blinding in these studies at various points in time, one of those can be removed. When a patient takes open-label drug, of course, from that point forward in the study, they are no longer blinded to subsequent treatment status, but they still remain blinded to their initial treatment status.

So all that is to say, we feel very much aligned with FDA, with FDA's guidance and through that constructive dialogue have landed what we think is a very reasonable and thoughtful approach to demonstrating safety and effectiveness in these programs.

Our next question comes from Ben Burnett with Wells Fargo.

I'll add my congratulations to the data. I wanted to ask just about the placebo response. I was just -- it looked pretty low, and it looked like kind of nominal values for both drug and placebo were maybe a bit lower than was anticipated from the Phase II. Just curious if you could comment on that and maybe also just contextualize some of the remission rates relative to standard of care drugs in anxiety.

Yes. Thanks so much, Ben. You're absolutely right. I mean the thing that gets missed, a lot of times when studies do not show significance, placebo gets blamed, which may be the case, may not be the case. But the reality is placebo effect isn't a placebo effect really. It's the effect of participating in a study, right? Placebo doesn't actually do anything, or else it would be a bad placebo. And so when we think of the "placebo effect", it's really something that is going to accrue to both -- to all arms that are participating in the same trial the same way. And that's the case here, right?

So in our Phase II study, we obviously had a much larger placebo effect. There's reasons to believe that a study with 5 arms with an 80% likelihood of getting a dose of drug could demonstrate that. But we still saw an effect size of 0.81 there. We've seen an effect size of 0.81 here. And so while placebo numbers certainly change and interestingly, we saw virtually flat line for the drug from week 1 to week 12 in terms of HAM-A scores in this study, placebo scores change over time. That's really what drove any of the changes in separation between the 2 arms over the course of the 12 weeks today's data.

So when we think of that, we don't look at placebo as a sort of isolated thing. It's just a fact that in a study where a single intervention is given, where patients are then followed for 3 months with no subsequent intervention and patients have a 50% chance of getting drug is likely they're going to have somewhat of a lower placebo than we've seen in the past. Now compared to other studies in the field, we're seeing actually a much larger placebo. Some of the pivotal studies in our field have shown 3 or so point placebo effect. Now we have a study where we've shown around 5 and a study where we've shown a little over 6 here.

So we think that we're actually seeing a pretty robust placebo effect, and we're still exceeding that by a wide margin and a very large effect size. And I guess in terms of contextualizing the remission and response rates, that's something that's also dramatically affected by this exact dynamic, right? Adding 10 points of a placebo response to both arms is going to make any fixed numerical cutoff, whether it be a percentage or a nominal cutoff seem a lot larger.

The fact is we're seeing much higher rates of remission of response. And as Dan said, of mild -- attainment of mild or better symptoms, which I think is really sort of most important real-world clinical target. We're seeing much more of that in the 120 arm than we have with placebo. And we're also seeing over the course of the 52 weeks that with subsequent treatment availability and subsequent treatments, patients continue to accrue and we get more and more pickup approaching well in excess of 50% in that mild or better category.

Our next question comes from Francois Brisebois with LifeSci Capital.

Congrats on the data here. I was just wondering, is there -- in terms of the end of session criteria list, is there something where, obviously, the language has been worked on and discussed with the FDA, but is there something about specific patients that are ready to leave earlier? And maybe if you can compare and contrast with an MDD patient that although they are pretty long episodes, but just the chronic nature of GAD versus MDD? Just trying to get a little more color on what would make someone be able to leave earlier than someone else.

Thanks. Thank you so much, Francois, I'll turn it over to Dan.

Yes. Frank, that's a question that we have been really interested in trying to answer like a lot of things in medicine and in psychiatry, trying to predict outcomes from a priori data, from baseline data is something that everyone has tried to do for as long as we've been treating people in the field. While we would love to be able to tell you we know what predicts that there's some patient profile, some knowable thing that predicts precise session length, -- thus far, we really just haven't been able to identify anything.

We noticed this about half hour longer session duration in the GAD study than the MDD study. And at some level, the best we can do so far is attribute that to anxiety that folks are in the clinic. And even though they, in many cases, are feeling a lot better in terms of their anxiety by the end of the session, they still know that they felt anxiety last time they were outside of the clinic. And so there's a tendency in anxiety disorders to engage in a degree of what's called anxious avoidance.

So the sense we got in talking to our sites, which we do an awful lot when we try to understand what's happening in these sessions, during the sessions, at the end of sessions, it sounds like in some cases, these data are likely pushed just a bit longer by patients saying, I'd just like to be here a bit longer. And that's okay. I mean a big part of this is that the session dynamics are -- to our mind, inexorably linked to the effects of the drug in terms of efficacy.

And so there's a degree of personalization that is intrinsic to the treatment with these drugs. It's mostly internal personalization. And a part of that is people having the time to both have the transient effects of the drug and to feel like they've gotten back to a place where they're ready to head back to their lives. And so we've encouraged sites to lean into that degree of comfort for folks as they come through the end of their sessions. And so that's the best we can tell you so far. We've got plenty of sessions left to measure, and we're going to keep measuring everything we can and looking for correlations.

I'll add just one brief comment to that, which is -- maybe 2, which is that we have yet to meet or talk to one of these anxiety patients who says, I've been living with anxiety for 20-plus years. It's severe. I can't handle this, but I'm unwilling to stay in the clinic for an extra 30 minutes or so. It just doesn't happen. The efficacy we're seeing is to a degree where someone with a probably lifelong, certainly multi-decade effect can be in a room for a day and walk out the door, having a reasonable expectation of profound effect that may take some time, but that time is very well worth.

It. And I think that translates to in the same conversations we have with the investigators in our studies, with providers out in the world. They see the need. They work in this field to try to make people better. If every once in a while, someone has to stick around for an extra 30 minutes. I don't know about everyone on the phone, but we've certainly worked after hours before and haven't had any problems doing that every once in a while when you need to. So -- we're going to be continuing to try to understand these factors to try to be able to best inform practice, but we're really, really encouraged by all that we're seeing and the realities of what this drug could offer.

Our next question comes from Jay Olson with Oppenheimer.

Congratulations on these milestone results. On the HAM-A scale, did you see any particular symptomatic relief that especially stands out? And we're curious about anything you could share on cognitive or fatigue-related symptoms. And then based on this dramatic effect size in GAD, do you think DT120 may also provide benefits to patients with panic disorder?

Yes. Thanks so much for the question, Jay. I'll turn it over to Dan to talk about the symptoms and all the asks. One comment I'll make really quickly is that, as Dan noted, the baseline MADRS score, one of the things that was really interesting to us looking across the Phase II and Phase III studies is that the baseline MADRS scores in this study were around 14.

Now we continue to sort of try to isolate the anxiety features here. We know there's a huge degree of overlap between both the HAM and MADRS. There's a huge degree of overlap between the diagnostic criteria and the experience of GAD and MDD. In studies for regulatory purposes, we have to try to really isolate those variables. So we don't get into this with historical concerns around pseudo specificity. And we feel like we've very much done that here. We had much lower baseline MADRS scores, about half of the MADRS scores at baseline. And that translated into a lower baseline presentation of depressed mood, which is an important and very common feature in anxiety and on the HAM-A.

So we kind of removed a couple of points of baseline severity by getting to the correct isolated population, the part of the Venn diagram that doesn't overlap as much. And in so doing, we also took away the ability to improve depressed mood symptoms, which given the Emerge data, we feel like is probably something that would have moved pretty meaningfully since we showed that effect in MDD in particular, and we've seen that effect really pronounced in past studies. So that also is one of the things that we think may contribute to the sort of nominal differences both in baseline in terms of the overall scores and how they shift between studies and why, again, those nominal scores aren't the best comparator across studies or programs. I'll turn it over to Dan to comment on the other specifics.

Jay, I think you picked up a bit of my editorializing there about domains. And so yes, I mean, a remarkable thing here. The HAM-A by virtue of trying to assess the full spectrum of the experience of GAD is a multi-domain instrument in a way that, say, the MADRS isn't, which has made it a difficult thing to move. The disease GAD is hard to make better and the instrument we use to measure it is also hard to move, which creates a dual challenge in studies for GAD. It's one of the reasons here we are 20 years after the last FDA approval for a drug in GAD. It's just -- it's a hard thing to do.

One of the remarkable things we've noted already, we haven't had these data a whole lot longer than you have now. But one of the things we've been able to do is take a look at an item level analysis, and we were really just found it incredibly remarkable what we were able to move that we see items in the somatic scale moving, in the cognitive scale moving, certainly in the fatigue scale moving that -- and of course, the psychic anxiety scale. We didn't have a whole lot of room to move in depression, as Rob said, because we isolated out GAD as much as we could from folks who are depressed. But yes, across the scale, we see movement in symptom domains.

And that is remarkable in part because patients come in with sort of an individualized pattern on the MA where their particular experience of the disease is manifest in different areas of elevation. So the fact that we see this movement across these different domains of the scale means that for each patient, we're treating their individual pattern back down toward this mild remission state.

As far as panic goes, there's about -- epidemiologically, there's about a 25% overlap between panic and GAD. But in the treatment-seeking population, consistent with what we saw in these data, a lot of people out there who are not treatment seeking despite having GAD, in the treatment-seeking population, that overlap can get up to be like 50%, panic can often precede the development of GAD. There's some pattern-based reasons for that.

And so while we wouldn't want to go outside of where we've tested the drug and make any claims there, just that known comorbidity and the ability to reduce anxiety in comorbid patients would suggest that for someone whose baseline anxiety starts high, being able to move them down ought to have an ameliorating effect on the frequency and intensity of the panic disorder. So it's a great hypothesis, great direction to look. And of course, we're interested in all of the disorders that tend to accompany GAD and MDD.

Our next question comes from Sumant Kulkarni with Canaccord Genuity.

[indiscernible] for Sumant. Congrats on the data. One question about the Part B portion of your trial. Were patients allowed to go back on to their background therapies? And if they were, like what proportion of patients elected to do so? And could this have any implications on a potential REMS program?

Yes. Thanks so much for the question. I'll turn that again over to Dan.

Yes. So the easy answer is no, that if folks stay in the trial, they can't go on any anxiolytic or antidepressant. So for that full year for people to stay in the trial, no anxiolytics. Now, allowed to is a different question, which is that at all times when people participate in our studies, our sites and our PIs and the clinicians involved make sure to do what's best for the patient. So in cases where someone should go on another therapy that isn't the study drug, the best course of action is for them to withdraw from the study and get the treatment they need. And we always encourage that far more important than keeping people in the study. But as you see from our retention numbers, the vast majority of patients were able to stay in the study without needing to restart any other anxiolytic or antidepressant.

Our next question comes from Pete Stavropoulos from Cantor.

Rob, Dan, Brandi and tream, congrats on another robust data set. It's not typical to see an effect size seen with DT120 in GAD in this Phase III. So when you combine that with the proportion of patients that achieved mild to better category and response and remission rates, you see along with the longer-term Part B data, what might that mean for the number of doses for DT120 that may be required over the course of a year for anxiety and for potential pricing implications for potential pricing given the durability you see here, but also in MDD?

Yes. Thanks so much for the question, Pete. I think one of the interesting features there is that, of course, this is very intuitive, but the patients who do the best after a single dose need the least number of doses. And we see this very clearly in the data. It's someone who takes a single dose as a multi-month look out in some for an entire year in a far improved clinical state without the need for any subsequent treatment, that's a remarkable outcome. That's not the case with everyone, certainly.

What we have seen is that the need for subsequent treatment and the number of treatments in anxiety appears to be a little bit less than what we've seen in depression. And that may very well be a feature of the disorders that when we achieve a good response in anxiety population, there seems to be a sort of trait change that occurs, where we see a long-lasting reorientation to experience the disorder and a real long-lasting effect.

And so we're going to continue to accrue a ton of data across these indications, and that will inform everything from how we think about informing prescribers and sharing information on the need for retreatment and the likely dynamics of retreatment. It's also going to inform everything we have to decide and move forward with on the commercial and market access and pricing side. So a lot to be finalized, a lot to be shared over the coming months and years. But everything is pointing us in a direction where we're seeing whether it's a single dose or a few doses, this profound efficacy over the course of a long multi-month period. And that gives us an enormous excitement about every one of those dynamics.

Our next question comes from Christopher Chen with Baird.

Congrats on the data. Just maybe zooming out big picture, just a BD question. There's obviously been a lot of interest from big pharma with psychedelics-based companies, particularly the recent Lilly, ataiBeckley deal. Just big picture, can you discuss whether the nature of any inbound interest has changed since Emerge? And now with Voyage data, do you anticipate additional interest? And how willing are you to listen to those?

Yes. Thanks so much for the question, Chris. One of the -- with data that look like what we've been able to generate this summer, I would be shocked if there's anyone who's come across and hasn't had a degree of interest. So wherever that is, we think that these are really eye-opening data and are -- put this drug in the best possible position, we have shown an ability here. We're having an incredible ability to prosecute these clinical programs, regulatory programs, and I think we've shown an ability over the last 5, 6 years to really know and do this in a remarkably efficient and thoughtful way.

And so our focus is on doing the best thing to drive value for our shareholders, to do the best thing to drive value for patients. And we have continued to build an absolutely incredible commercial team that's ready to go out and put this in the world in the way that we know it can be done with the most profound impact. So that's where our focus remains. That's what our commitment to doing is. And again, we're appreciative of everyone in the world's interest in the things we're doing, whether it be those on the call or those anywhere, but we're heads down and focused on the goal here.

Our next question comes from Arabella Ng with H.C. Wainwright & Co.

Congrats on the data. I was just wondering with maybe the potential you mentioned to explore a submission that would allow GAD and MDD in the label. I was wondering if you could comment on the MADRS for those with comorbid MDD in this trial? And then also, I guess, of the 40%, what their baseline MADRS was?

Yes. I just very briefly, what -- it's really an interesting analysis. When we think of the Venn diagram of the overlap between GAD and MDD, we, of course, have seen remarkable effect in the whole circle of GAD and Voyage showed effect size of 0.81, the whole circle of MDD and Emerge showed an effect size of 0.83.

When we look at changes within these studies, there's even more pronounced effect in patients with anxiety who were in a depressive episode and in patients who had elevated depression scores in our GAD studies, even though they're not in a depressive episode. So we think that, that's an overlapping part of circles where we're seeing even larger effects. That just gives us the confidence that no matter where you look, whether it's isolated GAD, isolated MDD or the overlap, what we're seeing a really pronounced efficacy. And that, of course, is what you'd hope to see in these populations.

Our next question comes from Ami Fadia with Needham.

Congrats on the really strong data here. I had a question about some of the statistics that the FDA is going to require in the real-world setting and wanted to sort of contrast that with the guidance that they provided to the industry for the clinical trials. So my question is, what is the qualification and the number of professionals that the FDA will require in the real-world setting to be monitoring patients? The guidance also talked about the need for a physician to be reachable within 15 minutes in case of a medical emergency. So I'm curious if you think that, that would be required in the real-world setting as well.

Yes. Thanks so much for the question, Ami. I mean we're obviously going to have those discussions over the course of a review cycle if we're able to get an NDA on file. And we wouldn't want to sort of jump and get ahead of ourselves in speaking for FDA or anything of that nature. What we can say is that when we look at other precedent programs that have had rigid requirements in clinical development, when they transition to real-world setting in the REMS and the considerations for access and public health are required to be considered and should be considered, those dynamics change dramatically.

We've also had a number of drugs with, I think, arguably a more -- certainly more acute safety consideration, things like volatile anesthetics that don't specify how anesthesiology should be practiced. And so we -- there's a delicate balance, of course, with any of these things. We and everyone want these drugs to be delivered safely in an appropriately controlled setting without overspecifying things that would restrict access and restrict the benefit that the patients could expect.

So commenting on any one of these is a sort of overall approach that has to be weighed here. And I think, again, the most encouraging thing across the board is the willingness with FDA and with all of the stakeholders to sit down and have these discussions. We have a really unique opportunity to design a system that can maximize the goods that we hope to achieve here. It's really rare to have an opportunity in medicine and the willingness of all those stakeholders to come together to bring different perspectives and to get us hopefully to a point that maximizes that is something that we're encouraged by and has certainly been an active participant in shaping. So we're incredibly excited about navigating that and navigating all the ways here.

Our next question comes from Justin Walsh with JonesTrading.

I was wondering if you can comment on treatment arm patients that chose not to receive an open-label dose of DT120. Curious both about the potential rationale for not receiving another dose as well as possible durability of the effect for a single dose of DT120.

Yes. I'll turn it over to Dan briefly. And it's maybe worth commenting too on the folks who decided not to continue on in Part B of the study, which aren't that many of, but what we thought were a kind of interesting population.

Yes. So in order to stay in the study, when folks were eligible for symptom trigger treatment based on their HAM-A, they had to within a month have that treatment. And it turns out we didn't really have anybody decide not to. That's not why folks left the study. And so -- but what Rob mentioned here is interesting, which is the people who chose not to go on to Part B of the study after Part A, and one thing that, that clearly cost us is the folks who had done extraordinarily well after a single dose and couldn't really imagine a reason that they'd want to stay in a study where they were going to get additional doses because they couldn't imagine a reason they need an additional dose.

So a slight ability to make some longer-term year-long efficacy claims may have been lost with those folks who moved on. But ultimately, for people who don't hit the retreatment trigger and stay in the study, that gives us exactly what you say, the ability to follow people fully in their initial blinded allocation with everybody remaining in that fully blinded state for a full year to look at durability of the blinded initial dose. So like we've said repeatedly about the Part B, it creates a complicated somewhat multi-axial data set that's different than the Part A data, but it also gives us an enormous ability to look at different features of the drug, both in that initial allocation over the long term and what retreatment patterns can look like.

That concludes the allotted time for the Q&A session. I will now hand back to Rob Barrow for closing remarks.

Yes. Thank you so much, and thanks again, everyone, for being here today. We've had quite a summer. It's been incredibly exciting to be amidst so much pivotal data and to now have generated extraordinarily compelling data across 3 studies, across 2 pivotal studies in 2 different indications this summer. We always internally talk about just appreciating this moment and what's going to lie ahead of us. It's, I think, hard to -- even for us to fully appreciate the profound impact this could have on people's lives.

And I know with GAD in particular, there are many, many people in my life who have been affected by this disorder and to see the excitement over the last several years when we talk about the possibility of something actually changing that and changing what they can hope to expect here. That's why we do this. I think that's why we are dedicated to getting the right people in the organization and having the right strategy so that we can bring this out to the world, hopefully, in a way that really does maximize the good that can be done here.

Psychiatry has been waiting for far too long broadly for new treatments, but for anxiety in particular, the clock that we had up as some of you dialed into the webcast is something that many of us, I certainly keep on my desktop every single day and look at every single day that goes by another day that the patients don't have something that seems to be potentially transformative for them. So we are not going to waste a single moment between here and what lies ahead of us.

And we, again, I think incredibly grateful for everyone internally in the company who have been a part of this, who everyone has been connected with making this possible. And that includes every single person sitting on the phone today who's been following along, who's been a supporter, who's been part of this journey and will be in the future. So thank you, and we're excited to reconvene here in a few weeks in September to share results from our third pivotal this summer. Hope everyone has a great rest of the week, and again, I appreciate your time.

This concludes today's conference call. You may now disconnect.

Good afternoon. I am Gita Jain, Head of Investor Relations, and I want to thank you for joining us today for Definium Therapeutics Second Quarter 2026 Financial Results and Recent Highlights Conference Call. [Operator Instructions] This webcast is live on the Investors section of Definium's webcast at definiumtx.com, and a replay will be available after the webcast.

Leading the call today will be Rob Barrow, our Chief Executive Officer, who is joined by Dr. Dan Karlin, our Chief Medical Officer; Brandi Roberts, our Chief Financial Officer; and Matt Wiley, our Chief Commercial Officer.

During today's call, we will be making certain forward-looking statements, including, without limitation, statements about the potential safety, efficacy and regulatory and clinical progress of our product candidates, our anticipated cash runway and our future expectations, plans, partnerships and prospects.

These statements are subject to various risks such as changes in market conditions and difficulties associated with research and development and regulatory approval processes. These and other risk factors are described in the filings made with the SEC and applicable Canadian securities regulators, including our annual report on Form 10-K and Form 10-Q filed today.

Forward-looking statements are based on the assumptions, opinions and estimates of management at the date the statements are made, including the nonoccurrence of the risks and uncertainties that are described in the filings made with the SEC and the applicable Canadian securities regulators or other significant events occurring outside of Definium's normal course of business. You are cautioned not to place undue reliance on these forward-looking statements, which are made as of today, August 6, 2026.

Definium disclaims any obligation to update such statements even if management's views change, except as required by law. As announced in our earnings release, we anticipate presenting top line results from Voyage, our first Phase III study of DT120 ODT in generalized anxiety disorder, or GAD, during the week of August 10, 2026. As such, we will not be holding a Q&A session at the conclusion of today's prepared remarks.

With that, let me turn the call over to Rob.

Thank you, Gita, and thank you, everyone, for joining us today. Psychiatry has waited decades for therapies capable of fundamentally changing outcomes for patients. We believe that future is now coming into view. The unmet need has never been greater, and there is growing recognition that patients deserve treatments capable of delivering transformational outcomes. We are proud that Definium is leading the way in defining this next chapter, delivering pivotal evidence on DT120 ODT in pursuit of a best-in-class profile targeting some of psychiatry's largest and most underserved indications.

First half of this year marked a key period of inflection and growth for our organization. In June, we reported positive top line results from Emerge, our first Phase III study of DT120 ODT in major depressive disorder, or MDD. These results established a new benchmark in the field, having demonstrated what we believe to be the largest treatment effect ever reported in a Phase III MDD study.

Taken together, the rapid and durable efficacy and favorable tolerability that we have consistently observed throughout the DT120 development program strengthens our confidence that DT120 has the potential to meaningfully change the treatment paradigm for patients living with anxiety, depression and post-traumatic stress disorder or PTSD. We continue to make major progress across our pipeline, having completed enrollment in both Voyage and Panorama, our 2 Phase III studies in GAD. Initiated enrollment in Ascend, our second Phase III study in MDD from which we expect top line data in 2027 and advanced preparations for Haven, our planned Phase III study in PTSD, which we expect to initiate in 2027.

Looking ahead, we are in what we believe is one of the most important periods in our company's evolution. Next week, we plan to share top line results from Voyage, and we expect to share top line results from Panorama in September. Given that there has not been a new drug approved for this highly prevalent and burdensome disorder in almost 20 years, we believe there's an extraordinary opportunity to deliver a first and best-in-class treatment for GAD.

In parallel to our clinical progress, we continue to efficiently advance toward a potential NDA submission for DT120 ODT.

Throughout the development program, we have worked closely with FDA, maintaining a constructive dialogue that has shaped our program and aligned with expectations for the field. We believe the agency's recently finalized guidance closely reflects this alignment and the principles that have guided our regulatory strategy from the outset. We've also continued growing and strengthening our organization to deliver on the clinical, regulatory and commercial milestones ahead.

Over the course of the year, we have significantly expanded our commercial capabilities in preparation for the potential launch of DT120 ODT if approved, and we have strengthened our balance sheet with an upsized public offering that generated approximately $805 million in gross proceeds.

With our strong financial position and operational momentum, we are well positioned to continue advancing our R&D programs while preparing for a launch of DT120 ODT that reflects both the scale of the commercial opportunity and more importantly, the magnitude of patient need. Our progress is a result of disciplined execution of our team and our commitment to delivering meaningful value for patients and shareholders.

With that, I'll turn the call over to Dan to review our clinical programs in more detail.

As Rob highlighted, our positive Phase III Emerge results represent an important milestone, not only for the DT120 program, but for the field of psychiatry. As a psychiatrist, what is most exciting to me is the consistent profile of DT120 ODT we have seen across the development program, rapid onset of action, durable clinical benefit and a favorable tolerability profile. We believe this combination has the potential to fundamentally change how anxiety, depression and PTSD are treated.

Emerge enrolled 149 participants with moderate to severe MDD. The study population had a mean baseline Montgomery-Åsberg Depression Rating Scale or MADRS score of 34.5 and approximately half of participants in the study had previously been failed by 2 or more antidepressant therapies. Background antidepressant and anxiolytic medications were discontinued before randomization and no psychotherapy was provided as a component of the study, allowing us to evaluate DT120 as a true monotherapy.

The study met all of its primary and key secondary endpoints with highly statistically significant results across multiple clinically meaningful measures. DT120 demonstrated an 8.1 point placebo-adjusted improvement on the MADRS at week 6 with a p-value of less than 0.0001, corresponding to an effect size of approximately 0.83 for the primary endpoint. To our knowledge, this represents the largest treatment effect ever reported in a Phase III trial in MDD.

Importantly, after a single dose of DT120 ODT, efficacy was evident as early as week 1 remained statistically significant at every subsequent assessment and persisted through week 12. Beyond the primary outcome measure, we observed statistically significant improvements across all key secondary endpoints and a favorable tolerability profile. We are extremely encouraged by the Emerge results and look forward to delivering pivotal data in GAD. GAD affects millions of patients worldwide, yet treatment options have not changed over the past 2 decades. With the available approved medications, many patients continue to experience inadequate symptom control, delayed onset of benefit, poor tolerability and the burden of taking chronic daily pharmacotherapy.

Our objective with DT120 is fundamentally different, rapid and durable clinical benefit from a single treatment session that can be reinforced with intermittent retreatment as needed based on patient presentation. Our confidence in the DT120 program is grounded in the consistency of the evidence generated to date. In our Phase II GAD study, DT120 demonstrated rapidly clinically meaningful improvements that were sustained through 12 weeks following treatment. Voyage and Panorama are intended to rigorously confirm those findings in 2 independent well-controlled pivotal studies.

Voyage and Panorama were initially designed with approximately 90% powered to detect a 5-point placebo-adjusted treatment effect. Based on the protocol-specified blinded sample size reestimation, which assessed variance of the primary outcome measure and dropout rates, both studies would be expected to have greater than 99% power to detect a 5-point placebo-adjusted treatment effect.

Notably, while the studies were powered to detect a 5-point difference, we believe a placebo-adjusted improvement of 4 points or greater at week 12 would compare favorably with the currently available treatments and other investigational products in development.

Beyond DT120, we continue to advance DT402 in autism spectrum disorder, or ASD. We believe this program represents an important long-term opportunity given the significant unmet need and the absence of FDA-approved therapies that directly address the core social communication challenges associated with ASD.

Across the development programs, we are incredibly excited by the results we've been able to produce to date and the ones we expect to share in the near term.

Now I'll turn the call over to Matt to comment on our ongoing commercial preparations as we seek to translate clinical excellence into commercial success.

Thanks, Dan. I'm excited to spend a few minutes sharing more about our accelerating commercial momentum for DT120, which has been further strengthened by the positive Phase III Emerge results. These results have given us greater confidence in DT120's potential to deliver meaningful, rapid and durable benefit for patients with MDD and GAD. In our market research, both patient populations have clearly expressed dissatisfaction with current treatment options and have responded positively to the DT120 product profile.

On the heels of Emerge, we are moving with urgency to further build a fully integrated commercial apparatus designed to deliver on the full potential of DT120 adoption, if approved. A strong recent example of this execution is our Wired for Worry campaign launched in July. This campaign is designed to raise awareness of the persistent burden and underlying neurobiology of GAD, highlight key unmet needs and equip clinicians to better identify patients who may benefit from new treatment options.

Early feedback has been highly positive, and the campaign is already driving meaningful engagement as we near the upcoming GAD data readouts. At the same time, we are rapidly expanding our commercial team and building our critical operational capabilities. We are hiring and onboarding key talent across marketing, market access, sales and commercial operations while executing on essential launch activities, including promotional message development, payer value narratives and engagement, distribution model design and detailed deployment planning. These efforts are advancing in parallel with the build-out of our centralized patient support services, reimbursement pathways, field operational readiness and HCP engagement initiatives, all aligned to ensure a strong, seamless launch.

Throughout this process, we are focused on making the patient and provider experience exceptional, leveraging the same unique insights and disciplined execution that have defined our R&D approach. We are highly confident in the clinical profile of DT120, our go-to-market strategy and our commercial readiness. We believe our recent MDD and upcoming GAD pivotal data, combined with the momentum from market conditioning efforts and our accelerated infrastructure build, position Definium exceptionally well for a successful launch and to set the standard for this new and exciting treatment modality.

With that, I'll turn it over to Brandi for our financial results.

Thank you, Matt. Before reviewing our financial results, I'd like to briefly discuss the financing we completed during the quarter and how it positions Definium for the years ahead. In June, we completed an upsized underwritten public offering that generated approximately $758 million in net proceeds. We were pleased by the strong participation from both existing and new investors, and we believe the successful financing reflects growing confidence in DT120, our broader pipeline and our long-term vision for the company.

Importantly, this financing significantly strengthened our balance sheet, and we ended the quarter with approximately $1.1 billion in cash, cash equivalents and investments. Based on our current operating plans, we believe this capital is sufficient to fund planned operations into 2030. This strong financial position provides the resources to execute our strategy while maintaining financial flexibility. If DT120 is approved, our goal is to ensure it reaches the patients who need it and the providers who have long been seeking better treatment options. We continue to make significant investments in market access, medical affairs, provider education, patient support programs and other critical launch activities while simultaneously advancing our pivotal DT120 programs, DT402 program and broader R&D pipeline.

We believe this positions us to maximize the opportunity for DT120 and continue building long-term value across the organization.

I'll now turn to our financial results for the second quarter of 2026, which are detailed in the earnings press release we issued this afternoon. Research and development expenses were $48.7 million for the second quarter of 2026 compared to $29.8 million in the prior year period. The increase was primarily driven by higher DT120 program expenses and additional personnel costs as we expanded our R&D capabilities.

General and administrative expenses were $26.4 million compared to $11.1 million in the second quarter of 2025. The increase was primarily due to higher stock-based compensation, corporate and government affairs activities, personnel-related costs and commercial readiness investments. The year-over-year increase in both R&D and G&A expenses reflects continued investment across our clinical development programs, commercial readiness activities and broader organizational capabilities as we prepare for potential commercialization.

Overall, our operating expenses for the quarter were in line with our internal expectations. Net loss for the second quarter of 2026 was $159 million compared to $42.7 million for the second quarter of 2025. As a reminder, net loss can be significantly impacted by changes in the fair value of our 2022 USD financing warrants, which are mark-to-market each quarter. During the second quarter, the change in fair value of these warrants resulted in an $86.2 million noncash expense, primarily reflecting the increase in our share price from $18.90 at March 31, 2026, to $47.04 at June 30, 2026.

As we look ahead, our focus remains on disciplined execution and thoughtful capital allocation. We have an important period ahead of us, and we believe our strong financial position gives us the flexibility to invest in our key priorities while continuing to create long-term value for both patients and shareholders.

With that, I'll turn the call back to Rob.

Thanks, Brandi. I want to extend my sincere thanks to the entire Definium team for your tireless work to make our successes possible. The progress we have made reflects years of scientific rigor, disciplined execution and an unwavering commitment to developing therapies that have the potential to meaningfully improve the lives of patients living with anxiety, depression, PTSD and other serious psychiatric disorders.

As I said at the outset of today's call, we believe a new chapter for psychiatric care is on the horizon, and we cannot be more energized or excited to play a leading role in seeking to make that promise a reality.

In pursuit of that mission, we remain highly focused on executing against the clinical, regulatory and commercial objectives ahead of us. As we expect to share top line results from Voyage next week, we will not be holding a question-and-answer session following today's call. We look forward to discussing the results in greater detail after the data release, and thank you all for your continued support of Definium.

That concludes today's session. You may now disconnect.

Hello, and welcome to the Definium Therapeutics Phase III Emerge Top line results call. [Operator Instructions] As a reminder, this conference is being recorded today. If you have any objections, please disconnect at this time.

I would now like to pass the call over to Rob Barrow, Chief Executive Officer. Please proceed.

Hello, everyone, and thank you for joining us this morning. As the operator said, I'm Rob Barrow, CEO of Definium and joined today by our Chief Medical Officer, Dr. Dan Karlin; our Chief Financial Officer Brandi Roberts; and our Chief Commercial Officer, Matt Wiley. We couldn't be more excited to be here with you this morning to share the landmark results for Emerge.

Before we get started, please note that on today's call, we'll be making certain forward-looking statements. We'd encourage you to review our SEC filings for a discussion of the risks and uncertainties associated with these statements. Opportunities to share results like these today are exceedingly rare. We believe the findings being presented today has the potential to redefine what patients can expect in the treatment of major depressive disorder and position DT120 ODT as a potentially best-in-class product.

Major depressive disorder and generalized anxiety disorder Imposed an enormous burden on patients, families and our society and despite decades of research, the need for transformative new therapies remains. Before going any further, I want to take a moment to thank our study participants, investigators, study partners and our incredible team at Definium for making all of this possible. And deeply appreciative and honored to work together with you and for your trust, commitment and believe from what we're striving to achieve. Your efforts have brought us this remarkable moment and most importantly, have brought us one step closer to making our dream a reality.

We have an ambitious vision at Definium and believe that profound change in psychiatry is achievable. We set a high standard for our program sequin to prove that a single dose supervised in a clinical setting of DT120 ODT can deliver rapid, robust and durable efficacy and can offer new hope to the tens of millions of individuals living with depression, anxiety and other mental health disorders. We're, of course, here today to discuss the top line results from our Phase III Emerge study of DT120 ODT, our first pivotal study for the program.

It's my absolute pleasure to share highlights from the readout. Before turning the call over to Dan to discuss these results in greater detail. The Emerge study met all primary and key secondary endpoints and was highly statistically significant with a p-value of less than 0.0001. This was represented by an 8.1 point placebo-adjusted improvement on the MADRS at week 6, which was the primary endpoint of the study. This staggering [ effect ] was durable for the full duration of Part A with a 7.3-point placebo-adjusted improvement on the MADRS observed at week 12 and was further complemented by the rapid and significant improvements observed on the CGI-S as early as day 2.

DT120 ODT was generally well tolerated with no SAEs or suicidality signal in the study. And importantly, through our intentional granular approach to characterizing the dynamics of each dosing session. We're able to share further clarity on the efficient treatment session dynamics of DT120 ODT. The average time for participants to create the into study checklist was 5.8 hours with over 50% of participants clearing in hour 5 and all participants clearing the checklist by hour 8.

At a recent Investor and Analyst Day, we shared our belief that a durable response to at least four points represent a potentially best-in-class profile in the context of both historical and moderate antidepressants under development. Today's results far exceeded those expectations with efficacy at week 6, we've more than doubled that bar and which stands out as one of the large placebo-adjusted effects ever observed in a pivotal study of depression. We could not be more excited by these results and what they need for the potential to deliver on our mission and for the millions of patients in need.

And with that, I'll turn the call over to our CMO, Dr. Dan Karlin, to discuss the results in greater detail. Dan?

Thanks so much, Rob. Emerge is a Phase III study that consists of two parts. The initial part, Part A is a 12-week randomized, double-blind, placebo-controlled. This is a single-dose paradigm with DT120, 100 micrograms. This is a monotherapy. Participants were tapered off of any background antidepressant or anxiolytic. And those medicines were washed out prior to participation. There was no psychotherapeutic intervention that went alongside the drug. So it's truly a single-dose study of drug versus placebo.

The primary endpoint for the study was the MADRS at week 6 assessed by independent central raters who are blinded to treatment allocation and to visit number. The second part of the study, Part B was an extension phase where after that first 12-week double-blind period, participants remained in the study for 40 additional weeks and were eligible to receive up to 4 open label doses over those 40 weeks, if they were eligible by having a MADRS score of 20 or higher, meaning that they were moderate or worse on that scale.

149 participants were randomized and all received a double-blind dose of DT120, Of those 149 participants, 84% completed Part A, which was completely aligned with our expectations for the study and consistent with historical studies in the field. The demographics of the participants who participated in the study were well balanced and representative of the MDD population. Notably, you see here that we enrolled participants with a high degree of severity as shown by a baseline MADRS of 34.5, which is consistent with a baseline CGI-S of 4.8%. This puts these participants well into the severe category on the MADRS.

As anticipated, the extent of prior psychodelic use in the study is consistent with the general population, which is estimated to be about 15%. And prior LSD use is only 4%, which is also epidemiologically consistent with the general population and a small enough number, not to confound any outcomes of the study. Another look at disease severity here. We see that 34.5 MADRS along with the breakdown of the severity of the patients in the study with only 20 or so percent at moderate and the remainder in the severe category.

You also can note here the history of antidepressant use among these patients divides them nicely between people with zero or one episodes of prior antidepressant use and people who have been failed by two or more antidepressants. Clinically, we call that second category treatment-resistant depression. The length of the current depressive episode is consistent with the disease definition of MDD, with the majority of patients having a current depressive episode of less than one year and a fair number of the patients, approximately 25% having a current depressive episode length of one to two years. You'll note that none of these patients had an episode longer than two years at which point we start to look at diagnosis other than major depressive disorder.

The number of lifetime depressive episodes is nicely distributed between people who are relatively early in their course of illness and people who have been dealing with major depressive disorder for a significantly longer time.

At every measured time point, the treatment groups statistically and clinically exceeded the placebo group. That treatment group showed a difference at every time point with a p-value of less than 0.0001. There are a few categories that we look at when we describe the effect of the drug. Robustness. At the primary endpoint, we saw an 8.1 point separation from placebo. The primary endpoint was measured at week 6, which is the standard time point for showing antidepressant efficacy. We look at durability that single dose was effective out to week 12, where we saw a 7.3 point differentiation from placebo with that same level of statistical significance.

Rapidity is an incredibly important feature for people suffering from major depressive disorder. And as soon as week one, the first time point where we measured the measures, we saw a very strong 17.6 point total change from baseline and 14.2 point differentiation from placebo, which, of course, is also statistically significant with a p less than 0.001, This really remarkable rapid and robust response and tremendous separation from placebo give us enormous confidence in seeing this drug effect over time.

Another way of measuring disease severity is the CGI-S we see that the CGI-S curve describes effectively the same response as the MADRS. What's most notable about this is that the CGI-S is assessed by site-based raters, while the MADRS, as I said previously, is assessed by blinded centralized raters. These are two very different ways at looking at the same construct, which is how affected by MDD is the patient to the course of the study. These two different instruments assessed by raters with two different conditions describing effectively the same curve gives us tremendous confidence that the measured drug effect represents real change in these patients.

Another way of looking at the MADRS is remission and response. Here, you see remission numbers for a MADRS of less than or equal to 12, which is generally thought to correspond to no clinically significant depression. Our remission numbers there are 24% of the population at week 6 versus 3% for placebo. We also look at mild or better. Mild and better will come up as we talk about Part B, where the trigger for treatment in the open-label opportunities for retreatment is moderate or worse. So effectively, in Part B, we're treating to mild or better. At week 6, we see a rate of mild or better of 41% in the treatment group versus 13% in the placebo group.

Another way of looking at the MADRS scores which rather than using absolute cutoffs, uses a relative cutoff to where a patient starts at their baseline score. And here, we see the conventional definition of response of more than 50% change in score. 35% of treated patients versus 7% of placebo patients reach that 50% cutoff. Each of these measures of remission and response is highly statistically significant. We looked at subgroup analyses to ensure that no subgroup was disproportionately responsible for the observed overall effect. Across each of these analyses, we did not identify any subgroup that could be independently responsible for that observed effect. This is particularly notable when we look at previous MDD medications.

As I said before, we had a significant number of folks who had two or more prior medication failures. And in that case, we did not see a disproportionately high or low treatment response in that group relative to people who have been failed by one or no medicines.

Overall, DT120 ODT was well tolerated, and the adverse event profile was consistent with what we've observed in prior studies, 99% of adverse events were mild to moderate in severity. Most treatment-emergent adverse events, occurred on and resolved on dosing day, no treatment-emergent adverse events led to study withdrawal. There were no serious adverse events. There was no incidence of suicidal or self-injurious behavior. And there was no indication of increased suicide risk or suicide-related risk in the study.

Here, we see a more detailed view of treatment-emergent adverse events. As I said previously, these treatment-emergent adverse events were Mild to Moderate in severity, with one exception for a severe adverse event, there was an episode of exacerbation of chronic back pain that occurred 6 weeks after dosing. One thing that's notable on the TEAE slide here is that we have a 99% rate of treatment-emergent adverse events in the treatment group. We have an expected profile with treatment-emergent adverse events. And the fact that we are picking these up in the study is suggestive of a high-quality clinical conduct at the study sites.

There were no treatment-emergent adverse events that led to study discontinuation. These are the common treatment-emergent adverse events. And these, as I said before, completely consistent with what we expect from the study drug. These are perceptual, effective thought processing and behavioral changes that are expected during dosing day and generally resolved by the end of dosing day.

Rob mentioned this before, but we think it's really important to reiterate the treatment session dynamics are remarkably constrained in the 5- to 8-hour window. We used a structured end of session checklist that assess participants to safely leave the treatment session. As Rob said, 57% of participants cleared that end of session checklist at hour 5 and 100% cleared by hour 8. We believe this translates very cleanly into clinical practice where the end of session checklist can be easily implemented under any subsequent REMS program.

Now we get to talk about Part B. As I mentioned before, this is the 40-week extension phase where participants have the opportunity to receive up to four open-label treatments if they qualify by having a score of 20 or higher representing moderate or worse symptoms on the MADRS. At the time of our analysis, 94 participants had entered the extension population in Part B. Based on the way that these studies enroll with an increasing rate of enrollment over the course of the conduct of the study, we had a limited number of participants who had progressed beyond week 28 at the time of the data cut we're discussing today.

Therefore, our ability to meaningfully discuss data beyond week 28 is somewhat limited. So what we'll focus on today are results through week 28 and the participants who reached that point. The demographics of Part B are obviously going to be similar to the demographics of Part A from which they are selected with lower MADRS scores representing both the treatment and placebo effect of the participants who completed Part A. This treatment pattern slide gives you a sense of how participants entering Part B have progressed through the first three months of Part B with those opportunities for open-label treatment.

As we anticipated, multiple treatment patterns are emerging with most participants receiving only one or two open label doses across the first six months of the total study. Here, we see longitudinal efficacy moving from Part A to Part B. With the availability of open-label dosing, we see continued reduction in MADRS scores in both groups. Those receiving placebo and part A begin to converge with those who received DT120 ODT in Part A. The results from this Part B give us great confidence in the real-world treatment paradigm and give us our first sense of potential longer-term multi-dose efficacy and durability for DT120 ODT.

As with Part A, we can look at response and remission over time in Part B. What we see here is that across each of those measures, the treatment groups converge at about 50% mild or better, MADRS less than equal to 12 remission and 50% response. This, again, gives us enormous confidence in our ability to ultimately show multi-dose drug efficacy and safety in the real world.

Thank you very much, and I'll turn it back over to Rob.

Thanks so much, Dan. Our goal of Definium is to enable a new treatment paradigm that could profoundly reshape clinical practice in psychiatry. We believe the landmark results shared today are another important step in pursuit of that goal. With the incredible momentum heading into our upcoming Phase III readouts, beginning with the Voyage and Panorama studies in the months ahead, cannot be more excited for the future of the DT120 ODT program and the patients we aim to serve.

Given the enormous unmet need in these areas with over 4 million patients failed by today's treatment options, the strong desire from patients and providers and the large and growing sites of care, we believe there is a unique opportunity to deliver significant impact in value in the years ahead. We see two distinct drivers of this value creation opportunity. Our continued commitment to excellence in clinical and regulatory execution as we continue to advance our pipeline and pursue regulatory approval for DT120 ODT and setting the standard for commercial impact and execution to bring this clinical promise to patients as impactfully as possible.

We're working tirelessly to build Definium into a psychiatry powerhouse that can set a new standard for what patients and providers can hope to expect from care. Before we go to Q&A, I want to say again that special thanks to our team at Definium. We've built an organization of exceptional people who are deeply passionate about our mission and the patients we serve and none of this would be possible without your unwavering dedication and tireless effort. It is an honor and a privilege to work alongside each of you every day and I cannot wait to see what the future holds for us.

And with that, we'll open up the Q&A line. Thank you.

[Operator Instructions] We'll take our first question from Andrew Tsai with Jefferies.

I really appreciate you taking the question. So in this study, can you remind us what percentage of MDD patients also had Comorbid -- GAD or elevated anxiety. And what did you see on the HAM-A scores for that subgroup of patients? Just thought I'd ask. So we could have another supportive data point for your Phase III GAD readouts coming up very soon.

Yes. Thanks so much for the question, Andrew, I'll turn it over to Dan.

Yes. Thanks, Andrew. And it's a really good question. we had observed a GAD diagnosis rate is about 1/4. So 25% of these patients had a GAD diagnosis, which is actually pretty high in an MDD population due to the features of the diagnosis. GAD is often not diagnosed. And so while many GAD patients will have received an MDD diagnosis along the way, that has more to do with epidemiological features related to making the diagnosis than actually having the experience of GAD.

While we don't have the HAM-A data available in this top line readout, we do know there was a high level of background anxiety in part because MADRS also assesses for anxiety. What we see consistently is that in folks with higher symptomology, whether that's depressive symptomology or anxious symptomology, we are able to move those scales further. So we're really confident in our ability to move anxiety scores in the MDD population. And of course, based on our prior Phase II research, we know that we are able to move anxiety scores in folks with GAD not in a major depressive episode.

We'll take our next question from Marc Goodman with Leerink.

Yes. I'm curious about this end of session data that you have, our 5, 6, 7, 8 to percent of patients that lasted that long with respect to their experience and how you expected this to play out with respect to the label as well as the real world and how different you'd expect that to be and just your conversations with FDA about it right now.

Yes. Thanks so much for the question, Marc. At a high level, it be, of course, premature to talk about labeling and REMS as we have yet to submit an NDA for the program. But based on our dialogue with FDA and the sort of implicit realities of the fact that in these studies, while for research purposes, we kept everyone under observation for the full 8 hours, if any patients -- we didn't call them into study, but if any patients had progressed beyond that 8 hours, this checklist was what was going to be used to determine their safety to subsequently and monitoring during the dosing session.

So there's some sort of implicit reality that this end of checklist -- end of study -- or excuse me, end of session checklist is appropriate to inform the end of that monitoring. And as a result, we've had a very specific conversation with FDA over time, all in service of trying to reach a goal that appropriately monitors patients but doesn't place an undue burden on patients or providers. Because we're talking about an extended intervention, of course, a patient who has a return to normality of perception by hour 5, It's hard to see what the value in holding that patient under observation for many more hours would be.

So we think the approach and the very specific and intentional conversations we've had with FDA over the course of the development program, have charted a path to bringing this into the regulatory discussions at the NDA stage. And then, of course, as we see with products like Spravato out in the market today, using a similar framework to both study a minimum standard for when patients need to be in the clinic under observation, but then using a checklist such as this to determine, when they can then safely leave observation.

We'll take our next question from David Amsellem with Piper Sandler.

Thanks. Can you hear me?

Yes.

Okay. Sorry about that. So I have a commercialization question here, which is -- as you think about the magnitude of effect, the rapidity of effect and the fact that this is a single treatment on a single day. Do you envision significant usage potentially as a frontline or second-line option. And I realize that might be putting the cart before the horse here. Obviously, you still got to get it approved. There's additional data readouts. But as you think about what you've shown this morning, how do you see the usage paradigm, particularly in patients that have not had significant antidepressant exposure playing out?

Yes. Thanks so much for the question, David. At a high level, and then I'll turn it over to Matt, maybe add some detail. But at a high level, of course, our expectation is that early adoption would be in patients who have been failed by two or more prior therapies. So we see this with virtually all new branded products in psychiatry in these indications.

The intentional choice to go after the broad MDD and GAD labels, though, certainly opens up the possibility that over time, either as we build evidence or as the overall landscape changes and the recognition of the value that such a profound shift in patient expectations and improvement can lend not only to those patients but to the overall system. We certainly think there are opportunities to broaden out where this treatment option could be available and try to have the broadest impact being siloed in a small corner of the market is certainly an early step, but to really drive the full potential of what we see with DT120 in this field and this -- the promise of these results, we do think quite expansively over time.

But in the near term, our laser focused on getting the launch right, if we're able to get the product approved and to making sure that in the early adopters, we see a really good uptake and good results out in the clinical world.

Matt, I'll turn it over to you to add any color there.

I agree with all of that. I mean the product profiles that we've tested market research, this data exceeds what has been tested to date. So there's more evidence to collect in market to understand how physicians and payers will react to it. But the data does open the opportunity for earlier line treatment downstream, as Rob said, and we're very excited about that.

We'll take our next question from Paul Matteis with Stifel.

As it relates to your guys' long-term retreatment data, I thought that was super interesting. Can you remind us how you're thinking about what constitutes a long-term exposure for your FDA retreatment database?

Do patients need to be retreated a certain number of times per year to count as like an ICH guidelines 1-year exposure and maybe more broadly, talk about just like the filing scenarios here and your level of conviction that one MDD study could be enough? Or is that still sort of an open question and all dependent on the GAD readouts.

Yes. Thanks so much for the questions, Paul. I'll take the second question first and then turn it over to Dan to talk about retreatment and safety. In our interactions with FDA, and I just want to take a moment, we couldn't be here without the thoughtful partnership of FDA and the division psychiatry. they've really, over the course of the 8-plus years I've been working in this field, been great thought with partners in all of this and been really data-driven and thoughtful in their approach.

Of course, with drugs like this, the complexity of dynamics like retreatment and safety are somewhat unique from a regulatory standpoint. You need a regulator who is both thoughtful and exercises the good clinical judgment and discretion throughout. Yes. As -- going into this readout and over the course of the last several months, I think we've had several conversations with investors and the broader world about that potential. And certainly, even by long-established regulatory and evidentiary standards for approvals of products, there is a pathway that has existed for one study approvals when there's strongly compelling evidence.

And so of course, our intent with such evidences to go have a conversation with FDA and they've, again, been very engaged with all of this dialogue over the course of both our JD and MDD program. So we absolutely intend to go have that conversation with FDA and certainly believe we'll have a receptive engaged audience and partner in those discussions. We absolutely hold ourselves to the highest standards of generating evidence, but when there is such a profound need and the results are so compelling, if today's results are compelling, I'm not sure what would be -- we certainly see and want to pursue every opportunity to accelerate access for patients because there is such an enormous need. And based on the data we have in hand to date, there seems to be a really unique opportunity to benefit those patients.

And the same will apply in Dan's discussion, I'm sure of the ICH requirements, but I'll turn over to him to comment there.

Yes. Without reiterating too much of what Rob said about FDA as an incredibly collaborative regulator in this enterprise. I guess I can make a general comment about long-term exposure, which is that the designs of our study in this case in our other Phase III studies, and of course, our Phase II study are all very intentional and meant to meet multiple goals. One of those goals is thinking about what does a year of exposure mean when you have a drug that is fundamentally unique in psychiatry in that exposures are spaced out intermittent and likely triggered by need by clinical symptoms.

And the reason that we have this year-long study with about as close to real-world opportunities for open-label treatment as you can get in a clinical study like that is because that gets to as close as you can get to what a year of exposure to the drug should look like and will look like in the real world. So in our discussions with the FDA, we've obviously addressed exactly this question, what does the year of exposure look like to a drug that is intermittently dose, based on clinical need.

And what we've come to is the studies that we've designed where folks get the opportunity for exposure should they need it over the course of the year. We're confident that these designs bring us toward the safety database that represents real world likely exposures and generates great evidence for the safety of the drug in that paradigm.

Next question, our next question comes from Gavin Clark Gartner with Evercore ISI.

I thought that the subset effect, the forest plot that you showed, showing a consistency of effect in various subgroups, especially the patients who had failed more prior antidepressants was really interesting. I was curious if that consistency of effect was maintained out to the 12-week time point. And I appreciate just the top line results. But curious if you had a chance to look at any other factors like length of depressive episode, patients with comorbid anxiety or anything else like that?

Yes. Thanks so much, Gavin. We are still early in digesting the full data sets, of course, so there will be, I think, some really interesting finding as we progress through that. The forest plots in our week 6 and at week 12 as we've been able to analyze them at this point. Really just speak to the consistency of effect. And as Dan alluded, the reality that we aren't seeing a particular group that is responsible for driving or not driving a treatment effect at this point.

Certainly, the other features that we talked about, Dan alluded to the relative incidence of past exposure to psychedelic something that's come under a regulatory discussion historically. There too, we saw that those with past exposure to psychedelics didn't differ from those who had no past exposure to psychedelics and any sort of statistical way. And so what we're really finding is that where we have reliable subgroup analyses. And I say reliable because, of course, with small ends for a subgroup, such as that one, you can get statistical wobble, but we haven't seen anything yet that statistically rises to a level of explainability that would explain those results. And that's true at week 6 and at week 12.

I think to a larger point as well, when you have a magnitude of effect as large as what we've seen here in a study of this size, it's really unlikely that you're going to find any subgroup that was the somehow fundamental driver of that mean a magnitude of mean effect of this size kind of has to be a population effect. And so we're really confident that this outcome represents our ability to move this scale across the population of MDD patients that generalizes out into the MDD patients seeking care in the real world.

Next question comes from Francois Brisebois with LifeSci Capital, LLC.

Great. So I was just wondering about that 5- to 8-hour window to get out. Was there something there that you've seen with maybe the patients -- the stratification a little bit? Is it like the more severe patients take longer? And if you can touch on maybe the impact of the ODT formulation to fit in that window of 100% of patients getting out at 8 weeks. And then if you could just touch on also the bar going forward for GAD, does that impact anything? We see the powering going forward for 5, but any thoughts there for the GAD readouts and expectations on that side?

I'll turn the first question on the subgroups of in the session over to Dan.

Yes. I mean it's a great question, Frank. It's something we're obviously very interested in because as we move through this process and towards submission and if successful, ultimately into the clinic. Of course, we'd like to provide as much of priority guidance to treaters about what they can reasonably expect, both in the session and after the session from an efficacy standpoint, a lot like the previous question where we look at subgroups and try to make predictions.

At this point, nothing stands out that allow us for this sort of priority prediction of session length. But of course, as we speak, we're gathering more and more session data, and we'll continue to investigate every angle there to try to track down any features that might be predictive of really anything about what happens with folks when they get the drug. We're thrilled with the performance of the ODT formulation. This oral disintegrating tablet has a predictable onset and clearly a predictable resolution of symptoms.

And notably from the AE profile, and I didn't say this before, but I could have -- the gastrointestinal AEs are markedly reduced versus the powder and capsule formulation we used in Phase 2. So across the board, we're really excited about the ODT formulation. Of course, we're also using this new checklist that we devised for the Phase III studies after the Phase II so we've kind of got two variables that are changing session time from our previous experience. So attributing change to one or the other would always be a bit tricky. But again, like I said, we're going to keep looking at every feature we can that might offer predictive value to treaters who ultimately use this in the world that were successful.

And I'll just add briefly that the -- both of those changes were in service of what we have done from the beginning of this program, which is to start with the end in mind to really think about the impact we're going to have and how we can get this product out to patients in the most impactful way and the ODT formulation, the steps, the incremental changes and the data-driven approach to inform both the dose selection, the dosage form the way we monitor and the way we collect those data to really granularly assess and granularly describe exactly what's happening is incredibly important, and I think it's important for the entire field to be able to appropriately make arguments and make data-driven, data informed decisions and present those decisions and arguments to FDA so that we can have -- something that's grounded in science, something that's grounded in the data and what can be safely done because we absolutely are committed to patient safety while trying to maximize the opportunity out in the world.

I think you asked about the bar in GAD II -- of course, we're overwhelmed with excitement by the data today. We've seen quite exciting historical data from our Phase II study in GAD as well. And so we continue to have really strong conviction the GAD studies, as we reported out from the sample size of your estimation are quite highly powered. And really our desire is to have positive studies that enable us to take to chart the path forward and to move forward with regulatory submission, so we need positive studies is really the bar.

Of course, what we said previously is that we think something that's four points or better really stands out. in JD in the context of a disorder where there has not been an approval since 2007, almost 20 years. We think that compelling evidence really will stand out above that 4 point bar and we're excited to get to those freed outs for both Voyage and Panorama in Q3.

Our next question comes from Brian Abrahams with RBC Capital Markets.

Congratulations on the data. Just given the magnitude of effect you're seeing here, I'm curious, do you plan to apply for breakthrough status, what the implications of that might be in terms of regulatory interactions. And if you are able to get an expedited path across both indications, anything beyond the additional Phase III readouts in GAD that would potentially be gating for commercial launch and scale up here?

Yes. Thanks so much for the question, Brian. We intend to not talk about some speculative things out in the future in terms of our regulatory engagements as both Dan and I said, we have an incredible respect for and in partnership with FDA and Dr. Farchione in division psychiatry and have had such a constructive dialogue. We certainly always pursue every opportunity to chart an efficient path to bring this product to market as long as we're not introducing undue risk or lowering any sort of standard for the program.

We're highly, highly committed to doing this the right way as efficiently and as quickly as possible. We're going to continue to have that dialogue in a number of venues and a number of ways, both through meetings and through the various submissions that are available to us with FDA. And as that progresses and as we have clarity on the outcomes of those discussions, we'll, of course, be sharing that more broadly. And in terms of what else comes after that, if we're in a fortunate position to get an approval for this product.

We have been building an incredible team led by Matt here. A commercial organization that will stand -- our test of excellence, just like our clinical regulatory and the whole organization has over the past number of years. And so to bring that leadership to bring in those who have a ton of experience navigating complex launches, programs with REMS, controlled substances and psychiatry, we really think we're at the forefront of this field and are going to continue building in that direction. And as always, try to set ourselves apart and set a new standard for what everyone should be expecting from this field from psychiatry at large.

Next question comes from Sumant Kulkarni with Canaccord Genuity.

Clearly, it's not difficult to see that placebo-adjusted major score change, you saw with DT120 in a Phase III for depression. When you combine that with the response and remission rates you saw and the longer-term Part B data, what might that mean for the number of doses of DT120 that might be required over the course of a year for depression and for potential pricing given the solid durability you see here, especially relative to the number of times the patient might have to go into the clinic as Spravato as an example.

The staggering efficacy we saw in Part A of the study really is not normal. I think that, that really cannot be overstated and is just how unique this is. And of course, while any sort of cross-study comparisons always have their limitations, right? Each study has a different design and different sites and -- well, of course, recruit different patients and have different things like placebo responses that can influence outcomes across the board when we look at placebo-adjusted changes in this study we see efficacy that stands out.

And so that means things like a 9.8 point MADRS separation at week 4. You stack that up against 6.8 points for Spravato at their week 4 time point in their monotherapy study for TRD. I mean that's the difference of one session with an average duration of 5.8 hours versus 32 hours in the clinic across 16 sessions for [indiscernible]. To get better efficacy, more efficiently and are quite different in this distinct and more profound underlying change is what we hear qualitatively from the basis of these studies.

Again, we have a very high bar for how we think not only of the standards of our data, but what we expect from this program and any context put up against any data that we have seen in depression. Today this study and this drug continues to exceed those expectations and really stand apart. So we think that there is enormous degree of opportunity here and enormous degree of enthusiasm, of course, from us, but also broadly from the field of psychiatry and from the patients we want to treat.

Our next question comes from Jay Olson with Oppenheimer.

Congratulations on these landmark results. This is great news for patients and their families. Since you saw no increase in suicidal ideation, do you think that would be an important differentiator for DT120, especially for moving into earlier lines of treatment in terms of not requiring the patient to fail SSRI treatments to have box warnings for suicidality?

Yes. Thanks so much for the question, Jay. I mean, what we see is that there tend to be a feature of depression, and that's true whether it be labels for MDD or TRD or bipolar depression, all tend to carry that box warning. And I think that a reasonable expectation that most products will continue to, unless there -- even products like Spravato that are approved to treat suicide ideation and behavior in MDD carry that box warning.

It is a feature of MDD and something that prescribers and patients should be made aware of. The really encouraging thing that we see. And we don't want to take a deductive view of this from not seeing suicidality Signal. But what, of course, enters the risk for suicidality is when patients have an early activation, but do not have improvement in mood, and to see such profound acute effect.

As Dan described, category shifts on the CGI-S over the course of the first week. A 14-point placebo-adjusted change at week 1 on the MADRS to get such a rapid response. I mean that's the thing that's driving such enormous adoption of things like Spravato the world is the fact that patients can come in and quickly thereafter, leave better, the change here is that they also stay better. They were able to show that they not only acutely improve on average, but that change is durable for at least 12 weeks thereafter. So we're going to be absolutely focused on continuing to craft that narrative and share those data and make sure that, that translates out into the world. But I don't know that we would point just the lack of suicidality risk as a single differentiator.

Our next question comes from Christopher Chen with Baird.

Congrats on the data. Just kind of going ahead and looking ahead to Ascend, just a quick question. If there is any kind of color on enrollment updates there and maybe thoughts on possibly how this data might spur enrollment for Ascend.

Yes. Thanks so much, Chris. We don't have an update that we're going to be sharing the day on Ascend enrollment. We have seen a high degree of engagement from our sites and -- that's true across the Emerge and Ascend studies and Voyage Panorama studies in every study we've conducted, what we hear, again, qualitatively quite often is that when sites are running studies of daily drugs. And when they're running studies with DT120, again, these are anecdotes, so take them with appropriate grain of salt.

But these sites tell us that patients really don't want to be taking daily drugs. They tend to have a preference for going into studies where they have an opportunity to take a drug to be in a clinic for a day and then potentially come out quite a bit better and impacted over the course of several months. So we expect that enrollment and the momentum we have across our clinical programs to discontinue. And of course, are incredibly excited, not only get to the Ascend readout next year, but to get in very near term here to our two pillar readouts in JD.

That concludes a lot of time for the Q&A session. I will now hand back to management for closing remarks.

Yes. Thank you, everyone, for being here today. But before we close, I just want to say a brief thank you to everyone who's been involved in this process. To be on the cusp of delivering a new product like this is something that's really special to be a part of, and especially a part of no matter whether you're inside of the company or whether you're working with us in any capacity or supporting this in any capacity.

And I think to zoom out for just a second, well, of course, we're here to discuss the study and our organization and the progress we've been making we have a real opportunity to actually change the landscape for these patients. We have been heading in the wrong direction for quite a while in the treatment of mental health disorders. And to have that opportunity to have an organization that can deliver on that vision is something that we certainly feel very proud to be a part of and a high degree of responsibility to do appropriately and to do well and again, whether you're sitting on the call here or involved with us directly in any day-to-day sort of operational role.

I want to thank you for being a part of this and for making this possible and -- for believing in that future that we do, that we can really make a profound change in psychiatry and profound change for these patients. So we're very excited about the months and years ahead of us and we look forward to sharing in those successes, hopefully, over the course. Thank you.

This concludes today's conference call. You may now disconnect.

Good afternoon. I am Gita Jain, Head of Investor Relations, and thank you for joining us today for Definium Therapeutics First Quarter 2026 Financial Results and Recent Highlights Conference Call. [Operator Instructions] This webcast is live on the Investors section of Definium's website at definiutx.com, and a replay will be available after the webcast.

Leading the call today will be Rob Barrow, our Chief Executive Officer, who is joined by Dr. Dan Karlin, our Chief Medical Officer; Brandi Roberts, our Chief Financial Officer; and Matt Wiley, our Chief Commercial Officer.

During today's call, we will be making certain forward-looking statements, including, without limitation, statements about the potential safety, efficacy and regulatory and clinical progress of our product candidates, our anticipated cash runway and our future expectations, plans, partnerships and prospects. These statements are subject to various risks such as changes in market conditions and difficulties associated with research and development and regulatory approval processes.

These and other risk factors are described in the filings made with the SEC and the applicable Canadian securities regulators, including our annual report on Form 10-K and our Form 10-Q filed today. Forward-looking statements are based on the assumptions, opinions and estimates of management at the date the statements are made, including the nonoccurrence of the risks and uncertainties are described in the filings made with the SEC and the applicable Canadian securities regulators or other significant events occurring outside of Definium's normal course of business.

You are cautioned not to place undue reliance on these forward-looking statements, which are made as of today, May 7, 2026. Definium disclaims any obligation to update such statements even if management's views change, except as required by law.

With that, let me turn the call over to Rob.

Thank you, Gita, and thank you all for joining us today. The first quarter of 2026 marked a strong start to what we believe will be a pivotal year for Definium. We remain highly focused on disciplined execution as we have advanced our late-stage clinical programs, prepared for multiple near-term data readouts and continue to build an incredible team to lead our potential commercialization efforts.

As we discussed at our Investor and Analyst Day a few weeks ago, Definium is entering a period of meaningful clinical inflection. Our lead program, DT120 ODT, is advancing with 4 ongoing Phase III studies across major depressive disorder, or MDD, and generalized anxiety disorder, or GAD, with top line data from Emerge expected later this quarter, followed by Voyage and Panorama in the third quarter. Our Phase III programs are designed to evaluate outcomes that we believe would represent a meaningful advance for patients, physicians in the field of psychiatry. These include not only the magnitude of symptom improvement but also safety, tolerability and durability of response following a single administration, dimensions we believe will be critical in differentiating DT120 ODT in today's treatment landscape.

We're also encouraged by the increasing recognition of the significant unmet need in these indications. With 3 Phase III readouts anticipated across 2 of the largest indications in psychiatry, Definium is approaching an important moment for the company and for the patients we aim to help. With breakthrough therapy designation for DT120 and GAD, we've established a constructive working relationship with FDA, and we will move as efficiently as possible towards an NDA submission, subject to positive pivotal data.

Beyond our ongoing Phase III programs, we plan to expand development of DT120 ODT into additional indications, including post-traumatic stress disorder, or PTSD, with the planned initiation of our Haven study in 2027. We believe this represents an important opportunity to further leverage the potential of DT120 across areas of high unmet need.

Overall, we continue to believe in DT120 ODT as a potential best-in-class product candidate, one that could help redefine what's possible for the millions of people living with depression, anxiety and PTSD who remain underserved by existing treatments.

I'll now turn it over to Dan to go into more detail on our clinical programs. Dan?

Thanks, Rob. I'll provide an update on the status of our clinical programs with a focus on where each of our late-stage studies stands today and how those studies were designed to assess what we believe would constitute a clinically meaningful outcome, starting with DT120 ODT.

Our lead program continues to advance across Phase III studies in major depressive disorder, generalized anxiety disorder and now post-traumatic stress disorder. In Emerge, our first Phase III study in MDD, enrollment is complete with 149 participants. We are now in the final stages of trial execution and data preparation, and we remain on track to report top line results later this quarter.

In GAD, we are rapidly approaching top line data readouts for our 2 pivotal studies, Voyage and Panorama. Enrollment in Voyage is complete with 214 participants. We have exceeded our updated enrollment target of 200 participants in Panorama and expect to complete enrollment this month. We continue to expect top line data from Voyage early in the third quarter and Panorama late in the third quarter.

Across our pivotal program, our focus has been on rigorous execution, data quality and consistency across studies and sites. These are large, well-controlled trials designed to evaluate the magnitude of improvement alongside safety and durability of response following a single administration of DT120 ODT. Given our confidence in the clinical profile of DT120 and the strong evidence we have generated to date, our approach is uniquely designed to establish the durability of a single treatment for at least 12 weeks.

Our Phase III studies in MDD and GAD were initially powered to detect a placebo-adjusted difference of 5 points. As part of the protocol-specified design, we conducted sample size re-estimations in Voyage and Panorama. These analyses were performed without unblinding treatment assignments and were intended to assess key nuisance parameters, standard deviation and dropout rates to support the maintenance of the intended statistical power. Based on these blinded analyses, which were conducted when half of participants reached the 12-week time point, Voyage and Panorama are now powered at 99% or greater to detect a 5-point placebo-adjusted difference, assuming these nuisance parameters remain consistent in the final study analysis.

For Emerge, the study was powered at 80% to detect a 5-point placebo-adjusted change with statistical significance expected at a little over a 3-point difference based on certain nuisance parameter assumptions. We selected this level of power intentionally as we believe a 3-point or more difference represents an appropriate threshold for clinical meaningfulness in MDD. It's also worth noting that Emerge has a 6-week primary endpoint compared to 12 weeks for Voyage and Panorama, mitigating the risk of an elevated dropout rate in the primary analysis.

Additionally, while the studies were powered to detect a 5-point difference, we believe that a placebo-adjusted improvement of 4 points or greater 6 to 12 weeks after treatment would compare favorably to currently available treatments for GAD and MDD and other product candidates in the psychedelic category. Durability remains a particularly important dimension for psychedelics. In our Phase II program in GAD, DT120 demonstrated durability through 12 weeks following a single administration of 100 micrograms.

Our Phase III trials are designed to further evaluate consistency and duration of response over time. Through Part B of these studies, patients are followed for up to 1 year, which we believe will provide important information to inform potential labeling, including how frequently treatment may be needed.

Beyond DT120, we are excited to also be advancing our Phase II study of DT402 in autism spectrum disorder, or ASD. DT402, the R-enantiomer MDMA has shown promising prosocial effects with a potentially favorable tolerability profile. We are developing DT402 to target the core characteristics of ASD, specifically addressing social communication that is central to the experience of the disorder. We see this program as a significant opportunity given the high unmet need, the increasing prevalence of ASD and no FDA-approved therapies that specifically address these core characteristics.

As we look ahead, the next 5 months represent a significant culmination of thoughtful trial design, disciplined execution and years of work focused on addressing some of the most pressing unmet needs in psychiatry. With multiple Phase III readouts approaching, we believe we are well positioned to deliver decisive data on DT120.

With that, I'll turn the call over to Matt to discuss our commercial strategy and the broader treatment landscape. Matt?

Thanks, Dan. I'll spend a few minutes discussing the commercial opportunity for DT120, building on what we shared at our Investor and Analyst Day in April.

As we discussed, GAD and MDD represent very large and persistently underserved markets. Many existing medicines are constrained by delayed onset, partial or inconsistent efficacy and tolerability issues that drive high discontinuation rates. Across this landscape, roughly 4.2 million U.S. adults have cycled through 2 or more treatments without sustained benefit, a population that sits at the center of our initial launch focus. We believe that these patients and the physicians treating them are actively looking for a next-generation option that works differently and can deliver durable improvement without the need for chronic daily dosing.

To put the scale of this opportunity in perspective and using Spravato's average annual price as a surrogate, capturing just 1% of the total addressable market in these indications represents potential for a roughly $2 billion annual revenue opportunity. Our targeting model is built directly around the substantial unmet need. We have identified high-volume health care practitioners, primarily psychiatrists and psychiatric nurse practitioners who manage concentrated populations of these specific patients. These high-volume prescribers are located within psychiatric practices, behavioral health networks and select integrated health systems where these patients most often receive care.

We have mapped these priority targets in detail and plan to focus our launch efforts on engaging these clinicians, particularly those who have experience with or have expressed interest in novel in-office interventions and supported by care teams capable of monitoring patients during the dosing day. We believe this approach will enable us to reach a meaningful number of appropriate patients from the outset while establishing a strong foundation for scalable adoption.

One of the points we highlighted at our Investor and Analyst Day is the growing awareness of DT120 among clinicians. Through ongoing engagement, we've seen increasing familiarity with its clinical profile and strong interest as a potential new treatment option that could help patients move beyond therapies that are no longer providing adequate or lasting relief. We also shared data showing that patients discontinue current treatments at a high rate, often due to lack of efficacy or tolerability. These challenges are especially pronounced among patients who have been failed by 2 or more prior therapies, reinforcing the substantial opportunity for differentiated innovations like DT120.

Our commercial strategy is shaped by these realities. We are focused on how this therapy can be introduced in a way that is scalable, accessible and practical within real-world care settings without the necessity of chronic interventions. A key element of our planning includes a centralized hub support model and additional field support to enable a frictionless process of adoption and delivery.

In parallel, we continue to engage with physicians, payers and other stakeholders to better understand decision drivers around adoption, patient identification and reimbursement frameworks. By pairing a well-articulated unmet need in a receptive market with our disciplined patient-centric commercial strategy, Definium is very well positioned as we near pivotal data readouts and advance DT120 towards potential commercial launch.

With that, I'll turn it over to Brandi to discuss our financial results.

Thanks, Matt. Before walking through our financial results, I want to briefly set the context for how we're thinking about capital deployment as we move through an important phase for Definium. As we entered 2026, we were pleased to have the financial flexibility to accelerate several key initiatives in parallel, including ongoing Phase III execution, NDA preparation activities, market access priorities and continued engagement with key opinion leaders and leading practitioners. These investments are intended to support our path forward and if DT120 is approved, position the company to be well prepared for a robust, thoughtful commercial launch.

We've also been encouraged by the continued evolution of our investor base in 2026 with strong engagement from existing shareholders and growing interest from new investors as we made progress across our programs. We believe this reflects increasing recognition of the opportunity ahead as well as confidence in our disciplined approach to execution and capital allocation.

I'll now turn to our financial results for Q1 2026, which are detailed in the earnings release we issued this afternoon. Research and development expenses were $41.5 million compared to $23.4 million for Q1 2025. The net increase of $18.1 million was primarily driven by increases of $15.2 million in DT120 program expenses, $3.2 million in internal personnel costs as a result of expanding our R&D capabilities and $0.3 million in DT402 program expenses, partially offset by a $0.6 million reduction in preclinical and other program expenses.

For Q1 2026, general and administrative expenses were $17.7 million compared to $8.8 million for Q1 2025. The net increase of $8.9 million was primarily due to increases of $3.9 million in stock-based compensation expenses, $1.4 million in personnel-related expenses, $1.4 million in commercial preparedness related expenses, $1.4 million in corporate and government affairs expenses and $1.2 million in legal and patent expenses, partially offset by a $0.4 million reduction in other miscellaneous administrative expenses. The year-over-year increase in G&A expenses reflects deliberate investment to support a more mature organization as we prepare for our anticipated Phase III top-line data readouts and potential commercialization.

Overall, our R&D and G&A expenses for the first quarter were in line with our internal expectations as we continue to make meaningful progress across the DT120 and DT402 programs.

Net loss for Q1 2026 was $77.1 million compared to $23.3 million for Q1 2025. As a reminder, our net loss can be significantly impacted by changes in the fair value of our 2022 USD financing warrants, which are mark-to-market each quarter. For Q1 2026, the impact on net loss from the change in fair value was $20 million, reflecting an increase in our share price from $13.39 at December 31, 2025, to $18.90 at March 31, 2026.

Turning to the balance sheet. We ended Q1 2026 with $373.4 million in cash, cash equivalents and investments. We believe our capital position provides sufficient runway to fund planned operations through multiple anticipated clinical readouts and into 2028.

2026 is shaping up to be a data-rich and strategically important year for Definium. Our financial position allows us to remain focused on disciplined execution while maintaining the flexibility needed to support our priorities and continue building long-term value for shareholders.

With that, I'll turn the call back to Rob.

Thanks, Brandi. After years of thoughtful trial design and focused execution, we are entering a period of numerous pivotal milestones that we expect will define the next chapter for Definium in our broader field. As we mark mental health awareness month, the urgency of advancing new treatment options and the responsibility we carry for patients feels especially pronounced.

Before we close, I want to say thank you to our incredible team, the investigators and their teams and the hundreds of patients who have made this work possible. With that, we're happy to take your questions.

[Operator Instructions] Your first question [indiscernible].

You cut out for a second. This is for Paul. This is [ Emily ] on for Paul Matteis at Stifel. We just had a quick question on assuming you have success in MDD and anxiety this year, could you maybe speak more to your thoughts around how much long-term safety and retreatment data you would need for approval? And in these long-term data, would patients need to retreat a certain amount of time to count as a long-term exposure for safety?

Great. Yes. Thanks so much, Emily. I'll speak briefly to this and then turn it over to Dan to maybe elaborate. We've had a great dialogue with FDA over the past several years and obviously building towards an eventual plan for NDA submission, so just the positive data and all has to happen to get ready for an NDA, which we're very well positioned for.

In terms of safety data and what's required, we feel really comfortable with the completion of Part A and the data that we'll have available at the time of filing and various milestones between here and there. We have sufficient safety exposure, both single dose and over longer periods of time. Of course, the interesting dynamic with drugs that you don't have to take continuously or daily or a very short fixed interval like the treatments we have today is that treatment patterns that diverge across different patient populations or different patients can mean that 6 months of treatment can look like one dose or multiple doses.

And so we're really interested in characterizing, of course, in our Phase III program. But regardless, we feel very well positioned with the studies we're conducting that we'll be in a great position to move forward. So we have positive Phase III data. Dan, do you want to add any color to that?

Yes. I mean I guess I could elaborate just a tiny bit on part of the value of the Part Bs of these studies where we're able to deliver triggered treatment based on people having moderate symptoms of GAD or MDD or worse, moderate or severe. And the value of that is multifold really, which is that, one, it helps keep people in the Part A of the study, as you saw from our announced sample size re-estimation outputs, our dropout rates are really quite remarkably low in part because people know that they have this opportunity if they're still sick to get open-label treatment in Part B.

The ability to follow folks long term for up to a year after their initial blinded dose is another advantage of these studies, right? So for folks who get to mild illness or better, we just get to keep watching them in that initial controlled blinded state unless they get sick again and until they get sick again if they, in fact, do. So that's another advantage.

And then as Rob said, in those Part Bs, we get to give up to 4 additional open-label treatments contingent on people developing moderate illness or worse. So that will give us the ability to start to really carefully characterize across these studies, the patterns of treatment that emerge when treating people with moderate or worse symptoms, which maps pretty well on to what we think would likely happen in the real world, if approved. So with all of those data in hand, we're confident that we will have everything we need to both inform FDA and then, of course, to inform the clinical and patient community if we do get approved.

Our next question comes from the line of David Amsellem with Piper Sandler.

So just a couple from me. One, in terms of the patient experience. In terms of patient monitoring, how confident are you that in practice, only one dosing session monitor will be needed to monitor the patients? So that's number one, sort of, I guess, REMS-related question on that front. And then secondly, I have a question on the PTSD Haven study. Just a little bit of color, if you can, on the thought process behind running Haven, just a straight up active versus placebo as opposed to including a low 50-microgram dose arm. Just love to get your thought process on that.

Thanks, David. Yes, Dan, I'll turn it back over to you.

Yes. Great question. So the -- the situation in the clinical trials, of course, is that per FDA direction, we have an in-person lead monitor and then a secondary monitor who can watch remotely via video. And that's been the condition for conduct of clinical trials based on FDA direction. Throughout the trials, we have made every effort to collect regulatory-grade data on what those monitors are doing to provide for assistance and comfort for the patients up to and including what the role of that second monitor actually ends up being.

All of this is in service of making the case that single monitor is absolutely something that should be enabled in the real world. That's our position. In the longer term here, if you look at other therapies that have acute consciousness altering effects, things like monitoring ratios haven't been explicitly specified. At the end of the day, it's been left to clinical discretion and clinical judgment to ensure that patients are safely monitored. Of course, there's some contents in existing REMS, and we'll expect to have content in our REMS that relate to monitoring.

But with the evidence that we're accumulating along the way, adheres to the evidence that we've been able to establish for what constitutes safety and efficacy.

I can comment on PTSD as well, if you'd like, Rob?

Yes, please, that sounds great.

Yes, sure. So across the Phase III program, we have combined studies, right? We've got studies with 2 arms. And then in 2 cases, we've added this lower enrolling 50-microgram confounding arm, right? And that's not an analytical arm. It's not an arm where we're interested in the performance of the 50-microgram drug. Rather, those arms have existed to confound the understanding of people in the other arms as to what they got. So in each case, for GAD and MDD, our first study in the condition, we used a 2-arm design with inert placebo, which we continue to believe is the appropriate control condition for testing psychiatric medications, including DT120 and any other psychedelic for that matter.

So that's what we did in PTSD. We think head-to-head is the best way to establish evidence of efficacy. And as we gather the accumulated evidence and as we're able to read out the evidence from these other 3 studies that we're conducting and ultimately from Ascend, which we guided starting imminently, all of that will accumulate to help us understand what, if any, effect that 50-microgram dose arm has on the understanding of people in the other arms as to what dose of drug they got and whether they got a treatment dose or not and also whether that has any effect on the measured outcomes.

So as we gain more knowledge and information about the performance of these different studies with the different control and compounding conditions, that will allow us to think about future studies and the design of those studies. But for primary evidence of efficacy, we continue to believe head-to-head is the right control condition.

Our next question comes from the line of Andrew Tsai of Jefferies.

This is Brian Castiglioni on Andrew Tsai. Just 2 questions. First on patient journey. You mentioned Phase III 5- to 8-hour will be a patient journey as opposed to up to 12 hours in the Phase II. Can you just talk a bit about what gets you closer to the 5-hour journey as opposed to 8? What do you need to establish with the FDA incentives to make it happen? Secondly, on placebo response. Your placebo response in phase II, the GAD study was actually very high when compared to other GAD studies. How are you thinking placebo might trend in the phase IIIs? Then same goes for the phase III MDD study as well.

Yes. Thanks so much, Brian. So yes, I think in terms of the first question and the criteria, some of the changes, and we highlighted this a few weeks ago at our event. Both formulation where we use an orally dissolving tablet in our Phase III program, where we see faster absorption, we think could translate into a better profile in terms of resolution of the symptoms. But also the way we've approached this, it's been intentional from day 1. We started with little information about the actual safety requirements and monitoring dynamics in these studies when we were going into our phase II program. We included a higher dose, 200 mcg dose in phase II.

Therefore conservatively, and I think appropriately conservatively, extended the monitoring period in phase II out to 12 hours and had an extremely lengthy set of criteria that were being measured to assess when patients could end the monitoring session. Based on those learnings, based on those data from the phase II study, we made revisions, both, of course, to the formulation, but also to that procedure, that checklist that we're using. In phase III, we feel quite confident that we'll be moving in a shorter direction. That's what we certainly are seeing so far.

I think that combined with the reality that the change from a 12-hour monitoring period to an 8-hour monitoring period being required for all the participants in the study was driven by discussions with FDA and based on those data. So we feel quite confident that we're heading in the right direction there. Regardless, within that window, we see a really attractive clinical profile, one that means that patients aren't shuffled through and rushed out the door, and one that means that providers have a low turnover, high efficiency delivery to those patients.

In terms of the second question, placebo response. You rightly noted we had a remarkably high placebo response from the phase II study. If we just focus on the GAD symptoms or GAD HAM-A scores for a moment, what we saw there is, and this would be consistent across any modality in almost any scale. The fact that an 80% likelihood for patients to be receiving some dose of drug tends to drive up placebo response. We also saw that around a third of patients who received placebo guessed they were on drug. The presence of several lower doses likely really enhance that placebo response.

There are also dynamics with the dropout of patients where we didn't have anything to offer patients beyond the initial dose in Phase II, that we now in Phase III have part B, and patients are guaranteed access to open-label drug if they continue on through the 12 weeks of the study. All of those dynamics, we think played a role in the Phase II. As we look to the Phase III program, having a lower allocation ratio and having a reason for patients to stay in the study, should both reduce at least to and perhaps even below historical averages for the placebo response. That would be true we'd expect in both GAD and in MDD. I think we see this from other programs as well.

We look at other studies in our category. We look at the pivotal studies for Spravato. We're seeing lower placebo responses than we have historically seen for antidepressant in daily drug studies. It wouldn't be surprising if we saw a lower than average placebo response across the phase III programs here. But given that we've exceeded such a high placebo by such a wide margin in Phase II, we feel, you know, quite confident no matter what that we'll be in a great position heading into the Phase III data.

Our next question comes from the line of Marc Goodman of Leerink Partners.

This is Basma on for Marc. Thank you for taking our questions. Our first question is about the PTSD program. Can you remind us again of your convictions regarding the dose using the PTSD? Why do you think it's going to be efficacious? Also, can you remind us of the study powering assumptions? The second question is, do you think for the submission in MDD or the GAD, whatever comes next, that you can leverage the safety data from the GAD, or you're going to have to collect another set of exposure data in the relevant patient population? That's it for us.

I'll take the second one first and then turn it over to Dan. You know, we certainly expect to have exposure from pivotal studies and efficacy studies in any population that we're conducting research in, of course. ICH guidelines aren't specific for patient exposures, aren't disease or disorder specific. Certainly would expect a huge population requirement like you see from ICH E1 or anything. Dan, I'll turn it over to you to the other one.

Yes. Great question about PTSD and, you know, having done our dose range finding study in phase II and getting great confidence in our phase III dose and dose in this formulation through some transitional PK work that we've done there, gave us the confidence to go forward in GAD and MDD. As you note, the confidence also to go forward in PTSD with that dose.

We have every reason to think that from a symptomatic perspective, from a disease definition overlap perspective, from a scale overlap perspective, that all of those come into alignment and that there's no real reason to think that the variations that make up these differently defined diseases, but that fundamentally have such tremendous overlap would call for any additional dose adjustment moving forward. We go into PTSD with the same confidence we went into to MDD with the dose that we selected initially for patients with primary GAD. From a powering perspective, we continue to look at this like 5-point change on the scale as being a really good sweet spot for us to aim for.

You know, we're continuing to think about that across the scales, whether the scale is the HAM-A for GAD, the MADRS for MDD or the CAPS for PTSD.

Our next question comes from the line of Francois Brisebois of LifeSci Capital.

You talk about the overlap here, and I just want maybe a better understanding of it seems like MDD is more episodic, but with GAD and just in terms of, you know, probability of success or whatnot of the trials, is there, you know, is there more confidence in one versus the other? To that point, is there anything about the disease itself with GAD that could trigger a higher placebo response, or is this more from the kind of trial design, we think, like you mentioned?

Thanks so much, Franc. I'll turn that one back over to Dan as well.

It's a great question, Franc. We've said this in a few different ways, obviously we've introduced some new slides from the deck now to look at the GAD MDD overlap. As you noted, it really is in the vast majority of patients, something of a temporal distinction that these are folks who, you know, if they have MDD, it's because they have had or are currently in a major depressive episode. Major depressive episodes by their definition end, they have start points and end points, whereas GAD you really think of as that constitutive background state of anxiety. What we do know is that the longer that someone has high anxiety, the more likely they are to have a major depressive episode.

The more major depressive episodes and the more severe major depressive episodes people have, the more likely they are to have high levels of anxiety in the background. When we think about probability of success, it's a really interesting question. Historically, MDD has been an easier target for all classes of antidepressants than GAD with those same antidepressants. In part, that's due to the fact that we're in the case of MDD, helping folks go to a state that they were in if not recently, at least fairly recently in the last, you know, a year or 2 years at the most, and often much more recently than that.

It's more like resetting a state that the person will get back to and has been in more recently, whereas GAD is more of a change to a state that someone probably hasn't been in in quite some time because of the longitudinal nature of the disease. MDD has historically been an easier target and that in part is what gives us great confidence. We also, of course, saw in phase II that we were able to move the MADRS pretty dramatically in the GAD patients we were treating, despite the fact that they were starting lower than we would ordinarily start people in an MDD study. Which means, of course, there's less room on the scale to move in, and we still saw quite a bit of movement.

All of that together continues to give us real confidence in our MDD studies. As for placebo and GAD, probably that's not what's at play here. I think that as Rob spoke to already here and as we talk about kind of often, the design of that study both led to a higher actual placebo response with 5 arms or active, and the likelihood of getting drug being so high will drive an actual higher placebo response, particularly because there are these lower dose arms that may or may not feel like something to someone, so people on placebo could very easily mistakenly think they were on drug.

Also with the dropout rate and the data replacement strategy, taking that already actual high placebo response and making the measured placebo response, actually overrepresent the background real placebo response. That's probably more causal than the disease state itself.

Thank you for that. Maybe if I could jump in quick with Matt. Matt, you made a comment there that you guys have shared before, can you just help us understand, we don't hear this much, 1% penetration of the TAM equals to about $2 billion. Can you help us understand how that TAM, how do you handle the overlap of MDD and GAD to get to that number? On the commercial side too, can you just help us, you know, remind us what the learnings are from the J-code implications for Spravato and how that might have triggered sales? Thank you.

Sure. The 4.2 million patient number that I cite is, it includes any of those patients who have both. These are unique patients that we've identified. These are all patients 18 and over. That is the true TAM. We've taken into account any of the overlap. If they have a dual diagnosis, they are deduped. In regards to the J-code for Spravato, I think what that does is it gives us good confidence that there's a path forward to submit for a J-code for DT120 as well. That's been in our plans and that's an operating assumption to submit once we get into market if DT120 is approved.

Our next question comes from the line of Pete Stavropoulos of Cantor.

Congrats on the quarter. For the MDD OLE, you set the trigger for redosing at a MADRS score of 20 or greater. Could you help us understand why 20 was chosen? Through your market research, is that level of severity a threshold where healthcare practitioners would likely recommend to patients another dosing session?

Thanks so much. I'll turn it over to Dan as well.

Yes, great question, Samantha. Across our studies, what we've decided to do in the part Bs is set the threshold on the scale at the line between mild and moderate. There are a couple. You know, obviously on all these scales, that's somewhat arbitrary, right? The scale designers pick numbers and those get psychometrically tested and validated, and those numbers become the thresholds for the life of the scale at some level.

We thought the threshold between mild and moderate was particularly interesting because, yes, in talking to the wide community of prescribers and treaters out there, this certainly seems like the level at which people would consider even medication at all, let alone a, you know, more intensive and likely expensive medication. That threshold also corresponds with an interesting change, which is a little less scale-based, but the practical reality is that when we think about mild versus moderate illness, moderate is where people start to accumulate functional deficits, where the symptoms of the disorder become severe enough that they interfere with activities of life, activities of daily living, whether they're school, work, family, whatever.

That seemed to us to be the reasonable place to draw the line in the studies and a likely threshold that would be applied clinically, though by no means would it be a necessary threshold for clinicians to follow. Of course, in the end of the day, clinical judgment rules everything. These scales, because of their intensiveness of administration, are not often used in clinical practice. What we assume will happen with real prescribers based on the conversations we've had with those folks is that if in their assessment they assess someone to have functional deficits from their disorder, that will very much push them in the direction of using therapies like ours.

I'll add one bit of color there too, Sam, which is just that, you know, while there's a lot of discussion, of course, about the various sort of subsets of MDD and the patient populations who have not previously responded to SRIs as being some sort of unique entity, the real thing we see, both in terms of patient experience and in terms of health economic outcomes, and all the things that actually drive benefit both personal and functionally and economically, is improving the severity.

Finding patients who have severe symptoms and improving those down to a state where that functional deficit is improved meaningfully. That's why we set the threshold for treatment there. It's also why we're so focused on looking at the severity of these populations rather than siloing ourselves into a small subset of the population that just didn't respond to 2 past SRIs.

Very clear. If I can just sneak in one more question. With interventional psychiatry being increasingly integrated into practices and healthcare systems, what preparations are underway at clinics to pivot and deliver DT120 operationally? Maybe what are you hearing as you do your commercial prep work?

Matt, I'll turn it over to you.

Thanks, Sam, for the question. What we're hearing from clinicians, especially those that are doing high volumes of intervention today, is that they have been prepping for the psychedelics coming to market and that they're allocating space for that. We feel pretty encouraged by the anticipation and the receptivity of the market for these interventions as they make their way into market. Certainly there's a high anticipation for DT120 and some of the data that we shared just a couple of weeks ago, I think really highlights the momentum and the receptivity of the market.

We're encouraged by all those different facets and we believe that our targeting model really does help to prioritize those physicians who are, A, receptive to the drug concept and, B, have the capability and the capacity to accommodate these patients for treatment.

Our next question comes on the line of Matthew Hershenhorn of Oppenheimer.

Congrats on all the progress. Thanks for taking our questions, and thanks again for hosting us 2 weeks ago at your event. Very insightful and really appreciate it. The question we had was just as you talk to clinics, what are some of the economic incentives they have to modify capacity for DT120, especially considering away from Spravato? If you see time-based reimbursement and less friction arising from patient turnover compared to Spravato as potential advantages, and perhaps if you have any estimate on how many clinics it would take to eventually treat 100,000 patients per year, just considering likely capacity, we'd really appreciate it.

Yes. Thanks for the question. You know, regarding the practice economics, certainly we recognize that that's top of mind for physicians, and we are in the process of building out clear direction on what will be available at launch and also those codes that we want to secure post-launch, make sure that physicians are adequately reimbursed for the administration. I think the way that the clinics have been thinking about this, at least early on, has been to allocate certain amount of space, and then their anticipation is to judge the market and judge the volumes that are coming in to determine whether they need to allocate additional space to their clinics. You know, this is something that's really going to be determined as we get into market.

As we get closer, we'll have a lot more market research to share on what we think that volume and capacity will be, both in market and then in downstream, in years thereafter.

One additional question quickly was just on PTSD, if you could please talk about any differentiated advantages for DT120 just compared to the other psychedelics, psilocybin and DMT, specifically for this indication, just thinking of the various symptoms there. If you have any input or discussions with the VA, just considering the prevalence amongst veterans there, informing enrollment criteria or any data collection that they could potentially be interested in, would definitely appreciate it.

Thanks so much, Matt. Dan, you want to take that one?

Yes, happy to. There we go. Off mute. One of the things that we hear from sites quite a bit about the characteristics of DT120 and the patient experience with DT120 is that it is very well tolerated, particularly emotionally. That people find the onset of the drug, its action, while it's at its sort of plateau effect, and then the gentle return to a normal state of consciousness to be tolerated well and also to be pleasant in ways that other drugs may not be. Particularly with folks with, you know, high levels of anxious arousal, that's probably a good thing, right?

That we want folks who are particularly attuned to their surroundings and attuned to that sort of hypervigilance that happens with PTSD to have that sort of experience, to have a predictable and gentle experience that allows them both the time to have the experience that they're having while they're at the plateau, but also to have that predictable onset and offset. We think that really is a differentiated advantage of the drug itself.

You know, what I didn't say was the second half there about the VA and, you know, we've been working with VA researchers on our research to date. Of course, as we move into the world of PTSD, we will continue to deepen and strengthen those relationships. Of course, we're continually seeking advice from experts across the different conditions we work with. The VA expertise in PTSD will be really important to the design and execution of those studies as it has been in our studies to date.

Our next question comes from the line of Sumant Kulkarni of Canaccord Genuity.

I have 3. First, what are your latest thoughts on a filing strategy? Will you file both GAD and MDD at the same time, or do you think GAD, which will have 2 phase III readouts earlier, will be your first targeted indication? That's the first question.

Yes. Thanks, Sumant. You know, obviously we're having a lot of discussions with FDA and have been around that appropriate strategy. I think what we've of course have seen also a lot coming out of FDA about thinking for filing on studies where there is a high degree of overlap. There's a long regulatory and legal precedent when there are highly overlapping indications for a single study to be supportive of expansion into that indication. You know, obviously some of that's going to be contingent on how compelling data are across the studies and particularly in MDD, right?

If we see a smaller effect, I think obviously we have less compelling evidence than if there's an extraordinarily large effect that we're observing that would imply, you know, quite small studies needed to replicate that. Some of it's going to be ultimately informed by the data and subsequent discussions with FDA, but we feel quite confident in the position for filing DT120. Regardless of whether that's filed concurrently or sequentially, we think we'll be in a great position to go after both these markets hopefully, as we get in the market and get into the patient population if we're fortunate enough to get a drug approved.

Got it. Thanks. Second, for Matt on commercialization, both GAD and MDD present very large opportunities, but which one do you think could prove more challenging to crack for DT120 and why?

Thanks, Sumant. Look, we feel like the unmet needs for both these indications are high, and there is great receptivity in our market research for both indications. Our targeting model, our value proposition is really aimed at both indications. You know, we don't have a favorite. We do believe that there are a lot of patients out there that need help and need this treatment. If approved, we believe that we're going after both markets should we have a dual indication with equal measure. Keep in mind too that the diagnosis of GAD is not as reflective in the claims data as MDD simply because there haven't been any novel treatments in a couple decades.

We do believe that there's a lot of GAD out there that isn't adequately diagnosed in the ICD-10 data. We believe that that will also change with therapeutic intervention that meets that need.

All right. Last one is almost perhaps a philosophical question. What are the real world advantages and disadvantages of receiving a commissioner's national priority voucher?

Yes. Thanks, Sumant. It's a good question, one, you know, I think obviously anything that we can do to accelerate and be more efficient in development, we certainly are interested in entertaining. That's why we've been going at a really lightning speed, and we opened this IND in like less than about 4 years ago. We've been going at an incredible pace of development. Those are the things that we can of course control and, you know, put in all the time and effort and do the research the right way to move program forward to pivotal data, which we have coming up very soon. What comes after that, obviously with novel programs with FDA, there certainly can be advantages. There's also potential risks.

I think one thing that's particularly, you know, important for our program too is this opportunity to potentially go after both of these indications. If we're in that position, you know, I think there's a lot being navigated in terms of which both one or the other would potentially benefit from something like a CMPV. You know, we've of course seen some positives come out of that. We've seen some risks associated with that. We're going to keep with our great dialogue with FDA and continue to look for opportunities to accelerate anywhere we can. Right now, getting the data and going as efficiently from there to towards an NDA application is where we're focused.

Our next question comes from the line of Chris Chen of Baird.

Congrats on the progress. Just regarding the Emerge readout, I'm just curious how granular your patient time to discharge data will be? If you do go slightly over, you know, that 8-hour window, is it still possible to still secure a label with an 8-hour treatment window? Thanks.

Yes. Thanks, Chris. We are extremely detail-oriented in everything we do and try to get really precise definition of all of the important characteristics of these studies. We'll do the same in terms of how we, you know, have been doing analyzing the end-of-study checklist and when patients can be cleared for monitoring. Of course, those dynamics, we'll be looking at everything from, you know, means to side effects to individual patients and anything that could be useful there. You know, it's going to be something that we're quite interested in, and we feel, you know, quite excited about being able to present some data from.

Our next question comes from the line of Patrick Trucchio of H.C. Wainwright & Co.

It's Arabella on for Patrick. Thank you so much for taking the question. I guess now that DEA rescheduling can be done after a successful phase III, how much time is that realistically actually going to save? I guess, how are you thinking about initiating those conversations once you get the data? I was also just wondering if you could comment on DT402 in ASD, and what kind of metrics or signals that you're looking for to move the program forward. Thank you.

Thanks, Arabella. I think you're referring to the executive order that President Trump signed indicating the DEA should look at their scheduling assessment after phase III data, not after FDA approval. If that were to be implemented directly and DEA could, as a result, make a decision on scheduling at the same time of an NDA approval, that could save, you know, 90 days, which is the timeline right now to get to an interim final rule and an issuance of the schedule for the approved product.

There's a real opportunity and something we've been actually quite engaged with for a while, exploring opportunities to not shortcut anything, but to streamline the process and enhance the collaboration across agencies within the federal government to make that timeline from FDA approval to patients actually getting access to the drug as short as possible. With such a huge need and such an opportunity to address that need, we shouldn't be waiting any days that we don't have to get these drugs to patients. We're quite excited about that opportunity and continue to have great dialogue with FDA, with CSS at FDA and whenever we are able to with DEA.

To your second question, I'll turn it over to Dan to briefly touch on DT402.

Yes. Thanks for asking about DT402. We'd love to get a chance to talk about it. As we've said before, we're doing a pretty interesting signal of efficacy study in ASD. In order to do that across the course of a day, we've combined a set of measures that we're able to do repeatedly through the day, right? To look at the dynamics of pre-dose, early in the dosing experience, late in the dosing experience, again, as the drug wears off.

To do that, we've constructed what might be a little bit skinnier instruments than you'd ordinarily use for regulatory approach, but that have the components of those, you know, the construct components of those instruments that can be asked reasonably quickly and repeatedly through the day. We've got patient-reported outcomes, we've got clinician observation outcomes, caregiver observation outcomes, and some digital markers, some sort of novel digital behavioral markers that look at things like voice and facial expression and eye tracking, all rolled into what is a pretty dense day of dosing with as many different measures as we could comfortably for the patient experience fit into that dosing day.

Our next question comes from the line of Ami Fadia of Needham & Company.

How much data do you need from the part B of the studies where you're examining how long it takes for patients to, you know, take that second or third or 4th dose before you submit for approval and to be able to, you know, inform the circumstances of retreatment in the label? Also, how much data do you think you need to have the conversations with payers around, you know, coverage and pricing? A second question is just with regards to the capacity in the market with the number of clinics that are out there today.

In order to really achieve sort of the peak potential, how much expansion do you think there needs to be in terms of the number of clinics that are equipped to treat with psychedelics in the U.S., and what's sort of the timeframe or what are some bottlenecks that you think exist in order to, you know, see that type of expansion? Thank you.

Yes. Thanks so much, Ami. Yes, we're absolutely, you know, confident in our position as we approach top-line data and getting the data from part A. It's worth just pointing, you know, pointing out briefly that in precedent drug approvals, particularly with antidepressants where we have a lot of precedents, most of those drugs are approved on acute studies with post-marketing commitments to conduct longer-term chronic studies. We are pushing the bounds of what an acute study can do in this way. A single dose, we're following patients for 12 weeks and GAD, a primary endpoint at that 12 weeks, which is, you know, patients with GAD do not spontaneously have 12 weeks of significant improvement.

That approach is one of the important components of what drives our confidence in being in a great position with the part A data. Of course, the part B data will be useful to inform intervals for retreatment and sort of over time retreatment patterns, what happens upon subsequent retreatment, all the things we're trying to characterize there. We already have quite a bit of that part B data, and we'll continue to aggregate that across all of our programs throughout the, you know, the remainder of this year and as we continue to progress towards NDA filing.

In terms of capacity, you know, we think that this is something that is significantly underappreciated by a lot of folks, which is that the capacity that exists today is really far in excess, I think what any of the models that are out there projects for adoption. We do not see a sort of capacity constraint. One of the things for those of you who were in attendance in New York a few weeks ago with us, is to bring a little bit of clarity and sort of demystify what it actually means to set up a treatment room.

If you have a room and a site that is willing to spend a few hundred dollars on making it a little bit more comfortable, that might be better for patients. If you have a room that someone can be for an extended period of time, in a current treatment facility, that's enough. We do not see that there being a substantial financial or sort of logistical bottleneck. People use the term infrastructure, though, that's far too heavy-handed of a word. You know, we think there's plenty of capacity today.

There will, we expect, be a lot more capacity growth over time and with what we intend to do, which is provide the best support to the patients and providers out in the field so that they can adopt and get treatment if they so desire. You know, we think there'll be a great incentive and a great desire to adopt both treatment centers and, you know, for patients to come in for treatment.

Thank you. This concludes the question and answer session. I'll now turn it back to CEO, Rob Barrow, for closing remarks.

Okay. Well, thank you everyone for joining us today. We're very excited about the quarters ahead with 3 pivotal readouts anticipated across the second and third quarter. We'll look forward to sharing those data in due course. Thank you all.

Thank you for your participation in today's conference. This is a concluded program. You may now disconnect.

All right. Well, first of all, I want to thank everyone for coming and joining us here today. It's an incredibly exciting time for us. It's an exciting time for our field, and it's great to see everyone here. Many of you, we have spent a lot of time with over the last 5 years, and you've watched not only as we as an organization, but as the entire field has unfolded and has really built to this point where now the promise of what we've been talking about for a long time is coming to fruition and the degree of visibility we're seeing for our field is really taking shape. So we couldn't be more excited to be here with you today.

And again, I want to appreciate all of you for coming here and spending your morning and afternoon with us. Before we get started, forward-looking statements. We'll be saying things about the future that I refer you to all of our filings and the disclaimers, both here and in our SEC filings. We have a great lineup today and great speakers. I'll talk about in a second. I'll be brief and then turn it over to Dan, our CMO. We'll have a Q&A session, both with our panel a little bit.

And at the end of the event, there's a QR code here at the bottom, right, and it will show up later. both for folks who are in the room and online, if you can ask questions via that QR code, you can type them in any time the present, we'll field them and compile them to the end of the presentation. You hear from me, hear from Dan Karlin, our Chief Medical Officer; and Matt Wiley, our Chief Commercial Officer, along with Brandy Robert, our Chief Financial Officer, throughout the day. We're also incredibly excited to have Britty Albright, Andrew Penn and Shannon Sarker here with us today. These folks are directly involved in the research and the delivery of both psychiatric treatments and the research with psychedelics.

The ability to get these drugs out into the world is going to be dependent on folks just like this. And hopefully, throughout the day and through the discussion with them, we hope everyone leaves with an understanding of just how feasible this is and how much this can come into being over the next few years. I'm, of course, standing here, but I want to represent and thank everyone who's part of our organization who has had a role in getting us to this point in time. We feel an enormous sense of privilege and responsibility and really excitement for where we are today and where we're going into the future. The need has never been greater for the diseases we're trying to treat.

The growth of anxiety and depression has been faster than anyone would like to see, of course. And we're talking about millions of patients whose lives are dramatically altered by these disorders. Some of these things are so prevalent that we don't fully even appreciate how impactful they are because underlying these big numbers that we'll talk about are individuals' lives who are disrupted and who are wrecked by cycles of hope and grief and despair because the drugs we have, because of the treatments we have today don't do a good enough job for them. and we're here to hopefully change that.

We, from day 1, have had a very aspirational view of what can be accomplished. If we focus on the right science, if we don't get distracted by exceptionalism and traditions from the past that aren't relevant to modern research, and we really do the right studies. We do the right approach to this research, then we have a chance to actually have a major impact in the world and get these products to the patients who so desperately need them. So what does that mean, right? Patients today show up, they get cycled through medications and most don't get the kind of relief that they're hoping for.

We're talking about patients who get a single dose of drug, spend 5 to 8 hours in a clinical setting, can come for months thereafter in many cases in clinical remission in the data we've seen so far. And this could apply broadly to the 50-plus million individuals who are impacted by neurosychiatric disorders. I think it also gets overlooked, I think, very frequently is just what the patient journey is like for these folks. Again, we all know many people who are taking SSRIs who have gone to the doctor, have had a depressive episode, who have anxiety and who get the drugs and stay on these drugs for a very long time.

For the patients who we expect to be able to help first. [indiscernible] gets overlooked that patients come in. They have symptoms, they get prescribed the drug, not the path for these patients today. Even when they're getting the drug, they are starting to work, there's a really burdensome adverse event profile for the products we have available today. There's a logistical burden of coming back into the clinic even for daily drugs, for weekly checkups to make sure that you have got the right dose, titrating up the dose, augmenting with other doses.

And ultimately is just back to cycles over and over and again through the half dozen to dozen medications that we have approved. For these folks, there has not been anything as promising and as exciting as what we're seeing for the field of psychiatry today and what we're fortunate to be carrying forward. We often get a lot of questions about the drug we're developing, VT120, LSD-ODT, which we're taking forward and having pivotal clinical trials right now. We're coming to the Phase III readouts this year. And while there's often a conversation about, well, this class of psychedelics, don't all the things sort of feel the same.

And yet again, I think it misses the underlying reality. And this is the precision and the science we need to be focused on here. This weekend, everyone who followed our field, and I think everyone in biotech saw an executive order that drew attention and gave prominence to the need and the promise of this category of drugs. And it's remarkable to us that I don't think many people may have noticed this, almost 83 years to the day -- the day after that executive order was signed was 83 years after, Albert Hoffman first was exposed to LSD, which ignited research into this entire field. It's not a mistake that we're coming back to this time because we have had these drugs sitting on the shelf for nonscientific reasons. And now the modern science allows us to carry this forward into the world with the highest quality data and the highest scientific rigor.

LSD has been the longest study molecule. It's the one that kicked off interest in the field. It's the most potent. We've seen at every level and no matter how we interrogate [indiscernible] 20, its unique profile, we believe, makes it stand out as a potential only development, but among the drugs that are available to patients today. And of course, we have to go out and prove that with our Phase III data, but it's something that we aspire to do, and we'll have data very soon to prove that. And our approach to doing this also is critically focused on providing patients and providers the best support, the best care, hopefully, that they have ever received. We've built -- I couldn't be more proud of the team we've put in place and been able to attract to this effort over the last 5 years who come at this with a clear-eyed view of the right science, the right way to tackle the opportunity in the real world and a strategy to go out and do that.

And executing on that today and in the years ahead is what's going to drive not only our success, but success for these patients who desperately need it.

Before I turn it over to Dan, I'm going to share a few updates more specific to our program now. All of you know our GAD and MDD programs. We've got 3 pivotal readouts. We're starting our second pivotal study in MDD. And today, we're excited to expand that even further and announce a Phase III study that will be starting in 2027 to study VT-120 in post-traumatic stress disorder.

Covering these 3 indications effectively covers the vast, vast majority of all patients who show with neurotic psychiatric disorders. It broadens out the potential both in the scope of the populations and the focus on the symptoms that they present with. And we're incredibly excited to expand this and move forward into a third indication with our lead program.

A few other updates. All of you heard recently our outcome from our VOYAGE sample size reestimation in both of our Phase III studies in generalized anxiety disorder, we had a blinded reestimation. We looked halfway through the study to assess whether we had correctly assumed the right standard deviation and the right not valuable rate in the study. So we reported that those numbers were considerably lower than we had planned for in the VOYAGE study. And the same is true even with an excitingly 6% nonviable rate in our PANORAMA study.

The quality of the data that we'll be able to present based on that ability to retain patients in the study is just remarkable. And based on these assumptions, based on the results from the sample size reestimation, we're actually able to lower the sample size in PANORAMA to a total enrollment of 200 patients. That study has 99% power. And in both studies, less than a 2.5 point delta would result -- we would expect, assuming all these parameters hold would result in a statistically positive study.

So as we approach study designs, if we get to clinical relevance, clinical significance, the statistical significance should follow. This, of course, gives us an incredibly high degree of power going into these readouts to give us decisive answers about whether we can replicate the incredibly exciting findings we had in Phase II. With that, VOYAGE, we're recently happy to pass the milestone that the study enrollment is complete, and we're on track for an early Q3 readout for our first GAD study.

And this is, of course, going to follow our first Phase III readout in major depressive disorder, which will happen in late Q2. For PANORAMA, as I said, the target enrollment is now at 200 patients. We have exceeded that enrollment at this point. So screening is now closed in that study.

For ethical and practical reasons, patients who are already in the screening process are going to continue through. But we're excited to rapidly be approaching completion of enrollment in that study, which will bring us with great clarity into now 3 readouts across the second and third quarters of this year with PANORAMA coming out in late Q3.

Most of you know our Phase II data, but coming to these readouts gives us just an enormous degree of excitement because of the profound impact we were able to demonstrate in Phase II. An effect size that was more than double the standard of care, a magnitude of response that was staggering in the context of current therapies. And the fact that we saw both rapid and durable remission out to 12 weeks, this is a longer endpoint after a single dose than anyone is even seeking to prove. And now we're going to have multiple Phase III readouts across the 2 biggest indications in psychiatry with data out to 12 weeks and even beyond.

In Phase II, we saw a roughly 48% clinical remission rate at week 12 and an AE profile that was unremarkable. Patients are in an observed setting. We go to great lengths to make sure we capture adverse events appropriately. So for regulatory and clinical purposes. And what we saw is a relatively benign and favorable adverse event profile that puts us in a great position as we come to these Phase III readouts. We also uniquely were able to demonstrate a dose response across a wide range, down from 25 micrograms up to 200 micrograms, which clearly answered questions around what's driving the drug's effect and what isn't.

What we found is that because virtually all patients knew they were on drug regardless of the dose they received, but we still saw a dose response functional unblinding is talked about quite a lot, cannot be the explanatory. It's not the thing that was driving the clinical response. It clearly was a dose dependency based on the activity of the drug in our view. And that, of course, then supports going into our Phase III readouts where we have a head-to-head study and a 3-arm study, giving us complementary designs across 3 studies in GAD and 2 studies in MDD that we hope to take forward to FDA very quickly thereafter. You'll hear from Dan in a second about the overlap between these disorders.

I think there's often a degree of familiarity, but a lack of clarity in terms of exactly how we think about the overlap between anxiety and depression. And what we saw and what gives us so much confidence going into our first depression readout, which now is the first of the 3 this year, is the fact that we saw very similar response profile, magnitude and separation on MADS scores on depression symptoms. Now again, Dan will talk about what underlies that. But as we head into this readout, we couldn't be more excited or more confident going into our depression readout.

And finally, just talking about the magnitude of impact on patients, right? We all look at means and averages. And of course, that's what drives the statistical proof of whether we're seeing efficacy or not in these studies. For an individual patient, moving patients from what was a starting point of quite severe disease, whether we measure on the HAM-A or the Clinical Global Impressions of severity scale and being able to move patients -- the median patient was at or below remission on anxiety scores in our Phase II. So that level of profound impact.

And the way we approached our Phase III design is trying to treat patients who have moderate or worse severity because what we've come to learn through extensive real-world and AOR work is that by bringing patients from moderate or severe impact of the disorder down to mild or remission, we're able to just drive enormous value for the health care system and of course, most importantly, value for these patients and their ability to function in their lives. So the last I'll leave you with is trying to put these results in context. We've shared this before.

Whether we look at the absolute magnitude of change, which is an important feature or we look at the placebo-adjusted change, the magnitude of response we were able to demonstrate in Phase II stands out both in anxiety symptoms in the context of approved anxiety therapies. But also when we look at the newest generation of antidepressants and drugs that are indicated to treat depression, whether it be from major depressive disorder, bipolar disorder or others, the magnitude and separation we saw stacks up incredibly well.

And as we get into the MDD population and patients in depressive episodes, we're just as excited to look at the Phase III data. Of course, we need to see in this population exactly the kind of response we're able to drive. But of course, anything that comes close to what we're able to see in Phase II gives us enormous excitement for how this could impact patients out in the real world.

With that, I'm going to turn it over to Dan and keep going with the program.

The irony of coming up here to talk about anxiety to all of the staff who've been working for the past few months to make this happen, and I can't be really overstated. But let me go into a little bit more about what Rob was talking about here, which is we've said this to many of you before. But when we think about the categories that are GAD and MDD, really, what we're talking about is these 2 clusters of symptoms, which are anxiety and depression.

And obviously, from a DSM perspective, from a psychiatry perspective, from a regulatory perspective, we have to draw boxes around a set of symptoms that are severe enough to call a disorder. But the reality is that anxiety and depression symptoms coexist. And the way that we conceive of them coexisting is that anxiety is the background state that people tend to experience starting pretty early in life and that persists through adult and it can fluctuate, of course, because everybody, whether they have a neurotic illness or not, experiences the day-to-day fluctuations of life. But anxiety symptoms tend to be fairly constant even as they fluctuate a little bit around the person's baseline. Whereas when we think about MDD and what that actually is, it's defined by having had a major depressive episode. And each time someone has a major depressive episode, the odds that they have a subsequent one go up and it's very likely that their background anxiety worsens.

So when we think about the relationship between these 2 conditions, what we're really talking about is more of a temporal relationship, that most people who have a major depressive episode will have had background anxiety. And when they're between major depressive episodes when they're what we call eutthymic or normal mood, they likely have a high degree of background residual anxiety. So when we think about residual symptoms of depression, those are often anxiety symptoms. And over time, these things, whether treated or not with the treatments we have available, tend to worsen. How do we sort of correlate that with the more sort of specific instruments we use, the more numerical instruments we use.

Well, these are the DSM diagnostic criteria for GAD on the left and MDD on the right. And what you see is that there is that tremendous overlap that you can get a GAD diagnosis with only items that are part of the MDD disease definition. But item 1 for both of these is really the definitional and the differentiated symptom of the 2 disorders. One is the anxiety, the other is the anhedonic, the low mood part of depression. And we see that manifest in the scales as well. And this is really pretty dramatic, more dramatic than the diagnostic clusters because what you'll see here is that of the psychic symptoms of anxiety that are measured on the HAM-A, they all correlate to items from the MADRS.

And if you do some math with these correlations, what you discover is that you can get to severe on either scale with constructs that come from the other scale. This is the extent of the overlap of the conditions. And between our ability to move the MADRS in Phase II and this construct overlap, we have tremendous confidence in our ability to treat people in a major depressive episode.

So let's talk a little bit more about the Phase III program. Rob went over this slide already. Of course, we've now told you our intention to go into PTSD. Really excited about the ability to move that. And when you think about these 3 disorders taken in concert, we just talked about GAD and MDD overlap, PTSD has very much the same set of symptoms as MDD and GAD, but it has an attributable cause.

And often, what we find is that the people who having suffered a trauma, of course, not everybody who has trauma goes on to develop PTSD, but that the people who ultimately develop PTSD after a trauma are folks who had this background symptomology regardless whether diagnosed or not. These are people who are often prone to anxiety and low mood. So what gives us this confidence in our Phase III outcome? We obviously have the IIb results that Rob just reviewed with you that I don't think would have been news to anybody.

We have our ongoing strong relationships with our sites. So at the end of the day, the research that's conducted at sites depends on the quality of those sites, and we are extraordinarily confident that our relationships with the sites, the time we've spent building those relationships over the past 5 years and the ongoing close management of the sites, our close relationships with them in an ongoing way through the conduct of the study means that the study conduct will be high integrity.

We continue to have a dialogue with FDA that we find to be very productive and engaged. We think that we've built confidence in the agency and what we are doing and buy-in for our study plans. The Phase III designs particularly the Part Bs where we keep people in the study and allow them to get open-label treatment if they have moderate or worse symptoms. We anticipated that, that would drive retention. And what you've now seen in the sample size reestimation readouts confirms that those Part Bs kept people in the study regardless of how they were feeling, regardless of their ability or their belief of their first treatment, they stayed in the study because they wanted the opportunity to have ongoing treatment.

And ultimately, everything we've done, we get the question sometimes, well, how have you changed your study designs based on the feedback that came from other people's studies and the conversation in the public. We haven't. We led that conversation. We were at the front edge of those conversations and the choices we made at the outset are the choices that everyone else has now come around to do in their studies. And this is just an example of that, right? Here are our Phase III studies, including our newly announced PTSD study. And what you see here is that across indications and across studies, we employ completely compatible and in the case of PANORAMA and ASCEND, slightly complementary designs that ultimately, what we're measuring and in whom across these studies is aligned with the indication, the time points, slightly variable, but we're measuring it essentially at the same times.

And all of this is intended to, in concert, allow us to build a body of evidence that says across these indications, across a couple of different control conditions, we are able to reliably see the same drug effect. And that gives us increasing confidence across these indications that the measured drug effect in these studies represents a real drug effect that will translate into the real world, if approved. Who we get into the trials matters as much as anything, right? When you think about what the science of drug development is, it's testing the drug in the indication you're interested in that is in the right people with the right intervention at the right time. So what gives us confidence that we're getting the right people into the studies. And ultimately, it is an eligibility process, right? All of this is about what you do from when the patient shows up to when you enroll them to when you dose them.

And we have an eligibility process that plays on our tight site relationships, right, that plays on the desire of the sites to have a successful study, a high integrity study but doesn't depend entirely on that. We have a multi-stakeholder setup where each participant who's enrolled is assessed by the site, but is also assessed by 2 separate sets of blinded remote central raters, one for diagnostic assessment, which is the MGH SAFR program and one for severity, which are the central raters, the same people who ultimately assess the outcomes.

And so we get this 3-part verification to ensure that everybody we get into the study is who we want in the study. And our folks, our internal employees are reviewing every set of eligibility outcomes as well. So each thing that is done in the eligibility assessment gets reviewed by internal staff to make sure we're not just doing a box checking exercise, but that everything about the participant makes sense in concert. And so the people that we want to study ultimately are the people who we do study.

Another design decision that when we made it was maybe not what everybody else is doing. In fact, it almost certainly was not what everybody else is doing. We decided from the outset in Phase II to assess drug effect in the absence of any sort of diadic psychotherapeutic intervention. If you look around the field today, it's what a lot of people are saying they're doing.

When we decided to do this, that wasn't what was happening. And we can assure you, and we will continue to that from our Phase II on, what we are assessing is a drug effect in the absence of any sort of preparatory therapy, in the absence of any therapy in the room during the session and in the absence of therapy after the drug session. We are confident, again, that the measured drug effect is a real drug effect. And so what does that look like in the course of the day? We have moving slides now. We can do that in a room. It's harder to do it when we're putting them on the web. Patient goes into the room, dosing session monitor is there. Patient takes the drug.

Because of our oral disintegrating tablet formulation within 15 to 30 minutes, if the patient, in fact, got active drug, they begin to feel that active drug. The ODT formulation brings that in from about an hour for a tablet. Now the upshot there is the time spent in the room where the patient is not experiencing drug isn't time that helps the person get better.

So everything about this formulation is intended to maximally make that day efficient for the participant and efficient for the clinical trial staff. From hours 2 to 4, the patient has reached the sort of peak and plateau of the experience. At this point, the effects of the drug are fairly constant. This is where we think the bulk of the therapeutic action of the drug is happening. And then by hours 4 to 6, the effects of the drug start to wane. One of the things that is particularly notable about the 120 experience is that the off-ramp from the experience is smooth that people come back to their normal perception, their normal emotional state, the normal cognitive state in a way that is comfortable for them, that there's not a rapid return or a rapid loss of the symptoms, but instead people sensorium comes back to them in a way that feels comfortable.

And then from hours 6 to 8, people hit the point of being back to a place where they're able to leave the clinic and leave a monitoring setting. Of course, in the research, studies, we keep people in for 8 hours. For one reason, that preserves the blind of other study staff. If everyone who -- if people were allowed to leave at, say, hour 5, they're better. maybe half of people would be ready to leave and half wouldn't. That would be another source of potential staff unblinding. So -- but what we've been doing, we'll show you in a slide in a second, is starting at hour 5, we're assessing folks for readiness to leave.

So we start to understand the real dynamics at the end of that session and when in the real world, folks will likely be ready to leave. We've spoken to this before, but this is a little more detail on the end of session checklist. Now in Phase II, we kept people in for a fixed minimum of 12 hours. And beginning at hour 8, we used a 23-item scale to assess for any evidence of the acute effects of the drug.

Based on the evidence that we were able to accumulate using that scale starting at hour 8, we went to FDA and proposed an 8-hour minimum in Phase III, and we brought FDA a scale that we thought was an appropriate one to assess for safety. That's an 8-item questionnaire that we call the end of session checklist, and we've been administering that starting at hour 5 to really understand what the dynamics at the end of the session look like.

What we think this adds up to is the ability to, at the time of labeling and REMS negotiations, talk about a 5- to 8-hour session length, okay? So we've come down from 12 when we started, all the way down to 5 to 8 is what we'll be proposing at the end of this. So all of that adds up to a set of methods that give us and we hope give you confidence that when we bring you Phase III data it's data that represents a real measured drug effect and a measured drug effect that ought to translate into the real world, that we measure the right people, that we use the right comparator, which we continue to maintain that the right statistical comparator is inert placebo that we controlled for functional unblinding, both through the conduct of the Phase II, as Rob explained, that our Phase II dose comparison gives us great confidence that the observed effect isn't due to functional blinding.

And in Phase III, 2 studies with a 50-microgram controlled arm, not a comparator arm, give us additional confidence that it's not just knowing the drug that, for some reason, leads to people reporting that they feel better, but it's the actual drug that helps them to feel better. So all of this, we're very confident puts us on an excellent path to bring the data that we get from these Phase III studies and submit an extraordinarily high-quality NDA.

So what will we show you when we bring you these Phase III data? These aren't the data. These are just the form of data. It'd be a big surprise if we were to show you data. So we'll show you the demographics, right? We want to assure you that we got the right people. We were measuring the right thing in the right people. We'll, of course, give primary efficacy outcomes. That's the MADRS at week 6. We'll also give additional secondary outcomes at week 6 and week 12. We'll bring you safety data, so full safety table and data on suicidality measured with the CSSRS. We'll talk to you about dosing session dynamics, including what we were able to measure as safe end times per session, so how long people were in and when they were safe to leave based on that end of session checklist. And we'll bring you some data from the extension phase. We didn't talk about it very much today yet, but those Part Bs are incredibly interesting, right? The Part Bs give us a couple of things.

They give us a real-world-like treatment dynamic where folks who are moderately ill or worse are able to receive treatment no more frequently than monthly, but up to 4 treatments in that open-label period. But an incredibly interesting additional thing that we get from the Part B is that unlike a traditional open-label extension. So if we were giving daily drug, someone finishes the double-blind period, they enter a traditional open-label extension, the first day they're in it, they're now in that open-label state.

Because we are doing triggered treatment, and this is really important. It's a key difference because we're doing triggered treatment unless someone gets open-label treatment and until someone gets open-label treatment, if they do, they remain in that original blinded controlled state for the full year of the study. And we'll give you as much as we're able from the folks who run through that Part B when we do -- when we give you the data.

Now obviously, what we won't have is the full set of Part B data. There'll still be folks in that Part B, but we certainly want to tell you what we're able to know based on the people who've been in the Part B and completed the Part B. And we'll give you some preliminary information on retreatment patterns. Obviously, retreatment patterns can emerge over time as more people are in longer, but we'll at least have some early idea of what sort of treatment patterns we're seeing.

So as we reach the end of this section of the presentation. We are accountable for numbers, right? What we're accountable to, to regulators, to HCPs, to payers are the sorts of mean change that we can drive in a mean change difference from placebo. What you see here is our study design overlaid with what we were able to show in Part B. We are able to detect a very small change. These studies in certain ways, were overpowered. That's what we discovered in the SRE that some of the assumptions we made about the powering of the study dependent on people's behavioral changes based on the addition of Part B.

Those behavioral changes exceeded what we expected. So the studies ended up even more powered than we thought they were. We can detect a change down in the high 1 to low 2 range. Comparative treatments, in sum of studies that look across the different studies of them are generating about 3 to 4-point changes.

Our assumption for these studies was a 5-point change. Anything over 4, we're pleased with it. Everything -- anything over 4 puts currently available treatments in a very different light, right? If you think about a treatment where you have to take it every day, accumulate side effects over time and get a 3 to maybe 4-point change versus a treatment that can generate that sort of change with a single dose persist over time without a persistent adverse event.

We're talking about a paradigm shift, a best-in-class profile of these drugs. The Phase IIb results stand where they are, right? We're talking 7 and 6.4 point changes over placebo in the Phase II. Anything above 4 best-in-class profile, and we expect that we can do even better. Members only tell a part of the story, right? They're absolutely critical. We're accountable to you. We're accountable to everybody for those members.

But behind the numbers, real patient experience, real people's experience, people that you might know, right, the people in all of our lives who suffer from anxiety and depression. And after all of this, after all of the technical details here, we thought it was really important to sort of bring that home. And so what we're about to show you is someone who participated in the Phase II study for GAD and what that was like for them.

I think if I press the button one more time, it will start.

[Presentation]

Having seen that a couple of times, I still have to sit with it for a second. There's something to be said about -- using a microphone. There's something to be said about someone organically coming to so many of the same conclusions that we have and hearing unprompted much of the language that I'm confident we've used with many of you coming directly from a patient, and it is moving each time. So much of what we are trying to do here with you today is to make this feel as real to you as it feels to us.

Rob started by saying what an honor this is. And I think each of us feels both an enormous obligation to the drug we're developing, but also to the patients, as you just saw, the participants in our trial and the patients who, if we're approved, will ultimately benefit and an obligation to the professionals who will be the conduit for this drug into the world and to patients to change lives.

And so we wanted today to bring up some folks who are exactly the sorts of clinicians, the sorts of treaters who will ultimately be the folks who interact with our drug and with the patients who can benefit.

So I'll let everybody introduce yourselves, starting down here with Brittany, and we'll go from there. And yes, we can ask these around as we need to.

Hi, everyone. First of all, thank you so much for being here. I know you have many other obligations, but the fact that you all care about my patient population speaks volumes. My background is I trained in Boston at Mass General McLean Hospital in psychiatry and just as much in psychotherapy.

And then I did an addiction psychiatry fellowship at the Medical University of South Carolina. And about 10 years ago, I felt forced to become an entrepreneur and start my own practice because the way I was seeing psychiatric care delivered in the community and in academic centers was not consistent with my values of holistic care where we're not striving for symptom reduction, we're striving for patient wellness and ideally to work myself out of a job. And so I currently own a large private practice. We have around 30 clinicians and 3 treatment centers. And I've accidentally become an interventional psychiatrist because our traditional therapeutics have failed my patients. And as a result, we do transcranial magnetic stimulation, and we've delivered over 10,000 S-ketamine treatments.

Thanks, Brittany. Hi, everyone. I'm Andrew Penn. I'm trained as a psychiatric nurse practitioner. I trained at UCSF in San Francisco, and we like to joke that UCSF stands for you can stay forever.

And so I'm currently a professor there as well as directing nursing operations for a start-up interventional psychiatry company called Salma Health. In my time at UCSF, I've had the good opportunity of being able to not only treat many patients, but also work in research, psychedelic research, working on interventional studies around MDD with psilocybin and worked on the MDMA PTSD study many years ago.

So I've got -- I've had a chance to sit in the room with folks as they've gone through these treatments and really get to see firsthand what this looks like, which reflects a lot of what Mary spoke about and also have been in psychiatry long enough to really know the shortcomings of our current treatments, which is one of the reasons why I'm here today.

Hi, everyone. My name is Shannon Sarkar, and I'm a licensed professional counselor in Atlanta, Georgia. I recently got my PhD last year in counselor education. So I'm really passionate about helping support counselors in their journey and becoming better counselors. But I got into the psychedelic field in 2022. I started working with a research facility in Atlanta. And my role has been a dosing monitor -- session monitor. And what I do is I sit with the patients and I hang out with them. And it's been really great being a part of all of the different clinical trials that I've seen. And yes, what I'm really passionate about so.

That's awesome. Why don't you keep that microphone? I start with you...

And so clearly, we brought up some folks who maybe aren't necessarily the phenotype that you would ordinarily hear from in an event like this. And we tried to bring folks with different training, different experience, different backgrounds to speak to the perspectives that they have on the world that they occupy today.

So I'll start right there with -- we talk about anxiety and depression a lot, and I tried to talk to anxiety and depression in my little section there. But I'd love to hear that from your perspective, when you think about patients with anxiety and depression, how do you think about the impact on their lives? How do you think about making a diagnosis? And then what does that lead to in terms of treatment options and responses to those treatments?

Yes. It's a great question. And I wanted to mention too that I have luckily been a part of all the different phases for the GAD study. So that's been great. So that's definitely...

Aside from enrolling in our trial, which is obviously the best...

But yes, so definitely work -- I'm mostly focused with the anxiety studies, but have worked with a lot of participants who have come in and have been working -- sorry, have had a history of moderate to severe anxiety, had lots of different treatments that have not really worked in the past. And when they get here to this point, there's -- they get here and they're like, wow, this actually has helped. And it makes me wonder about what earlier access and intervention can really do to help support them.

Yes.

That's great. Yes. Andrew, thoughts on.

Yes. So as a clinician, MDD and GAD are really your bread and butter. I mean it's what you see all day. And diagnostically, as you pointed out, Dan, they're really quite similar. The way you end up diagnosing often becomes what somebody's chief complaint is. If somebody comes in and says, I'm anxious all the time, I can't relax, then it becomes GAD. If they come in, they say, I'm sad and I can't sleep well, you say it's MDD. But otherwise, the overlap is the same. And I've been practicing long enough to when we used to give benzodiazepines freely. Typically, people would walk out of my office with a prescription for a benzodiazepine and an SSRI with the goal of taking them off the benzodiazepine after 6 weeks, probably about 50% successful. Now clinicians won't touch benzodiazepines. But the problem is we haven't really given them an alternative. So people end up suffering with anxiety. They get a little bit of help from SSRIs sometimes if they can tolerate the medications. But in general, there's a big gap in what people need in terms of their treatment and what they're getting.

I'm here pleading for change because I'm actually somewhat embarrassed of my field. When you look at the state of major depressive disorder and generalized anxiety disorder, we're no better at treating it today for first episode than we were over 50 years ago. We're stuck in the dark ages. And when you compare our disease states to cancer, to oncology, we are extremely behind. And that's why I'm so excited by the hope and the possibility of new therapeutics. such as this medication that we're discussing today. Even when there are treatments that may work, for example, we do have some new treatments for major depressive disorder and particularly treatment-resistant depression. They don't fully address generalized anxiety disorder. We have not had a new therapeutic for generalized anxiety disorder in what, over a decade, Dan?

Almost 2, yes.

It's shameful.

Really, really helpful and good thoughts on the disorders. When you think about someone coming in, in distress, so patients come to us because they're in some sort of distress or they realize they're in distress, something usually prompts the first visit. What do you have to offer in terms of feeling better quickly?

Psychotherapy is always #1, but psychotherapy lifestyle changes can take weeks, months and having lost several patients to suicide, I can't wait for that. I need rapidly acting treatment. And that's why if you feel my emotions coming out, it's because I'm thinking of all those patients I've lost over the years because I haven't had rapidly acting treatments.

Yes. As a risk of repetition, what we used to do is benzodiazepens because they would work reliably quickly. But since those have become more surveilled and discouraged, we don't do that so much. So a lot of times, really what's happening is patients are leaving our offices with a hope that maybe 3 to 6 weeks from now, this medication will start to work. And there's another challenge with the anxious population, which is tolerability because patients with anxiety often are highly sensitive to the side effects of medication. And so a lot of times, you get these false starts, where they'll take it for 2 or 3 days, feel some maybe GI distress and say, I can't keep doing this. I got to stop. And so you often end up with these sort of false starts where you never really find out if they're going to benefit from the medication. And a lot of those folks sadly give up on treatment because they feel like if this is how it's going to be, I don't want to do it. And so the idea of being able to get somebody better quickly and not have to continue taking medication on a daily basis would be very appealing to a lot of my patients.

Yes. To add on, from what I've seen in my work, people are already anxious because they've been trying to find so many different treatment options. And once they come in and we're able to provide like a prep session with them and kind of educate them about the process and tell them about how it really does work quickly. It really -- that prep session really sets the tone for the treatment outcome. And yes, I really believe that, that rapid onset is very, very important to the treatment process and the momentum and the motivation.

I mean it's excellent thoughts. I was supposed to remind you all, by the way, that QR code, if you put questions in, I will at least be able to pull a couple up for the panel. So if you have questions as this goes on. And if we can't get to questions today, we will certainly find a way to answer them -- so put your questions in if you've got them. I've got a couple for you already. But let's stick with the thread that Andrew, you opened there about side effects. And I'm curious about the experience both of side effects from drugs in these patients, but also long-term drug taking and loss of efficacy and sort of what the -- what those dynamics are like for the patient experience with what we have available from a pharmacology perspective today.

We have a very fancy term for that in our field. We call it poop out. Tachyphylaxis is a technical term for it. But it's another form of disappointment for patients. So I mean, imagine you feel miserable, something helps you for 6 months. And then slowly, as each day goes by, you notice this is working less and less. And then the question becomes for both the patient and the clinician, what do we do next? And a lot of times, what we do is we change it to a different medication. We hope that this will work better, maybe we augment, but we end up doing this again and again and again. And a lot of times, what we find is that people have less response each time we do this. So the idea of really getting people better, not having them have to take a regular medication and then perhaps they come back a couple of times a year or something like that, however long the durability is it's a paradigm shift. And we've done this to some extent with things like esketamine, but those are fairly short intervals. You're coming in every couple of weeks, maybe every 3 weeks. So the idea of somebody getting 4, 5, 6 months of durability from a treatment is really unheard of in pharmacology.

When I give a patient an antidepressant, the data shows that within 6 months, if they have major depressive disorder, they will have discontinued that medication. And their risk of relapse is exceedingly high if they were even in remission to start, but it's at least 40% within the following 6 months. And so often, in my job, my day-to-day job, it's just this never-ending cycle of constant turnover of more and more and more pills and our patients end up on polypharmacy. And like Andrew said, the longer that we wait to get them into remission, the less likely they are to ever achieve remission or to certainly achieve wellness. Depression is toxic to the brain. It truly leaves a scar. And we need to approach depression and anxiety disorders with urgency that we would oncology because these illnesses truly metastasize not just in the brain, but throughout the entire body. Patients with depression and with anxiety disorders have significantly higher rates of cardiovascular disease, of oncological disorders, of substance use disorders. So we're talking massive morbidity and mortality that's unnecessary if we adequately and aggressively treated these illnesses right away.

Yes, that makes a ton of sense. I mean I'm struck by a study I read forever ago now that showed that the predictor of mortality after an MI when you control for the severity of the MI is depression, right? I mean it's the extent to which that this manifests somatically can't be overstated. Shannon, let's go back to you for a second because you have some experience in the specific area. And then I think for Britney and Andrew will talk a little bit about what does it take to give these drugs? What is it -- what do you need? What's the burden to be in the room? And then we'll kind of morph that into what would it take to have a practice that was ready to do it?

Yes. What would it take? I think, again, I talked about more access and timing, better timing is really important. And I I think doing a lot of patient education and helping clinicians to really help support and help the participants feel really safe in the process is critical. I really believe that the prep sessions, again, set the tone for the treatment process, and I really believe that focusing on helping clinicians support them is really important in terms of tolerability and durability and things like that because you're having the clinician in the room with them, you're not doing psychotherapy, but you are supporting them and providing immediacy in that moment. So I think, yes, having well-rounded clinicians that can really create a safe and supportive environment for them to really let go and experience that could be really helpful.

Yes, go ahead. You take it away. What would it take for a practice to be ready to do a thing like this if they're not today?

I sat with a lot of people in these sessions. And despite what people see on TV, they're less remarkable in the room than you might imagine, right? So a lot of times, it's actually very quiet. I actually look forward to these days because they are a less busy day for me. I'm in one place the whole time. And I get to sort of sit with people quietly while they have this experience. And a lot of times, they actually don't need a lot of intervention. Really, it's more about presence and the ability to be with somebody in that state. And then getting to the passroom, making sure they're drinking water. I'm a nurse by training. So this comes very naturally to me, the idea that we're kind of attending a natural unfolding process kind of like we do in childbirth or death that really we're kind of holding that space so that people can do their own inner work and making sure they're safe. But really, it's not a huge lift in terms of actual labor. I mean seeing a full slate of patients is a lot more work in the course of the day, honestly.

I can speak more to the operational perspective. I started my practice when I had a 3-month-old baby and a 2-year-old daughter, and I had $5,000 and a husband who was a car salesman working long, non, I had no business becoming an entrepreneur, but why not? And we've done it -- and it was all me by myself, but fortunately, I've grown a team, and we've done it very slowly, very intentionally. I've never had to borrow any money with the exception of a real estate commercial loan for the office space. And I found that as long as you do it slowly and intentionally, it's feasible.

And when I added esketamine to my practice as soon as it got FDA approved in 2019, I was so impressed by the data that in the very conservative south, I knew it would be successful and it has. And it's because the treatment truly helps for treatment-resistant depression, unfortunately, not for generalized anxiety disorder. But I've noticed on those days where I'm practicing and seeing a lot of esketamine patients, my levels of burnout are so much lower because I know I have an effective treatment to offer to patients besides just the same pills over and over and over again.

Yes. And so in your practice, are there -- I talked before about 5- to 8-hour treatment days. Are there treatments that you offer that you think have an analog? I mean, obviously, esketamine has a 2-hour monitoring period. Are there treatments that have sort of an analogous kind of full treatment day kind of timing?

Absolutely. We also offer accelerated transcranial magnetic stimulation, and that can sometimes be up to 10 hours in a day. And we're willing to do it if that's the right thing to do for the patients.

Okay. Yes, that makes a lot of sense. And long day, but if it's the right thing, right? So a question actually came in from the audience that wasn't on our list. So you're ready to think on your feet here. The question was about -- and I just didn't think to ask you this when we were planning, but the provider receptivity. There's -- the question specifically said there's this concern that there may be a bottleneck at the provider level as folks who obviously lead organizations and lead your company and Shannon, your experience just doing the work. What do you think about the sorts of providers who would be amenable to participating in treatments like this? Do you see that receptivity growing? And sort of is there a phenotype of provider who might be more or less interested?

I think these treatments will be implemented first in outpatient private practice psychiatry clinics that focus on interventional treatments like ketamine, esketamine and TMS. Currently, there's around 2,000 SPRAVATO treatment centers in the country. And I imagine most of these treatment centers will be very interested. And Andrew and I are both very involved in psychiatric education on a national level. And this year, we actually launched a private practice psychiatry summit to help to educate and equip and prepare clinicians to be able to offer these treatments as soon as they're FDA approved.

So only about 1% of people who would be eligible for procedural treatments in psychiatry get them. And part of that reason -- there's a lot of reasons for that. I mean some of them are insurance and structural and such, but part of it is also the mindset of our profession. Because we've trained, we've become familiar with this 30-minute return visit, med check, make some small adjustments and them back come back 4 weeks later. So there is a paradigm shift that needs to happen.

But I think what's going to happen once the sort of successes of these treatments that -- like the one we're talking about today become more common, clinicians are going to want to be part of that. Because really, if we -- to what you were saying earlier about really being kind of disappointed in our profession that we need to do better. I want to have the same enthusiasm that my oncology colleagues have because when oncology sees a patient, we have all these different options, and we know this is the efficacy data for them.

I want to have that level of enthusiasm for treating the things that we treat. And I think as this grows, that will build because the profession is ready for something new.

And just to add on to that, I think that education is really important too, and providing more opportunities for clinicians to learn about this field because you don't really know -- we don't have access to it in our academic settings very rarely and very little continuing education. And so I think just being very mindful and intentional about education and really providing the data, the evidence-based data that's out there, because I honestly feel like a lot of people don't really know what's out there. And so being able to show it, I think, can really help.

Dan, I also just want to add one thing about the psychotherapy aspect because historically, if you're familiar with the psychedelic space, a lot of times the way this was packaged was drug plus psychotherapy. And it was assumed that, that those 2 were essential to go together. And I think what this data is interesting is that it shows that those 2 actually can be disentangled from each other, which creates incredible improvement in ease of operations because when you're trying to combine, say, even 2 -- because a lot of the studies had 2 therapists, 2 therapists for these many hours, for this many repetitions, it's an operational nightmare.

So to really be able to make -- I think what you've shown is that you can deliver this safely and effectively with a lighter touch that doesn't require that. That doesn't stop people from going out and seeking their own psychotherapy to sort out what they've learned about themselves in that session. But I think what it shows is that the 2 don't necessarily need to be bundled, which will definitely increase the operational viability of this.

I mean obviously, intentional in that regard and by no means guaranteed to work, but now that it has, we're really happy about that. I think we've one -- probably time for one more audience question. And we've been on the provider side of things. But as people who see patients, and we just all got to see a patient together, but what do you think about patient receptivity? When you think about your environment, your practices and your patient population, is this something that patients are going to be the question was really patients be willing to do this when this is -- if approved, is this something that if you were to offer it, your patients would say, sure, let's try it.

I've actually started discussing these treatments and particularly the one that we're discussing today with my patients already because they're suffering now. And it's my responsibility to embed hope into the conversation. And I find it's all about how you frame treatments. I was the first SPRAVATO clinic in all of South Carolina, and there was a lot of skepticism when that launched, but I explained it from a medical scientific perspective.

Again, comparing it to oncology, to chemotherapy, who wants to sign up for a drug that causes you to lose all your hair and vomit, not just for 1 day, but for days on end. It's all about how you frame it. I get to tell my patients instead of having side effects every single day from an oral antidepressant, emotional blunting, sexual side effects, weight gain, you get to choose the day that you have side effects. And you may not have to come back for another treatment for several weeks. And when you frame it in that way, patients are much more receptive.

And my plan already is I'm actually building a brand-new office space. We'll have 12 treatment rooms. We'll work on a Saturday that where patients don't even have to take time off of work. And so if our clinicians are busy seeing med management throughout the week, no problem. We'll do these treatments on a Saturday, and we can treat multiple patients at a time. So even if clinicians are not receptive to offering this treatment right away, I am confident my patients will drive from all over the state. They'll drive hours just like I saw with SPRAVATO back 2019, 2020.

It's hard to follow up.

That is hard to follow up. I'm just amazed by your ambition and your entrepreneurial spirit. It's funny when I first heard about this development process, I was talking to some friends who are involved in psychedelics and LSD for anxiety really because sometimes people associate LSD with anxiety.

And I think it just speaks to the sort of pluripotent nature of psychedelics is that the same drug in a different context, some of the research work that I'm doing in San Francisco with Robin Car at Harris is looking at the importance of context. And I think what this data shows is that this delivered in that context not only is safe, that the side effects are quite predictable and they're manageable in that particular context and that most importantly, that it works.

Closing thoughts, Shannon?

Yes. Just some closing thoughts. Yes, I think that patient receptivity has a lot to do with Yes. Sorry...

Yes. So you're good. Yes. I've seen in my practice that a lot of people -- it goes back to talking about that rapid onset and really wanting something to work faster. And I think that is really what attracts people to this and the patients that I've worked with is that idea that this can work quick because, again, there's been years of trying to find some sort of treatment. And then this rapid onset is attractive, and it makes people feel more motivated and excited and hopeful.

Awesome. All right. Well, please join me in thanking these wonderful folks for coming up here, and they will be around after we finish today. So obviously, happy to answer questions and chat with you. And that is it for me. Now I get to welcome Matt Wiley, who is our wonderful Chief Commercial Officer, and we get to exit the stage.

Well, I'm thrilled that the questions about both physician and patient receptivity to psychedelics came up because we are going to cover that in the commercial section. I am going to spend the next 20 minutes or so talking about commercial readiness and the commercial opportunity.

I'll start with this, that we're building out an infrastructure in commercial that is really built for purpose for the introduction of DT-120. There is not a specific playbook for this type of intervention that's coming to market. Certainly, there are surrogates we can learn from, but this is going to have a very unique market entry strategy associated with it. And so we're building out the organization to fit that strategy. I'm going to walk you through the market opportunity.

Of course, as I just mentioned, the provider and patient dynamics that do favor the introduction of DT-120 and an evidence-based view of product adoption as well as the commercial infrastructure I just discussed. So there are 4 converging forces that really clear the path to the successful launch of VT120.roider readiness, reimbursement precedent that exists today, patient demand for better treatments and our own operational timing, all are intersecting with the introduction of VT-120 if approved.

Providers are primed and ready for this drug coming to market and increasingly so, and we see that in the market research. So physicians have moved from skepticism really to active interest in interventional and psychedelic modalities. And precedents like esketamine have really cleared a path and established reimbursement pathways that we can leverage as we get to market.

Patients want better therapeutics, better treatments, and it's now our time to execute and help those patients get to DT120. Now we talk as a company often about the size of this market. We talk about the 50 million-plus patients that suffer with GAD or MDD. Those are prevalence numbers. What we really focus on from a commercial perspective is that patient population that we can access immediately at launch. Sometimes you have markets that need to be built as you go into market. That's not true here.

For those patients who have been failed by 2 or more therapies, that number represents over 4 million patients. So this is a large opportunity. We're targeting with our market entry strategy, those patients that are most likely to benefit from the value that DT-120 will bring to the market if approved. This is a significant opportunity, a significant market, and we have the right framework in place and the right conditions for the beachhead strategy that you can see here on the right-hand side that will help establish DP-120 in market.

Now that is market entry. As we think about 5 or 10 years post launch, how could this market evolve? And the market can evolve pretty significantly with different levers. So awareness, access and new treatment options should help this market continue to evolve and grow over time. Our forecasts are grounded certainly in the beachhead strategy. But as we help move those patients that are in the community from walking around and undiagnosed to awareness and screening, we believe that we can increase in time the diagnosis rate of GAD and MDD and ultimately, PTSD as well. Increased treatment of mental health disorders, certainly, having drugs like VT-120 in market is going to drive some behaviors.

There are a lot of patients out there that are currently diagnosed, and we see this in claims data that are not receiving treatment today. So new treatments as they emerge may bring those patients back in to see a clinician about treatment. And then removing barriers for access. There are certain treatment realities that DT-120 will face as far as the number of therapeutics that are worked through with the payers. And that could change over time. And as they see the value of something like DT-120 in market, we believe that the access barriers could get eroded even further in time.

Now psychiatry has been a very unique specialty in the fact that this specialty does adopt innovation quite readily. And so we've seen that this track record of embracing innovation from the SSRIs to the atypical antipsychotics, the TMS to esketamine and certainly downstream the psychedelic class. These are interventions that are precise and very differentiated. And certainly, DT-120 should benefit from the paradigm that exists in this specialty. Now every new major psychiatric class has reached multibillion dollar peak year sales. And so we've seen this with the SSRIs, the SNRIs, the atypicals and the glutamatergics more recently. And peak year sales are reaching anywhere between $9 billion to $3 billion at peak.

Obviously, those all the way to the right are still prior to peak year sales. Psychedelics really are positioned to be the next major class of drugs, and DT-120 is positioned to lead that class. Commercial success of each prior class was driven by a combination of unmet need, mechanistic novelty clinician willingness to prescribe. And all 3 factors are present and arguably stronger for DT-120 if approved. Now we use this not necessarily to forecast, but it is a good set of surrogates to gut check our PKR forecast to see even with all of the operational challenges and realities that every single class face coming to market, this gives us good benchmarking data that we can leverage. Now Rob talked about the patient journey.

And for both GAD and MDD, this patient journey is long and arduous. It can take years for patients to actually get to the proper diagnosis. Patients will move through their -- the first intervention, which would be either an SSRI or SNRI and then move into augmentation, switching and often years of trial and error. And this leads to frustration and ultimately can lead to patients either dropping out of the system or continuing to seek that treatment without any benefit of remission. So one thing to note here, and I think it is important, it dovetails on something Dr. Albright said about the GAD patients. I mean, these are patients who -- they're highly comorbid with MDD. Oftentimes, those symptoms get left untreated and unresolved as well. And so having a drug that's pursuing both indications can be very helpful.

The intersection point for DT120 really is where they're cycling and moving DT-120 up into that treatment paradigm to intercept these patients earlier so they get to remission. The patient journeys for both these conditions should not look like this. in 10 years. And we expect that with the introduction of our drug, we can change this. Now when we talk about unmet need, and we can look at the patient journey quite a bit, but we examine this directly with patients. And so in this particular study, patient preference study, 100 patients in this research. And when asked about their current treatment, their satisfaction rate.

And I'm just going to orient you to the top bar here that they were satisfied with how it relieves their symptoms. The #1 reason that they're taking a drug, by the way, is to relieve their symptoms. only 5% were very satisfied. 28% were very dissatisfied with their treatment. So this really does highlight the unmet need and the dissatisfaction in the market. Patients are not getting well, and they certainly need to have something better in the armamentarium. One of the other things that is really important about these therapeutic classes, and I can't overstate this, is that patient persistency is a real issue. So this is a monthly snapshot of branded drugs that are on the market today. And you can see that by month 3, roughly 30% of the patients taking those drugs is eroded. Now this is directly from claims data.

So what we see also on a weekly basis, week 8, week 12 are even lower. So we do see that the persistency is a real issue. And this does a disservice to all 3 constituents. The providers are not able to keep patients on the therapeutic long enough to have a real trial. And this doesn't matter whether it's a retail PO drug or whether it's an interventional drug like esketamine. Second are the patients. And so the patients may be dropping off for a myriad of different reasons, whether it's side effects, whether it's out of patient -- out-of-pocket costs, whether it's insurance issues.

Certainly, lack of efficacy could be one of those as well. This just leads to their frustration. And then finally, for the payers, they're paying for a drug that never really gets the full opportunity to work in these patients. So the most expensive drug a payer is paying for is the one that the patients quit on, and that happens quite a bit. As we think about physicians in this market and the receptivity let's focus first on the psychedelic class as a whole. More than half of the physicians that we've done market research with are positive -- have a positive view of the psychedelic class that's coming to market. And this has been a pretty durable response over the last 3 waves of this research that we've done, this awareness research. And roughly 36% are neutral category and some are hesitant.

We've seen an additional market research how we can move those that are from a neutral category, specifically with DP120 or those that are hesitant into positive on the class. So we do have a plan for that. Now we see that the number on the right actually changed. But this is 58% of HCP surveyed have positive views of DT-120. So this is DT120 specific. And the things that they cite, that's nearly 60%. The things that they cite as important to them, the quick onset of action, the symptom resolution, the durability of response, the unique mechanism of action, those are all things that really resonate with physicians.

Additionally, and this is something that we just learned a couple of weeks ago in our last awareness survey is that the awareness of DT120 and formerly MM-120 has grown pretty significantly wave over wave. So Wave 2 was conducted in 2024, and there was an awareness of roughly 27% from those clinicians. And I believe that the medical team has done an outstanding job working with key opinion leaders. Certainly, our data has been presented in multiple formats over the last couple of years, and the MSL activity is bearing fruit, and we're seeing that rise to 64%. So there is a readiness for DT-120 coming to market.

Physicians are aware that it is coming and seem to have a pretty positive view on the profile. I'm going to share with you some data about our target market. So the target market, and I'm going to talk a bit about our targeting methodology in a few slides. But these are our decile 7 to 10. So this represents 40% of the opportunity that we see. We've prioritized those physicians based on a number of factors through predictive modeling. And what we found in the research, those decile 7 to 10, not only do they intend to prescribe DT-120 when approved, but they also intend to administer it in their practice. That is a very unique finding.

And when we look across to how they're viewing esketamine today and what they actually do with it, 26% of these same prescribers are prescribing esketamine and also administering in the practice. So there is a delta there that we're currently exploring to truly understand this. But one of the hypotheses here is that the prescribers viewing the profile look at this as a single intervention and not a commitment to build out infrastructure to manage that patient every week. And so that may be the difference. And we're excited, though, by the fact that clinicians are this positive and definitely have an appetite to leverage this asset when it's in market.

Talk about the appeal to patients. DT-120, for those patients who have been failed by 2 drugs, the expectation or the likelihood to try DT-120 is 40%. And this is from market research that was conducted last year. When we -- when those patients have failed 3 or 4 different treatment options, that jumps to 60%.

And then those that have been failed by 5 or more treatments jumps up to 65%. So the longer down the pathway of the patient journey, the more failures that they've had to endure, the more likely this patient population will be raising their hand for DP120 if approved. This is encouraging news because there are a lot of them. When we interact with payers, they also have similar response that we see with physicians.

Now this is based on a GAD product profile, but those elements that are important to the payers, rapid onset, efficacy, durability response, all of those things do matter to payers. The first-in-class MOA. So there are a lot of different drugs, obviously, that they can put on formularies and approve, but having differentiated MOA and in this case, is an anxiolytic MOA was very positive for the payers. And then lastly, the onetime oral dosing. So this is very unique for the payers and the fact that they get to pay for the drug and then see how it works over the next 3 months. It also -- and payers get there on their own.

We've seen this in payer advisory boards where they immediately understand that taking a drug like DT-120 would reduce any of the compliance or persistency concerns that they see with other therapeutics. So they get there on their own. So -- when asked specifically how they're thinking about covering both the psychedelic class and specifically DT-120, they are anchoring to what they know today, which is esketamine. And so that is the most logical surrogate. They expect the annual price for DT-120 to be in line with that of SPRAVATO.

And just to kind of put a fine point on that, the range of pricing for SPRAVATO per label, lowest dose, lowest frequency is about $28,000 a year and the highest dose, highest frequency is about $70,000 a year. So that is the range that they're pegging us to. They indicate that FDA-approved treatments will be covered. They don't see any reason why they shouldn't be, but that they would be managed, and they would be managed very similarly to what they're doing with esketamine today.

Typically with step edits prior authorization. Now the chart on the right puts a finer point on this, which is esketamine approvals on prescriptions over the last year, this 2025 data. And you see that whether it's commercial, Medicaid, Medicare, payers are covering esketamine at better than 85%. So this is the type of access we should expect over time. Now this is not going to be immediate, but this gives us a good line of sight into how the payers are thinking and the type of payer coverage we should expect over time. I mentioned I would talk a bit about our targeting model. And our targeting model was very thoughtfully derived.

We used a lot of different inputs that we learned in market research or through additional analytics. We start this model based on where the patients are. So there's no logical surrogate for a drug like DT-120. Nothing has really been launched in GAD in almost 20 years. And having a dual indication really forces us into a patient identification model. That's exactly what we've done.

We've used patient concentrations, those that have failed through multiple medications, those that are complex patients, those that have had emergency interventions. Those are the type of patients that we know are going to be hand raisers at the very beginning, and they've been prioritized in quantities based on physician target.

Now the physician targets are also prioritized by a number of different factors, including adoption behavior. So when we think about the adoption curve, there are innovators and there are early adopters. The innovators, those that are very rapid have a rapid history of adopting new branded therapeutics, they're at the very top of the list with those patients. And then, of course, anyone who is actively doing certain interventions factor into this model as well. So we get the best of all worlds here. This gives us a very nice map to deploy a sales team towards. But that's not the only support mechanism we're going to have for clinicians and patients in the field. So field sales is obvious.

We will have reimbursement support as part of the field apparatus and site of care support as well. Our philosophy is that we want high-touch partnership-oriented touch points with our clinicians is very similar to how we conducted our clinical development program. We also intend to launch a hub model. This is a comprehensive model that's designed specifically to remove friction in any of the process. So whether it's REMS management, benefits investigation, prior authorization support, affordability support for patients and, of course, case management and how the drug gets to the clinician.

All of that will be handled through a hub service model that is designed specifically to accelerate the process from prescription to drug in patient. Access barriers are known risk. And so we are putting this model in place to ensure that we can neutralize them to the best of our ability. I'm going to end here, and you've seen the chart on the right before. Using the esketamine surrogate, for every 100,000 patients, you're looking at a potential gross revenue of somewhere between $3 billion, almost $3 billion and $7 billion.

Now the way I like to look at these things is based on a 4.2 million patient TAM for every share point is roughly $2 billion in gross revenue. This opportunity is not something we take for granted. It's going to be earned through flawless execution as we get ready to market the drug. And so we're working in concert with our Phase III readouts and with the regulatory pathway to ensure that we have the right commercial execution to get us to this launch effectively. And that kind of leads us back to where we started. Execution is key, and we're committed to doing just that.

And so with that, I'm going to hand over to Brandi Roberts, our CFO.

Hi, everybody. I'm the shortest of the team. Before we get to Q&A, I wanted to talk about building long-term shareholder value. You've heard a lot today about what we've been focused on over the last 5 years, and we're tremendously proud of the value that we've built to date. You've heard about our scientific rigor, the unmet need that we are trying to address, the significant progress we've made on our clinical trials and how we're building out our commercial strategy.

And we really look at this as the tip of the spear. We believe that there is long-term value to be created, and we are excited about what comes next and what we're focused on over the next few years. I did want to take a moment and talk about one of the key drivers of our strategy and building long-term value, and that is really our layered IP strategy. As a new chemical entity, DT-120 is eligible for 5 years of exclusivity, and that would be extended by 30 months if a generic were to try to come and look at one of our patents. And so that is one level of our IP strategy. But we also have a robust patent protection that goes across composition, formulation and methods of use with issued patents that extend into the early to mid-2040s.

And we continue to look for ways to expand our patent portfolio as additional insights emerge. And so we're even looking for ways to extend that time period even further into the 2040s. So very excited about what the team has done here to make sure that we are protecting our core asset, and we have done this in a multilayered approach. In terms of takeaways and what I really want people to leave with today, again, we've talked about a lot of the scientific rigor that has been put into our approach to date.

We believe that these are significantly large market opportunities. We know that patients need better options, and we have the ability to do this at scale. And starting with GAD, obviously, we've talked about GAD, MDD and now PTSD. But with GAD, we have the ability to have the first drug approval since 2007, and that could be a very, very big change. You've heard from the panel today about how patients with GAD have struggled. And so we believe that we have a significant ability to impact the market and make a significant impact across psychiatry. We're incredibly well positioned for success. We talked about our compelling Phase IIb results, the rigorousness of our Phase III program and how that's been put together, how we think about differentiating ourselves in terms of our strategy and the indications that we've pursued as well as the execution of those clinical trials.

And we've developed an experienced incredible team that knows how to get this to the next level. And so when you think about what to watch for over the next 12 to 18 months, we've got multiple anticipated 2026 readouts coming soon. I've been very excited to say IMerge data coming later this quarter, followed with VOYAGE in early Q3 and then PANORAMA in late Q3. So in the next 6 months, 3 very big top line data readouts that will really inform the strategy of this company moving forward. Obviously, we're still very focused on the ASCEND study execution. So more to come there.

And then the evolution of the commercial opportunity as we talk more about that as we get to our data readouts. Really, the value of this company is done by looking at 2 key areas. One is the clinical and regulatory execution. And so thinking about our top line data readouts for our 3 studies as the next upcoming events there. But in parallel, also that commercial strategy and making sure that we're taking into consideration all of the items that will make this a tremendous success commercially if we are approved and the data supports that. And so we look forward to continuing that value creation over time, and we look forward to taking some Q&A and making sure that we've addressed everything. I think you guys would say that we developed a very robust schedule today. We've covered a lot of ground, but we want to make sure that we can get to Q&A as well.

Before I do move to that, I did want to note that after we're done, there is an on-site dosing room. So we've locked one up so that people can see what that looks like. It's on the other side of the lobby of where people entered. And then we do would love for people to stay for lunch and be able to continue to ask questions. So with that, I will take it to the Q&A that's come over the Internet first, and then we'll also take some in-person questions, but I would like to invite the management team up for Q&A. QR code just in case you want to put them in online as well.

All right. So I wanted to thank everybody for putting in Q&A. A lot of them we did go through as we went through the rest of the information during the prepared remarks, but I did want to get to one that was talking about coordination across multiple agencies as we look to regulatory approval. And the question was, how is Definium engaging at the policy and advocacy level? How do you work with the different industry coalitions, patient advocacy groups and the policymakers in Washington, if we could go through that a bit.

I'll start there. We've spent a lot of time over the last several years building awareness. I think each of us has spent time in state capitals and in D.C. having these conversations. And of course, we saw this past weekend, the highest office in Milan commenting and taking action on that. So we have yet again tried to lead the way in this and be fairly thoughtful, right, not take strategies that would uniquely benefit us at the cost of patient access, but really opening up the field. We have ways of winning.

We want to win on our execution. We want to win on the strategy that we're pursuing. We want to win if we have the best drug. At the end of the day, these patients need as many options as we possibly can. And so one of the ways we've been doing that is through cooperation with other organizations to build awareness, to work with patient advocacy groups. We've done a lot of that, of course, ourselves as well.

We had a lot of -- again, a lot of success in building those coalitions and building that awareness and having these conversations across the board at every level of government and every branch of government have been really encouraged by where we are today and what that means for the future. Again, I think whether we talked about our organization, the opportunity or about policy and advocacy, the reality is we are just getting started.

Sitting here today, I think a lot of folks don't -- can't sort of see around the corner in the future, really appreciate what we believe is the opportunity. And we are going to do everything within our power to make that opportunity maximize and come into the world in a way that when we look back 10 years from now, we're in a better place than we were. These patients are in a much better place, and it's going to require everybody.

The fact that -- the fact that there's that widespread recognition that we can go into any office in D.C. and have these conversations. I don't know that 10 years ago, we were there. So this moment has converged in a way that uniquely gives us that opportunity to do this the right way and do this with a really, really ambitious goal.

Great. Another question that came in was related to our expectations for the EMERGE data readout. And the question was, should we expect similar types of data for the GAD readouts as well?

Yes. The primary outcome is 6 weeks on the MADRS for MDD and 12 weeks on the HAM-A for GAD, and that will be the real difference between the 2.

Okay. Kind of following that again, can you talk a little bit about what the NDA strategy would be and what we're thinking about currently?

What I'll say is that we opened our IND in early 2022. We will have our Phase III studies in hand along the time lines we've been talking about today for 2 studies in GAD and 1 in MDD by the end of the third quarter of this year is our expectation. That is moving at a remarkably fast pace in development. 5 years start to finish in the development program is an industry standard that we've heard even Lilly talk about aspiring to.

And so for us to be able to execute on that just speaks to how we approach these these problems. When there's an urgency of need and there's a magnitude of need like we face, we don't sit on our hands in anything we do, and we're going to approach our NDA just the same way. We've got an incredible team. We all spend some time with him at lunch, leading that charge, leading the way, who led some of the most important approvals recently in psychiatry, and they're going to hopefully have the opportunity to do that again if we deliver high-quality data later this year.

All right. Next one is related to PTSD. And can you talk a little bit further about the confidence that you have in going into PTSD and how you came to that?

Yes. I mean -- so PTSD is obviously sort of the third leg of the stool of neurotic illness. And we really -- when we think about these illnesses, and I showed you a little bit before about the temporality of them. But often diagnosis isn't just temporality, it's what the patient says about their experience of their life.

And so as over time, the just definition of PTSD has expanded in recognition of the fact that us setting very high and arbitrary standards for the amount of trauma it should take for someone to be sick as a result, we've been able to broaden that disease definition. But of course, what happens when you broaden disease definition, you get more overlap between those definitions at the intersections. And it is that overlap that in part gives us such high confidence -- there's obviously a deep historical research with LSD that provided us the confidence to start this project in the first place.

But the accumulated evidence that we see -- and I'll say at a somewhat more subtle level, the sort of change that people experience in our studies, and you saw a patient describing that isn't one of a specific symptom got reduced, right? When you treat someone with an SRI or an SGA, a second-generation antipsychotic, the experience is one of suppression. I feel less of X. Now if X symptom was very disturbing to someone feeling less of it, of course, is a good thing.

People tend to also feel less of everything. And Brittany talked about emotional blunting before, which is absolutely something we see with suppressive treatments. But it's the description of life feeling different. that gives us such broad transdiagnostic confidence. And that speaks to the why as well, which is that though there is a 50% to 70% overlap between GAD, MDD and PTSD regardless of the source of the trauma, we really thought it was important to get out there and work on true claims in PTSD for those folks who aren't sitting at the intersection or for the folks who understand their PTSD to be the primary source of their distress so that clinicians and patients can have confidence in treating that diagnosis as the primary diagnosis as well if we're able to be approved in the indication.

All right. I'm going to give one to Matt. Can you talk about the SPRAVATO learnings and how that might impact commercial strategy as we progress?

Sure. I mean there's a lot to learn from different surrogates and esketamine is no different. Certainly, having clear road maps for what to expect for clinicians, the reimbursement pathways, et cetera, are really important. Having that hub model in place will be very important at launch to reduce any friction. There's a lot of friction early in the process with esketamine. And so that's a key learning.

There's a lot of good that has come out of the surrogate. And so we also are leveraging that the experience that payers have had with esketamine Reimbursement pathways that have emerged give us some confidence. For instance, pursuing a permanent J-code post FDA approval is one of those. J&J received their permanent J-code in January. That's an encouraging development for us as well. And so these are things that clearly, we leverage.

We leverage the best of all worlds and ketamine is just one of them. But certainly, we have learned from what they've done extraordinarily well and some things that we believe that we can improve on when we go to market.

I'm going to overlay one other thing, which is more philosophical. But when...

A trap that has so often fallen into is being reactive to a world that does exist without realizing the world can and wants to change. And whether you talk to patients or providers or anyone who is involved in actually getting drugs to patients, the need is there, the desire is there, the mechanisms are there to actually make a different future possible.

When that is the case, it is a mistake to simply look at the world today and say, we must fit into that box. If that was all we could do, we would be left in the current state, we would never improve. And the philosophical learning, and I think this is where we've seen a correction happen that has put us in this world today where we see all of a sudden a rapid expansion of centers and volume and everything with SPRAVATO is a new world coming into being, right? When SPRAVATO first launched, the number of clinics that exist today didn't that drug was not positioned to be in the market that it is in today.

And so while, yes, there are certainly things we will leverage and can leverage, not only from SPRATO, but from the recognition and embrace of the potential for treating psychiatric disorders, the way we approach these problems and the way we approach everything is to not be constrained by what has been, but to see into the future of what we think is possible and what we can invest in to make that happen.

All right. The next question is a little bit more color on the Panorama sample size reestimation. And so looking at the updated end of 200, could you talk a little bit about your thoughts in terms of the nuisance parameters? And if any of them were to worsen a little bit, how you look at the evaluable end for Panorama?

Well, one important feature, and Dan certainly can add some commentary is that while we, of course, in the conduct of studies, there's always a sort of temporal mismatch between when you have learnings and when you can react to those things, right? As I said, the new target is 200. We've already exceeded that target.

And so we've stopped screening patients, but have a number of patients already there, too. So we'll even accrue further patients, we would expect as we get to the end of enrollment over the coming weeks. So the numbers we show, of course, will vary almost certainly, right? The things that you learn halfway through a study are never -- or very rarely the exact same. But we've gotten to a point of enough evidence. And why we do the sample reestimations is when we do is that the learnings we've had to that point gives us reasonable confidence that we're in the right area.

The other thing is that the way the temporary estimation, of course, is a blended model of all of the patients. And so there will almost certainly be variances have lower distance parameters as well, right? When you unpull the data, you get rid of the variance is explained by the intergroup differences. And while that typically isn't significant, it does tend to drop the individual group and then the unblinded pool variance that you see at the end of the day. And so there will be undoubtedly some degree of wobble, but we feel quite confident.

I think the thing that -- again, somewhat philosophically how we approach research, sizing studies and doing studies that are statistically significant but are clinically meaningless is in no one's best interest. It's a bad use of capital. It's a bad use of researchers and everyone's time because really, if we're not going to have something that is meaningfully different that can actually be beneficial, showing that a 1-point separation was statistically positive doesn't mean a whole heck of a lot.

And so we've sized these studies and where we are today, where we expect to be in enrollment across all the studies we're conducting give us a high degree of confidence, right, really a lot of comfort that even if we see -- if we just see a clinically meaningful result that it should translate into statistical...

I don't know if you want to add.

I think the only -- we're like switching roles today, and you're being philosophical, and I'm going to talk about numbers for a second. The 200 was a protocol-specified edge of what that analysis could lead to. So we didn't -- we're not like cutting to the bone here and risking statistical significance. If there weren't that protocol-specified sort of minimum that we could have gone to, we could have gone quite a bit lower based on those nuisance parameters. So we're very confident that we're preserving not only the power to detect, as Rob says, maybe a clinically less significant result, but we are extraordinarily well powered to detect the clinically meaningful results that we anticipate in that study.

Okay. One more on EMERGE data. Can you expand on some of the secondary outcomes that you would anticipate putting out at top line?

Yes, absolutely. So like I said, other time points and clinical global impression is one of our prespecified secondaries. And so we will absolutely be able to show you multiple time points on both the MADRS and the CGI.

All right. I wanted to open it up for any questions in the audience. Andrew?

Andrew Tai from Jefferies. So in your Phase II paper in the anxiety study, I think we noticed that maybe 75% of your patients on the 100-microgram dose had comorbid depression, which I think justifies why you're pursuing MDD. So when EMERGE data reads out first, will you -- what percentage of those patients will have comorbid GAD for the investor community to have comfort or read across to read across to your Phase III studies?

I wasn't supposed to give it away.

So we will certainly provide you data on comorbid diagnoses. I think the really critical thing to understand about comorbidity in these studies is that we needed to define 2 separate patient populations, right? So that from a regulatory -- everybody knows about the overlap, that's no mystery. From a regulatory perspective, it is really important to have distinctive populations. And historically, for MDD studies, and certainly this is the current standard as well, you're treating people in a current major depressive episode, right? To do an MDD study of people with a history of -- right, once you have a major depressive episode, you have MDD. And so to treat people with historical depressive episodes, not in a current episode wouldn't make a ton of sense.

Similarly, in the GAD study, to treat people in a major depressive episode doesn't make sense, right? When someone is actually in a major depressive episode, that becomes the primary diagnosis. So in the major depressive disorder studies, people are definitionally in a current major depressive episode. In the GAD studies, regardless of history, they are not. And we'll provide data on comorbidity.

But epidemiologically, based both on the construct of the disorders and just what we know from epidemiological studies of overlap, we expect to find a 50% plus level of comorbidity. All that said, the conversation with the agency, right, these protocols all go to the agency. So they know how we're defining these populations, and we have buy-in on the definitions of the population.

Okay. More questions. Paul if I I was going to say, Paul.

Paul from Stifel. Kind of a question on the same tune of comorbidity. When we've talked to clinicians who use PRAVATO today, they often treat patients who are more complex on average and most of the GAD patients tend to also have depression. So if you get a label for depression, how do you think about that changing the forecast of the drug within that population, given that they're already sort of, I guess, incorporated in the GAD forecast?

And then separately, commercially, do you think there's a way you can change the referral pattern to get some of these, I guess, GAD only is more of an oversimplification, but like primary GAD patients that are in a PCP practice or somewhere else to actually get to treat -- get to go to one of these centers?

So as it relates to the comorbid patients as part of our forecast, that's accounted for. We certainly see overlap. The overlap is over 50% per prevalence, but what we see in the actual claims data is somewhere around 35% to 40%. So we do account for that. And as we think about the type of patient that is going to be a hand raiser early, they are the more complex patient. They are likely more comorbid with these 2 conditions. So that's a patient population that we feel will be in our sweet spot initially in our beachhead. As it relates to the referral patterns from PCPs, our targeting model, our beachhead strategy is really focused where the patients are today. And that is a purposefully designed approach.

Our top 5 deciles, we're going to get to 50% of the patients. They have been prioritized by, again, those physicians that are most likely to prescribe and those patients that are in the highest volume in those practices that have these comorbidities as you described and also fail through multiple therapeutics. That's where we start. Certainly, downstream, we can examine additional opportunities to drive referral patterns and to help these patients that are struggling in primary care get to a psychiatrist specialist to help them get access to this treatment.

And I might just add that for patients, the sort of, let's say, community patients who never had a major depressive episode, just anxious, we not had a lot to offer them. Talking about Cymbalta is the last time anyone even got a label and Cymbalta was not aggressively marketed for anxiety. And so the last time we're talking almost 20 years, it will be 20 years since we really had a pharmacological intervention to offer these folks.

Meanwhile, you can't read about benzodiazepines without reading about their harms in both the context of the overdose epidemic and increasing sort of accumulating evidence for the risks of long-term benzo use. So in essence, nothing new brought to them and being barged with the message that the thing that might make you feel better at least transiently is really bad for you. So while we obviously need to target the launch somewhat narrowly, we can very reasonably expect that for these anxiety patients who've had nothing new in a really long time, there will just be such.

All right. I'm going to go to Gavin.

I'm going to stand up so you guys can see me.

All right. Thanks for putting on the session. This is really great. On the end of session tech list and the discharge period, what do you think you need to demonstrate in the Phase IIIs for the 5- to 8-hour monitoring period to be viable? Like there's probably not a hard cutoff, but hypothetically, if 0% of patients are ready for discharge at 5 hours versus 70% at 5 hours, that could theoretically be a different regulatory scenario. So I'm curious how you guys are thinking about that.

Yes. I think it's exactly the point. There's not necessarily a bright line. When we're talking about drug labels and REMS, which are, of course, an extension of the label are intended to set the minimum conditions for safe and effective use of a drug, requiring physicians and requiring patients to sit around for maybe minutes, but certainly hours after the effects of a drug have resolved is not a thing we have seen happen in drug labeling ever. We have -- we talk about volatile anesthetics, people lose consciousness from life support effectively, cut open tie back together and thin out the door as soon as they can know who they are, where they are and they can ambulate out the door. That sort of framework exists in medicine today. And so while there is not certainly a bright line, we need to build evidence to show the magnitude of patients and what that additional burden would be, right?

If a drug label were to say that everyone has to stay in a clinical setting for much hours past when the symptoms are resolved, an undue unnecessary burden being put on both patients, providers and our health care system to pay for people to sit around for no benefit. And so we're, of course, going to be looking at every which way, the number of patients that are cleared at a certain point of time. And if it so happens that no one is clear to go at hour 5 or 6, then we'll tell you that, and that's the world we will live in.

And I think what we've seen both from our sites and from providers and all of our research is that there's -- we heard it 10 hours for concentrated TMS. It's not a problem, right? We're going to be able to work with wherever we land with this, particularly in a setting where patients can come from much further because they're not required to come in once a week or once a month, hopefully, right? But at the end of the day, if we see a majority of patients are clear to go at a particular point in time, it's hard to argue that, that isn't a pretty clear compelling set of evidence to say, yes, beyond that, there's going to be some individuals who need more monitoring, but not on average, not for your average patient is going to walk in the door.

That's fair. And are you planning to show this data with the top line results also? Absolutely.

All right. I so apologize. We are at time, but we will be available over lunch for additional questions. And I just wanted to turn it over to Rob for some closing remarks.

Yes. I just want to thank again, everyone, for being here today. And many of you have, as I said at the outset, have both spent your time with us and supported and been a part of this. And no matter who it is and what role we're all playing in this, the ability to actually make a difference is a remarkable responsibility and something we take incredibly seriously in terms of how we operate, what we do and what we aspire to do. So thank you for being here today. Thank you for being a part of this as we go forward. And coming up in a few months here, we'll have some hopefully really exciting data set to be sharing with everybody.

Thank you.

Good afternoon, and welcome to the Definium Therapeutics Full Year 2025 Financial Results and Business Update Webcast. [Operator Instructions] The webcast is live on the Investor and Media section of the Definium website at definiumtx.com, and a replay will be available after the webcast.

I would now like to introduce Gita Jain, Head of Investor Relations of Definium. Please go ahead.

Thank you, operator, and good afternoon, everyone. Thank you for joining us today for a discussion of Definium's full year 2025 financial results and business update. Leading the call today will be Rob Barrow, our Chief Executive Officer, who is joined by Dr. Dan Karlin, our Chief Medical Officer; Brandi Roberts, our Chief Financial Officer; and Matt Wiley, our Chief Commercial Officer. An audio recording and webcast replay for today's conference call will also be available online as detailed in the press release announcement for this call.

During today's call, we will be making certain forward-looking statements, including, without limitation, statements about the potential safety, efficacy and regulatory and clinical progress of our product candidates, our anticipated cash runway and our future expectations, plans, partnerships and prospects. These statements are subject to various risks such as changes in market conditions and difficulties associated with research and development and regulatory approval processes. These and other risk factors are described in the filings made with the SEC and applicable Canadian securities regulators, including our annual report on Form 10-K filed today.

Forward-looking statements are based on the assumptions, opinions and estimates of management at the date the statements are made, including the nonoccurrence of the risks and uncertainties that are described in the filings made with the SEC and the applicable Canadian securities regulators or other significant events occurring outside of Definium's normal course of business. You are cautioned not to place undue reliance on these forward-looking statements, which are made as of today, February 26, 2026. Definium disclaims any obligation to update such statements even if management's views change, except as required by law.

With that, let me turn the call over to Rob.

Thank you, Gita, and thank you, everyone, for joining our call today.

We are incredibly excited to share today's updates as we rapidly approach our anticipated pivotal readouts for lysergide tartrate or DT120 ODT in generalized anxiety disorder and major depressive disorder in the months ahead. The momentum is palpable both across our development programs and in the world of psychiatry as we prepare for the adoption of psychedelics as potentially transformative new treatment options. We continue to believe in the potential of DT120 ODT as a best-in-class product candidate. And over the past year, our team has yet again set the standards for scientific rigor, efficiency and thoughtfulness and execution.

As I reflect on 2025, I could not be prouder of our team and the progress we have made. Over the course of the last year, we rapidly progressed our late-stage pipeline, significantly strengthened our balance sheet and continued to expand our world-class leadership team and Board of Directors to drive our next phase of growth. Through ongoing engagement with the FDA under the breakthrough therapy designation program, we reached alignment on many key aspects of our development and submission strategy, positioning us to maximize the speed and efficiency of our NDA submission for DT120 ODT, subject to positive trial readouts later this year.

Our commercial strategy and organizational readiness have mirrored these R&D successes with the addition of key commercial leadership led by Matt Wiley, who joined as our Chief Commercial Officer in March 2025. We've seen strong engagement across the spectrum, positioning us to deliver on our aim to yet again define the standard of excellence in the adoption of psychedelics. We began 2026 with the launch of Definium Therapeutics, a refreshed brand that reflects the evolution of our company and our leadership in psychiatry.

Our differentiated strategy grounded in disciplined execution, scientific rigor and an ambitious view of the impact we can drive positions us to develop scalable, accessible treatments and drive long-term value for our shareholders. With 3 Phase III readouts expected in 2026, the first of which is just months away, we expect the year ahead to be a pivotal one, both for Definium and psychiatry at large. Our goal is clear: to address the urgent need for a new class of drugs that can offer meaningful relief to the millions of people who are living with GAD and MDD, disorders that have long been underserved by treatments with high burden, moderate efficacy and often poor tolerability.

Building on our strong dose optimization Phase IIb study, which was published in JAMA last September, our clinical program for DT120 ODT consists of 4 pivotal Phase III studies, 2 in GAD, the Voyage and Panorama studies, and 2 in MDD, the Emerge and Ascend studies. I'm pleased to share today that Emerge, our first pivotal study in MDD, is fully enrolled, and we anticipate delivering top line data in late Q2. And while Emerge is the last of our 3 ongoing pivotal studies to be initiated, we could not be more excited to share this readout first across our Phase III programs.

This sequencing both provides the opportunity to establish evidence in a second major market indication and enables us to engage with FDA with ample time to explore potential opportunities for accelerating our regulatory submission strategy for the MDD and GAD indications. We've also made significant progress in launching Ascend, our second pivotal study in MDD. Our first sites in Ascend have been activated, and we anticipate first participant dosing by early Q2. On to our GAD program, we continue to see strong enrollment across Voyage and Panorama.

Enrollment in Voyage is approximately 80% complete. And based on the enrollment rate in current queue of patients, we expect to conclude enrollment in the coming weeks with top line data expected in early Q3. I'm also happy to share that with the preplanned blinded sample size re-estimation is complete with no required increase in sample size. Dan will be sharing further details on the sample size re-estimation in a few moments. Enrollment in Panorama, our second Phase III study in GAD is rapidly progressing, and we remain on track to deliver top line data in the second half of 2026.

We plan to provide a further enrollment update and to disclose the outcome of the Panorama blinded sample size re-estimation at our Investor and Analyst Day in April. Our team remains focused on delivering high-quality data across our Phase III studies, targeting 2 of the largest and most impactful indications in psychiatry. We continue to believe in the best-in-class potential of DT120 ODT and are dedicated to the scientific rigor and disciplined execution that has defined our organization and successes to date.

With that, I'll turn the call over to Dan to share additional details on our clinical programs.

Thanks, Rob.

We remain highly encouraged by the enrollment trends we are seeing across our Phase III GAD and MDD studies. We've been spending a lot of time with our sites and investigators, and there is a high degree of excitement and engagement as we get closer to delivering top line data. As Rob mentioned, we are especially excited to deliver Emerge as our first pivotal readout in late Q2. While our Phase II Montgomery-Asberg Depression Rating Scale, or MADRS, results in GAD have given us great clinical confidence through the design and execution of Emerge, we have not previously had the opportunity to establish the efficacy of DT120 in a dedicated MDD population with patients in a major depressive episode.

While GAD and MDD are substantially overlapping disorders, MDD is defined as an episodic illness with periods of euthymia or normal mood interrupted by major depressive episodes, which are characterized by dysthymia or depressed mood that must persist for at least 2 weeks and may last many months. GAD describes and is defined by a more continuous state of heightened anxiety. In our GAD program, starting with Phase IIb, we demonstrated DT120's remarkable ability to improve this continuous background condition, while our MDD program is intended to demonstrate the same effect on the course of major depressive episodes.

Taken together, these data suggest that if approved, DT120 may represent a data-driven evidence-based clinical choice for providers and patients with the potential to improve patient outcomes, whether the patient is currently in a major depressive episode or not. Each of our 4 pivotal studies across GAD and MDD is comprised of 2 parts. Part A, a 12-week randomized, double-blind, placebo-controlled parallel group period, assessing the safety and efficacy of a single dose of DT120 ODT versus placebo, and Part B, a 40-week extension period with opportunities for open-label treatment. The primary endpoint in our MDD studies is the change from baseline in MADRS score at week 6 between DT120 ODT 100 micrograms and placebo.

The MDD trials were designed with 80% powered to detect a 5-point improvement over placebo on this endpoint. The primary endpoint in our GAD studies is the change from baseline in the Hamilton Anxiety Scale, or HAM-A, at week 12 between DT120 ODT 100 micrograms and placebo. The GAD trials were designed to have 90% powered to detect a 5-point improvement over placebo on this endpoint. Our Phase III studies are modeled after our successful Phase IIb study in which we observed placebo-adjusted improvements of 7.7 points on the HAM-A and 6.4 points on the MADRS at week 12.

In the context of other approved pharmacotherapies, which have typically shown a placebo-adjusted effect of less than 4 points on these endpoints, we believe DT120 has the potential to be not only a best-in-class product among psychedelics, but among anxiolytics and antidepressants broadly. And while placebo-adjusted changes are critically important for establishing efficacy, the absolute magnitude of improvement may be a more representative measure of the real-world patient experience. This is where DT120 even further stood out, having demonstrated a 21.9 point absolute reduction in HAM-A scores at week 12, corresponding with a 48% clinical remission rate and a 65% response rate.

In addressing comorbid depressive symptoms, we saw an 18.7-point absolute reduction in MADRS scores at week 12. I'll now recap progress with our MDD studies. Enrollment is complete, and we expect to deliver top line data from Emerge in late Q2. Based on the progress in Emerge, we are moving forward with the execution of our second pivotal MDD study, Ascend. In Ascend, we are targeting enrollment of approximately 175 participants randomized 2:1:2 to receive DT120 ODT 100 micrograms, 50 micrograms or placebo. Our first sites in Ascend have been activated, and we expect to begin dosing by early Q2.

We expect Ascend to continue to benefit from operational efficiencies that enabled the rapid enrollment of Emerge, including the ability to fast track select sites that participated in Emerge and those that are actively enrolling in our GAD program. Regarding our GAD program, we are in the final stages of enrollment in Voyage with completion anticipated in the coming weeks. In Voyage, we are targeting enrollment of approximately 200 participants randomized 1:1 to DT120 ODT 100 micrograms or placebo, while in Panorama, we are targeting enrollment of 250 participants randomized 2:1:2 to DT120 ODT 100 micrograms, 50 micrograms or placebo.

Each GAD study includes a sample size re-estimation that allows for adjustment of the target enrollment based on a blinded evaluation of nuisance parameters. As Rob mentioned previously, we completed the sample size re-estimation for Voyage and determined that no increase in the trial sample size is required. In the initial study power calculation, we assumed a standard deviation of 10 points and a non-evaluable rate of 15% at week 12. Among the first 100 participants who completed week 12, we saw a model-based standard deviation of 6.7 points on the HAM-A and a non-evaluable rate of 10%.

These observations suggest that the study's ability to detect a statistically significant drug effect substantially exceeds the planned power. In fact, if these nuisance parameters were to remain unchanged from the final analysis, this would imply that the study has over 99% power to detect a 5-point difference on the HAM-A and that the minimum difference required to achieve statistical significance would be less than 2 points. Beyond DT120, we are excited to have initiated our Phase II study of DT402 in autism spectrum disorder, or ASD, in late 2025. DT402, the R enantiomer of MDMA, has shown promising prosocial effects with a potentially favorable tolerability profile.

We're developing DT402 to target the core symptoms of ASD, specifically addressing social communication that is central to the experience of the disorder. We believe this program represents another significant treatment opportunity given the high unmet need, the increasing prevalence of ASD and no FDA-approved therapies that specifically address these core symptoms. Having completed a Phase I single-ascending dose study that characterized the tolerability, pharmacokinetics and pharmacodynamics of DT402 in healthy adult volunteers, we dosed the first participant in our Phase IIa study and initial data is expected later this year.

This study is a single-dose open-label design, assessing early signals of efficacy in up to 20 adult participants with ASD. The objectives and endpoints of the study are designed to characterize the pharmacodynamics and clinical effects of DT402 across multiple functional domains. Across our late-stage pipeline, we are making strong progress and rapidly approaching multiple pivotal readouts for our DT120 ODT program. We believe the remarkable profile of DT120 has the potential to be best-in-class among GAD and MDD pharmacotherapies, and we are confident in our strategy and execution to drive the broadest possible impact for the millions of patients in need.

Now I'll turn it over to Matt for commercial comments on DT120.

Thanks, Dan.

As an organization, we are deeply committed to and focused on impeccable commercial readiness for the potential launches in GAD and MDD. Over the past year, we've comprehensively mapped the provider landscape nationwide, and in close collaboration with our cross-functional internal teams, prioritized key states for launch. If approved, we are fully positioned to execute rapidly and with precision. Our vision for Definium commercialization is to deliver a genuinely high-touch white glove experience for our providers, one that extends the collaborative partnership-oriented approach that has distinguished us throughout our clinical development and with our trial sites.

This philosophy has been a key differentiator for us, and we intend to make it a foundational element of our commercial model. We fully appreciate that providers will have multifaceted needs beyond just product information. They will seek clear guidance on REMS certification, regulatory requirements, operational integration and reimbursement pathways. Accordingly, we are building the robust infrastructure and cross-functional teams required to address these elements seamlessly and support providers from day 1. To strengthen our launch capabilities, we've assembled an exceptional commercial leadership team over the past year in marketing, market access and operations.

This leadership team comes with deep experience in navigating complex launches, including experience with REMS and scheduled drugs. Their proven track record gives us tremendous confidence as we prepare for launch. We look forward to sharing more detail on our commercialization strategy at our upcoming Analyst Day on April 22. But stepping back, our message is simple. We are preparing to introduce something meaningfully different. Historically, when new classes of medicines have been introduced in psychiatry, they have generated significant value and delivered multibillion-dollar opportunities.

We believe DT120 has the potential not only to participate in that kind of opportunity, but to improve on what has come before, most importantly, for patients who urgently need more than better.

With that, I'll turn our call over to Brandi to discuss our full year 2025 results. Brandi?

Thanks, Matt.

Research and development expenses were $117.7 million for the year ended December 31, 2025, compared to $65.3 million for the year ended December 31, 2024, representing an increase of $52.4 million. This increase was primarily driven by $44.7 million in higher DT120 program expenses, $9.3 million in internal personnel costs, reflecting expanded research and development capabilities, and $0.4 million in preclinical and other program expenses, partially offset by a $2 million reduction in DT402 program expenses. General and administrative expenses were $48.6 million for the year ended December 31, 2025, compared to $38.6 million for the year ended December 31, 2024, an increase of $10 million.

The increase was primarily attributable to $6 million in professional services and pre-commercialization activities, $3.6 million in personnel-related expenses to support expanded operational activities, $0.7 million in directors' deferred share unit expense driven by our year-over-year stock price appreciation, and $0.5 million in other administrative expenses, partially offset by a $0.8 million reduction in legal and patent-related expenses. Overall, our R&D and G&A expenses for 2025 were in line with our internal expectations as we continue to make significant progress across the DT120 and DT402 programs.

Net loss for the year ended December 31, 2025, was $183.8 million compared to $108.7 million for the year ended December 31, 2024. As a reminder, our net loss can be significantly impacted by changes in the fair value of our 2022 USD financing warrants. During 2025, the change in fair value was $22.8 million, reflecting an increase in our stock price from $6.96 at December 31, 2024, to $13.39 at December 31, 2025. We ended 2025 with cash, cash equivalents and investments of $411.6 million compared to $273.7 million at year-end 2024. Based on our current operating plan and anticipated milestones, we believe our cash, cash equivalents and investments as of December 31, 2025, will be sufficient to fund operations into 2028.

We are pleased to enter 2026 with the financial flexibility to accelerate several key initiatives, including NDA preparation, market access priority activities, market research and KOL education. These investments are intended to support our path to market, and if DT120 ODT is approved, enable a well-prepared and robust commercial launch. We are also encouraged by the continued evolution of our investor base with strong engagement from existing shareholders and growing interest from new investors as we progress through 2025. As we look ahead to a very important year in 2026, our focus remains on disciplined execution, thoughtful capital allocation and advancing our programs in a way that supports long-term value creation.

I'll now turn the call back to Rob for our closing remarks.

Thank you, Brandi.

2025 was a year of bold ambition and disciplined execution. In 2026, Definium is set to deliver some of psychiatry's most important data, highlighting our progress and ambition to bring novel scalable therapies to patients underserved by today's standard of care. With a strong balance sheet and a late-stage pipeline with multiple catalysts in the months ahead, we're excited to continue driving value for our shareholders and the millions of patients who deserve more than better. Of course, none of this progress will be possible without our exceptional team whose passion, commitment and unmatched execution continue to set the standard for our field.

Thank you again for joining our call today. We will now open the line for questions.

[Operator Instructions] Our first question coming from the line of Andrew Tsai with Jefferies.

For this interim that you did, it's very interesting for Voyage. I'm curious in the hypothetical scenario where the DMC asked or recommended you to upsize the trial, what would have been effectively the placebo-adjusted delta for that to happen, give or take? And just to confirm, there were no other scenarios with this interim such as stopping for futility or even stopping for success?

Yes. Thanks so much for the question, Andrew. So this is -- first of all, it was a blinded sample size re-estimation. And so an important feature of that analysis is that we don't ever unblind the study. We don't do any inferential testing. And as a result, we don't actually learn anything about the performance of the 2 groups independently or in relation to one another. Effectively, you can think of it as looking at the right side, right of the plus or minus on the 95% confidence interval to assess the standard error and ensure that the assumptions we made at the beginning of the study are reflected or we don't lose power because we've made the wrong assumptions. And so there was no implication.

There's no learnings or inference that can be derived either from this analysis or for any other outcome of the analysis. But we are certainly excited to see that we're good with the assumptions we made. And if anything, as Dan mentioned during the call, have certainly adequate power at 99% or greater if the current variables hold, nuisance parameters hold. And we're eager to get to the study results and ultimately do that inferential test and look at the performance of 120 versus placebo.

Wow. Okay. And then really quickly, by the time you top line the Voyage data now in early Q3, would you consider piecemealing some of the Part B open-label extension data just to further showcase how durable a single dose of 120 could be? Otherwise, when would you share the open-label portion?

Yes, absolutely. I think one of the things we've been really focused on is, of course, the durability and the response patterns over the course of an entire year. And of course, in all of the studies have been running for quite a while now. And so as we continue to accrue patients who have gone through certain milestones and either events of retreatment or have made it through a fixed interval of time, we'll have, of course, increasing data and increasing confidence in those data to be able to share some insights. So we haven't firmed up a commitment to exactly when we would present Part B data.

So we certainly don't want to get ahead of ourselves, and we present data that we don't feel are representative or that we're not confident in at any time. So we'll certainly be taking a look at that. And as we accrue those data, be it at any of the readouts from the ongoing studies or at another time, we'll have an opportunity to share as much insights as we possibly can about the performance in Part A and Part B.

Our next question coming from the line of Mark Goodman with Leerink.

This is Basma on for Mark. Our first question is on the interim look. Again, have you conducted the interim look for Panorama as well or not yet? And -- or are you planning to do it once you hit 80% enrollment similar to Voyage? And also regarding the MDD, when are you going to plan to do the interim look exactly for the Emerge trial? Our second question is for the GAD readout. What are your expectations regarding the remission rate? What would you consider as a good and differentiated rate versus the standard of care? That's it for us.

Yes. Thanks so much, Basma. So in terms of the interim analysis for Voyage, we, of course, announced that today. For Panorama, our second pivotal study in GAD, we'll be sharing additional details and enrollment updates at our Analyst Day in April. For the 2 MDD studies, of course, Emerge is now fully enrolled and the data -- top line data that we'd be sharing would be the completed final top line analysis from that study. So we're not conducting an interim look on either of the MDD studies as currently. In terms of GAD and the remission rate, I'll turn it over to Dan to maybe comment about our thinking around response patterns and ultimately what drives patient experience and value in this population.

Yes. It's a great question about the remission rate because we've obviously talked about that from our Phase IIb outcomes. I think it's important to note that mostly what we know about pharmacotherapy-induced remission rate come from MDD studies. And in MDD, what we see in SRIs, the first-line treatment that's most commonly used, attributable remission rate in the real world is something in the 10% to 30% range. But of course, it's difficult to necessarily interpret those data because MDD is necessarily a cyclical illness so that when a major depressive episode is resolved, whether with meds or without, then that is a period of remission from those symptoms.

We made some design choices in Phase III for both GAD and MDD, which was to target open-label treatment of the Part B treatments to the threshold between mild and moderate illness on the scales on the HAM-A and the MADRS. So in this case, what we are really looking at is given the availability of open-label treatment in the Part B, are we able to treat people down into that mild or better range reliably with the redosing. So while we're not priority specifying what we would hope for from an absolute remission rate, what we're intending here to do is to get people out of moderate or worse illness and see how well we can keep them in mild or better.

Our next question coming from the line of Evie [indiscernible] with Evercore ISI.

You have Evie on for Gavin. Congratulations on all the progress made this year. It's great to see that the SSRE is now complete. Any color you could provide on enrollment and how it is trending for the second GAD and MDD trial seeing as Voyage data is now expected by early 3Q? And our second question is in addition to the SSRE and variability, can you speak to anything else giving you incremental confidence? Could be something like baseline characteristics, OLE rollover, retention, screen failures or anything like that?

Yes. Thanks so much for the question. So in terms of enrollment updates, of course, with Emerge, our first MDD study now fully enrolled and with data expected in late Q2, we've just been overwhelmed by how fast we're able to enroll that study and how excited we think that represents the field and the researchers who are working on the study have been and are about the potential here. We certainly are, and our team has done an incredible job at executing on these studies. In terms of Voyage, we shared that approximately 80% enrollment, and we continue to see incredibly strong enrollment with our best months yet and we absolutely are seeing the continued growth and acceleration of enrollment across the program.

So for our second study for Panorama, again, we'll be sharing further updates at our Analyst Day in April, but we've been encouraged across the board and really happy with where we are in enrollment in that study. Ascend, we're also, of course, will be starting in the coming weeks. We're really excited to get studies activated really faster than I think even we anticipated and the ability to get studies DEA activated and DEA approvals in place in a matter of just a few weeks has allowed us to really accelerate the start of that second study in MDD. So really across the board, we've been very encouraged by the enrollment trends and where that positions us for 3 pivotal readouts over the course of this year.

In terms of incremental confidence, we won't be commenting on specific variables or what we're seeing in those variables. So we are extraordinarily confident in the profile of 120. And as Dan mentioned during his prepared remarks, with the observed parameters that we saw in the interim analysis for Voyage, that would imply a quite high, over 99% power to detect a 5-point difference and less than 2 points required in terms of the separation between the groups in order to achieve a statistically positive result if those nuisance variables are the same at the end of the study as they were at the interim analysis.

So that gives us quite a bit of confidence if the study only has to show a couple of points difference to get a statistically positive outcome, of course, we would hope to see better than that. We think that a 4-point difference between the arms is something we'd really like to see that would really stand out as the best drug we've seen and the best results we've seen in GAD to date. And so we're certainly excited to deliver those data. But all that we're seeing across all of the studies gives us continued confidence in the program and positioning us really well for these readouts later in the year.

Our next question coming from the line of Brian Abrahams with RBC Capital Markets.

Congrats on all the progress and looking forward to a very exciting data rich year. Two for me. I guess, first, you've had some slight changes in the enrollment time lines versus prior expectations in both directions. And I guess I'm curious the impact that has on your views of the addressable populations of patients with these respective conditions who may be interested in a psychedelic.

And then just with the interim passing and obviously, the low variability in dropouts, it sounds like a very narrow delta could still be statistically significant in Voyage. So can you maybe elaborate a little bit more on your latest views on clinically meaningful delta? And really how would hitting stat sig with a smaller delta potentially impact your plans in Panorama as well as how you'd see the drug positioned commercially?

Yes. Thanks so much, Brian. And both great questions. I'll turn it over to Dan to talk about the first one. And just Dan, maybe you can reflect on how we think about these populations and also how these patients, of course, show up in trials and show up for clinical attention.

Yes. It's an excellent question and a good observation. And while the time line changes don't necessarily change how we think about the patient population, certainly, what we know is that in the current environment of psychiatry with the drugs that are currently available, MDD has been a target of both drug development and clinical focus for really the last 30 years or so and left GAD a bit behind with no new drugs approved in GAD since 2007. The reality is that this is a massively overlapping patient population and that while GAD is a more continuous sort of background condition that people live with this experience day by day, and in many cases, for much of their life. And that both makes people not necessarily seek care. They're sort of used to being the way they are, even if it is quite disruptive to their lives.

But it's not an acute change that people notice in their lives as they do when they enter a major depressive episode, which often drive people to seek care. So we're really excited about the opportunity to potentially provide a drug here that regardless of what induces someone to go seek care, whether it's this ongoing state of anxiety or newly developed anxiety or entering a major depressive episode, which represents a real state change for them. The way we think about this is that regardless of the driver of the presentation that we intend to provide a body of evidence that demonstrates that DT120 would be a good choice for the patient. So that gives us some temporal flexibility for people in the course of their lives and in the course of their illness.

Yes. Thanks, Dan. Brian, in terms of your second question about the clinical meaningfulness, it also is a great one. And I think really important contextually, both in terms of that difference and in terms of the overall magnitude of change. I think there is certainly a lot of different approaches out there to these concepts. In our minds, Dan mentioned this a little bit in the prepared remarks, but in the real world, patients, of course, don't get placebo. So while we definitely want to demonstrate as largely a placebo-adjusted response as we can, observing an absolute magnitude of change that stands out relative to the other options that are available, there are always limitations comparing across studies and such. But -- and we think that's an important variable to focus on as well.

When it comes down to that placebo-adjusted change, again, when we're talking about drugs that we believe have the potential to be transformative, we think that should also be reflected in terms of the consistency with which patients are seeing the benefit and the magnitude of that benefit over placebo. And so while, yes, we're very encouraged when we have a low clinical bar relative to where we started and where we powered the study, we absolutely would like to see a change that stands out and continues to stand out as we saw in Phase II. And in GAD, when we look at the landscape of currently approved therapies, not one of them consistently delivers at or above a 4-point delta over placebo in those studies.

And so if we're seeing a magnitude of change that's as large or larger than those and the placebo-adjusted change that's larger than 4 points, it's hard not to get incredibly excited about that in our mind. So while we don't set a sort of bright line on any of these kinds of concepts, we very much are looking for data that impress and data that get us and we think payers and providers and everyone excited about the potential because we certainly believe it's there and hope the data stands up to support that.

Our next question coming from the line of François Brisebois with LifeSci Capital.

A lot of interesting questions, a lot of interesting answers, too. And I was just wondering, so you touched on the 4-point kind of bar that is not a hard bar or anything, but something that you've been mentioning on the GAD side. Can you just remind us, now that MDD will be first, can you just kind of do the same exercise in terms of what you'd like to see and compare it to what's been seen for MDD? And maybe also remind everyone what you had seen previously on the MADRS side in the prior trial and maybe caveats around what you had seen because the trial wasn't necessarily for that originally.

Yes. Thanks so much for the question, Frank. I mean, again, when we look at the landscape of approved products and products that are in development, we continue to be encouraged qualitatively in the research we've done to date. Dan mentioned that we saw is in the GAD population with milder illness. I think we really focus a lot on the severity of both MDD and GAD because those severity are representative of impact on patients and drive a lot of the burden and the value. And so as we think about the response, we think about severity and that overall magnitude of change. And that's again where we saw really impressive results on both symptom sets, on anxiety symptoms and depression symptoms.

So -- and we saw a 6.4-point difference between 120 and placebo in MADRS scores that was starting from a lower point than what we would expect in a dedicated MDD population of patients in a major depressive episode. We'll certainly be painting that picture, I think, more comprehensively as we get to the Analyst Day in April. And I think as we get closer and closer to the readouts, we want to set full context for those expectations and just the realities of that landscape. But when we look at -- roughly, when we look at that today, again, seeing an effect, a placebo-adjusted effect that is greater than 4 points seems quite important.

And seeing a double-digit absolute magnitude of change also seems quite important in our minds. And that's true, especially in the MDD population where taking patients from severe depression symptoms to high, moderate or low severe wouldn't represent a major change in our minds. And so as we think about this readout, we again want to see a large absolute magnitude of change and as large of a placebo-adjusted change as the drug can deliver.

Okay. Maybe if I could sneak in just the last one there. In terms of -- when you do some work on it, you hear a lot of comments around, well, from going from the Phase II to Phase III, it's totally normal to get a smaller delta with placebo. Is that something that makes sense to people? Is there a reason behind that? Or is that just kind of protecting yourself a little bit?

Yes. No, I think the reality is that we certainly -- in historical studies in psychiatry, there are studies at times where that happens. I think where we see -- and we've seen this in schizophrenia, we've seen in a number of other indications as well, where some of the best-performing drugs continue to not see that sort of compression as they progress in development. And so the design changes, operational changes, those sorts of things can have an impact, and that's why we've been so encouraged with our approach in Phase III. And we designed our Phase II program to be exactly executed and designed like a Phase III study, although we thought it critically important to establish a dose response and select the appropriate dose to take into the pivotal studies, which is why we did the Phase II the way we did.

That also means we made minuscule operational changes between the Phase II and Phase III study. So we're virtually doing the same thing over again is just with 2 or 3 arms instead of 5 arms as we did in Phase II. So that again gives us a lot of confidence. And then a number of dynamics in the study design that we think will drive better patient retention through the primary outcome in these studies. Dan mentioned that the non-evaluable rate that we saw in the interim analysis in Voyage was 10%. You compare that to over 25% in our Phase II data, which we think is largely driven by the fact that we're seeing with the Part B, the 9-month extension period, patients have an ability to access open-label 120 if they complete the full 12-week blinded control period. And so all of those dynamics give us a lot of confidence about the operationalization of these studies and give us a lot of confidence as we approach data.

Our next question coming from the line of Pete Stavropoulos with Cantor Fitzgerald.

Nice to see the progress. First one, just curious to hear how you're thinking about a potential filing strategy if the 2 GAD Phase IIIs are positive and if the first Phase III MDD study Emerge is positive, will you complete 2 MDD studies before filing an sNDA? Or is there a reason to wait for the second study?

Yes. Thanks so much for the question, Pete. It'd be premature to comment specifically on filing strategy given that we don't have data in hand. But certainly, we think that the stronger the data, the more compelling an argument that a sponsor can make, and that's true across the board. And so we'll be looking very closely at the data. And if we're seeing an impressive result, both placebo-adjusted and absolute magnitude of change, something that gets us quite excited, we will very much be engaging in those conversations to explore the most efficient pathway forward for both the indications.

Okay. And then just to touch on your earlier stage asset, 402. If you can give us a little bit of color in terms of assessing clinical effect, which scales are key for you? And in your deck and in the PR -- in today's PR, it mentions functional biomarkers. Can you just elaborate on that?

Yes, I'll turn that one over to Dan to comment on...

Yes. Happy to comment on that, and thanks for asking about 402. Obviously, with all the excitement around 120, sometimes we don't get a chance to comment on this as much as we'd like to because we're really excited about the program. We've gotten through a single-ascending dose safety study, which gives us good data for dosing in a single dose paradigm, which is exactly what we've said we've done, which is to bring the drug forward in a single dose open-label paradigm. And the question of measurement in ASD is always an interesting one. You're asking after the scales and the Vineland and other scales that have been used in attempts at approval before, of course, with no approved drugs for the core symptoms of the disorder, the right measure at the right time remains...

It sounds like a very narrow delta could still be statistically significant in Voyage. So can you maybe elaborate a little bit more on your latest views on clinically meaningful delta? And really how would hitting stat sig with a smaller delta potentially impact your plans in Panorama as well as how you'd see the drug positioned commercially?

Yes. Thanks so much, Brian. And both interaction, social communication and the other domains where we think that the drug will be effective. So considering measurement from the outset and very much thinking about measurement techniques that can track along with the drug through its phases of development and ultimately through to regulatory submission if we -- if and when we get there and potentially even measures that could travel with the drug out into the world if it's approved.

Congrats once again.

Our next question coming from the line of Christopher Chen with Baird.

Congrats on the progress. I had a question regarding MDD. So one of the things we hear about SPRAVATO is that it's good at alleviating symptoms of TRD, but not so good at increasing overall productivity of daily life, like just work -- productivity at work, one example. So I know you're measuring a number of quality of life metrics in Emerge, but I'm particularly interested in the WPAI. And so if you don't mind just expanding on your expectations there? And can you provide any high-level color on what you're hearing about how these patients are doing beyond just MDD symptom alleviation? And then I have one more after that.

Yes. Thanks, Chris. I'll turn it over to Dan to talk about WPAI. I guess I'd first say that with the dosing regimen that's required to go into a clinic for multiple hours, multiple or at least one time a week for a long time, being at work is certainly going to be a thing that drives productivity. So a treatment where you don't have to come in infrequently, which is if we're able to establish the same kind of durability as we've seen in trials so far, certainly something that we think would differentiate 120 from anything that's out there in the world today would be a pretty important impact, right? It's -- going to the doctor's office once or twice a week is quite a burden.

And so even beyond the actual measurable productivity, the presence at work and being able to do that is going to be an important driver and certainly something that also shows up in patient satisfaction and overall utilization of the drug we would think. But I'll turn it over to Dan to elaborate maybe on the WPAI.

Yes. The domains that the WPAI look at absenteeism, not being able to make it work, presenteeism being impaired while at work and sort of tries to assess an overall percentage of impairment while at work. And of course, this isn't a primary outcome, and we're not looking to try to demonstrate efficacy overall based on a scale like this. But I think as you observed, this is really important, right, that just having a lower reported set of symptoms or suppressed symptoms doesn't necessarily mean that someone is back able to do the things that they need to do and want to do in their lives.

And we very much are oriented toward the idea that just as we saw in Phase II that the experience of participants after treatment because, of course, unlike SPRAVATO, where the treatment is a continuous intermittent course, we anticipate having long periods of time between treatment if such retreatment is even always necessary. And the way that folks describe their experience post treatment in the Phase II was less about, as you're pointing out, sort of symptom suppression and more about having an outlook that was changed as it relates to the future of GAD, and obviously, as we hope to see in MDD as it relates to sort of the anhedonic or inability to take pleasure in activities that would generally give the person pleasure.

So we are measuring WPAI and other scales of function and participation in life for exactly that reason because we remain optimistic and hopeful that the sort of change that we see with DT120 represents a more whole person change toward a state of what could be called recovery.

Great. That's very helpful. And then just a quick one. Are you collecting time to just -- patient time to discharge data in these trials? And if so, are you seeing anything that may suggest any shifts from that 6- to 8-hour monitoring period?

Yes, it's a great question. And we are absolutely collecting high granularity data. We think it's critically important to have data-driven arguments and a data-driven understanding of what's happening on a dosing day and to ultimately characterize that to inform regulatory discussions. We start assessing. We have a structured set of assessments that we measure on an hourly basis starting at hour 5. And we, of course, observe all patients regardless of the dose or whether they receive placebo through hour 8 in the study. And at the end of the day, we expect to have, again, a high granularity assessment of the different domains and ultimately, the time to which patients are able to be discharged safely, we think, from a treatment session.

So we, of course -- given that we have a number of open-label treatment sessions, we have some insights there, which we can't share quite yet in great detail. We want to again aggregate enough data to feel confident in sharing that before we do so. But certainly, as we progress and as we get to a top line readout, we think it's really important given the nature of these drugs to start characterizing that, something we've been doing with a really thoughtful approach beginning with our Phase II study and certainly being refined and giving us increasing confidence as we've gotten through the conduct of a Phase III program.

Our next question coming from the line of Patrick Trucchio with H.C. Wainwright.

This is Arabella on for Patrick. Congrats on all the progress. We're looking forward to the upcoming readouts. Since Panorama also includes European sites, are there any meaningful differences in diagnostic practice, placebo behavior or standard of care that could introduce additional variability?

Yes, I'll turn that one over to Dan.

It's an excellent question and a good observation. The Panorama study does include European sites. And while there are, as you note, in the practice of psychiatry, regional variations even within the United States, different areas of the country have different practice patterns. And so the diagnostic criteria remain the same, the way they're applied can be different from place to place. We work our way through that by being very highly specified in our protocols. So diagnostic criteria that we use are standard from one country to the next and one site to the next, of course. And the way they're applied is standardized and that standardization is supervised and monitored from beyond the site level that all of our participants have really a 3-part confirmatory set of assessments, only one of which is based on the site assessment.

We have central diagnostic confirmation and central severity confirmation so that it takes that kind of site variability out. Another advantage to the patient population is because we take both in the case of GAD, which as you know, as the European sites and MDD, which hasn't, because we aren't predicating enrollment in our studies on some set of past treatments or having been failed by some set of past treatments, local treatment pattern variation is not going to have an impact on who we bring into the trial. So we are incredibly confident that across sites here in the States and sites in Europe that we're getting the participants who we intend to get into the study. And because we're testing as a monotherapy, of course, we're getting participants independent of what might be local practice patterns for the treatment of these disorders.

Great. And then really quickly, I know we already touched on it, but specifically for GAD, and I know it's still early, if both Voyage and Panorama are positive, would that allow you to file? Or is there any additional long-term safety data or anything else that might gate submitting an NDA?

Of course, it's premature to talk finally about a filing strategy and filing dynamics until we had a final discussion with FDA at a pre-NDA meeting. But based on a really positive dialogue we've had with FDA throughout our pivotal programs, we feel highly encouraged that delivering Part A data, durability data out to 12 weeks is what we need for filing. And so as we get to top line data from these studies, we're already doing a ton of work to get ourselves ready to be in a position to file as quickly as possible and again, try to set that standard for how efficient and how quickly we can go to race across the finish line.

Our next question coming from the line of Ami Fadia with Needham & Company.

Congrats on all the progress. My question was on -- I have got 2. Firstly, just on the MDD program. You indicated that the study is 80% powered to show a 5-point change. And in your GAD study on MADRS, you've seen a 6.4-point change. What I want to understand is from a commercial perspective, in order to be able to tap into a meaningful portion of the MDD market, not just the really -- the patients that are treatment resistant, what type of a profile would you like to see? And then secondly, as you think about the regulatory landscape and how that's changing and the recent FDA stance on [Audio Gap]

[Audio Gap] and flexibility, although we are going to continue to hold ourselves to the highest standards of rigor. That all said, these are highly overlapping indications, and we are seeing, of course, and measuring symptoms of anxiety and symptoms of depression across all 4 of the studies. And so aggregating a large body of evidence if we're seeing consistent results across multiple studies across multiple domains with a high degree of both stand-alone and placebo-adjusted change. And the better the data are, the stronger the arguments are going to be whether it's 1, 2 or more studies for any program.

And so we'll certainly take all of that into consideration and depending on the strength and the magnitude of responses that we're seeing across these studies, be in a position to chart a regulatory path forward there. To the first point, again, I think it's a little bit premature to talk overly precisely about segmentation about exactly where this would land in the commercial setting. I'll turn it over to Matt to maybe comment just how we think about that and the sort of expectations and hopes we would think about for both commercial adoption and for reimbursement as such.

Yes. Thanks, Rob, and thanks for the question. As it pertains to the patient profile in MDD, first of all, we take a step back and look at both of these indications. These are highly prevalent indications. There are over 50 million patients in the United States for both indications. And there's a still very significant unmet need. As we conduct market research with HCPs, we see that the unmet need is greater than 70% across both the indications.

So even with the care that they have access to today, there's still something left significantly lacking in the treatment paradigm. So we know that payers do manage drugs and branded drugs that enter the market typically have a step or two. And so we believe that, that can narrow the overall addressable market slightly. But there are, for both GAD and MDD, a significant number of patients that are going to benefit if approved, from DT120.

Our next question coming from the line of Sumant Kulkarni with Canaccord.

As we eagerly await all the data you expect to announce this year. I have 2 questions, one on product development and the other on the commercial side. First, conceptually, we think investors are perhaps somewhat unfairly holding psychedelic therapeutics to a higher bar on point separations on scales in clinical trials. But our view for some time now has been that where the bar really should be different versus standard of care is on durability of effect.

Is that a fair real-world characterization from your perspective? And I'm asking that because I don't think I heard an explicit callout for durability in your earlier answer on clinical relevance of a STAT6 on HAM-A and perhaps even more so on MADRS.

Yes. No, thanks so much for the question, Sumant. When we think about durability, there both the practical limitations of how long out in time you can look at single-dose durability in a placebo-controlled manner. There are certainly insights that we can gain beyond that. And in our conduct of the studies, we'll be looking the response patterns and the ultimate duration to events beyond just a 12-week period. But when we look at the landscape, 12 weeks is the outer bound of what most studies, particularly drugs that don't require a long time, for instance, SRIs can take many weeks to show any sort of activity.

And so of course, sponsor in those studies would wait well beyond that to try to drive that separation. But when we think about the durability and our dialogue with regulators to date, the ability to show durability at 12 weeks past a single intervention is really at or close to the highest bar one could set for a drug. And so part of the decision-making in the design of our Phase III program was to have our primary endpoint be at that time, we would be showing if successful in these studies, really the longest durability of response that we could hope to or could hope to be established with -- in a parallel group phase of the study.

And that stands out among all of the product candidates that we're seeing in late-stage development, certainly in our field. So we absolutely agree that durability is important and that durability well beyond a few weeks after a single treatment or the last treatment of drug is really meaningful and why we've designed our studies the way we have.

Got it. Yes, that's really why I was asking because you've shown really good durability so far. And on the commercial side, Matt, you mentioned a "high-touch white glove experience." So what are your latest thoughts on pricing in MDD and GAD, at least relative to SPRAVATO for TRD, if that's still a good benchmark? And what fraction of that high-touch white glove experience can be paid for by insurers?

Yes, thanks so much, Sumant. Yes, I'll just say briefly, I think -- and I'll turn it over to Matt. I think the -- when we think of pricing, it's really premature to talk specifically about pricing. But when we think about the dynamics, we continue to believe and sort of build conviction in our belief that the failure of currently available therapies to address a patient's depression or anything else is not a good proxy to define a population. And that what we see also in a lot of our HEOR work is that severity is a huge driver of disease burden. It shouldn't be surprising.

The fact that drugs that don't work particularly well in a population haven't worked in the population doesn't mean that those who were underserved by those therapies are worse off necessarily. And so while we understand the dynamics of likely not being a first-line therapy for everyone, we do think that those distinctions are somewhat artificial and as a result, something that we both can look at within our subpopulation in our studies, but wouldn't sort of shy away from things like SPRAVATO as a comparator given the sort of artificiality of that distinction. But I'll turn it over to Matt to comment further on that.

Yes. So Sumant, as we think about the high-touch or white glove type of orientation we have for this launch is really to remove any friction that a patient or provider could experience. And so that will involve a hub service model, being really clear on the reimbursement pathway, how to bill and code, et cetera, ensuring that the patient out of pocket is not an obstacle, basically removing any of the obstacles to get to therapy as quickly as possible. That's our ambition. That's what we're building towards, whether it's through field team and high-touch field team exposure to either HCPs or otherwise in market access and ensuring that we have a seamless hub model that really helps coordinate all of the different touch points to ensure that the patient experience is positive.

And that's all the time we have for our question-and-answer session. I will now turn the call back over to Mr. Rob Barrow for any closing remarks.

I want to thank everyone again for joining us on the call today. We are incredibly excited to come to our top line readout for Emerge first in the months ahead. And with 3 pivotal readouts across the course of the year, we think this is really a defining year for us and are incredibly excited to get to those data readouts. So thank you again for joining us today, and I hope you'll join us at our upcoming events in April and thereafter.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and you may now disconnect.

Good afternoon, everyone, and welcome to day 3 of the 44th Annual JPMorgan Healthcare Conference here in San Francisco. My name is Alex Kramer, and I'm a member of the health care investment banking team here at JPMorgan.

It is my pleasure to introduce our next presenting company, the recently rebranded Definium Therapeutics,. Today's presentation will be given by CEO, Rob Barrow. Following Rob's prepared remarks, there will be some time we'll leave at the end for some Q&A. And for that portion, Rob will be joined by Dan Karlin, CMO; Brandi Roberts, CFO; and Matt Wiley, CCO.

And with that, it's my pleasure to turn the mic over to you, Rob.

Thanks so much, Alex, and thanks, everyone, for being here today. We're incredibly excited about our organization and all the progress we've had over the last several years and all the progress we have ahead of us. Part of -- I'll say the forward-looking statements thing before we get started, and please refer to all of our disclaimers in our filings.

But as Alex mentioned, we recently have rebranded and come with a new presentation of the same organization, the same science, but really wanted to enter this period of time where we have multiple pivotal readouts we'll be talking about with a whole new look and really an ability to establish ourselves and own an area where we've been fortunate to be leaders in a space that's incredibly exciting in psychiatry. And we've made some really important decisions over the last several years of our development program, the rigor that's gone into the scientific approach of our development of DT120, LSD or lysergide that we have in multiple Phase III studies and the expansive view, the balanced view of what we have for what the potential impact could be, we're incredibly excited about.

The number, 50 million U.S. adults that are impacted by anxiety and depression. It is a number that is so large that we kind of think of it as almost inconceivable. And I think it gets lost just how impactful this is, just how many of these patients either are undiagnosed because they don't know that there are good treatment options available to them or if they are treated or underserved by those treatments. Most patients are getting treated today are not served by the options we have. We haven't had really any innovation and meaningful innovation, particularly in generalized anxiety disorder in the last 20 years. As approval in generalized anxiety disorder was Cymbalta 2007.

So we look at this number, we look at the extraordinary impact it's having on our society. We have, again, an expansive view of what could be possible here. We have 50 million people who lives are disrupted and impacted by these disorders. It's growing at about a 5% rate per year, which means hundreds of thousands or millions of people are being impacted by disorders that are debilitating. And despite psychiatrists' best efforts with the treatment options we have available, largely what we've seen over the past 30, 40 years is a recycling of mechanisms, outdated frameworks, even language that talks about patients being treatment resistant as opposed to the fact that the drugs are just failing those patients. And the reality that now we face a world in which deaths of despair continue to grow despite practitioners' best efforts and of course, patients' attempts and desires to get better. And so we entered this world with an opportunity to have a meaningful and expansive impact.

We're taking a drug that's been around for a long time. It's been around for 80 years. LSD was discovered in the 1930s. And it really drove the early interest in this field that we've commonly referred to as psychedelics that target important systems in the brain target have so far demonstrated incredible activity in a wide range of indications. But it's a molecule that had an extraordinary promise early in research in psychiatry and addiction medicine. But for a complex set of factors, it escaped that medical use and then has been set on the shelf for a long time. It's only in the last several years that, that research was picked up, and we were incredibly fortunate to bring it forward with an even better product and one that we're incredibly excited to deliver pivotal data on later this year.

Building on the momentum we've had over the past several years, we are expecting three pivotal readouts, two in generalized anxiety disorder, in major depressive disorder. With the support of many of you and an incredible set of investors, we've been able to accelerate our filing strategy and preparedness for NDA and really start to establish our pre-commercial footprint, get out into the world such that if we're successful in getting an approval for DT120, that we can have the most rapid and expansive impact of any product in the field. And that's enabled by the fact that what we've seen so far is best-in-class profile on a number of aspects, not only within the field of psychedelics, but within the broader field of psychiatry, and the best efficacy we've ever seen in these disorders.

And of course, we're continuing to build the organization. We've grown significantly over the past several years and are incredibly excited by the talented group of drug developers and the thoughtful approach, the approach that we believe will let us as an organization and will let DT120 as a drug stand out in this class and really drive this meaningful change.

Touching on our Phase II data, we saw an effect in generalized anxiety disorder. It was a 5-arm dose response study, the only dose response study that has been conducted in this class. We saw an effect size in this study. These are patients who came into the study with severe anxiety, received a single dose of drug and were followed for 12 weeks. At the end of that 12 weeks, we saw an effect size of 0.81, which is more than double the standard of care, SRIs, benzodiazepines. That effect was rapid. It was observable within 24 hours of treatment. It was durable for 12 weeks with no loss of activity over that 12-week period, and it corresponded with about a 50% a 48% remission rate in those patients. So of every patient, every two patients who came in the door, one of those patients left in remission with no detectable anxiety symptoms.

So we look at the landscape of these available therapies. And again, there's been so little innovation in the last 20 years. Over that period, the prevalence of generalized anxiety disorders as our first indication has tripled. High-quality recent epidemiological studies estimate that 10% of U.S. adults suffer from generalized anxiety disorder. Compared to those approved products, we saw not only an extraordinarily large placebo response in the study, but we saw a drug effect that surpassed that by double the margin of those approved therapies, almost a 22-point reduction from baseline on the Hamilton Anxiety scale, the primary outcome measure. And again, this is 12 weeks, three months after a single administration of the drug.

So based on that compelling Phase II data that we put out in 2024 and received a breakthrough therapy designation for that program that we designed a Phase III program across two indications, GAD and MDD, the two largest indications in psychiatry, two of the largest and most impactful indications in all of medicine.

Two complementary studies in both of these indications, Voyage and Panorama, which are GAD studies are ongoing and anticipated to read out later this year and two studies in major depressive disorder, one of which is ongoing currently and one of which will -- Ascend will be starting around midyear 2026. Both the studies in GAD are powered, 90% detected 5-point difference, even though, again, we saw a 7.7 unit difference in the Phase II study in major depressive disorder, similarly 80% power for a 5-point difference. We could not be more excited and we could have a high degree of conviction about this program and about our alignment with FDA, real opportunity to demonstrate the strongest, the most robust evidence that we have seen in this field in a long time.

And even beyond the potential to have a best-in-class drug, you would think with the magnitude of the problem and with the magnitude of the impact of these disorders on patients, that patients would be receiving extraordinary care. And I think we all know that, that's not really the case.

Patients are often shuffled through care have to -- for the various demands to site, despite practitioners' best efforts are shuffled through care have to come in for multiple rapid visits and then are shuffled out the door, largely end up switching medications, having add-on medications by the time multiple products have been unsuccessful at treating their symptoms are left without any real meaningful options.

And so with a drug like DT120, where patients come in for a single dose in a monitored clinical setting, we not only have the chance to drive the best clinical profile for a drug, but also to completely rethink patient care. What it could mean for a patient whose life is significantly impacted by anxiety or depression to come in for a day to get treated and to leave that treatment session meaningfully improved and meaningfully improved for a long time thereafter, something we're trying to characterize more granularly in our pivotal studies.

And the market is -- again, I think in these settings gets somewhat overlooked, just how much demand there is from not only patients, but from providers. Psychiatrists have not had new tools in a very, very long time. And they want to help patients. They want to get these patients better. When we go out and do market research, we see a high degree of motivation by these prescribers to bring something new to their patients. 75% of these numbers that we show here are all trying to quantify a reality that we see, which is an overwhelming desire for something that is different and something that sort of reorient them in their care of patients to potentially drive this meaningful long-lasting change.

Patients with GAD with MDD, of course, don't want to feel that way. They want to go about their lives, not with symptoms suppressed, but with a new orientation with the ability to feel more better and be better, not just to feel less. When we talk to payers, and we do a lot of work with payers because, of course, this is something that is novel, it's something that is innovative and it's going to require all of the collective stakeholders to be engaged. We see a really positive reaction, positive reception.

Of course, we're not there yet. We don't have the product on the market. But in these conversations, everyone recognizes the magnitude of the need, the magnitude of the human cost for payers, the magnitude on their budgets and the health care utilization. And it's an extraordinary opportunity in a market that is really primed for something new, and we believe we have something to offer going forward.

When we look at psychiatry, again, this is something new is something that is not delivered exactly the way we do it today. And it requires being thoughtful about the future we can ultimately generate. When we look at new entrants in psychiatry, new classes of drugs, it started in the early 1990s, over 30 years ago with the introduction of Prozac and Zoloft. Those are large drugs at the time. And we sort of roll this forward into today's world and think about new classes of drug in psychiatry, it's not just us. There are other companies as well, right? The opportunity is extraordinary. There's millions and millions of patients who are in need and who we can ultimately hope to treat. And it is why every time there's a new class of drugs that enters the market, it tends to support multi-blockbuster drugs and many of them.

In many cases, as you see here, $5 billion to $7-plus billion drugs. Just speaks again to the extraordinary we think that psychedelics really could represent an entirely new era, a whole new opportunity to really transform psychiatric care and rethink what it means to get care for these disorders. And that's why we've aimed for the broadest indications, why our development approach has intentionally been designed to enable the broadest potential uptake in the most number of settings, of course, within -- with a thoughtful eye to safety and the requirements for safe use, but one that doesn't artificially prevent the patients in need from getting care. We think that for those patients and for us as an organization, there is an incredible opportunity that we can hopefully deliver on in the future.

When we frame this opportunity up, again, it's -- I keep coming back to it, but it's hard to conceive of these numbers, 27 million or 50 million patients, 27 who are receiving medication for GAD and MDD in the U.S. alone. And we look at some of the new interventional psychiatry drugs and Spravato is a good example. That's, of course, a wide range of pricing due to the differences in dose and frequency that can be administered. But it comes down to about $28,000 to $70,000 per year for a patient who has prescribed Spravato today if they stay on regimen and stay on the drug for the duration of that year.

And so we look at this, again, 50 million patients, 27 million who are receiving drugs in these indications. Even looking at the sort of midpoint of that pricing range, we're talking about what could represent for every 100,000 patients of around $4.9 billion, up to $7 billion if you're treating 100,000 patients at the high end of that pricing range, which is in our engagement with payers, the sort of analog that they benchmark us to.

And to make this a little more bite-sized, we thought San Francis, we're all sitting here. And you could be excused for asking with something this new, something that necessarily isn't available today in the way that we hope to deliver it, how is this going to work? How is this going to scale? How are we going to actually get this out in the world and treat -- even hope to aspire to treat that many patients. But when we make a little more bite size and boil it down into what it would actually require to make this possible, we said let's just look at the city we're sitting in, look at the metro area, what you could drive to or walk to from here. the nearest interventional psychiatry clinics is within five blocks of where we're all sitting right now.

San Francisco represents about 1.4% of the U.S. population. For those 100,000 patients, that would mean about 1,400 patients here in the Bay Area getting treated. It's 44 clinics that are raising their hands saying, we will be early adopters. This product is approved. We want to deliver, we want to prescribe. We want to help our patients with what you're offering.

If we're just looking at those 44 clinics, that means that they need to treat about 32 patients per 100,000 nationwide. It's 2 to 3 per month in the calendar year. This is something that is doable. It is tangible. And when we approach this, of course, we are going out to these sites. We're talking to these providers, talking to patients and payers and all of the stakeholders that need to be, again, on board and supportive to make this full realization of this potential possible.

We believe that there is a definite path to make this happen. And that, of course, this is the beginning. We want to make a meaningful change on the trajectory of the disorders that we're seeking to treat, right? Just making the problem a little bit less worse than it was last year is not the goal. It shouldn't be the goal for anyone in our field of psychiatry in general, the goal needs to be, can we have an impact? Can we aspire to a place where we're actually changing that trajectory where we're enabling patients to get better. And looking back 10 years from now, we say, you know what, the problem is improving on the whole. That's what we aspire to do. And again, we believe it is something that is tangible. It is something that we can actually make happen.

This scales nationwide. We look at the whole country, there's about 7,000 health care providers, prescribers who treat about half of the GAD patients who are in most need. All we have to do is continue to scale this up, right? It's not just San Francisco. We're not going to treat -- we're not even aiming in the early days, right, to treat 100,000 patients in the Bay Area. But when we think about that scale nationwide and we look at each of these states, we look at each of these areas. We look at each of these clinics, again, not that much has to be done on an individual clinic or individual provider basis to get to some really extraordinary numbers that could have a massive impact in these areas.

So, as we look forward to the future, two big drivers, of course, clinical regulatory execution. We've been incredibly excited about the data we've had to date. We anticipate delivering three Phase III readouts this year. We have a fourth Phase III study -- a second study in depression that will be up and running midyear.

In parallel to that, we're already progressing to optimize that care model. Think about how patients can be best served, how clinics can be best served and how we can play the most effective role in facilitating that, making that possible for these patients to get the best care possible. We're continuing to expand our footprint, expand our engagement, also doing work to accelerate and broaden the possibility to get this to the most markets possible.

These are controlled substance. It's going to require scheduling, not only nationally, but at the state level, and we're already doing a lot of work to try to make sure that everyone on the ground is educated and is aware of the kind of impact this could have and is making it possible for patients to get access as early as possible. And we're building the organization to do it.

And again, we think we own the science and know how to execute and have shown this repeatedly across our R&D program and intend to do that as we progress into a commercial organization. We also have earlier-stage products that are developing in the pipeline with our first data coming in the years ahead and the year ahead for DT402 in autism spectrum disorder. And we're thinking, again, more expansively even beyond the indications we're pursuing and the drugs we're pursuing today. what we think will ultimately be an extraordinary value creation, not only for our shareholders and for us as an organization, but really importantly, for the patients and the providers that are impacted by these disorders today.

So again, a defining year for not only us, but for the entire field, one that we've -- our leaders and one that we've been able to establish, I think, the most rigorous science, the highest standards of that science with the most aspirational view of what can be done, what we can achieve, what we can drive for these patients. We anticipate our first readout second quarter of this year, additional readout for Merge, our first MDD trial midyear. Second readout in GAD Panorama, which we expect in the second half of the year, we'll be having a number of events throughout the year to continue educating everyone to continue to build clarity coming into these data and coming into this future that we hope to build.

So thank you again for being here today. Thank you for being a part of this and helping us drive this future that we think is possible. We really do believe that change is needed, change is deserved and that we can play a really impactful role in driving that future. Take any questions. Thank you.

So you've taken a different path than some other players in the space. Can you just talk about the thought process behind running clinical programs in both MDD and GAD that have helped you cast a much wider net in terms of the addressable or potential addressable market here?

Yes. It comes back to the need, right? It comes back to -- when we have something -- I think anyone who's been following the field will hear about the sort of transformational potential that everyone describes. While we, of course, understand the dynamics that nothing goes from 0 to 100 miles an hour instantly. That there's necessarily an uptake curve, there's necessarily a progression, but we need to think aspirationally about what's possible, think about the ultimate need, thinking about the lack of utility for the options that are there today. And for the options that are there, some patients are getting better, of course, not everything is bad. Some of these drugs are working well. Some of the patients are served, but far too many are not. And so to think about someone that has a field changing a practice-changing potential, but not aspire to actually change the practice seems limiting, self-limiting to us, right?

Why not aspire to get to a place eventually where we can really reshape the field. And that's gone into every decision we've made from how we've approached the delivery protocols in our trials to how we think about the strategy for labeling, how we think about the data we try to accumulate and make arguments for and what we ultimately hope will be labeling discussions and REMS discussions if we get to that point in the process.

So, it all comes down to, again, viewing the -- we talk about the balance of -- you can't talk about transformation analysis without really thinking broadly and thinking about that magnitude of impact. And so this informed everything about who we are, how we operate and the decisions we make in that process.

And then I guess just building on that a little bit. So in previous psychiatry studies, we've typically seen a narrowing of results from Phase II to Phase III and obviously, a couple of pivotal Phase III readouts this year. Placebo seems to be usually getting a little bit bigger and then just the drug effect getting a little bit smaller. So can you just talk to us about what gives you confidence that you guys won't experience that or the company won't experience that?

Yes. And I'll turn it over to our CMO, Dr. Dan Karlin to talk about it a bit.

Yes. Thanks, Rob. And clearly, we're aware of that, right? This is no secret in psychiatry that the placebo effect has been the nemesis of psychiatric drug development for quite some time, or at least it's the attributable enemy, right? And when you have drugs that don't work very well for most people, then you get wiped out by placebo effect because participating in trials makes people a little bit better.

As we work through the design of our Phase II and into the design of our Phase III, we took that into consideration. In the Phase II, we robustly exceeded a very large placebo effect. In fact, the nearly 14-point placebo effect in our Phase II would make the placebo in that trial the best GAD drug ever approved. if we were just trying to approve a placebo for GAD, of course, we're not.

And there are a couple of reasons for that. One is the actual size of that placebo effect. So what did patients who got placebo in the trial experience. And in part, we had a large placebo effect because in the Phase II, there was an 80% chance that you got drug at all as a participant. The higher the chance of getting drug, the larger the actual placebo effect. That is to say the more likely someone is to get drug, the more likely they are to feel better in the study. So our real placebo effect was quite high.

Also in that study, we took patients off of their background medicine, gave them a single shot at getting treatment, so they could either get one of the four doses or placebo and then they didn't get anything else for the rest of the 12-week observation period. That's asking a lot of participants. It's particularly asking a lot of participants who don't feel better. So we had a disproportionate rate of folks who didn't feel well after getting their dose leaving the study. That means we lost the folks from the study who are doing the worst on placebo. A conservative data replacement strategy meant that we were filling in their data with the folks who did the best on placebo. So not only did we have a high actual placebo effect, we slightly overrepresented that placebo effect in the reported data.

In Phase III -- first Phase III, 50-50 chance of getting drug, that will push down the actual placebo response, and we've included a 40-week extension phase in each of the studies where folks can get open-label treatment up to 4x. That means there's increased motivation to stay in the study even if you're not doing well. So we're also less likely to overrepresent the actual placebo effect. So, by all accounts, our somewhat unprecedentedly high reported placebo effect in Phase II will come down in Phase III, and we have no reason to think the drug will perform any less well.

And then so I guess, what would you say are the most compelling or differentiated aspects of DT120?

There hasn't been an opportunity in psychiatry before to give somebody a single or a few doses of drug separated by weeks or months and have their disease state remain substantively changed. When we talk to participants from our Phase II and we talk to folks who've had the opportunity to participate in other trials of the drug, the way people talk about how they feel isn't the way people talk when they've gotten, say, an SRI.

People who get treated for GAD or MDD with an SRI talk to you about suppression. I feel less bad. I feel less of everything in general, right? People tend to feel a little bit emotionally numbed. But for folks who felt basically mostly bad, feeling basically mostly less means feeling mostly less bad. That's a good thing for some people. Patients who are treated successfully in our studies don't talk about symptoms. They talk about a different outlook on life, a different relationship to themselves, a different relationship to their own lives. That is remarkably differentiated from anything else we have to offer in psychopharmacology today.

Stephen Scott with Morgan Health. I guess two questions. First is on the payer economics. How do you guys think about the trade-off between bringing this to market like at a lower price point and positioning it as more of a first-line treatment versus -- it strikes me like Spravato might be a little bit of a rip-off for payers given generic ketamine and maybe even TMS can deliver similar outcomes.

The second is like the care delivery economics. Is this something you think like many psychiatry clinics will be able to offer? Or will it be more of a sort of regional center of excellence model where clinics can do high volume and like build the infrastructure needed to?

Yes. I'll turn to Matt Wiley, our Chief Commercial Officer, maybe.

Yes. So, as we think about pricing, obviously, there's quite a bit of work to be done between now and launch. The value proposition will continue to evolve as we get our Phase III data. However, as Rob presented and what we see in market research and through advisory boards with payers, their expectation is, a, that they're going to pay for it; and b, they're benchmarking the price point to what they see on an annual basis with Spravato.

Is there an opportunity to dial that up or down? We'll examine that between now and launch. The pricing decision is always made just post PDUFA and just before you launch into the trade. So we'll get to that point.

As it pertains to practice economics and centers of excellence versus a larger swath of physicians adopting, what we've seen in market research is this opportunity to cast a wider net for physicians. I mean, when you think about treatments that require ongoing commitment, Spravato is a good example, where patients have to come in a couple of times a week for the first four weeks and then weekly thereafter. That's a commitment for both the patient and the physician.

So -- and that's a commitment on proximity to the clinic location. It's also a commitment to office space and staff. With a drug like DT120, you have this opportunity to treat the patient and then see over a 12-week period how the patient responds and whether they need pretreatment beyond that. So it's not the same level of commitment and market research has borne that out that there are a lot more physicians that plan to adopt this in their practice than we see in the same practices with esketamine.

And then I guess just building off of that, can you talk a little bit more about commercial preparedness? I know you talked a lot about the market opportunity. I guess what's been done or what is there to be done this year on the commercial readiness front?

I can turn it over to Matt.

Yes. So there's quite a bit that we have done. We've built out a comprehensive launch plan, everything from our product positioning, which we're not going to necessarily go into. But that gives us the line of sight on our message platform. We've built out our targeting model, which I can talk about a little bit. We have also built out a pretty good framework for our go-to-market market access strategy.

We're now building our trade and distribution and compendia strategy and so forth. So surround sound, there's a lot to do this year. We're building out the other components of the team and starting with market access field teams and hiring ahead of sales later this year. Those are the sorts of things that we're building out from an infrastructure perspective to get ready.

And then I guess, since you offered it up, can you just talk a little bit about the initial targeting strategy and model?

Sure. I mean it's been almost 20 years since a drug is launched for generalized anxiety disorder. So there's not a natural surrogate drug to examine for targeting, not that we would necessarily do that anyway. So the way that we build our target model, the predicate is where the diagnosed generalized anxiety disorder patients are today in concentrations. And then we have prioritized that targeting model based on various factors for patients, those that are going to raise their hand first for a drug like DT120 and those physicians that we believe will adopt very quickly.

And after building the model, we did market test it. We did a pretty robust quant research study. And what we found in that study is that better than 50% of the HCPs that we spoke to that are high decile, so decile 7 to 10 represents 40% of the GAD patients intend to both prescribe and administer DT120 in their practice. You have another 20% or so that intend to prescribe and refer out. And just to take that a step further, when we look at all of the deciles in our targeting model, 6 to 10, we see that roughly 30% expect to adopt or write their first prescription within the first three months of the drug is available.

Now one of the natural questions is, are you targeting the esketamine clinics? And are those part of your targeting thesis? And the answer is no, that's not how we went about this. We actually would do -- as we would do with any targeting for launch is the exact process that we went through. However, when we examine our target model post hoc, we see that we are capturing 80% of the esketamine prescribers. Now that's not the esketamine registered REMS physicians because they don't all prescribe and they're not all active. But we are capturing 80% of those that are active with patients.

I was just wondering about the stigma of this class of medications in your kind of market research. I mean, you kind of had the data for Spravato. Given the scale of sales, there's very little like TV advertising or print advertising. Obviously, that's a question for Janssen about how they choose to market their medication. But I was just wondering, was this stigma an issue that came up when you're doing your market research, both on the patient side and on the provider side with this class of medications.

I'll initially address it, which is to say that the word stigma is a bit broad and encompasses so many aspects of this, right? There is a reality that this drug in particular, started in medicine, started in the lab, right, started in a Swiss medchem lab, found a place in psychiatric research and addiction medicine research resided there with extraordinary excitement and promise early on. And through a number of complex factors, didn't precipitate some sociocultural thing. But in the context of what was happening in the world, there was a dynamic that created certainly a wide range of commentary and views and what could loosely be called stigma through that time. And certainly, that is not something that anyone can't remake history. That's a reality that we deal with.

But when we go out to providers, when we talk to patients, when the question is, if I have an option to get a treatment with something, and I could feel better, meaningfully better. we have to measure -- again, as Dan said, we measure symptom reduction. That's what can be labeled. That's what we can do in clinical research. But qualitatively, what we hear is people say, I felt better after getting this. The concerns about what the perception may have been historically, we've never heard it come up in those conversations. And while there are small -- there certainly are small pockets of folks who say, I don't know about this. When we present them with the science, we present them with data and say, here's what we're seeing, and this isn't about handwaving and something extra medical.

This is about like any other intervention, psychiatry is full of perceptual alterations, whether they be blunting, changing behavior, wide range of options. We present that and say, look, one time and for months thereafter, we've shown an improvement, very little stands the way and saying, okay, I would certainly give that a try. And I very much, in many cases, I'm very excited about the potential to give that a try.

Do you think there's like -- I mean, so okay, the prevalence figures you gave for MDD and GAD, obviously, across the whole population. Do you think there's like old people or younger people, there's any demographic difference in people who might be more receptive to this kind of treatment?

Yes. And that shows in the research for sure, right? I mean I think the most fascinating thing is that it also intersects with the epidemiological data on the need, too, right? Those most receptive are the populations that are presenting the highest levels of anxiety and depression. So there's sort of a natural fit, natural match there that makes sense.

So there are certainly variations in that. And that's going to, again, dictate some degree of who is the first person to raise their hand, who are the early adopters. And one thing we know from, again, look at any other drugs that have a meaningful broad population level kind of impact, it starts there. It starts there. It starts with the groups who say, oh yes, I'm going to try this. And then over time, when the other reality about these high prevalence things is that everyone knows someone.

So when someone's close relationship says, well, I tried this and it made me think this happened, made me better in some way, the likelihood of the sort of network effect for the next person is, okay, well, yes, I'll try that, too. And that's when we see these areas where there's a broad expansion and opportunity to really have, again, that broad-based impact that we hope to achieve.

And I guess maybe just one more and this one might be for you, Brandi. Can you just talk about the fact that you raised, I think it was $250 million or so in October of last year. But at the time, you were already funded through the data. So can you just talk a little bit about the rationale? And then, I guess, just what to expect from a sort of OpEx or cash burn perspective this year?

Yes, absolutely. So, as Rob said, we have a really high conviction about the potential for DT120, and we have really big aspirations. We want to be able to get this drug to the market at scale.

And so that additional funding lets us do three main things. First of all, really accelerate some of the commercial-related activities that Matt was talking about. So in addition to our market access strategy, we're also highly engaged with KOLs doing a lot there as well as a ton on NDA preparation. And so being able to accelerate those activities puts us in a really good spot for 2026 and beyond. Additionally, it let us accelerate our plans for our second MDD study. And having a broad data set for both MDD and GAD gives us the best chance to really hit these two big indications in psychiatry. So that was very fundamental to bringing in the additional funding. And thirdly, bringing in quality long-term investors who really share our vision and want to be part of the next stage of growth with us was also really helpful. So it's great to be in a good position and have the cash that we need to really propel ourselves forward for 2026 and beyond as we look to the next steps with DT120 and the rest of our pipeline.

Great. And I think with that, we're out of time. So thank you again for the presentation.

Thank you so much.

Good day, and thank you for standing by. Welcome to the MindMed Third Quarter Earnings Conference Call and webcast. [Operator Instructions] Please be advised that this conference is being recorded.

I would now like to hand the conference over to our first speaker today, Gita Jain, Head of IR. Please go ahead.

Thank you, operator, and good afternoon, everyone. Thank you for joining us today for a discussion of MindMed's Third Quarter 2025 Business Highlights and Financial Results. Leading the call today will be Rob Barrow, our Chief Executive Officer. Dr. Dan Karlin, our Chief Medical Officer; and Brandi Roberts, our Chief Financial Officer, are also on the call.

An audio recording and webcast replay for today's conference call will also be available online as detailed in the press release announcement for this call. During today's call, we'll be making certain forward-looking statements, including, without limitation, statements about the potential safety, efficacy and regulatory and clinical progress of our product candidates, our anticipated cash runway and our future expectations, plans, partnerships and prospects.

These statements are subject to various risks such as changes in market conditions and difficulties associated with research and development and regulatory approval processes. These and other risk factors are described in the filings made with the SEC and applicable Canadian securities regulators, including our annual report on Form 10-K and our Form 10-Q filed today.

Forward-looking statements are based on the assumptions, opinions and estimates of management at the date the statements are made, including the non-occurrence of the risks and uncertainties that are described in the filings made with the SEC and applicable Canadian securities regulators or other significant events occurring outside of MindMed's normal course of business.

You are cautioned not to place undue reliance on these forward-looking statements, which are made as of today, November 6, 2025. MindMed disclaims any obligation to update such statements even if management's views change, except as required by law.

With that, let me turn the call over to Rob.

Thank you, Gita, and thank you, everyone, for joining our call today. We delivered another solid quarter, advancing our clinical programs and continuing to build one of the most robust late-stage pipelines in our field. In addition, this quarter saw the publication of our full Phase IIb clinical trial results in the Journal of the American Medical Association, highlighting the rigor and impact of the clinical results we have generated to-date.

Building on this scientific momentum, we successfully completed an underwritten public offering last week, raising approximately $259 million in gross proceeds. This additional capital further strengthens our balance sheet and enables us to strategically accelerate the development of MM120 and MM402.

We continue to expand and strengthen our investor base, welcoming in new high-quality health care dedicated funds and mutual funds while deepening support from our long-term shareholders. This financing underscores the strength of our science and positions us for a transformational 2026, a pivotal year ahead with 3 top line Phase III data readouts expected between our generalized anxiety disorder, or GAD, and major depressive disorder or MDD programs.

Enrollment is strong and steady across our ongoing pivotal studies of MM120. We reiterate our guidance and continue to expect top line results from Voyage in the first half of 2026 and Panorama in the second half of 2026. Due to faster-than-anticipated enrollment in the past quarter, top line results from the Emerge study are now anticipated in mid-2026, an update from our prior guidance of second half of 2026.

We are also excited to share further details of Ascend, our second Phase III study of MM120 in MDD, which we expect to initiate in mid-2026. We continue to deploy resources and operationalize our programs with remarkable efficiency in pursuit of approvals in both GAD and MDD, 2 of the most prevalent and burdensome psychiatric disorders.

Over the course of 2025, we have continued our constructive dialogue with FDA and believe we are well positioned to deliver on an expeditious path forward in both indications. For far too long, patients struggling with anxiety and depression have been significantly underserved by current treatments. Many cycle through multiple therapies with limited success. They're looking for something different, a safe and effective new treatment option that they feel confident will deliver meaningful change, not just symptom suppression.

Based on the safety, efficacy and durability we have demonstrated with MM120 ODT to date, we believe it has the potential to represent such a transformative option, addressing anxiety and depression through an efficient patient-centered delivery model. It's also important to remember that the results we have generated to date have been achieved with a single dose administered as a monotherapy without co-administered psychotherapy.

We believe that MM120 ODT could integrate well into the existing health care infrastructure using well-established reimbursement codes covering evaluation, prescribing and monitoring in addition to the actual treatment itself. Our goal is to reduce administrative barriers to adoption and help ensure that providers are appropriately compensated for their time and services.

With regard to our additional R&D activities, we are pleased to share an important update on our second asset in the pipeline, MM402 or the R-enantiomer of MDMA. Having already completed a single ascending dose Phase I study of MM402 in healthy adult volunteers, we plan to initiate a Phase IIa study in participants with autism spectrum disorder, or ASD, by the end of 2025.

We believe ASD represents another significant opportunity with growing prevalence and substantial unmet need. As we approach the last few months of 2025, our team remains laser-focused on executing our ongoing studies and laying the groundwork for a transformational 2026 and beyond.

Looking ahead, we anticipate 3 pivotal data readouts of MM120 ODT for GAD and MDD in 2026, the initiation of our second pivotal study in MDD in 2026, the advancement of MM402 in ASD into a Phase II study by the end of 2025 and further advancement of our go-to-market strategy as we prepare for the potential launch of MM120 ODT. With strong momentum across all fronts, we're working hard to bring transformative treatment options to the many patients needing new alternatives.

With that, I'll turn the call over to Dan for an update on our clinical programs.

Thanks, Rob. We continue to be highly encouraged by the enrollment trends we are seeing across our pivotal Phase III studies. As Rob mentioned earlier, in GAD, we expect to report Voyage results in the first half of 2026 and Panorama results in the second half of 2026. Given the especially strong enrollment in our ongoing MDD study, Emerge, we are excited to now be in a position to report results from Emerge in mid-2026.

This quarter, we also saw the publication of our full Phase IIb trial results in the Journal of the American Medical Association, or JAMA. It's a big moment, not just for us, but for the entire field of psychiatry. This study represents the most robust randomized, placebo-controlled trial of Lysergic D-tartrate or LSD in a psychiatric population using today's modern scientific standards.

This trial evaluated a single treatment across 4 dose levels, 25, 50, 100 and 200 micrograms and demonstrated compelling clinical activity with a statistically significant dose response. Our optimal 100-microgram dose showed both rapid and durable effects with a statistically significant 7.7-point greater reduction in HAM-A versus placebo at week 12. Additionally, 65% of patients in the 100-microgram cohort showed clinical response and 48% achieved remission 12 weeks after the single administration of MM120.

Moving to our Phase III program. Our GAD studies each have 2 parts: Part A, a 12-week randomized, double-blind, placebo-controlled assessment of MM120 ODT versus placebo; and Part B, a 40-week extension phase with open-label treatment opportunities to evaluate long-term durability and response patterns. In Voyage, we are targeting enrollment of approximately 200 participants who are being randomized 1:1 to MM120 ODT 100 micrograms or placebo, while in Panorama, we are targeting enrollment of 250 participants who are being randomized 2:1:2 to MM120 ODT 100 micrograms, 50 micrograms or placebo.

These Phase III studies are modeled after our successful Phase IIb study using the Hamilton Anxiety Scale, or HAM-A, as the primary outcome measure. This was the outcome measure used for the approval of existing GAD therapies. The primary endpoint in our Phase III studies is the HAM-A change from baseline to week 12.

Building on the success of our Phase IIb results, even though we observed a 7.7 point placebo-adjusted improvement in Phase IIb, we've designed our Phase III trials to have 90% power to detect a 5-point improvement over placebo. We've also designed our Phase III trials to address functional unblinding, a topic that is often raised when discussing research methods being used to investigate drugs in the broad psychedelic category.

Clearly, MM120 ODT and other drugs in the category have a distinctive set of perceptual, cognitive and emotional effects at the time of administration. While the phenomenological nature of these effects is unique to the category, the vast majority of approved psychiatric drugs also have acute effects that result in participant unblinding. Even so, in order to maximize the integrity, reliability, interpretability and generalizability of our research, we have implemented a set of interventions intended to address this and other methodological considerations across our Phase IIb and Phase III programs.

These include using central raters who are blinded to both treatment assignment and visit number, incorporating questionnaires to assess potential expectancy bias and unblinding, and in multiple of our studies, including additional control arms that are substantially perceivable by participants but are not of interest in assessments of clinical efficacy.

Our continued interactions with FDA further support alignment with the rigor and design of our approach, reinforcing our belief that our development strategy can deliver definitive, clear and compelling evidence of the safety and efficacy of MM120 ODT in GAD and MDD.

Turning to our MDD program. We are pursuing a similar approach to our GAD program, which includes 2 pivotal studies following the same 2-part design. Both of our pivotal MDD studies, Emerge and Ascend are comprised of 2 parts: Part A, a 12-week randomized, double-blind, placebo-controlled parallel group period assessing the efficacy and safety of a single dose of MM120 ODT versus placebo; and Part B, a 40-week extension period with opportunities for open-label treatment.

The primary endpoint in each study is change from baseline in the Montgomery-Asberg Depression Rating Scale or MADRS, at week 6 between MM120 ODT 100 micrograms and placebo. In Emerge, we are targeting enrollment of at least 140 participants randomized 1:1 to MM120 ODT 100 micrograms or placebo. We now anticipate top line data from Emerge in mid-2026.

In our second pivotal MDD study, Ascend, we are targeting enrollment of at least 175 participants randomized 2:1:2 to receive MM120, 100 micrograms, 50 micrograms or placebo. We expect to initiate Ascend in mid-2026.

Moving to our next pipeline candidate. We are excited to share our plans to advance MM402, the R-enantiomer of MDMA. In preclinical studies, MM402 has shown promising prosocial effects with a potentially superior tolerability profile compared to both racemic MDMA and the S-enantiomer of MDMA. We're developing MM402 to target the core symptoms of autism spectrum disorder, specifically addressing social communication challenges. We believe this program represents another significant treatment opportunity given the high unmet need, the increasing prevalence of ASD and no FDA-approved therapies that specifically address these core symptoms.

Having completed a Phase I single-ascending dose study that characterized the tolerability, pharmacokinetics and pharmacodynamics of MM402 in healthy adult volunteers, we plan to initiate a Phase IIa study later this year. This study will be a single-dose open-label design, assessing early signals of efficacy in up to 20 adult participants with ASD. The objectives and endpoints of the study are designed to characterize the pharmacodynamics and clinical effects of MM402 in adults with ASD across multiple functional domains.

In summary, we are efficiently executing across our pipeline. Our pivotal Phase III programs for MM120 ODT in GAD and MDD remain on track for data readouts next year, and we plan to initiate Ascend, our second Phase III MDD trial in mid-2026. As we progress MM120 ODT towards commercialization, we are also excited to advance our MM402 program for ASD, furthering our mission to develop breakthrough treatments for underserved patients.

With that, I'll turn the call over to Brandi to discuss our third quarter financial results. Brandi?

Thanks, Dan. Turning to our financial results for the quarter ended September 30, 2025, we ended the quarter with cash, cash equivalents and investments totaling $209.1 million. As Rob noted earlier, we successfully completed an underwritten public offering last week, raising $258.9 million in gross proceeds.

After deducting underwriter commissions and expenses, net proceeds are $242.8 million. We're very pleased with the outcome of our recent financing, which puts us in an excellent position for the future. We were encouraged by the strong level of high-quality investor interest in MindMed and in our development programs, a clear reflection of the confidence the investment community has in our mission. This funding allows us to accelerate key initiatives that will set MM120 up for success, including NDA preparation, state prioritization efforts for scheduling, market research and KOL education, among others.

These efforts position us well to move quickly in the years ahead, pursuing submission of an NDA for MM120 ODT as soon as possible, and if approved, executing a robust and well-prepared commercial launch. Based on the company's current operating plan and anticipated R&D milestones, the company believes that its cash, cash equivalents and investments as of September 30, 2025, along with the net proceeds from their recent offering, are sufficient to fund the company's operations into 2028.

Expenses for the third quarter of 2025 were in line with our internal expectations as we continue to make significant progress with MM120 and MM402. R&D expenses were $31 million for the third quarter of 2025 compared to $17.2 million for the third quarter of 2024, an increase of $13.8 million. The overall increase was primarily due to increases of $11.7 million in MM120 program expenses, $2.5 million in internal personnel costs, reflecting expanded research and development capabilities and $200,000 in preclinical and other program expenses. These amounts were partially offset by a $600,000 reduction in MM402 program expenses.

G&A expenses were $14.7 million for the third quarter of 2025 compared to $7.6 million for the third quarter of 2024, an increase of $7.1 million. The increase was primarily due to increases of $3 million in personnel-related expenses, $2 million in commercial preparedness related expenses, $1.6 million in corporate affairs expenses and $500,000 in other miscellaneous administrative expenses.

Net loss for the third quarter of 2025 was $67.3 million compared to $13.7 million for the same period in 2024. Note that our net loss can be impacted dramatically by the changes in the fair value of our 2022 USD financing warrants from quarter-to-quarter as our stock price fluctuates. The change in fair value for the third quarter was $22.5 million as our stock price increased from $6.49 at June 30, 2025, to $11.79 at September 30, 2025.

I'll also note that warrant exercises related to the 2022 financing have brought in approximately $2.5 million of cash this year with an additional $17.6 million of potential funding remaining prior to the warrant expirations in 2027.

With that, I'll now turn it back over to Rob for closing remarks.

Thank you, Brandi. This year has been one of bold ambition and disciplined execution. We're delivering on our programs and actively shaping the future we believe is possible. Enrollment remains strong across all 3 of our ongoing pivotal trials, Voyage, Panorama and Emerge, and we are eager to continue this momentum with the initiation of our second pivotal MDD trial, Ascend in mid-2026.

At the same time, we're advancing MM402 into a Phase II study, a meaningful milestone as we work to bring much needed innovation to the ASD community. 2026 is shaping up to be a defining year in our evolution, one where science, purpose and precision converge to advance the therapeutic potential of MM120 in our broader pipeline.

With a strong balance sheet and a late-stage pipeline with multiple catalysts in the year ahead, we're excited to continue driving value for our shareholders and the millions of patients who deserve more than better. Of course, none of this progress will be possible without our exceptional team whose passion, commitment and unmatched execution continue to set the standard for our field.

Thank you, again, for joining our call today. We will now open the line for questions.

[Operator Instructions] And now we're going to take our first question. And it comes from the line of Gavin Clark-Gartner from Evercore.

This is Yesha on for Gavin. We just had a brief one on the blinded sample size re-estimation. Mostly wondering if this has been completed. And if so, given that the trial size expectation is still 200 patients, is it reasonable to assume that the trial is not being upsized?

Thanks so much, Yesha. Yes, we haven't disclosed anything about a public disclosure of our sample size re-estimation. And I don't know you're referring to the ability to increase the sample size to maintain 90% power in both Voyage and Panorama, our 2 GAD studies. So, we continue to be excited by enrollment and on track for a readout in that program next year but have yet to say anything publicly about those announcements.

Now we're going to our next question. And the question comes from the line of Pete Stavropoulos from Cantor Fitzgerald.

This is Sarah Medeiros on for Pete. Congrats on the progress in your quarter. Really two questions for you. The first one being, just curious to know how easy or difficult it is to find patients that are willing to enroll in the psychedelic -- that are willing to enroll that are psychedelic inexperienced and they're naive with all the attention focused on this class of drugs for psychiatric indications. And is there a specific demographic that are willing to enroll such as age of patients?

Yes. Thanks so much for the question, Sarah. I'll turn that over to Dan to maybe fill.

Yes. So -- well, I would never say that enrolling a trial is easy because obviously, that's something that we pursue on a daily basis and think about how to get the right patients into our trials. What we have maintained and what we strive for is a representative sample so that we see a background epidemiological rate of people who have some psychedelic experience hovering around 15%. And that tends to be what we aim for in our studies. We want to have a sample that looks like the general GAD population. And so that's what we ended up with in our Phase IIb study, and that's what we're striving for in our Phase III study, where we're using meaningfully the same inclusion/exclusion criteria.

So, despite there being attention on these studies and attention on the category, of course, for those of us who are in it, that attention is much more obvious. Many of the participants who encounter our studies are just people who are looking for studies for their GAD or MDD. And for the vast majority don't find the studies because they're specifically looking for a study in the psychedelic category or even necessarily our study.

Great. And just a follow-up, your earlier-stage asset, MM402, can you help us understand the biological and therapeutic rationale and ASP and what outcomes would look like and potentially study design in terms of chronic administration? And are you looking at-home administration?

It's a great question. And obviously, a lot of the attention on the company recently has been on our lead asset, of course, that we're very excited about MM402. The interesting feature of how we are thinking about using R-MDMA or MM402 is that in our development plan, we are developing it as a drug that would be taken either daily or as needed.

So, the analogous set of drugs would be psychostimulants and ADHD, where people with attentional difficulties are able to use psychostimulants to enhance their ability to pay attention when they're in environments or doing activities that would benefit from that. So, depending on the conversation people have with their doctor that might be at school or for family events or whatever else is deemed appropriate by the care provider and the patient working together.

So, we very much see 402 working in that direction. The specific acute effects and transient effects, obviously of 402 or R-MDMA are enhanced social awareness, social communication. People become more attuned to their own emotions, potentially the emotions of others. And of course, a core challenge for folks who have ASD is and can be a difficulty with those sorts of social communication situations and awareness of emotions in themselves and others. So, we think the very direct effect of the drug while it's on board is exactly what will support people with those challenges.

As we've now disclosed, we're moving toward an early sign of efficacy study where we'll look for indications that the drug is doing the thing that we think it will, based on the preclinical and some academic clinical evidence. And obviously, that will guide our ongoing development of the drug.

Now we're going to take our next question. And the question comes from the line of Brian Abrahams from RBC Capital Markets.

This is Nevin on for Brian. Congrats on a good quarter so far and all the updates. Just had a question on some of the read-throughs or potential read-throughs, I guess, we saw from one of the other competitors in the field who had recently updated on a more accelerated time line as well for one of their studies. Is there perhaps an underlying reason as to why, in this case, the Emerge study got accelerated, but not the GAV studies and I think with the competitor as well, it was in a depression study. So, does it have anything to do with the particular indication that you're looking at? Or does that have more to do with the excitement around psychedelics?

And then, is there any additional clarity or granularity you might be able to provide on the timing for Voyage and Panorama readout? I guess, how has the pace of enrollment in those pivotals compared to what you saw in the Phase IIb?

Yes. Thanks so much for the question, Nevin. Yes, obviously, we can't speak to other companies and what they're doing in their trials, but we've been really encouraged across the board and enrollment has been strong across all 3 of our ongoing studies. And, again, we continue to be really encouraged and committed to hitting our timelines with readouts next year.

With Emerge, we certainly got started with that study quite early in terms of the window of time we had initially indicated and continue to see enrollment strong across the board. We don't certainly believe there's any distinct difference between GAD and MDD and continue to see a lot of engagement and throughput and randomizations across all 3 of the studies. So, we're on track and excited about getting 2 top line readouts as guided next year.

And if I may just ask a follow-up as well. So, given that the Emerge study looks like it's -- will read out a little over a year after it started, could we assume a similar time frame for the Ascend trial as well, perhaps maybe a little bit more just given the increased sample size?

And then I guess kind of a broader question, just given some of the recent -- given the recent fundraise and kind of the strong cash position, why not just initiate the MDD studies or the Phase III Ascend study even sooner? Why, I guess, wait -- or what's the rationale for waiting until the first one reads out?

Yes. Thanks. With the recent financing, and we feel incredibly fortunate with the support we've received and where it positions us going into next year, and we're accelerating on everything that we're doing. So, we are certainly not sitting on our hands and waiting for anything. We like to set timelines where we feel confident we can deliver, and that's really informed how we thought about the timelines that have been announced. But of course, any opportunity we have to accelerate those timelines and bring in study initiations and bring in data readouts earlier than anticipated, we certainly will take advantage of those. So, all systems go across the board in both programs and everything we're doing.

And now we're going to take our next question. And the question comes from the line of Matthew Hershenhorn from Oppenheimer.

Congrats on all the progress. So, congrats on the JAMA publication. Could you please share any physician feedback you've received on that so far? And generally, just what that publication means for the psychiatry community? And are there any details from the data, just based on your discussions that you believe might still remain underappreciated? And then I just had one follow-up.

Yes, I'll turn that over to Dan.

Yes. Everything about the way we planned, conducted and ultimately wrote about that study was meant to be digestible, familiar study design and analytic plan that physicians and others in the space would be able to read and fully understand. We've made real effort to make claims that were deeply supported by the evidence we were able to generate, and obviously, the conclusions we were able to draw from the study that have allowed us to move forward with breakthrough designation and into a Phase III program that looks in many -- basically all design ways, except for the number of arms, nearly identical to the successful Phase II.

So, I think across the board, that's recognized and appreciated in the physician community and in all the other stakeholders we engage with. So, the reaction has been overwhelmingly positive. And we're proud of the work we did, and we're really glad for what it indicates about what we anticipate being able to show in the Phase III programs.

I think when it comes to underappreciated perhaps the nature of a single monotherapy intervention without any sort of assisted therapy being able to induce remission in just under 50% of the patient population who start with, on average, severe GAD and looking 12 weeks later and seeing that sort of remission rate from a single intervention. I think even -- no matter how much we look at these data and we look at them probably more than anybody, that still strikes me as just being truly, truly a remarkable opportunity for potential sea change in psychiatry.

And then the one other question we had was just, if you don't mind, talk about just from the commercial opportunity, how you plan to practically manage patients considering the 8-hour in-clinic administration time, just considering we get a lot of questions on the perceived challenges that you could potentially solve for in the real-world setting. And maybe if you could talk about that in the context of SPRAVATO in terms of the aggregate treatment time over a year, would definitely appreciate it.

Yes. Thanks so much. I think that when we talk about Spravato, obviously, there's been a lot of attention paid, and it's really encouraging. I think it's -- the most encouraging signals there are the reality that psychiatry has and will adapt to the introduction of new treatment options. But the dynamics of -- as you referenced, the dynamics and the durability of response after Spravato session are in stark contrast to the long-lasting durable effects that we've seen so far with MM120.

So certainly, the -- there are some parallels. There are some dynamics from an infrastructure and delivery standpoint, things that have been worked out since the launch of Spravato that we certainly believe we can leverage. But it's really almost an apples-and-oranges comparison when we think about the kind of treatment dynamics and the benefits that we've been able to show so far in our clinical trials.

And so, that just speaks to the overwhelming desire for MM120 that we hear from both patients and providers when we go out and conduct research with those groups. And so, again, there's certainly -- MM120 is not and was not ever intended to be a replica of Spravato. We think it offers some significant advantages both in terms of the magnitude of change and the durability of that change. that positioned incredibly well.

So again, great learnings, great infrastructure that can be leveraged, but a totally different dynamic and one we think is quite favorable compared to any drugs that are on the market today for these indications.

And now we're going to take our next question. And the question comes from the line of François Brisebois from LifeSci Capital.

Just, the first one I had was on the market potential here between MDD and GAD. Can you just talk a little bit about the overlap? And obviously, these are massive, massive markets, but can one cannibalize the other here? Or just maybe a better understanding of the difference here between both?

Yes. I'll turn it over to Dan too to talk about it clinically in a second. I guess from a market opportunity, there certainly is a long history of drugs being labeled for both MDD, GAD and other indications in psychiatry. Some of the biggest drugs in psychiatry historically have been labeled for both of these indications. And typically, those drugs and speaking about SRIs here have started with an MDD label and then expanded into GAD, and we think that's representative of the challenges and the limitations of those drugs in treating GAD symptoms.

So, while there's certainly a high degree of overlap, we don't think about it as -- so much as cannibalizing anything as much as offering an opportunity to essentially treat 2 core symptom clusters that are overlapping in the diagnosis. But in an ideal outcome, any patient who walks in the door with anxiety or depression symptoms and qualifies as diagnosis could then be directed to MM120 if we're successful getting both of these indications on the label. But I'll turn it over to Dan maybe to comment a little bit more about the clinical presentation.

Yes. And thanks for the question, Frank. The overlap between these 2 disorders is a really interesting phenomenon. And the way that we have come to think of this is that while there are certainly patients who have a major depressive episode and as a result, are diagnosed with major depressive disorder who don't have GAD level of anxiety between their depressive episodes. So, while they're euthymic, they don't have depression.

And there are patients with GAD who have a high level of anxiety, which is more of a constant thing, not episodic, who don't go on to have a major depressive episode. For 50% to 80% of people who have either diagnosis, they would qualify for both. And that means that these are people who have had generally a pretty high level of background anxiety often for most of their lives. And because they don't really know you're not supposed to feel that way and until recently, there wasn't really a screening recommendation for anxiety disorders. So that, of course, changed in the last 3 years with USPSTF recommendations for anxiety screening.

It's kind of just like, this is how you're supposed to feel and people often have an intellectualized way of thinking about it, which is to say, well, the world is a scary and dangerous place. So of course, I'm anxious all the time. Many of those folks will then go on to have a major depressed episode at which point because of the episodic nature of the condition, they'll end up seeking care in a world where there was more screening for depression because that recommendation has been around for a lot longer and because there's just this change in condition from one day to the next.

So that will lead people then to potentially seek care on the onset of major depressive episode. So like Rob said, addressing one set of symptom of the symptom cluster, so getting to the anxiety side of things or the more anhedonic depression side of things rather than being worry about sort of cannibalizing a market, it's much more about being able to provide people an overall relief from their distress than drugs that they just have shown efficacy for ending a major depressive episode and leave people with this euthymic but highly anxious state between those depressive episodes.

So we're really enthusiastic about having been able to demonstrate the kind of efficacy we did in Phase II for GAD and the remarkable effect that we were able to show in those patients on MADRS scores. So, we're highly optimistic about our Phase III program in MDD as well. And again, just seeing this as additive benefit for people who, in the majority of cases are suffering from, in essence, both.

That's great. That's really helpful. And then, maybe just the last one. In terms of the KOL education that was brought up in terms of something to work on in the future. And -- but I was just wondering for a field that hasn't had a lot of new options in a long time, what do you think will be the biggest hurdles here with KOLs? Is it easy where the data kind of speaks for itself? Or do you expect the different tiers of KOLs where some guys are a lot more willing to try something new and maybe earlier in the treatment paradigm. I'm just wondering where you think the biggest challenges might be here for the KOL education process.

Yes. Having been out in the world in the conferences and working with a lot of these KOLs over the last several years, we are incredibly encouraged by the strong desire for something new and encouraged by the -- I think the respect that high-quality evidence has garnered from KOLs and from practicing psychiatrists almost at every level. And so, we can't -- almost can't overstate how enthusiastic many of those conversations are.

Now there are undoubtedly, detractors. There's a much smaller, but there will be a segment of practicing psychiatrists who likely don't want to deliver MM120. But what we see is an overwhelming majority in our conversations of KOLs, and again, practicing psychiatrists out in the world who -- many of them say, well, I'm not set up and wouldn't deliver any of the interventional psychiatry treatments today, but I certainly have an intent to do so with MM120, should it get approved.

And so, while there's going to be a major effort ahead so that we can shape the market and make sure that the world is fully aware of the exciting data we are generating, we don't see any sort of barrier in terms of getting that kind of engagement. And if anything, it's quite rare to see the kind of enthusiasm that we do as a field this far and in advance of pivotal readouts and it's going back several years now. So, I remain highly encouraged but highly focused on getting that messaging right and amplifying it to the greatest extent possible.

And does Spravato help here? Or do you consider it so different that it's not because someone prescribes Spravato that they're more likely to prescribe this here?

Well, we think any sort of infrastructure build-out that has happened certainly is something that we can leverage and for providers to -- quite frankly, for providers to be delivering as many treatment sessions of SPRAVATO as they have over the past several years and then to see something with higher magnitude, more durable effect that seems to drive a whole different kind of outcome for some of these patients. That contrast, we feel very good about and think positions us incredibly well.

So certainly, we think there is a segment of psychiatry that is delivering not only Spravato, but other interventional psychiatric treatments. And those tend to be some of the earlier adopters and some of those folks who are the most enthusiastic, but it is certainly not limited to Spravato centers or providers who are coming to us and talking about their enthusiasm for what MM120 could offer patients.

Now we're going to take our next question, and it comes from the line of Ami Fadia from Needham & Company.

Congrats on the quarter. My first question is, can you talk about the persistency rates of patients in Voyage and Panorama studies that you're seeing on a blinded basis and how that might be progressing relative to the dropout rates that you had assumed in the trial design?

And in terms of what we can expect from a communication perspective, should we assume that when you do conduct the sample size re-estimation, that will not be made public? And then I have 1 or 2 other questions.

Yes. Thanks so much for the question. We won't comment on ongoing studies or even unblinded data from those studies until we hit a point of having data and being able to announce fully the outcomes of a study. But we certainly have been really encouraged on a lot of the metrics, but -- and really all of the metrics that we've been measuring in the trials and continue to be committed to executing these studies with the highest quality and on time and get to results at appropriate time next year. And again, we haven't commented specifically on whether or not we would announce a sample re-estimation publicly or not.

Got it. And then, in the Panorama and the Ascend studies where you have 2 doses of MM120, once we sort of get the results and especially from a regulatory perspective, how much of a difference across the doses would you like to see or do you think the FDA would like to see in terms of efficacy and safety to be able to sort of address the functional unblinding question or maybe kind of a dose-dependent change across the doses question?

Well I think the important point there is about the need for programs to demonstrate dose response. So, when we think about things like functional unblinding, which are problems across all of psychiatry, anything really in the CNS, of course. We think demonstration of dose response is really critical and gives a high degree of confidence in there being a real treatment effect of a drug. And that's why we did the Phase II study we did and uniquely in our field have comprehensively characterized the dose response.

We have a study that has been completed and published and that we're really excited about, of course, that demonstrated both clinically from an observational standpoint, but also statistically that there is a dose response. And that was even in light of the fact that virtually all patients regardless of the dose of active drug they received reported being functionally unblinded by correctly guessing that they were on drug. And so, there's not really a question at this point in our minds about whether there is a dose response because we did a dedicated study to demonstrate that and that successfully proved that there is.

And so, the availability, the existence of the lower dose, the 50-microgram arm really is a sort of prospective use in the study and that it allows us in the [ consent ] process kind of confound expectations to effectively say to a patient, if you were to feel the effects of drug on the day of dosing, you can't assume it's the full real dose of drug.

It actually is the dose of drug in the prior study that we showed is functionally unblinding but does not have clinical activity in reducing anxiety symptoms. And so, it is a design element and a sort of functional control in the study. But in terms of the outcomes of the data, primary outcome measures in both Voyage and Panorama and in Emerge and Ascend is testing 100 micrograms versus placebo and no outcome of the 50-microgram group can alter the finding of that primary analysis. So, regardless of what happens in terms of the group response to 50 micrograms, we'll be seeking to clinically and statistically prove that MM120 100 micrograms is superior to placebo.

Got it. That's very helpful. Maybe my last question, if I could squeeze one in. The feedback that we've received from a lot of KOLs is that the key differentiating factor and maybe a huge unmet need is the potential to reduce the frequency of retreatment. Can you comment on any sort of follow-up or sort of experience from the Phase II that can throw some light on what is sort of the range of time frame within which patients will require a retreatment?

Yes. So, what we saw in terms of the average curves and response is that we didn't see any sort of deterioration of effect out to 12 weeks. And because of that, we can't really even attempt to project those curves and arrive at a time when we would anticipate reliably that patients would need a retreatment. And of course, we're trying to characterize that in Part B of our Phase III studies that are ongoing and planned.

We certainly hear and have looked at real-world use, the compassionate use programs and have been encouraged by the durability of LSD that can last well beyond 12 weeks in some of those studies and are really excited to characterize that in a robust fashion in our Phase III program. But it's a little bit premature to say decisively or exactly where we expect retreatment, although what we do know is that -- and we believe we have alignment around the right approach to characterizing this is to do exactly what we're doing in the Part B of the Phase III studies, which is to screen patients and when they have a recurrence of symptoms, having a 16 or greater or a MADRS of 20 greater depending on the study, the availability of open-label retreatment and to try to characterize those dynamics, the intervals between doses and the ultimate frequency over the course of a 12-month period in the study. So, really excited to get to those data, but a little bit premature to say so today.

And we're going to take our next question. And the question comes from the line of Sumant Kulkarni from Canaccord Genuity.

Nice to see the progress. I have a few. First, because MDD is more episodic versus GAD that has more chronic characteristics. Do you expect any difference in durability of effect with MM120? And what could that mean for a number of treatments per year for each indication? And would you expect price per treatment for MM120 to be the same in GAD and MDD? And then I have a follow-up.

Yes. Thanks so much, Sumant. I mean, exactly why we're doing the studies is to try to characterize that. We believe that based on what we've seen and that the curves as I was describing for both anxiety and depression symptoms in the Phase II, we saw somewhat similar response patterns. And so we're certainly very focused and very interested in characterizing those treatment responses and retreatment characteristics, and that will certainly inform everything from how we approach clinical regulatory and pricing discussions.

Got it. And the follow-up, if we look at Slide 23 in the MM120 commercial framework of your latest slide deck, it says psychotherapy is not offered or required, but may be added outside a dosing session based on individual needs and goals. So, in real-world usage, what percentage of patients do you think this might be applicable to? And how would that impact commercial or reimbursement-based variables?

Well, I think overall, we hope that every patient gets the availability of every treatment. We know that psychotherapy is not reimbursed particularly well today, and we don't -- it's not our position or place with MM120 to exactly change that. So certainly, we expect in the real world that some patients who are already in psychotherapy would be candidates for MM120 and could likely continue on.

We've certainly, again, from observations out in the world, seen both patients in academic studies and in real-world use who are administered a psychedelic and then decide to pursue psychotherapy thereafter. So, we, of course, want to have labeling and a development program that enables the widest adoption and the widest set of use cases for MM120 should get it approved and out in the world. But we do not, as part of the development program, require or deliver any sort of psychotherapy in our program.

And the next question comes from the line of Patrick Trucchio from H.C. Wainwright.

I have a couple of questions. The first is, I think you noted that the Phase III program in GAD is powered 90% to detect a 5-point improvement on the HAM-A. And I think that compare to the 7.7 point placebo-adjusted difference observed in the Phase IIb. I'm wondering if you can put that 5-point threshold into a clinical context. How should we think about the relevance to patients in real-world outcomes? And then just, I guess, a clarification for the depression program, Emerge, have you shared how that study is powered as well and your expectations heading into that mid-2026 data readout?

Yes. Thanks so much for the questions, Patrick. Yes, so when we look at the context of historical and currently approved products in generalized anxiety disorder, we typically see an under 5-point placebo-adjusted change and more commonly, somewhere in the mid-3 point over placebo. And on an absolute basis, typically in the low-teens in terms of the absolute magnitude of HAM-A improvement for the approved therapies.

And so, in that context, we saw almost 22-point improvement in the 7.7 placebo-adjusted delta in our Phase II study at 12 weeks after a single dose of drug. And so, we're trying to be, of course, conservative in powering assumptions so that we can give ourselves a good probability of success. And the same approach applies. We want to see a clinically meaningful change with -- in both GAD and in MDD, and that's how we've approached the powering and design of all 4 of the Phase III studies.

So I think, earlier, 2025 described as a year of constructive dialogue with the FDA. I'm wondering if you can elaborate on key areas of alignment that have been achieved so far and what still needs to be finalized ahead of potential NDA submissions? And as well, would you anticipate submitting the NDA for GAD with the 12-week data or would you be -- would you need longer-term data from Part B prior to submitting?

Yes. We've had an ongoing and incredibly constructive dialogue with FDA, and we're very grateful for their level of engagement under the breakthrough therapy designation program, and we've really taken advantage of that and try to seek an ongoing dialogue and a high degree of alignment on all the studies we're conducting, including in particular, the Phase III studies.

And so, we don't tend to speak about specific agency interactions on an ongoing basis, but we do believe there's a high degree of alignment. We believe the most important data is the data that we need to demonstrate the Part A from our Phase III studies to demonstrate at 12 weeks in GAD and at 6 weeks in MDD that we have 2 studies that show hopefully the safety and effectiveness of MM120.

So that's been our approach. And again, incredibly constructive dialogue. And as we progress and deliver pivotal data over the course of 2026, we'll continue that dialogue and do everything. The team has an incredible track record of hitting our milestones and being incredibly efficient with how we operationalize our program. We continue to do that in clinical development. We intend to do that through the remaining regulatory and commercial milestones lie ahead.

Lastly, I'm wondering if you're anticipating an FDA advisory committee meeting as part of the review process for GAD and/or MDD? And how is your clinical development program position you to prepare for that discussion?

Our approach has been to generate the strongest, most robust evidence and data package to stand up to any stakeholder in any form of scrutiny. And so, whether or not an advisory committee is required, we certainly will be prepared, but it's premature to say until we've got that stage of review cycle and had the dialogue with FDA at that point to say one way or another, whether an advisory committee would be required or not.

Now we'll go and take our next question. And it comes from the line of Christopher Chen from Baird.

Can you hear me now?

Yes, we can.

Okay. Great. Yes, I apologize. I think I'm having some connection issues. Congrats on the quarter. Just regarding the currently running Phase IIIs, can you talk a bit more about the safety monitoring in that interim 3-month period following the initial dosing? I'm just curious what guardrails are in place for patients and how you tow that line between ensuring support for these patients while not crossing over into psychotherapy? And then I do have a follow-up.

Yes, I'll turn it over to Dan.

Yes. I mean it's a great question. And obviously, we want to ensure the safety of people as they participate in our studies. Through the entire duration of the participation per participant, that's for the full year, folks are in regular contact with the site, and we do regular AE assessments. We do regular C-SSRSs to ensure that no one has developed suicidality.

We are very attentive to these things. But that kind of monitoring is completely consistent and coherent with the history of psychiatric drug development. And it says something about the category and assumptions that had been made prior to some of our research about what was required to do research in the category. And so, the difference between safety monitoring and if someone were to have a safety issue and then we needed to refer them out to a higher level of care, of course, we could do that.

At that point, the person would be discontinued from the study because that would be an event leading to early termination from the study. But none of that even borders attempts to change symptoms through an engagement and interaction. So, none of that -- in no way does any of that safety monitoring even touch on the sorts of interventions that would constitute psychotherapy.

I'll just make one final point to emphasize this. Psychotherapy is defined construct and something that has a long history. And I think there's been attempts to sort of conflict the meaning of what that is. And so, we are very intentional about how we instruct the sites to conduct the study, and that is to specifically not deliver psychotherapy in the [ conduct ] of our studies, and we've maintained a high degree of adherence to that through our development program.

Great. Great. No, super helpful. And then just real quick, just regarding the treatment session itself, do you have protocols in place just in the rare event that a patient might need to stay beyond that 8-hour time point? And then will the final data read include data on instances of that?

Premature right now to say exactly which data we'd be sharing at which point in time. We certainly intend to be complete with our disclosures at the time we have top line data from our Phase III studies. But we have plans in place and contingency plans in place for all sorts of eventualities as any clinical trial does. But we've been really encouraged with the ODT formulation and our approach to patient safety monitoring in Phase III.

I've been really encouraged by what we've been observing so far and throughout our development program and it's really aligned with our intention, which is to develop an incremental body of evidence that arrives at a really efficient delivery framework for hopefully labeling discussions and commercialization of the product.

Dear speakers, there are no further questions for today. This concludes today's conference call. Thank you for participating. You may now all disconnect. Have a nice day.