ATAI Life Sciences N.V. Stock

All right. Good morning, everyone, and thank you for joining us for AtaiBeckley's 2026 Investor Day.

Before we begin, I'd like to remind everyone that this call and presentation will contain forward-looking statements. These statements are subject to risks and uncertainties, and actual results may differ materially. We undertake no obligation to update our forward-looking statements, except as required by law. Additional information can be found in our SEC filings. With that, let's review the agenda.

We're really excited to walk you through our strategy, clinical progress and our vision for leading a new era in interventional psychiatry. Today's presentations will focus on how our lead asset, BPL-003, is positioned to deliver rapid-acting, durable and scalable treatment options for patients with treatment-resistant depression and beyond. After a short break, we'll then turn our focus to a roundtable discussion featuring leading experts in the field followed by a moderated Q&A with our management team and the key opinion leaders.

We have a full morning plan and I'm pleased to introduce Srini Rao, Co-Founder and CEO of AtaiBeckley, who will start the morning with an overview of AtaiBeckley's strategy and portfolio. Srini, over to you.

Great. Thank you, Jason, and thank you to every one of the audience who's made time to join us today on our Investor Day webcast. At AtaiBeckley, our mission is clear: to transform mental health care by developing next-generation psychedelic-based neuroplastogens that combine rapid onset, durable benefit and real-world scalability.

We're uniquely positioned to lead this category with an approach built on four core pillars. Number one, we focus on indications with high unmet medical need like treatment-resistant depression, or TRD, and social anxiety disorder, or SAD. Number two, we're advancing therapies designed for rapid acting and durable clinical impact with the goal of moving beyond daily or frequent intermittent dosing paradigms. Number three, we've designed our products from the outset for real-world scalability. This involves using practical and familiar routes of administration and plugging into established care delivery models. And finally, number four, we are diligent in protecting our innovations with a comprehensive IP portfolio across compounds, formulations and methods of use.

Together, these pillars define how we build, prioritize and deliver therapies that can truly shift the standard of care and transform patient outcomes in the mental health space.

Now on the next slide, you can see our pipeline which spans across the TRD and SAD clinical stage programs and also includes our emerging discovery stage assets. We will, of course, focus on BPL-003's recent progress and advancement in the Phase III pivotal studies for the remainder of this call.

Now let's take this opportunity to briefly touch on our other clinical programs, starting with VLS-01. This is a differentiated buccal film formulation of N,N-dimethyltryptamine or DMT that is being developed for TRD. In a Phase I clinical trial, VLS-01 demonstrated a promising profile that combines a short duration of subjective effects with encouraging tolerability. We are eagerly awaiting the top line data from the ongoing Elumina Phase IIb trial in the second half of this year.

I also want to talk briefly about EMP-01 and highlight the positive top line results we announced last week from an exploratory Phase IIa trial in SAD. What really sets EMP-01 apart from racemic MDMA is its unique pharmacology. By eliminating the S-enantiomer of racemic MDMA, we reduced the stimulant activity and strengthened serotonergic effects. As we mentioned last week, the Exploratory Phase IIa study, the first of its kind in general SAD with a psychedelic compound, met its primary endpoint on safety and tolerability and moreover demonstrated very encouraging early signals of efficacy. The consistent gains across secondary and exploratory endpoints combined with a differentiated subjective profile, provide meaningful validation of both our -- of the compound and our development approach.

Taken together, we are very proud of our leading portfolio of three high potential clinical assets and conditions with large unmet medical needs. So let's go on to the next slide.

Depression and anxiety represents some of the most prevalent and burdensome mental health conditions globally. In the U.S. alone, more than 20 million adults experience major depressive disorder each year, and over 30 million experience social anxiety disorder across their lifetime. These are massive patient populations, but more importantly, they are populations where treatment innovation has lagged. The opportunity is significant, and as we'll discuss, we believe our clinical and commercial strategies are aligned to capture it.

On the next slide, we expand on the unmet needs that continue to define the mental health landscape. Despite decades of available treatments, the reality is that many patients are still left without symptom relief for their mental health conditions. On top of that, most current therapies often take weeks to work if they work at all. Many require chronic daily or intermittent dosing that is often associated with undesirable side effects that many patients simply can't sustain. The burden is real and it manifests both chronically and economically.

What's becoming increasingly clear is that next-generation therapies must do more than merely suppress symptoms. They need to meaningfully reset the underlying circuits to drive these conditions to thus provide long-lasting benefit. That's exactly the gap that psychedelic-based neuroplastogens aims to fill.

The figure on the next slide lays out the mechanistic foundations behind our approach. Psychedelic-based neuroplastogens activate pathways that promote synaptic regeneration in neurogenesis, but they also disrupt maladaptive brain network activity. You can think of it as helping the brain escape entrenched patterns that often underlie treatment-resistant mood disorders.

The acute biological effects are associated, of course, with a unique subjective experience. Beyond psychedelic phenomena, this experience may involve emotional release, perceptual shifts and cognitive reframing.

Together, this combination of mechanistic neuroplasticity and the associated subjective experiences, are thought to underlie the rapid benefit seen with these compounds. This dual mechanism also seems to open a longer period of behavioral plasticity that in turn drives durable efficacy. This durability is critical to making intermittent dosing feasible. The shift to intermittent dosing promises to fuel the next phase of change and growth in the field of interventional psychiatry.

The next slide outlines the progression of interventional psychiatry from devices like rTMS to pharmacotherapy starting with ketamine and then on to esketamine. These compounds represented a paradigm shift for the space when they were first introduced as they were the first drugs to offer rapid symptom relief. However, they lack durability and thus require frequent redosing. First-generation psychedelic products based on psilocybin or LSD offer both rapid onset and durability. However, both require many hours in the clinic. This markedly increases complexity, limit scalability and increases the burden on patients.

This leads us to second-generation psychedelic-based products, the space where AtaiBeckley leads. Both BPL-003 and VLS-01 were purposefully designed for short, scalable in-clinic sessions. We've essentially taken the lessons from earlier interventional approaches, including SPRAVATO and design treatments that retain or possibly even improve upon efficacy while dramatically reducing complexity. This shift is foundational as it allows clinics to deliver high-impact treatments without sacrificing capacity and it makes these therapies accessible to many more patients.

The next slide highlights this core pillar of our commercial differentiation strategy. J&J has built the infrastructure that has led to SPRAVATO's commercial success with thousands of clinics nationwide that now operate under a workflow that includes pre-dose checks, on-site administration and post-dose monitoring. BPL-003 fits directly into that structure with a similarly short in-clinic stay and no need for psychotherapy or specialized equipment. As you can see, this is a critical differentiator from the rest of the late-stage psychedelic pipeline. The short in-clinic time allows clinics to maintain predictable patient schedules, maintain high throughput and operate within existing staffing models. For patients that dramatically reduces the burden of care, instead of weekly visits, BPL-003 has a potential for 4 to 6 short treatment sessions per year without compromising efficacy. This is what scalability looks like in interventional psychiatry and AtaiBeckley is the leader.

Now on the next slide, I want to highlight how the convergence of science, strategy and timing has put AtaiBeckley in this truly enviable leadership position. The pace of progress in this field has never been stronger, and it's clear that psychedelic therapies represent the next paradigm shift in the treatment of mental health conditions. Moreover, we're at a moment where regulatory clarity, clinical maturity and commercial precedent in psychedelic therapies are all converging. AtaiBeckley brings together the expertise, the clinical data and the purpose-built infrastructure to lead the shift towards second-generation psychedelic therapies. This alignment positions us uniquely to shape the future of interventional psychiatry.

And now on to the next slide. We have begun 2026 building upon our successes in 2025. BPL-003's Breakthrough Therapy designation positions us for enhanced engagement with the FDA and a potentially accelerated path towards approval. And now we've obtained alignment on our Phase III program with the agency, as we'll discuss shortly.

We have several important readouts and milestones ahead, including the initiation of our Phase III program and additional Phase II readouts across the pipeline. Following our M&A and IP expansion last year, our financing activities allowed us to end last year with just over $220 million in cash. Combined with our inclusion in the NASDAQ Biotechnology Index and successful U.S. redomiciliation, we're in a strong position to execute. Now we're excited to dive deeper with you on the BPL program and our commercial strategy.

I'm excited to hand this off to Kevin to go through the clinical summary of BPL-003 and the upcoming BPL-003 Phase III design and plan. Kevin?

Thank you, Srini. Yes, I mean, we are excited to share details about our BPL-003 program, the progress we've made so far and the next steps to come. Many of you are familiar with the BPL-003 program, but we'd like to start with an overview of the key features on the next slide.

BPL-003 is an intranasal dry powder formulation of mebufotenin benzoate. It's a serotonin receptor agonist with rapid onset and a short in-clinic monitoring time. Following positive Phase IIb results, where we saw rapid and durable effects after a single dose of BPL-003, it was granted FDA Breakthrough Therapy designation, reflecting both the strength of our data and the significant unmet need in TRD. After a successful end of Phase II meeting, we plan to initiate the first Phase III study in Q2 and the second in Q3 with final designs informed by FDA feedback. The FDA indicates their support for our proposed Phase III program reflecting a robust safety and efficacy profile across multiple Phase I and Phase II trials.

In clinic, most participants were deemed ready for discharge approximately 2 hours after dosing, which if replicated in Phase III, could support higher patient throughput in established workflows, as Srini alluded to. Collectively, the combination of the strong data package, momentum for Phase III and a convenient dosing provides a strong foundation for us to continue studying BPL-003 in the future.

Before diving into the Phase IIb data, I'd like to just take a step back on this slide to provide a quick background on the different routes of administration for psychedelic treatments. The treatment administration methods listed here can significantly shape a patient's clinical experience and impact how scalable treatment is in clinical practice. Among the options, the intranasal and buccal sublingual routes aligned most closely with real-world treatment requirements. They're familiar to clinicians, offer convenience to patients without compromising on predictable PK and a rapid onset, which are key considerations for scalability. BPL-003 uses an intranasal route of administration, which is important for its potential to be adopted in real-world clinical settings and to take advantage of existing interventional psychiatry workflows.

Now that we've set the scene, let's look at the Phase IIb data on the next slide.

As a whole, our Phase II data created a differentiated and well-rounded profile that gives us confidence in our advancement into Phase III. At a high level, we demonstrated that BPL-003 is fast-acting, durable, highly effective, well-tolerated and convenient in TRD. In the IIB, we saw the antidepressant effect of BPL take effect quickly with significant reduction in MADRS scores. The efficacy signal proved compelling and durable and with high response and remission rates. BPL was also well tolerated and provided convenient administration with only a 2-hour time to discharge readiness, supporting feasible real-world administration in a long-term maintenance setting.

Let's walk through the Phase IIb design on the next slide.

So our Phase IIb trial of BPL-003 was a randomized quadruple-masked study enrolling patients with moderate-to-severe TRD. Walking from the left of the slide, eligible patients were washed out if they were taking antidepressant medications and those that weren't -- were enrolled. All the patients were then randomized to 1 of 3 groups, either 12 milligrams, 8 milligrams or the control arm, 0.3 milligrams. The primary endpoint was the total MADRS score at day 29, change from baseline. And we followed patients up and took MADRS scores 1 day after dosing, the week later, day 8 and day 57. So that was really to establish the long-term durability of the effect.

And then at the end of that core study, participants who are eligible could then roll over and move into the open-label study where they could receive a single dose of 12 milligrams of BPL-003. In addition to that primary endpoint, we had secondary endpoints, which included the MADRS change from baseline, as I mentioned, at day 2, week 4 and week 8 as well as the effect of 8 milligrams at week 4, and we also looked at response and remission rates.

The design of the Phase IIb trial allowed us to measure both acute and long-term effects of BPL across the doses and repeat administrations, which provided critical insights into the timing of onset, the efficacy and the durability.

On the next slide, we see that a single dose of BPL-003 met the primary end point. We observed a statistically significant change in MADRS score at day 29, with effects sustained up to week 8. For the 8-milligram arm, the MADRS change was minus 12 from baseline and minus 6.2 when comparing to the 0.3 control arm. The 12 milligrams was 11.2 change from baseline with a 5.3 difference compared to the 0.3 control. I want to highlight that the treatment effect was quite significant as early as day 2 which reinforces BPL's fast-acting profile.

Looking at the blue and green lines on the chart, you'll note that the 12 and the 8 doses of BPL achieved comparable improvements in MADRS. The comparability is important because especially when we consider the safety data that we will talk through later on, which favored 8 milligrams. That combination of similar efficacy with a favorable safety profile is the key factor behind 8 milligrams as the Phase III dose. And I'll touch more on that in the following slides.

When placed alongside external data sets for context, and we're looking here at an overview of the MADRS outcomes across clinical studies in TRD, we can see that earlier time points, the change from baseline in MADRS score versus placebo or control looks similar across the COMP360 and SPRAVATO trials. You'll note that the durability or rate of change over time is also quite consistent across the two COMP360 trials. BPL's week 8 durability appears encouraging. However, these are indirect comparisons and, of course, different study designs. So not head-to-head. However, the longer-term treatment effect looks quite different. The efficacy signal for BPL-003 shown in the green line here remains durable to week 8. This data suggests that BPL may offer a more durable effect following a single administration. But we do want to caveat that these obvious limitations to this comparison, namely that it isn't a head-to-head study, and we're comparing Phase IIb data to other Phase III studies where study designs differ.

Before we move on to the open-label results, it's worth underscoring how patients actually move through the study. Not only did we see strong efficacy in the core phase, but participants who stayed engaged and the completion rates were high through both core and open label, and most who are eligible to move into the open label, chose to do so. The pattern of completion and rollover speaks to treatment experience that has proven to be practical and manageable from a patient experience standpoint. And that acceptability becomes even more meaningful as we look at how patients responded after receiving a second dose in the open label.

Here, I'd just like to provide another glance at the IIb trial design, specifically focusing on those key details in the open-label study. As mentioned before, the open-label aimed to assess efficacy and safety of a second 12-milligram dose over a further 8-week period. And results from the next slide of the open-label here reinforce the durability and reproducibility of the BPL effect.

After patients received a second dose, 12-milligram dose, we see an additional significant drop in the MADRS across all treatment groups. Even in patients who received the 0.3-milligram dose initially, the MADRS reductions were comparable to the antidepressant effects seen in patients who received 8 or 12 initially. More notably, patients who received an active dose of 8 or 12 initially showed a mean reduction in MADRS of 19 points at day 57 of the open label compared to the initial baseline.

This data also helped influence our decision to take the 8-milligram forward. What we saw is something that we hoped for but didn't necessarily expect. Here, where the 8-milligram looked as good as the 12, giving us a lower dose with similar efficacy, which is always a good thing. Together, the significant MADRS reductions and durable effects tell us that BPL remains efficacious over the long term with repeat dosing prolonging and deepening the initial improvement.

The next slide shows responder rates across the core and open-label studies, highlighting how responder rates change after administration of that second 12-milligram dose. On the left-hand side, responder rates during the core study reached the high 20s, low 30% range for the 8- and 12-milligram treatment arms. But importantly, after patients received the second dose, response rates significantly increased across all 3 treatment groups. The 8-milligram dose, followed by 12 appears to demonstrate the strongest response with a response rate of over 80% by the end of the open-label extension. The data here supports our dose selection decision for Phase III and we'll transition to that in the next section.

Similarly, remission rates across the core and open-label studies showed a very similar pattern, the one on the last slide. We see a steady rise in remission rates after the first initial dose that increases more noticeably after the second dose was administered. Again, the 8-milligram dose followed by the second 12-milligram dose demonstrates the most efficacious and durable response compared to the other two treatment arms. Remission rates reached 67% for the group at the end of the open-label extension, which is a substantial increase from what was achieved in the core study.

Just moving on to the safety and tolerability on this slide. We observed BPL was generally well tolerated across all doses with the vast majority of treatment-emergent adverse events being classified as mild or moderate in nature, and resolving quickly without intervention. What I'd like to emphasize on this slide is that when looking closely across the doses, the 8-milligram arm showed better safety profile than the 12, although both were very good with only one severe treatment-emergent adverse events, drug-related in the core study, the rest being mild or moderate. There were no serious drug-related adverse events reported in the core study and one serious drug-related adverse event reported in the open-label.

The table on the left here lists the most commonly reported drug-related side effects, which were generally as expected. What is encouraging is that most patients were deemed ready for discharge within 2 hours after dosing, which also remains consistent with our expectations and supports the potential for a highly convenient dosing experience in the clinic. The acute effects of 8 milligrams appear to be less intense and better tolerated than 12. It is worth noting that the adjunctive benzodiazepines were available to investigators for agitation, anxiety but they were never needed, which gives us additional reassurance about the overall containment of the experience.

In the context of the comparable efficacy you saw earlier, the balance between effectiveness and tolerability was a key driver behind selecting 8 milligrams as our go-forward dose for Phase III.

To bring all this data together on the next slide, there are a few takeaways from our Phase IIb program. The study is the largest study of mebufotenin conducted and met both primary and secondary endpoints, providing a high level of confidence as we prepare for Phase III. Both the 8- and 12-milligram active doses of BPL demonstrated rapid and durable antidepressant effects and resulted in a short psychedelic experience that allowed patients to be discharged after just 2 hours in clinic. Across doses, safety was favorable with 8 milligrams showing preferable safety profile and comparable efficacy, which is a key driver. The full evidence package so far certainly warrants continued clinical and commercial development of BPL. And we're really excited to show you the details of our planned Phase III program next.

So now let me move on to the next steps of the clinical development for BPL-003, the Phase III pivotal program.

The pivotal program for TRD is designed to generate the clinical and safety evidence regulators and clinicians expect while informing commercial uptake assumptions. Both single doses and two-dose induction regimes will be evaluated and each trial will include a 12-week core study followed by a 52-week open-label extension, supporting assessment of both acute efficacy and long-term maintenance of effect. During the open-label extension, retreatment will be individualized and will occur every 8 to 12 weeks, allowing for flexible maintenance dosing. Efficacy endpoints will be evaluated by remote, independent, blinded raters, to reduce the possibility of bias and study participants will not receive psychotherapy during the study period, which helps isolate the pharmacological effect in this design. The Phase III program is broadly supported by several essential factors, including FDA alignment, breakthrough therapy designation and a robust differentiating characteristics of BPL, such as the short in-clinic sessions, robust efficacy and early onset and the potential for 4 to 6 treatments per year over the long term.

Before we get into the Phase III program, I want to talk a little bit about the name ReConnection, which is what we've named our studies. We've heard from patients that treatment-resistant depression can feel like a disconnection from people, from daily life and from themselves. So the name ReConnection really reflects the core unmet need in TRD, helping patients to reengage in their lives, their relationships and themselves. And that is the outcome we're ultimately aiming to restore with our trials.

On the next slide, we show details about the dual Phase III program, aims to reflect regulatory confidence and generate robust comprehensive data. The BPL-003 trial design reflects both regulatory guidance and real-world stakeholder requirements by incorporating a long-term open-label extension and large participant sample size for safety. These elements are critical for building confidence in key stakeholders around safety, durability and real-world applicability. Furthermore, by confirming the robust efficacy of an 8-milligram dose across two independent well-executed trials, we aim to strengthen our evidence package and reinforce dose selection decisions.

Finally, the Phase III program is designed to support the flexibility and optionality of BPL over the long-term treatment by evaluating responder patterns and individualizing retreatment timing. These studies will clarify how BPL may be utilized in the real-world maintenance setting. Our overall approach to the dual trial Phase III program will broaden our evidence package across safety and efficacy, ensuring clinical adoption and commercial viability at launch.

The details here on the next slide depicts how each trial plays a complementary role within the broader Phase III program. At a high level, both studies share the same overarching objective, to demonstrate rapid and durable antidepressant effects with a short in-clinic session while also supporting the potential for flexible individualized retreatment over the long term. ReConnection-1 aims to establish robust efficacy and characterize the dose response. It will be a 3-arm randomized double-blind trial, evaluating 8 milligrams and 4-milligram doses against placebo using a single dose induction. The 4-milligram dose produces a reliably perceptible psychedelic effect, but with substantially lower intensity and shorter duration than 8 milligrams. This supports its selection as the lower dose control recommended for mitigating functional unblinding while maintaining the potential to detect a dose response relationship.

ReConnection-2 is a 2-arm study, comparing 8 milligrams of BPL against placebo using a 2-dose induction. The doses will be administered on day 1 and day 15. In both trials, change from baseline in MADRS total score will be measured at day 29, serving as the primary endpoint. Together, the two studies will allow the evaluation of two distinct induction regimens and strengthen the potential for flexible real-world treatment tailored to unique patient needs.

This slide and the next slide provide detailed designs about the studies. ReConnection-1 is designed to replicate and extend the treatment response that we saw in the Phase IIb study and to further characterize the dose response relationship. Participants in this trial will be randomized 2:1:2 across 3 treatment arms, 8 milligrams, 4 milligrams and placebo, respectively, for a single intranasal administration of BPL or placebo on day 1. Eight milligrams has been prioritized as the optimal dose based on the prior Phase I and Phase II data, as I outlined earlier. The inclusion of the 4-milligram arm will allow for a better characterization of the dose response relationship. The primary goal of this study is a strong foundation for labeling discussions and commercial positioning.

Reconnection-1, like ReConnection-2, will also include a 52-week open-label extension after the 12-week core part of the study is complete. The open label allows participants to receive individualized treatments with 8 milligrams every -- at 8- to 12-week intervals subject to predefined criteria. Incorporating a long-term open label extension was strongly supported by FDA feedback and is designed to generate the broader safety database needed for this chronic indication as well as to understand the maintenance of effect and real-world dosing patterns.

Similarly with ReConnection-2, it follows a largely aligned trial design to the first study with a 12-week double-blind core followed by the open-label extension. This study will randomize participants 1:1 to receive a 2-dose administration of either the BPL or placebo on days 1 and 15. While ReConnection-1 aims to define the dose response relationship for BPL, the second study will test the clinical potential of a 2-dose induction regimen, exploring the potential to increase the magnitude and durability of the initial response and inform real-world induction optionality.

The next slide shows the comparison of both pivotal trials and highlights how the overall Phase III program for BPL is structured to support a potential broad flexible label while maintaining and maximizing operational efficiencies. The core design elements across two trials, including primary endpoint and study time lines are intentionally aligned to reduce operational complexity and enable cross-trial data comparison. Together, these programs cover both single-dose and two-dose induction regimens along with individualized retreatment during the open label.

Now let's look at the future for BPL-003. Minutes from the end of Phase II meeting showed that the FDA indicated support for the -- and provided constructive feedback on the overall design and the key components of the proposed program, including the overall size of the safety database. In parallel, we're expecting a readout from the Phase IIa Part IV study this year. This is the 8 plus 8-milligram 2-dose induction open-label study, which will provide additional insights that may inform future clinical and commercial planning. We expect top line readouts from both Phase III trials in early 2029, subject to enrollment and operational variables, which will directly inform launch planning activities and our broadband commercial strategy.

Looking forward to the next few years, our key milestones reflect a well-planned and sequenced time line, which will position us for continued clinical investigation of BPL and future potential -- future approval and launch in TRD.

Now I'm going to hand it over to Ryan, our Chief Legal and Business Officer, to provide an intellectual property overview. Ryan?

Thank you, Kevin. Intellectual property is a critical pillar of our overarching business strategy. As you just heard, we're breaking new ground in mental health treatment and it's essential that we protect our innovations to capture their full value. My team's mandate has been to ensure that each of our core programs is safeguarded by a robust patent estate. As we move to the next slide, I'll begin providing a high-level overview of how we're achieving this objective and why it matters, particularly for our lead asset, BPL-003.

At the outset, I would note that our intellectual property strategy here at AtaiBeckley is comprehensive. Within this comprehensive strategy, we filed patents that cover both composition and method of use claims. And we craft those claims in light of and to align with each drug's target product profile, or TPP, as well as its intended labeling. In the simplest of terms, we look to protect what the product is and how it's used.

Starting on the left-hand side of the slide, composition claims may seek to protect the drug substance, the molecule itself, including specific salt forms and polymorphs as well as a drug product such as the formulation or dosage form. These composition claims ensure that would-be competitors cannot make or use the same claimed chemical compound or formulation, but they do so only once these claims have issued, an obvious but key distinction and a point of strength for us here at AtaiBeckley. Notably, these composition claims are indication agnostic, meaning that they cover the compound or formulation regardless of what disease it's used for.

As a specific example here in AtaiBeckley, we've successfully patented the benzoate salt form of 5-MeO-DMT also known as mebufotenin, and the inclusion of a key excipient, namely silicon dioxide in our proprietary intranasal powder formulation of BPL-003. In contrast to composition claims, method of use claims shown on the right-hand side protect the specific ways the product is used, which can include the indication as an example, in treating treatment-resistant depression, dosing regimens and even the route of administration in some cases.

These indication-specific claims are vital in our field and particularly with respect to naturally occurring or known compounds. For instance, even though 5-MeO-DMT is a known substance, no one can use our proprietary 5-MeO-DMT benzoate salt intranasal formulation to treat depression here in the United States without infringing upon our issued U.S. method patents. This dual approach securing both composition and method claims tailored to the target product profile is key for effective market exclusivity.

This approach also supports our Orange Book strategy wherein we align our patent claims with the final drug label so that the resulting patents can be listed in the FDA's Orange Book and thus get the full benefit from the Hatch-Waxman act. This Orange Book strategy ensures that if anyone tries to file a generic, they must contend with our issued patents, giving us the opportunity to legally challenge and potentially block entry of that generic until our Orange Book-listed patents expire.

In summary, our comprehensive IP strategy is designed to leave no gaps. We seek to protect the innovative molecule, the precise formulation and device as well as their use in our target indications. And we do so with an eye for ensuring that we get full benefit from the Hatch-Waxman act. On net, this approach provides a strong foundation for commercialization of the approved therapeutic and multiple layers of defense, making it very difficult for competitors to design around our patents.

Moving to the next slide. I'd like to specifically address the patent coverage we secured for BPL-003 here in the United States. Since that's our flagship program and our key market. As alluded to in the previous slide, and as we do with all of our programs here at AtaiBeckley, we have pursued a comprehensive IP strategy for BPL-003, including targeting key composition and method claims that are well aligned with and build upon the target product profile for BPL-003. We are very pleased with the results to date, both in terms of the strength of the issued claims and the duration of the issued patents that we've secured for this asset here in the United States.

Diving in with a bit more specificity, we have issued U.S. patents to protect various 5-MeO-DMT compositions, including BPL-003's drug substance, namely the 5-MeO-DMT benzoate salt as well as other potential salt forms and polymorphs of 5-MeO-DMT. These patents currently have a lifetime out to 2041.

Changing the focus to drug product claims, we also have issued U.S. patents on BPL-003's formulation as well as its route of administration. As discussed previously, one issued U.S. patent covers a proprietary intranasal dry powder formulation of 5-MeO-DMT combined with silicon dioxide as an excipient. This issued drug product patent provides us with Orange Book listable patent protection on BPL-003 to August of 2043, providing AtaiBeckley with an enviable period of potential market exclusivity.

To cover future possibilities and consistent with our comprehensive IP strategy, I should also note that we've secured issued U.S. patents protecting alternative routes of administering 5-MeO-DMT, such as sublingual and buccal. Finally, and with specific focus on method claims, we have secured issued method of use patents here in the United States for treating depression with 5-MeO-DMT, which similarly last into 2041.

Obviously, this slide is focused squarely on the issued patents we have achieved here in the United States. But our mission to transform patient outcomes by developing rapid-acting, durable and convenient mental health treatments extends beyond the U.S. and our global IP estate reflects these broader aspirations with strategic filings in major markets globally including Europe, United Kingdom, Canada, Asia and more. We have achieved patent grants in some of these markets, for example, in Europe and the United Kingdom, whereas others are in process. Where we secure patents abroad, we anticipate global patent protection time lines comparable to the United States.

So where does that put us? To put it plainly, BPL-003 is very well protected, particularly here in the U.S., pursuant to a comprehensive IP strategy that provides for exclusivity potentially through the mid-2040s with patent term extensions. This strategy also allows us to deter generic challenges by listing these patents in the Orange Book at such time as BPL-003 is approved. Taken together, we believe that our IP strategy and our success to date in executing on that strategy significantly derisked the commercial potential of BPL-003, giving us confidence that if we reach the market, we can operate without generic competition for over many years, allowing us to invest fully in the product success now.

With this backdrop, I will now turn it over to my colleague Kavita, who will discuss the BPL-003 commercial framework. Kavita?

Thank you so much, Ryan. And I'm really excited to be here, Kavita Panke, Senior Vice President of New Product, Planning and Commercial. And as Ryan said, I'll talk about the commercial vision and even our early go-to-market plan for BPL-003.

So let's take a look at the landscape we're operating in. Treatment-resistant depression, as we've heard, affects a huge number of people. And yet the market remains largely untapped. So the STAR*D trial showed that 1 in 3 individuals with major depressive disorder do not respond to 2 or more oral antidepressants. That's millions of people, 3 million to 4 million adults in the U.S., if not more, who are left without effective options.

So there has been progress. SPRAVATO has made meaningful inroads. But even so, it has reached less than 3% of those who qualify for TRD treatment which means over 95% of people with TRD are still not receiving an FDA-approved therapy.

And so why is that? When you look at the patient experience, it's really not surprising. People need treatments that work quickly, that last, and that don't require them to reorganize their lives to take these treatments. Frequent clinic visits, where they can't drive, must arrange support and lose hours of their day, create significant barriers that many just simply can't overcome. The burden of accessing care has actually become part of the disease burden itself.

So there is a real paradigm shift underway in psychiatry and one that moves us from simply managing symptoms to actually enabling durable, meaningful change. I've actually worked in this space for a pretty long time. And what we're seeing now, it feels different. It actually feels transformational.

So if we look on the left side of the slide, today, our tools are chronic antidepressants. They do help, they help many people. But they come with real limitations, slow onset, often taking weeks or months before we know whether they'll even work. Chronic side effects, and some of the most problematic like weight gain, sexual dysfunction, sleepiness that drive people off the treatment. And the burden of daily dosing or in the case of esketamine, SPRAVATO, frequent clinic visits that still require ongoing chronic administration. Ultimately, these treatments manage symptoms rather than creating lasting or root level change. Patients remain stuck in a cycle of maintenance and managing symptoms.

The vision for tomorrow looks very different. Psychedelic-based interventional psychiatry offers the potential for rapid efficacy. You could know within 1 day or 2, whether it's working for you. It offers the possibility of durable benefit paired with intermittent rather than chronic dosing. And it opens the door to neuroplastic change addressing underlying biology rather than just the symptoms. The future we're moving toward is one defined by rapid results, durable efficacy, infrequent dosing and the potential for lasting change.

So why BPL? You heard from Srini, from Kevin's deep dive into the data. But the story is actually very simple BPL-003 has the potential to deliver what I call a trifecta that TRD patients have been asking for. It looks fast, it's durable, and it's convenient, together in one treatment.

So here's what the data shows so far. Rapid improvement with a single dose showing effect by day 2. Durable benefit with a 6.2 point placebo-adjusted modest reduction at week 4, and this effect was sustained for 16 weeks in the open-label study for most patients. And true convenience, requiring a handful of treatments over the course of the year in 2-hour clinic visits. And this matters because it expands who can realistically access this care. People with demanding jobs, family responsibilities or long distances to travel, people who have been effectively shut out of current treatment-resistant depression treatments, they finally have an option that works for them, a trifecta of improvement.

So when we look at BPL against the competitive set, so the current standard of care as well as pipeline opportunities. It has a credible path to be best-in-class positioning, because it is the only asset in the category that aligns with the three attributes that consistently drive adoption and reimbursement: rapid-acting; durable; and convenient. And of course, importantly, while we cannot make direct comparisons without head-to-head data, the landscape makes the differentiation quite clear.

Oral standard of care, as I mentioned before, often slow onset, many don't respond to the drugs, and chronic daily use limit both effectiveness and adherence for patients. Esketamine, SPRAVATO, very meaningful innovation, but durability remains a challenge for many. We hear this quite a bit from clinicians who use the product as well as from patients. Roughly half of patients require biweekly or even weekly maintenance dosing, creating ongoing costs and operational burden. And the long-acting psychedelic pipeline programs, multi-hour in-clinic dosing sessions can introduce staffing, throughput and scalability real constraints that will slow adoption and limit reach.

So why is BPL positioned to lead in this space? It's the only program that aligns across all three high-value attributes: rapid, early onset of effect; durable sustained benefit without chronic maintenance; and convenience. A small handful number of short 2-hour sessions rather than multi-hour or weekly commitments.

The implication is straightforward, a treatment that delivers speed, durability and low operational burden expands the addressable TRD population and reduces friction across patients, providers and payers. This combination is rare in psychiatry, and it's why we believe BPL has the potential to truly reshape the paradigm.

So let's double-click into the current standard of care for TRD, SPRAVATO and the durability of effect in the induction phase. And keep in mind, once again, this is for illustrative purposes only and no head-to-head studies have been conducted.

What this graph attempts to do is it juxtaposes SPRAVATO's primary efficacy data, a change in MADRS total score from baseline, from their monotherapy trial against the BPL-003 Phase IIb 8-milligram data. What you see here is a comparable MADRS response curve, which took SPRAVATO 8 dosing sessions versus a single dose for BPL. And so think about that, compound that annually, and that's a lot of time, in-clinic dosing sessions, and health care utilization that is potentially saved with BPL-003. So what we can directionally conclude here is that SPRAVATO takes 8 doses to achieve a similar efficacy result that BPL can potentially achieve in a single dose.

Now let's shift and look at the maintenance therapy component. Based on an analysis of real-world SPRAVATO data, we note that about 70% of patients are being maintained on at least one dosing session per week. And the majority of patients are on the higher dose, 84-milligram dose by treatment session 6. So what you see on the left is the assumed annual cost of SPRAVATO and this is WAC-based pricing. What this translates to, if you put together the actual real-world utilization compared to the WAC prices, the real world cost is on the upper end of the $60,000 to $65,000 range.

So when we think about BPL, of course, it's early to provide any pricing guidance at this time. However, SPRAVATO is the best price anchor we have today. And if we deliver on our trifecta of value, similar or better efficacy with a single dose, rapid effect and convenient 2-hour dosing model. We believe there could be opportunity for premium pricing.

Our goal is to build a treatment model that puts patient safety and convenience at the center without requiring in-session psychotherapy and that can be deployed within today's interventional psychiatry infrastructure. So what I'm describing and what you see on this slide is not our clinical trial protocol, but it's our vision for real-world implementation with the specifics that will ultimately be guided by the data we produce. So this model mirrors familiar in-clinic workflows used across other therapeutic areas, making it straightforward for sites to adopt and scale.

So let me just break this down. There's the preparation session, where patients meet with their provider for education, expectations, questions, standardizing readiness and reducing variability. Then there's the dosing day. Patients come in, they check in, they move to a private room and receive the nasal spray dose from their provider. A trained health care professional remains with the patient throughout their experience. And there's efficient discharge. We anticipate a roughly 2-hour post-dose observation window similar to SPRAVATO, enabling predictable scheduling and higher clinic throughput. And then importantly, a follow-up visit conducted either in person or remotely, ensuring continuity without adding burden to the patient. And I want to underscore no psychotherapy requirement. So there's no need for specialized therapists dramatically reduces cost, staffing constraints and operational complexity.

So to summarize, our vision is a model that is simple, familiar and resource efficient, lowers barriers for providers, expands the number of clinics that can participate and increases patient access, especially in markets where staffing space and reimbursement are real constraints.

BPL-003's short in-clinic model creates a fundamentally stronger economic and operational profile for patients, providers and the health care system. So in an 8-hour clinic day, a 2-hour dosing window allows a provider to treat 3 patients per room, compared with one in a, let's say, 6-hour long session psychedelic model. Observation revenue is effectively the same, right? 6 total hours per room, so the real economic difference comes from the drug revenue. And in a buy-and-bill environment, the margin on drug administration far exceeds the margin on observation time. In fact, observation alone often doesn't cover the incremental staffing and monitoring costs.

So the takeaway is without meaningful drug revenue, interventional psychiatry simply may not be sustainable for many clinics. And the equation becomes straightforward. More patients dosed, more drug administered, more clinic revenue. A shorter sessions directly increases throughput and makes the model economically viable.

So I want to address three key advantages and real-world examples of a short in-clinic model. First, higher throughput and greater access clinics can treat more patients per day, opening the door to serving that 95% of TRD patients who currently aren't receiving an FDA-approved treatment and giving clinics more flexibility in scheduling.

Real-world practicality for patients. Let's think about this. A full day in-clinic model is unrealistic for most people. Life happens. There's work, there's child care, there's transportation, there's delays. If a clinic books one patient per room per day and that patient is late or needs extra time, the entire day collapses. A 2-hour model can really avoid this fragility.

And reduced provider burden and burnout, expecting a provider to remain engaged for 6 to 8 hours straight may not be feasible. Breaks, turnover and fatigue are real constraints and actually, caregiver burnout is already a growing issue in psychedelic monitoring. So shorter sessions dramatically reduce that strain. So across economics, operations and patient experience, a short in-clinic model is simply more scalable. It supports stronger clinic economics, increases patient throughput and lowers the burden on staff, which I think are key ingredients for broad adoption.

So next slide, BPL-003 supports a lean, highly targeted commercial model because the TRD interventional psychiatry market is already very concentrated and built on existing infrastructure. The treatment fits directly into current workflows, making it a true plug-and-play offering. So there's a concentrated prescriber base. So of the 6,000 to 7,000 REMS-certified SPRAVATO sites today, our data suggests that about 10% account for the majority of prescription volume, about 75% of the total volume. And so taken together, a really focused field force under 100 representatives can cover the highest value centers that already understand interventional psychiatry, did the hard work of organizing their clinics and are comfortable with similar models of care.

I want to talk about operational fit. These clinics can run SPRAVATO and BPL side-by-side potentially using the same room staff and processes. And that level of operational overlap is just not possible with long in-clinic psychedelic therapies that require dedicated rooms and multi-hour sessions.

And market readiness, we are actively building as we speak, the ecosystem with clinical leaders, high-volume practices, payers and patient advocacy groups to ensure early seamless adoption at launch. So this combination of concentrated demands, operational compatibility, and ecosystem engagement positions BPL for efficient, scalable commercialization.

So I want to conclude here. We are laser-focused and invested in treatment-resistant depression. But TRD is just the beginning for BPL. Beyond that, we are strategically exploring adjacent psychiatric disease areas that have scientific rationale, high unmet need and strong commercial potential. And as Srini mentioned in the onset, we also have a portfolio of exciting candidates to support optionality and broad impact in mental health.

So with that, we will take a short break and then I will come back, and I am super thrilled to introduce and to be able to participate in our next session, which we brought a set of panelists, experts, key opinion leaders in the field, Doctors Feifel, Wilkinson and Dr. Hendricks, who will have a chance to introduce themselves and their practice. And we'll talk about and share real-life perspectives on treatment-resistant depression, interventional psychiatry and the true potential and adoption of these new class of therapeutics.

So thank you so much. And with that, I think we are going to a short break.

[Break]

Hi, everyone. I think we're back from that short break. And maybe I'm biased, but I think this is going to be a really great part of the meeting and a great conversation.

So as I mentioned before, we went for break, but I'll reiterate, we are very excited to have three psychiatry key opinion leaders in the U.S. join us this morning for this session. And I'll -- in a moment, I'll let them introduce themselves. But the goal is really to really understand real-world treatment patterns, how we think about the treatment landscape and the pipeline potential and just real-world experiences on managing these patients.

So with that, we have Dr. Feifel, Dr. Wilkinson and Dr. Hendricks joining us. And maybe I will start with Dr. Wilkinson, if you can just introduce yourself where you practice and talk a little bit about your practice and the patients you see, and yes, and anything you want to share in your intro.

Sounds great. Thanks for having me here, Kavita. My name is Sam Wilkinson, I'm Associate Professor of psychiatry at Yale. I'm the Medical Director of the Yale Depression Research Program. I help run a combined research and clinical entity. The clinical service is a pretty busy interventional service. We do a lot of ECT, a lot of ketamine and/or SPRAVATO and a growing number of TMS treatments. In a given week, I think we have about 80 slots for either ketamine or SPRAVATO so those 2-, 2.5-hour slots. So yes, that's a little bit about me. I'm grateful to be here.

Sounds great. Thank you. Welcome. Dr. Hendricks, why don't you go next?

Hi, I'm Peter Hendricks. I'm a clinical psychologist, University Professor and Endowed Chair in the Department of Psychiatry and Behavioral Neurobiology here at UAB. My work centers on psychedelic approaches for mental health conditions. I've done that now for about 10 years, which is hard to believe. And I focus on depression, substance abuse disorders and related challenges. I have a practice here at UAB and also collaborate on clinical trials, provide consultation in academic and research settings. And I'll just say briefly that TRD patients I encounter or study typically have failed multiple antidepressant trials, 2, 3, 4 or more. They present with moderate-to-severe symptoms and span a broad demographic, working age adults often with comorbidities. And in our region, we see a mix of insurance types, commercial, Medicare, Medicaid and uninsured or self-pay which influences access to interventional options.

Great. Thank you so much. Thanks for being here. And Dr. Feifel?

Thank you for having me. So I'm a board-certified psychiatrist and a Professor Emeritus at the University of California, San Diego. I'm also a founder and CEO of interventional clinic called Kadima Neuropsychiatry Institute. I was a very early and enthusiastic adopter of interventional psychiatry. I think before it was -- before we described it as such, I started actually the first -- the very first ketamine clinic outside of research back at UCSD in 2008 and started doing TMS around that same time, when it was FDA approved. So I was very eager to move into different types of treatments that had been sort of dominating psychiatry for the previous half century. And in 2017, I gave up my tenure position to open up Kadima, and we do probably also about 80 treatments a week of either IV, IM, ketamine and SPRAVATO intermixed and sort of same treatment rooms, we do a very robust TMS program and a very large number of clinical trials, mainly with psychedelics.

Great. And maybe we'll start off with -- there was quite a bit in the session before about TRD sort of representing a large population of patients, yet this practical factors, convenience factors, things like that, make it sometimes difficult for these patients to access more of the interventional treatment. I'm wondering if you guys can comment a little bit more about that. Are there practical considerations that influence maybe what type of treatment you try next for these patients or if they are going to be able to adhere and stay on these treatments? If someone wanted to comment on that or I can pick on someone, but I'm sure there's a lot to say.

I can speak to this briefly. I'll start off. So we really started expanding our ketamine service prior to SPRAVATO FDA approval, probably around 2015, 2016. And this was in line with a very busy existing ECT service. And some of the executives we had to convince them that, look, we're not going to rob Peter to pay Paul. And that was not at all what happened. Our ECT service has not suffered.

So I think that speaks to the principle that there are just a lot of people -- and clearly, ECT is one thing. There's a lot of people with TRD who were not getting treatment with ECT, which prior to SPRAVATO and ketamine was one of the only things for TRD. A lot of this is related to the clinical profile and the side effect profile of ECT, but also the inconvenience of not being able to drive and so forth. You have that a lot with SPRAVATO. But it speaks to the principle, there's a number of patients out there that are not getting interventional treatments. And I think in part related to these factors of convenience and so forth.

Great. Anybody else want to comment on that?

Yes. People often ask me, including patients, what -- how do you decide? Which intervention, TMS, SPRAVATO, IV, ketamine. And the answer is that often it's driven by the practicalities of each of those.

First of all, ketamine is not covered by insurance, so there's a practicality of finances driving that treatment option. And then between TMS and SPRAVATO, they have different logistical requirements both of which are -- represent an inconvenience to patients, but it depends on which fits better. So one requires daily short treatments for a long period of time, 6 to 9 weeks, and they can drive each way. The SPRAVATO is less frequent but frequent twice a week for a month and once a week for a month and as needed each time longer sessions, 2.5 hours typically, and they can't drive. So somebody is -- it really depends on sometimes it's really just one is a nonstarter for whatever reason. So it is much as we wouldn't like it to be, we'd like it really to be driven by precise personalized clinical decisions, it's often just a matter of pragmatics.

Yes. Dr. Hendricks?

I'll just add to that trying not to be redundant, but to give some sense of the scope of the issue here just in Birmingham, Alabama, which is a relatively small city, the metro area is maybe 1 million. UAB likely has 15,000 patients with depression and 30% to 50% of those are TRD patients who cycle through several oral medication trials sometimes for years before interventional therapies enter the conversation. And as noted, this delay stems from stepwise guidelines, insurance requirements, patient provider hesitation around options that are viewed as invasive or require a fair amount of monitoring or travel as noted.

I'll be honest, I'm excited about this new option on the table, potential new option on the table, especially if it can facilitate conversations around earlier intervention, when this rapid symptom relief could be critical to prevent functional decline, hospitalization, suicidality. I just don't think I get to overstate the burden of prolonged inadequate response. It's just -- it's substantial. And I think tools like ketamine, esketamine and TMS are helpful for some. They've been shown to interrupt the cycle for some, but I'm personally not satisfied with the response and think we need something better. And not only something better that -- but something that occurs earlier could really improve outcomes and quality of life.

Yes. That's great. Thank you. And to this conversation, in your opinion, what are the key unmet needs? Like there's been a lot of innovation, right, in the space, in general, in depression, MDD. There's a lot of options in your toolbox. But what are -- we highlighted some earlier, but in your opinion, in your practice, I want to hear what are kind of the key unmet needs, especially for these refractory patients?

I always tell people in the space that there are kind of three factors. One is overall efficacy, the other is speed, and the other is side effects. And if you're trying to develop a new therapy, and it doesn't get at least one of those, then you're not really going to add value to what is in existence. And going back to this theme of convenience, with these novel interventional/psychedelic treatments, I really do think some of the true issues, again, assuming that they all have pretty good efficacy, which is mostly seeming to be the case. There's maybe some questions about that.

But the two factors, and I think you've already brought this up are how long is the monitoring and how frequent do patients have to be dosed. That will just determine so much of the logistics, so much of how clinics are able to adopt this. What -- as you pointed out here, and we recently learned from the there was a large analysis of the SPRAVATO REMS data that so many of these patients are coming in weekly, as the most common frequency of treatment. And so a lot of the clinics just fill up right? They don't have openings for new patients if they're treating all their patients weekly or so many of their patients weekly. So that's another aspect. I mean, SPRAVATO, it was slow in the beginning for the first couple of years, and it really has taken off is as people learn how to adopt and implement this. But clinics just fill up in part because really the most common dosing frequency is weekly.

So again, the three clinical factors enhance efficacy, rapid onset and improvement in side effects and then the two logistical factors. How long are these intervention treatment is going to take for observation and then how frequent do you have to redose. So much hangs on those factors.

Yes. Thank you.

I would definitely agree with Dr. Wilkinson about those three factors. I mean, those are the big three. And just to elaborate a little bit on them. Right now, with the relative innovations we've had in the last decade or two with TMS and ketamine, they really represent sort of somewhat of not overlapping very stark contrast that sometimes is dilemma for patients. The SPRAVATO can work fast, not as fast as it's the drug that was inspired by, ketamine, but it's not durable. So just to get it going, you need to come in 12 times over 2 months and then as Dr. Wilkinson mentioned, most people need to come in for maintenance on a frequent basis, not uncommonly once a week. I actually spoke to a patient yesterday that wanted to talk to me because she had done amazing with SPRAVATO until she was forced to go to once a week, because that's the label and she's now on maintenance for once a week with insurance won't cover more than once a week. So the durability is not very good.

On the other side, the TMS is not fast, although the durability is better, but then you have patients who are extremities. They're really in a difficult situation and need fast relief. So right now, we have these two treatments and you got to choose speed or durability and to be able to combine both would really, really be sort of an advance in the field.

And I just want to make two other quick comments. I mean, Dr. Wilkinson mentioned side effects. And I don't think that was really emphasized sort of in the presentation that when you're taking a drug every day, you're a prisoner to the chronic presence of the drug is -- sorry, of the drug in your body and those side effects when you're taking a drug once periodically, maybe every quarter or so and then no drug is in your system. I mean, that is a tremendous paradigm shift in the ability to kind of not suffer from those side effects.

And the last point I want to make is we talk about efficacy improvements. And we always think about this thing called TRD, which has a very specific definition of failing two antidepressants. But ask most patients who don't meet that criteria who will say -- and failing is usually not being -- not having your depressive symptoms reduced by more than 50%. So if you have a 55% improvement in your reduction in your symptoms, you're not treatment resistant, but ask those patients who aren't treatment resistant because they do get more than a 50% improvement, whether they are satisfied with their antidepressants. They'll say no. I still suffer a lot of symptoms although it's better. And no, the cost I pay is side effects like numbing or libido.

So we talk about this group of 1/3 of patients on medications who are on TRD, I think almost 100% of patients who are on the conventional medications would be interested in something that allows them a more complete symptom reduction and freedom from the side effects required produced by taking daily dosing.

Yes, I would agree wholeheartedly with that. I think most patients on SSRIs or SNRIs would say they feel a little better, not much, and there are a list of unpleasant side effects, often weight gain and sexual dysfunction, which are very unpleasant, sort of at the top of the list of side effects you'd rather not have.

I also wanted to mention that many of the patients that we see are socioeconomically disadvantaged. So any intervention that requires frequent visits can be a significant burden and can, I think, add to the sense of demoralization that nothing is quite working and what's suggested next is a rather significant investment of time and energy. And as noted, the response is just not adequate for many and the durability is variable. So there's clearly something that we need that can respond to the sort of demanding and sometimes chaotic lives that many people lead something that can be, as noted, not only durable, but rapid and that can be done in an efficient way.

Great. And with that, I do want to segue into the tomorrow, let's say, right? So the new potential intervention, the therapeutics, the psychedelics that are emerging, there seems to be kind of the longer-acting in-clinic programs and then the short acting. Can you talk a little bit about just your thoughts around that, how you see these playing together in the real world? And what are sort of the your practical kind of thoughts around those long versus short in-clinic times?

I don't know if we have an established order. I could break the model here and go further...

Let's do it. Yes.

I think this is a really interesting question. And I mean, the truth is we just don't know if the length of the experience is tied to more durable or more robust response. I think an argument could likely be made based on a limited number of animal studies or basic science studies but we just don't know. And I think at the moment, I would argue at least that for me to use a much longer-acting psychedelic, let's say, there's got to be a really good argument for that because it's otherwise, as noted, very inconvenient for the patients, very resource-intensive and it's just going to limit scalability substantially.

I think that shorter-acting compounds just have a tremendous advantage in that they work well with clinic workflow. So it's just -- it's unknown. And I think BPL-003 here is really unique because the mechanism of action might in fact, be unique, not only in that it's shorter acting, but the mechanism of action at the brain level might be different than other psychedelics as well that could give it a substantial advantage. But right now, I'm just -- I'm not sold on the idea that a longer experience is in any way more beneficial, but we'll have to see at the moment, a shorter-acting experience is far more practical.

Anyone else have thoughts on that?

I would say that I absolutely agree with Dr. Hendricks. And I would not have predicted this. I would have -- if you had asked me at the beginning of this revolution we are in studying psychedelics, it's is a longer trip. I'm going to produce better results. I would say, yes, it's nothing else, just sort of a longer exposure of the brain to this. And the results are proving my prediction wrong. So it's really interesting. It's the beauty -- that's beautiful about science, it teaches us things. So -- and that's great. That's great because obviously, it's self-evident that shorter subjective experiences or a quicker recovery time is an advantage.

And it may mean that the duration at least is not important or it may mean as Dr. Hendricks pointed out that BPL-003 has some advantageous mechanisms of action allowed us to produce comparable efficacy to some of the longer agents that we've seen in studies without that longer experience.

Yes.

I think also -- from a clinic consideration, there's the economics of this, right? If you have an 8-hour observation period, there's going to have to be a pretty substantial reimbursement for the clinics to want to implement these. And even aside from that, the logistics of dedicating 2 staff to one patient, the economic considerations for long versus short acting are quite disparate.

Yes. And to that point, Dr. Wilkinson, do you see like a BPL sort of slotting and given -- assuming that it sort of has that 2-hour dosing paradigm, the already established SPRAVATO sites. Could this sort of be a slot into that infrastructure kind of a plug-in sort of thing? So we talked about that in the presentation, but just wanted to get any of your thoughts in terms of how that kind of infrastructure and kind of economic piece sort of would fit in.

I would say very likely, yes. So I alluded to this earlier, but it took a long time for SPRAVATO to get taken up into practice, I think, because practitioners had to change their infrastructure, the way they approach this, the buy-and-bill modeling as well. It's not something they were used to. So there was a lot of kind of weed whacking going on to kind of forge that path. And there's inevitably going to be some with an agent like this. But assuming it's approved, it's going to be much, much, much easier because that path is there than if you had to start it from just the jungle, so to speak.

Yes. Anyone else have thoughts on that topic?

All right. So I want to shift gears and maybe talk about BPL. I mean that was, of course, the focus of the presentation and Kevin and Srini provided some of the clinical information around that program. And I know a couple of folks. I think David and Peter, you guys have experience with the product from a clinical trial perspective. Would love to sort of get your thoughts from what we heard from what we saw this morning and with your experience. What do you think about the data? What aspects do you think are particularly meaningful interesting, maybe differentiating from what you've got today in your toolbox?

Well, I'll jump in. I'm really stoked about the data. I mean, the efficacy was so great. So it hits all the marks, rapid onset durable. I mean, the study was 8 weeks, and I think Srini pointed out that at 8 weeks, it was holding steady. We may be seeing only a slight decrement whether that was a trend or not. So we really don't know how long a single dose last, but we know it last at least 8 weeks and it wasn't looking like it was about to poop out quickly.

And what also was interesting was that I don't really recall any other study where the peak effect wasn't at 24 hours, an interesting phenomena with BPL-003 was that the subsequent time points showed even a greater separation from placebo, especially with the 8 milligrams. So this is something, again, may go back to the somewhat unique mechanism, pharmacological mechanism. But usually, the way we think of psychedelic is like they blossom right off the bat and then it's a slow wilting over time, but BPL actually grew for the first couple of measurement points and then kind of started to hold steady. So I just -- who knows how long it's going to -- that's super cool and it's everything you would want if you were to put it in an order for a drug to treat depression.

Yes, I'll add to that, too. So I would first say since I'm a scientist first and foremost, I try to always maintain a very skeptical view and influenced by a famous philosopher, Karl Popper, who would say, you really need to bend over backwards to prove yourself wrong. And if you fail to do so, then perhaps you've had a success. But as I would be with any clinical trial, I was skeptical and really pleasantly surprised at the results for a number of reasons.

As we noted, the rather rapid, rather robust and durable effects were really wonderful to see. But also the safety profile was fantastic. And I say that in part because there's always going to be in the psychedelic world, some degree of use that occurs outside of controlled medical settings, naturalistic use. And it's unclear what's happening in those contexts. But now I'd like to say that the difference here would be akin to having a cavity filled in a dentist's office versus having a cavity filled by me in my basement. These are completely different things. You wouldn't want me filling your cavity. And I think the things that happen naturalistically can sometimes scare me.

But I think, again, these are completely different things. And the sort of concerns I may have had from the kind of unusual things that you see in the wild did not at all generalize to this clinical trial which was rigorous and objective. And despite my most skeptical view, I think we had data that really pleasantly surprised me. And like David, I feel really quite enthusiastic and excited now.

That's great. And when we think about patient types, patient characteristics within treatment-resistant depression, any characteristics or subpopulations come to mind that you think or maybe that you've seen in the clinical trials that can potentially maybe benefit from short-acting or BPL or that kind of thing? Like anything that sort of comes to mind at all?

Well, I'll just jump in really quickly because I have a thought. I mean the first is all potentially. I don't see any who wouldn't be considered. But the one thing that jumps to mind since so much of my work is with lower income patient populations that this could be especially beneficial given the time demands are significantly reduced.

Yes. Any other thoughts on that one?

I'd just say to follow up on that, a 2-hour treatment is feasible without having to give up a day of work, right? I mean we have a lot of patients who do SPRAVATO, but they just -- they couldn't give up the work. So they'll come at one of our later appointment times 4:00, 5:00. And so they get in a full day of work for the most part and then they do that. But with some of the longer ones, that's just not possible. I mean you're calling out for the full day if you do -- if you need to be in the clinic for 6 to 8 hours.

And one of the things, I think, David, when you and I had chatted about a little bit is even in this the clinic sort of the staff burnout and the need for maybe additional staff or longer hours for the staff based on a longer sessions. Any thoughts? Is that -- I feel like that theme is sort of coming up more and more, right, even just the caregiver burnout, and that type of thing for such long hours. And any thoughts or comments on that issue?

Right now, the requirements in the clinical trials are that the facilitators are licensed therapists. And so I assume that's probably going to be the requirements, at least initially when these drugs are approved. You have to think about that, that for a licensed therapist, that's a full day of clients that it's an opportunity cost, a big opportunity cost. And if you have -- like we contract our facilitators. So they -- I don't think a lot of them are willing to do it on a regular basis like multiple times a week because they wouldn't be able to have a practice, right? They have to be there for their patients, right? A 2-hour intervention or even doing two of those and still having half a day is much more practical to work into their to work into their professional careers.

Kavita, I'll say also, I think I have now personally administered psilocybin to close to 100 participants and was the lead therapists for many of these sessions, and they're demanding, they're long and they can also be characterized by like moments of significant anxiety on the part of participants, and it would not be unusual for someone to ask to leave. That's always anxiety provoking for the therapists. We certainly don't want anyone eloping the room, especially when their consciousness has been altered.

But those sessions are challenging. Now obviously, I think there could be a place for psilocybin as well, but 5-MeO-DMT is not just shorter acting psilocybin, and I think it's unique in many different ways, and it might be especially appropriate for certain mental health conditions like TRD. But I will say as someone who has administered psilocybin and been a part of these sessions, 5-MeO-DMT was a refreshing change, less demanding on us all. And I have to say like, in some ways, quite gratifying because to the degree that it was appropriate for me to observe this in some of these trials, I saw with my own eyes, participants who appeared to be depressed in every way at 8:00 a.m. and by 9 or 10 I saw a different person in front of me, someone who's animated, smiling and talking. And it's just remarkable to see like almost to the point, as I mentioned, as a skeptic, you can't believe what you're seeing.

That's actually a really good point. You can -- being an investigator and being responsible for assessing patients before they're leaving the clinic, you do really see a difference at the end of these sessions. I mean, patients are drained at the end of the long -- maybe they've been in this room. They've been -- the experience has been much longer, and they're really emotionally drained. I mean even if they have a great -- even if it was a positive experience, and they'll have a therapeutic effect. It's depleting to be -- to have a 4-, 6-, 8-hour subjective experience and also be in the same room and very different with BPL. It's almost like you come in for a visit, you do it and leave much more akin to our ketamine treatments where people are actually just more energetic when they leave because it wasn't such a draining logistical experience and subjective experience.

And Dr. Feifel, could I just follow up the -- when you -- the ketamine, the esketamine rooms that you have, do you see using those same rooms potentially for a product like BPL? Or would there have to be some changes or things like that? And of course, it's a matter of the data and what we see in the ultimate REMS program. But just curious on your thoughts around that.

Absolutely. In fact, we have rooms that are differently configured and larger for our clinical trial subjects because for the most part, those are longer sessions. And in the ketamine rooms, we have just -- patients are sitting in a chair, nice, comfortable reclining chair. Whereas if you're going to be around for 8 hours, you need to have a bed option, a chair option. You're having a facilitator present who also can't just stay in one place. So we have rooms that were designed with the idea of these longer treatments, but had they been two hours, they fit in perfectly with our ketamine treatments or SPRAVATO treatments. We could have used -- we could use those moves.

Great. And I think -- oh, Peter, I think you are on mute.

Sorry about that. I just wanted to add too, and this is coming from a place of like excitement, obviously, and optimism. But even when we're conducting studies with psilocybin to administer two or even three doses in a week would be pretty demanding on everybody. But my first thought after being a part of this Phase II trial with Beckley was, we could, in the clinic, administer several of these administrations in a day. So it's not just a matter of sort of practicality but also just sort of a psychological effect for the interventionists. I think that's something that would also be easier for them to do.

Just had another practical thing that isn't obvious unless you're sort of been doing these kinds of things, cancellations happen. We typically ever -- we do 15 ketamine/SPRAVATO treatments a day with multiple rooms being used concurrently. And cancellations happen and it's a 2-hour slot, but if you have a long treatment and a patient cancels for whatever reason, you can't. It's not something you can fill quickly because it requires people to have a -- like prepare for taking a whole day off. That's a huge economic loss, right, the cancellation.

And also, with the 2-hour session, you can't, on fairly short notice, fill that slot because patients can say, okay, I can come at this afternoon whereas that would not work if the whole session is 6 or 8 hours.

Yes. That is a fantastic point. Well, this has been great. I'm going to wrap with a question that I think you've all sort of got to in some ways. But how do you see in this future state, there are a number of innovations and options, hopefully, that are coming to market, patients definitely need new options. Well, how do you see BPL kind of fitting in? What's the positioning? Are there -- that broad patient base of TRD that are not currently still maybe cycling through oral antidepressants, is that an opportunity? What is sort of the -- where do you see this kind of fitting into your treatment armamentarium? And maybe I will pick on Dr. Wilkinson to share some thoughts on that.

Yes. So I think it will be a question of -- so taking out economic consideration, really, what I mean is third-party considerations and coverage and prior auths. Taking that out, I think it's a question of where does it fit with respect to ketamine and/or SPRAVATO. Certainly, if the data from Phase II, hold out for Phase III, it's a lot more convenient initially, there's going to be some hesitation with provider because it's a new thing, right? It's -- but I could envision where it goes first for a lot of patients, again, in part because of those very practical considerations. And if things unfold the way Phase II would indicate much, much less of a burden on time and so forth.

And there probably are going to be patients who, again, sort of come out of the woodwork, so to speak, like I started this with talking about how when we started launch a fairly large clinic in SPRAVATO/ketamine, it did not eat into our ECT patients because there was a number of patients just not willing to get ECT, but are still struggling. And I think that's probably going to be a similar thing, right? I mean the TRD population is anywhere from 1.5 million to 7 million people in America, depending on how you define it. And I think there's about 60,000 people who have had SPRAVATO. So there's a huge, huge portion who have not, for whatever reason, because of distance, because of accessibility or because they're like, yes, you just can't do twice a week for 4 weeks and then once a week and so forth.

So it's not always a necessary competing. But those patients will, so to speak, come out of the woodwork and say, yes, yes, yes, I could potentially do this treatment. So it does remain to be seen, I think, where it falls in line in the sort of treatment algorithm with respect to ketamine and/or SPRAVATO. But I can definitely see it coming first because of practical considerations alone.

Thank you. I'm going to do a final roll call. David, any thoughts on that?

I think Dr. Wilkinson really articulated it really well. I mean I think that I'm not one of those people who think that we're going to find great differences in different psychedelic agents across different indications. I think there's going to be a set of indications that psychedelics are for. And for the most part, they're going to be cross-indication efficacious with maybe some nuances. So I look at the results of BPL in TRD. And I see this is not just -- I see this as sort of probably representative of what we're going to see in those other indications that psychedelics are going to be useful for including anxiety and PTSD and things like that.

Great. Dr. Hendricks, any final thoughts from you?

Well, I'll be brief, but I think BPL could occupy a niche for rapid durable interventions with convenient administration. And it could potentially serve as a bridge or alternative to existing psychedelics or interventionals and time will tell. But I think the niche there is ultimately for rapid, durable and convenient administration.

Great. Well, thank you so much. With that, we'll close out this session. You guys have been great, some really, really good real-world feedback and so really appreciate you guys being here. And I'm going to turn it over to Jason for the rest of the session.

Yes. Great. Thanks, Kavita. Now I'll ask AtaiBeckley's team to also join here along with our key opinion leaders. We have a number of questions that came in, so we're going to start kind of going through those, and I'll pass those along to the appropriate people here.

So to start, there's some questions that came in from Andrew at Jefferies. Srini, I think I'll put this to you and perhaps Kevin to follow up here. He said, I know that you've said you've run two Phase III studies or will run two Phase III studies, we'll stop. That said, during your EOP2 meeting, did you ask the FDA if that Phase IIb can be a supportive pivotal study? And what did they say? Said another way, why wouldn't the Phase IIb be counted as one of the two supporting pivotal studies?

All right. Thanks, Jason. Actually, let me start by thanking the panelists. It's great to see all of you, and it was a really exciting discussion and clearly appreciate your support and enthusiasm for BPL-003.

So to answer the question around pivotal. So it's actually a more nuanced question than one would expect, right? So let me start by saying that the Phase IIb trial was met with a lot of enthusiasm at the agency. I mean it's always going to be viewed as a supportive trial, no matter what you do. And when you go to file an NDA, it's really the totality of data that is the key. So I've always said it's going to be two trials. The reason was this anticipation about what would be needed for a safety database, right? So the product is being dosed intermittently but it's being dosed intermittently in a chronic indication, right? So these folks are anticipated to get these drugs for an extended period of time. Just as we saw with SPRAVATO, right? I mean, that's why you needed a safety database.

But that said, what are you going to file with is a slightly different question. So let's just assume that one trial was quite robust. And for whatever reason, the other one was not, you would still file, right? There's no doubt about that. You are looking at the totality of evidence, again, highly supportive trial, a clear win on one of the Phase IIIs that is what you're looking for. And then, of course, nothing adverse and there's nothing fancy or nothing special or magical about 0.05 if that's partially what's behind this question. You basically do need that totality of evidence.

And I don't know, Kevin, if you've got anything to add to that.

No, I think you've summarized it well. I mean, the safety database is primary and actually having two trials that answer slightly different questions, I think, is also very helpful. So I mean, the landscape is, of course, changing. But I mean, importantly, we had this meeting and we got our minutes back after publications came out that suggested one trial approvals. I think that this is something that we may face later on. But for now and really for the safety database, we need to keep both.

Great. Maybe a follow-up question or a slightly separate question. But as we think about some of the trial differences between the Phase II and Phase IIIs, you're evaluating this at a longer time point. You're using a placebo now. One of these studies is doing 2x or the induction dosing, 2-dose induction dosing. So shouldn't the efficacy delta look even better in Phase III compared to Phase IIb? Can you talk a little bit about your confidence in that scenario happening? And I'll put this, again back to perhaps Srini and then, Kevin, if you want to follow up on that.

I mean we're obviously pretty enthusiastic about the design, right? So there's been certainly talk in the space about a potential efficacy delta, affirmative delta that happens when you go with a true placebo versus the low dose. It's speculation at this point. But these are bigger studies. We do have the 2-dose induction. We've got the actual placebo. So we're obviously pretty enthusiastic about the results.

Now can we say that we're going to -- are we going to power it differently? Are we going to expect something? I don't know. It's hard to say that right now. We don't have that data. We haven't got enough data from competitor trials, but still, we're pretty enthusiastic.

Yes. And I think -- I mean, I'd just add, I mean, the 4-week endpoint is important. I think that's proximal to dosing. And I think that was something we're really keen to get in. But as you say, Srini, I mean, I think there is a sort of factors in our favor, perhaps the 2-dose induction placebo comparator, but bigger trials, more variances often. So I think our assumption is that these may balance out and we'll be in a position to be pleasantly surprised if not.

Yes. The 4-week endpoint, I think, is worth reiterating. That is -- that was an important win. It was an important piece of insight that we gained from other programs that are out there, right? So SPRAVATO did use a 4-week endpoint. Others in the space that tended to use something that's a little bit later, specifically 6-week. Just bringing that in closer to administration for the first trial, replicating what we did in the Phase IIb is kind of critical. And of course, it does reduce the time from the second dose to the assessment. Of course, that doesn't change anything about durability. We've talked a lot about durability. Of course, these trials do, in fact, measure durability out to 12 weeks. So none of that changes, but bringing that primary endpoint into 4 weeks. I think certainly is -- it certainly helps put things in our favor.

Great. And maybe one more question here before we get a few questions to our doctors on the line as well. So both Phase III studies are now using a placebo. Could using a placebo work in your favor compared to an inactive dose. And the Phase IIb had a sub-active or sub-perceptual control of negative 5.8 points on MADRS. Would you expect placebo to show the same in these Phase III trials something higher or similar? Just if you could comment a little bit around that.

Look, I mean I think I'd sort of err on the same side of similar. I mean clearly, there are confidence intervals on those effects. And we're doing another trial. We're going to replicate that. I mean I do think prior evidence in other trials has suggested that an active control may dilute the treatment effect slightly. But I think the accuracy of estimation only gets better with repeat trials. So again, I think it would be nice to be in that position, but we're not banking on that certainly in our trial designs.

Okay. Great. I'm going to take a little bit of a different angle here. So Dr. Wilkinson, Feifel and Hendricks, we'll kind of go to you for these. And there's a number of questions that came in. Maybe a few repeats a little bit, but slightly nuanced, I think questions here.

So the first one being how prepared is the interventional psychiatry ecosystem to operationalize BPL-003? Are practices that provides SPRAVATO ready or getting ready to incorporate psychedelic-based therapies into their practice? So that's a question for all 3 of you. Maybe I'll pick on Dr. Wilkinson to start.

Yes. And I spoke to this earlier, but I guess the best way I can answer is they're going to be much, much more ready than they were for SPRAVATO. If the 2-hour time frame holds, it's going to be much, much easier to incorporate this into a practice that is already using SPRAVATO to treat TRD. Maybe some slight modifications. Obviously, a lot of it depends on how the Phase III data unfold. But if the 2-hour holds, it's slight modifications, but it's going to be much more fast out to do than it was to get SPRAVATO off the ground.

Well, I would definitely agree with that. I think the adjustments needed to pivot from SPRAVATO to a drug like BPL, are relatively minor, not 0, but relatively minor. The adjustments needed to pivot from SPRAVATO to a full day experience psychedelic are substantial.

I think you are on mute, Dr. Hendricks.

Sorry. It's challenging for me. I was going to mention also, if psilocybin is approved in late 2026 or early 2027, there's likely some paving of the way. And in this case, with an intervention that's a bit more or a lot more time intensive. So there could be a fair amount more readiness than we anticipate, but as mentioned, certainly more than ketamine.

Excellent. And maybe a little bit of a follow-up question here, but again, in a slightly nuanced way. Another question we had that came in was, has SPRAVATO increased interest in interventional psychiatry from a provider perspective, such as from your colleagues that have been practicing in the conventional way for years and also from incoming residents and/or fellows for individuals, trying to understand if infrastructure and practitioners will be there to facilitate growth of interventional psychiatry with the introduction of psychedelics?

Maybe we'll start with...

Yes, I'll start off. I think the answer is a clear yes. I mean SPRAVATO is inextricably linked with ketamine and the excitement that, that has generated and really, it's continued and just kind of expanded with the so-called psychedelics kind of whatever you want to call this renaissance that we're in the midst of. So there's a lot of interest. And within 4 or 5 years of SPRAVATO approval again, about 60,000 patients treated with ECT. TMS has been around since the mid-2000s and there's probably around 120,000 patients treated.

So I think very quickly -- and I don't think one is eaten into another, really. Again, I think it's just prior to SPRAVATO, TMS, the landscape is essentially ECT, which is a very, very important treatment, but there's a lot of cultural baggage. There are some side effects that many patients are unwilling to risk with ECT treatment. So yes, it's just -- it's expanded interest. I think it's expanded in the number of treatment centers that offer interventional services in one form or another.

Maybe go to Dr. Feifel next. Any additional comments?

Yes, in terms of the question of whether it's increased interest or -- I mean, I don't think providers think of it that way, like, oh, this is making me think about interventional psychiatry. But what I do see is that there were providers who -- obviously, those of us who were doing ketamine, it was just a seamless transition. But what was interesting was there's a number of providers now who still don't do ketamine because it was a bridge too far, the whole idea of intravenous and fairly deep experiences.

But when SPRAVATO came on board, especially also the FDA approval, I think gave them that level of comfort and it was much more of a -- I think of a stretch for them. So what we do see clinics now who are kind of doing mainly traditional things and have been sticking with traditional prescription med management that didn't join the interventional but have now adopted SPRAVATO. I think a lot of providers don't think of it even as interventional as that large of a shift in their practice is just, okay, I can do this. And that's interesting because it lowered that bar to adapt a new treatment.

Dr. Hendricks, anything else to add?

Again, trying not to add anything redundant. Look, I would say that the emerging literature on psychedelics has led to an increase in enthusiasm for psychedelic like SPRAVATO. Aside, a major medical center, say, like UAB will have an independent clinic dedicated to psychedelics separate from SPRAVATO. And there is no shortage of residents and others who want to know now how can we prepare ourselves for real-world use. And I anticipate we'll have a very active clinic that will be engaged with patient populations and training residents and collecting real-world data. So I would even say it's SPRAVATO aside, the literature on psychedelics alone has led to an increase in enthusiasm and conversations around preparedness.

Excellent. Thank you. There's a few other questions here. Maybe I'll ask two questions are pretty similar. So how do doctors see patient appropriateness for psilocybin versus 5-MeO versus ketamine? And perhaps a related question here is for your existing SPRAVATO patients, what would the clinical evidence need to look like to prompt the switch to psychedelic-based option?

And perhaps Dr. Hendricks, I'll start with you on that one, just to mix things up a little bit here.

Well, okay. So I'm a psychologist, keep that in mind, not a physician. I would work closely with physicians to determine medical appropriateness. But sort of from a psychological perspective. My sense is that given the intensity of the experience of psilocybin or as Dr. Feifel said, how sort of -- I don't want to say burdensome, but just that it can be a lengthy and tiring experience. It likely requires a bit more preparation and likely psychotherapy. I don't think that, that is the case. In fact, we know that isn't with BPL. So my first thought is that the big differentiation, again, is that we have a shorter acting, more convenient and scalable approach with BPL, and therefore, it might be more appropriate for people who are eager for a more convenient treatment.

Dr. Wilkinson, anything to follow up there?

Can you repeat the question? There was a lot packed in there.

Yes, of course. Kind of a two parts. So it's how do doctors see patient appropriateness for essentially the different approaches of modalities, psilocybin, 5-MeO, ketamine and kind of the follow-up there is for your existing SPRAVATO patients, what would the clinical evidence need to look like to prompt a switch perhaps to a psychedelic-based option?

I'll maybe start with the second question. And I would say I think the clinical evidence needs to look somewhat like SPRAVATO, right? If it's way less effective, then there's going to be a lot of hesitation. But the logistical factors are in favor of the -- a drug like BPL. We hit on these themes several times already. So if you're having to choose between a session twice a week for 4 weeks and then once a week and then something like that after indefinitely, or once every 2, 12 -- excuse me, on treatment every 8, maybe 12 weeks, that just looks a lot different logistically.

So if you're close to SPRAVATO evidence in terms of both, I would say, delta and overall improvement in something like a MADRS, then that's going to be -- with your logistical factors in your favor. I think that's going to be in your favor.

The first question, how do doctors make decisions about whether -- I don't think you can answer that one right now because all these things, except for SPRAVATO are still experimental. So doctors aren't faced with these questions. The doctors that are involved are running clinical trials and it's very protocolized and so forth. So there's really not any evidence or in my sense, in my opinion, that can help kind of open the window into doctors' decision-making about these treatments.

And maybe as a follow-up there, let's just kind of envision making treatment decisions if and when multiple psychedelics are on the market. What perhaps would kind of feed into that decision-making, effect size, depth of psychedelic experience, the safety profile, patient preference? I just kind of maybe talk through a little bit about the criteria there that you would potentially use.

Sure. Sure. So I know -- I hate to sound like a broken record, but some of the factors that I mentioned maybe an hour ago, so overall efficacy, speed of response, side effect profile on the clinical side, and then the logistical side, right, how often do I need to get retreated and then -- and how long are the treatment sessions. So within those 5 factors, I think a lot of decision-making will hang on those 5 factors.

Let me kind of flip the question to a sort of a different perspective. A lot of what drives patient -- sorry, providers' decisions are what their clients are demanding, right? So envision a future where, let's say, a current SPRAVATO provider is now faced with approved psilocybin, approved formulation of, let's say, LSD and approved BPL. And the data are kind of -- we project from what we've seen on those compounds so far. And providers are -- especially psychiatrists are conservative. If they're doing something and it seems familiar, there's momentum, inertia, I would say, to not necessarily change.

Well, they're going to have a lot of patients who are going to be reading about these newly approved things and they're going to be -- you're saying, why can't I have one of these, where I come in once every 4 months or so, instead of coming in like every week or every 2 weeks to get -- just to maintain. And if that provider is a little -- is going to push back on that, they're going to see that client -- they're going to not see that client. That client is going to go to another place, right? And then if we take that further among the agents, if you -- so we need to do is we need to think from the patient's perspective, this is a different world than even 20 years ago, patients are exposed to this stuff. They're aware, they research. It comes in front of them on their smartphones.

And so which one are you going to be like especially interested in among the -- you're definitely going to want to switch from SPRAVATO, so you don't have to come in all the time. Then among those psychedelics, which one are you going to pick? I mean, obviously, there's going to be differences by the time all these programs are done in some of the efficacy and the REMS and so forth. But all things being equal, a big factor is going to be how long do I need to rearrange my life to be in the clinic. So what are patients going to be demanding from their providers? That's what's going to make the decision.

All excellent points. I really appreciate that.

Let's maybe take a little pivot here. To Srini and then maybe as a follow-on to Kevin, what are the key assumptions that lead to an early 2029 top line readout from the Phase III trials for BPL? This is coming from Sumant from Canaccord. So maybe Srini, you can start there and then Kevin?

Okay. Sure. Yes. I mean, obviously, we have a lot of experience within the team at this point in getting these trials up and off the ground. And over some shifting time -- some shifting regimes as well. So it's been -- we have the requisite experience to really kind of understand time lines around this. There's still some things that can be unknown. Obviously, at this point, we are being conservative on our estimates. And of course, over time, we'll be -- as these trials progress, we'll be providing some additional updates as to when top line can -- when we anticipate top line.

I don't know, Kevin, if you have anything to add.

Yes. No, just to double down on that really. I mean, I think the two global Phase II trials have taught us a lot in terms of getting drug into country Schedule I substance is a thing but I think we've got that well worked out. We know a number of really good sites and investigators. And so I think that helps us a lot as well. So I think we've really -- we're sort of in the best place. It's something we've done before. But as you say, I think we really need to get those details lined up, and I think we should guide later on.

And Kevin, maybe as a follow-up there, a 2-part question here. Would the company consider that time line as conservative? And is there a potential for an interim readout for one or both of these studies?

Yes. I think it's realistic. And as I say, some of the unknowns will resolve themselves like getting drugs into country and getting licenses approved and that sort of thing. But I think it's a realistic time line based on our prior experience and this indication. And again, in terms of the readouts, what we're talking about here are the top line results for the core study, those are the 12-week double-blind phases for both studies. So we haven't guided any further on that, and we'll probably update as time goes by.

Okay. Great. And maybe staying with you here, is another question that came in is, what have you learned about staffing from the clinical studies you've ran so far? And how will that translate in real-world practices? How many monitors per patient? Could one staff member oversee multiple rooms? And what kind of credentials would likely be required?

Yes, that's a really good question. And I think one that is certainly, as an industry, we're working on quite carefully and I would certainly separate out what we need to do in a clinical trial versus what has to happen in clinical practice.

So in the clinical trial, we are still learning about this drug. We're still gathering data. And the regulators have got some clear guardrails around what should be done. So certainly, we need one qualified monitor to support the participants through the trial through the dosing day. And we need a backup person. It doesn't necessarily have to be in the room, but needs to be nearby and sort of there to step in if necessary. Now again, we have a shorter dosing duration here. So it's not that people have to take comfort breaks or that there's a very long session. But I think that is what we envisage for our Phase IIs. As I say, that's one monitor in the room.

And I think that is going to evolve over time. I don't think it's going to be less than one person in the room. Again, we have clear guidelines from regulators about what those qualifications need to be. But I do think that in time, we will have a better understanding of what the core competencies for this role are, what the training is that is required. And I think that will begin to define what the qualifications need to be. So in some ways, again, given the experimental nature of these compounds at the moment, it is important to err on the side of caution, and we have been cautious in terms of the qualifications. And that will change as clinical practice adapts and learns about these drugs.

And I mean maybe I can turn that over to the doctors on the call as well. And I don't know if there are any kind of comments or additions that you'd add to that.

Kevin, I think your point about the clinical requirements versus clinical trials is very poignant. But of course, a clinical practice often ends up being influenced by clinical trials because the FDA tends to especially with drugs like psychedelics where there's going to be REMS often requires that the clinical practice replicate what was shown to be safe and efficacious in the trial. So we can assume that -- and since I've been doing these studies, I've seen a very, very dramatic downgrading of the monitoring requirements. I think the companies are pushing for less and the FDA, as they see, the safety is agreeing to less. So the first studies that I was involved in always had two fully licensed therapists -- licensed and specifically trained in the room.

Now at this point, the standard is one licensed, qualified trained facilitator and one backup who's monitoring can -- who will be monitoring remotely on site, who is not licensed, especially. So unless that changes, that may be what the requirement is.

In clinical practice with a drug like BPL, if I use SPRAVATO as a model and ketamine, we can definitely monitor multiple patients simultaneously without a person in every room. That's what we do with our ketamine clinics. We have 4 or 5 patients that are monitored by CCTV. We have wireless blood pressure vitals and patients as needed. We have nurses and physician to go into patients as needed, especially after the first line. Maybe for the first experience it's new, there's a lot of anxiety, you might need a monitoring. But once patients kind of become familiar, they're coming in for their quarterly or 4-month dosing, they can -- for 2 hours, they can definitely be in the room without somebody from a clinical point of view, and being just monitored by a less than 1:1 ratio. So we'll see that will probably happen as the drug is out and AtaiBeckley and other companies are able to show good, safe results, those REMS may loosen over time.

I'd like to just add one point to that. I think the short durations psychedelics are particularly well suited, I believe. And of course, I'd like to get the take of the KOLs on the line, but they're particularly well suited to having less monitoring. And the reason for that statement is that if you look at the data that we've generated, the really -- the most intense period of the psychedelic experience is very short for these drugs. I mean we're talking about this 2-hour thing, but that is wheels up to the wheels down. That's everything, right?

If you're looking at what we refer to as SERS, which is Subjective Intensity Rating Scale and things like that when you're in the 5 and above range, for BPL, it's, what, 30 minutes, maybe 40 minutes. If you think about like a psilocybin or something, it's several hours, right? So it's many fold longer even. So that may allow us less monitoring over time. I mean it's just -- you can watch the patient, you can watch them remotely if something is going on, go in there and settle them down as appropriate as opposed to having to talk them through in a really extended period of time. But again, I throw that out to the KOLs to get their reaction to that.

I'll speak to that a little bit, not only the monitoring, but just the physical infrastructure demand. It may not be an obvious problem. But if you have an 8-hour session where patients are in an altered state. One of the -- how do you get patients to go to the bathroom, right? When long-acting psychedelic companies approach us and say, hey, we want you to run these trials, said, okay, you have to have this special space, and there has to be an adjacent bathroom because we don't want patients who are in an altered state stumbling through the hallway and interacting with other patient. And you don't have that same problem with if you're -- if by 90 minutes, 98% or whatever percent of the effect has resolved as your Cmax data suggests, it's not really that much -- most human beings can wait for 90 minutes. So that is another aspect to the -- just the logistical facility that a shorter period allows for.

I'll take that one step further. On the monitors end, if the FDAs would require a licensed facilitator to be in the room at all times. If you -- and this is something you don't foresee, but when you get -- when you start getting dent into the weeds of the study and you're thinking of the logistics, you realize you have an issue because if you have a 6 or longer hour session, those monitors need to take a break, right? And if you need some -- that means you need to have a backup available. And let's say like us, if we're contracting, that's a serious problem because you're paying for somebody who's going to be stepping in for short periods of time to give the monitor a break to go to the bathroom or to grab something to eat. Whereas if it's a 2-hour, a single monitor can do that. You put a half hour gap between patients. They go to take a break and they can go back in for 2 hours without needing a break in between. So little things like that, that are not obvious from the surface make a big difference in the economics.

I may add to that, too. So as I mentioned before, I'm a psychologist, you might wonder how a psychologist became interested in drug development. And I would say that it started with psilocybin and the impression or intuition that psilocybin could lend itself well to adjunctive psychotherapy or that some sort of preparation is needed, some sort of so-called integration is also needed. And then it could be helpful to have a trained mental health professional in the room, especially when difficulties arise. I think in the case of BPL, it's a completely different ball game. I don't think Atai is trying to make me redundant or put me out of a job, but I don't think I'm needed in this case, although I still find the subjective effects, the experiences that people have to be fascinating and the mechanisms are incredible.

And it's really amazing to hear the sort of stories that people have and to see this sort of rapid transformation. But I do think again, a rather significant upside is that the psychotherapy really may not be needed at all, which may not be a win for me as a psychologist, but certainly a win for the patient populations, and that's what I want more than anything else.

That's wonderful. Great conversation there. Maybe another kind of general question come in and Srini I'll pose this to you, and then maybe Ryan as a follow-up as it pertains to scheduling actually.

So how is AtaiBeckley working with lawmakers to reschedule DMT? Will this be done prior to approval or after approval? How long will this take? And there are a number of organizations that are proponents of advancing psychedelic therapies? What type of role are they playing in general? And are they helping to lay some of the groundwork for scheduling of these drugs?

So Srini, maybe you can take that. And then Ryan, if there's any follow-up there.

Yes, absolutely. So let me start with kind of the sort of the statutory process here, right? So what does Schedule I mean? It means that it's a drug that has an addictive profile and also has no approved medical use. That latter part is really key. So what typically happens, and this has happened before for things like Gamma-hydroxybutyrate, but also THC. What happens is that the drug gets approved by the FDA, and the FDA then petitions the DEA with an analysis called Eight Factor Analysis, et cetera. The DEA then -- typically, it's kind of a -- by definition -- well, the definition has shifted then, right? It's been approved. So the DEA will then down-schedule that product.

So going back to Gamma-hydroxybutyrate, that is still a drug abuse, it's still Schedule I, but as in its approved form of Xyrem, it is down scheduled. So just that product is down scheduled. The compound itself is not. So we're not necessarily advocating for DMT itself per se to be down schedule. We want our products, whether it's DMT or 5-MeO-DMT, et cetera, we'd want our products, the BPL-003 and VLS-01, just like COMPASS presumably wants COMP360 to be down scheduled, not psilocybin per se. So it's a slightly nuanced answer.

Now the DEA approval process statutorily is 90 days. So once the drug is approved, that is put forward by the FDA to the DEA, that's a 90-day process for them to do the differential down scheduling. So that's the general thing.

But I'll actually let -- hand it off to Ryan here to kind of give some of the -- some additional color as well as some of the organizations and some of their efforts there.

Absolutely, Srini. Thank you. I think you nailed obviously the big picture framework. The only thing I would add is that running parallel to the federal effort, of course, is also the state-specific efforts. We're actively engaged with APP and other psychedelic developers to ensure a systematic approach to communal development challenges, including descheduling.

I would say that our general view at AtaiBeckley is that we need to be and will be actively engaged in the lead up to commercialization to ensure that the amount of time and friction between a potential FDA approval. And the -- again, as you said, narrowly tailored descheduling at the state level is maximally reduced so that the patients get the benefit as expeditiously as possible following approval.

I would say the only other thing to add we do anticipate having the benefit of following certain longer-duration psychedelic developers like COMPASS Pathways with COMP360, which will presumably help us refine our specific approach to this issue for BPL-003.

Great. Thank you, Srini. Thank you, Ryan. Another question here is, and Srini, I'll pose this to you and then Kavita. Is Atai entertaining any conversations with big pharma or other potential partners to distribute or commercialize the product? Just maybe talk through a little bit about what potential commercialization might look like there?

Yes. I mean, obviously, we can't speak to any conversations until they become -- until they get to a certain point. But big picture, there has been a lot more inbound interest in this space. And I think a lot of that was driven, of course, by SPRAVATO's success over the past couple of years. So there's -- it's -- the interventional psychiatry pharmacotherapy space has really kind of hit the radar screens for many companies. So there's definitely interest from that perspective. And of course, the other catalyst here was AbbVie with the Gilgamesh transaction a little while ago. So those are things that really have driven it. And we will see and of course, we'll advise appropriately as things change there.

But I'll actually let Kavita kind of talk through the commercialization bit, which I think is unique for us here such that it's not a requirement really to have a big pharma partner for commercialization.

Yes, absolutely. Thanks, Srini. And I'll bring back some of the commentary I had earlier. We are fully prepared to commercialize alone. And I say that because this is a market -- I shared some data. This is a highly concentrated market in treatment-resistant depression, interventional psychiatry.

And even just looking at the SPRAVATO numbers, I think it's remarkable, we think about the 80-20 rule, this is actually 10% of the sites today that are treatment centers that are REM-certified SPRAVATO treatment centers are actually yielding the majority, 75% of the prescriptions.

So I think that, again, it sort of underscores that there is a very concentrated high-volume treatment center opportunity here. And because of everything that you've heard today, we believe that the operational fit within those -- that current infrastructure makes a lot of sense, and we are uniquely fit to slot into that. So yes, we are definitely preparing for commercializing alone and developing those relationships and market readiness as we speak to be able to do that.

Okay. Great. So I'm going to move on to another set of questions from Pete from Cantor. Kevin, maybe there's a little bit of a repeat here, but perhaps we can just talk to this a little bit. But for the Phase III studies, are you using sites that are psychiatry experienced, but not necessarily psychedelic experience? If so, what specific training or monitoring will you put in place to ensure consistent prep and dosing day procedures, some examples being patient prep, handling acute effects, discharge criteria, et cetera.

Yes. Look, I think the first aim is to use as many of the sites that we have worked with before who are not only psychedelic experience, but I think understand the BPL product or the VLS product. So I think that's our first step. But there will, of course, be others that haven't worked with BPL before. I think we are really benefiting from the fact that there has been a great capacity build due to the other Phase III trials that are ongoing at the moment.

So kind of globally, we are seeing greater bandwidth in the number of sites. That isn't to say that we aren't because of competitive influences at the sites, we aren't going to take some sites that are new to this endeavor. And again, we've stood up a number of psychedelic naive, but very experienced investigative sites on previous trials.

I think there are a couple of things that really help us here. The first actually is the central rating. So that is consistent. So our primary endpoint and our MADRS scores. I think the central rating, although it's operationally complex, really helps us. And obviously, we supervise that very carefully, and we do surveillance of those scores, but we have fewer raters and there is more consistency. We also have a very comprehensive participant support manual and training program, and that actually has got some patient-facing elements to it. It's also got some training of the monitors. And that's a key piece.

So I think making sure that the monitors are trained because actually that they deliver the support in a consistent way is an important piece. And that really speaks to expectation management, sort of equipoise around dosing and uncertainty and that sort of thing as well. So I think there's a lot of effort that we put into managing that process. And of course, we record those sessions, and we do assess those as well for consistency and quality, and we remediate if we need to.

And I think the other part is on adverse event monitoring. I mean, this is a sort of a strange place to be. People have rather kind of strange or difficult to describe adverse events. And so again, I mean, I think the field has really evolved as we've grappled with this problem, although it's not new. I mean, I think Esketamine, SPRAVATO had it, there are a number of other compounds that have dealt with similar things.

But I think making sure that we capture those adverse events in a way that is interpretable across sites. And that's not really a new site, old site problem. It's just a quality issue that we are very focused on. So I do think we're pretty confident that we'll take a sort of small percentage of new sites, but that we've got an onboarding process that is well set up to accommodate them.

Move on to another question here. So I'll start with Srini and then I think it would be really good to get our KOLs also to comment on this. But in a real-world practice setting, what would drive retreatment or redosing with BPL or other psychedelic agent? Would it be patient-driven with patients reaching out to the clinic if symptoms occur? Maybe just speak a little bit about that. So Srini, maybe I'll start with you and perhaps Kevin to comment on that, and then I think it would be great to have our doctors on the line also.

Yes. So we are -- there's been several points where we got some -- had some interesting discussions with the agency that we are keeping close to best because for competitive reasons. And obviously, some of this will be disclosed over time. The specifics on the retreatment criteria is certainly one of those things that we don't want to get into in detail at this point.

We have obviously mentioned that it can be 8 or 12 weeks. And -- most -- to the best of my knowledge, all the competitors are actually focused on 12 weeks. But because of the short duration -- the short duration nature of BPL-003, the question is, can you actually help patients that are basically kind of losing efficacy sooner. It's an option that may be available to us because of that short duration. So that's the only thing that I think we can say in terms of the details. But I don't know, Kevin, if you want to add anything to it. Otherwise, we can defer to the KOLs for how things happen in the real world.

Yes, I think that's right. I wouldn't really say much more about that. I think having some flexibility, and we've got obviously a sort of a range that we're thinking about, but the data will really drive where that lands. But I'll hand it over to the clinicians for your thoughts as well.

Well, I think that -- I think there's going to be parameters probably driven by FDA REMS and insurance. So with TMS, there's usually a minimal interval period before an insurance payer will be willing to reapprove another round with SPRAVATO, for example, I had mentioned that typically, once a week maintenance is maximal, which some people -- given its short durability isn't enough.

From a clinical point of view, there's 2 models. One is reactive when -- so when a patient starts to feel that they are losing some of that benefit. Given those other parameters are eliminated now, we just -- so somebody starts to feel they're drifting back, they call, they come in, which happens a lot with ketamine clinic because it's out of pocket and people don't want to be scheduled regularly if they're doing well, they'll kind of play it by year, especially if they get a point where they can go fairly long duration.

And then there's a further prophylactic model where you're scheduling it to prevent any relapse. And I think that probably what will end up happening if it's driven by clinical need, patients will figure out where their pivot point is when they need to come back and those will be kind of scheduled in advance. So mine lasts about 3 months and then I start to notice a decline. So I schedule out in 3 months because they want to be in the books for that.

And I'll just agree with that all and add to that also perhaps the point for enthusiasm here, at least on my end is the ability to intervene earlier before there's a sort of a lengthy period of demoralization after trying one SSRI or SNRI or some other treatment after another that really doesn't work. So there will be parameters, as mentioned, but I think we should be optimistic about being able to intervene earlier and prevent that lengthy period of demoralization.

I'll add on with respect to what David said about the reactive versus the kind of preventive approach, I think the reactive works pretty well for SPRAVATO because the interval is so short. You're seeing patients maybe once a week, once every other week, most in our clinic once every 4 weeks. But I think it is going to be -- that is going to be one of the slight shifts that I think would be important for patients to where if you get a dose of BPL, maybe you have a telehealth appointment that you schedule for 4 weeks from then.

And then -- and you kind of assess where they are maybe 8 weeks from then and try to kind of -- before patients really fall back to the depth of the point that they were before, try to catch them as that slope just starts to to become negative a little bit and you can get them in quickly. So that's my thought about the react. And again, the SPRAVATO will lay a lot of the groundwork there will have to be some tweaks as to the best treatment model that providers can offer.

Excellent. That's very helpful. Moving on here, and Kavita, I think I'll send this one to you. There's a question that came in. Given the rapid onset and relatively short session time of BPL, what do you see as the minimum durability threshold needed to compete with the 20, 30, 40, maybe even 50-plus annual SPRAVATO visits is 3-month durability a win?

Sure. I would say unequivocally, yes. When we think about and we shared some information that on average, SPRAVATO patients are on weekly maintenance, biweekly or weekly maintenance. So think about it coming into a clinic with the same 2-hour duration, same constraints, but every other month, that in of itself is game changing, and it was validated.

We talked to a lot of patients. We talked to a lot of -- we did some research on this, and they absolutely echo those comments. So while an even broader treatment frequency even better, I think every other month is absolutely a win, as you said, for patients as well as for clinics.

Appreciate that. Maybe going back to our clinicians. The question that came in that BPL reproduced its Phase II clinical profile in Phase III, what proportion of your TRD patients would you recommend this for? What patients would be good candidates versus SPRAVATO, for example? Maybe Dr. Feifel, it looks like you came off mute first, so we'll go with you.

I mean, assuming that it's SPRAVATO versus BPL as we know it from Phase IIb, I mean, who would I not -- I mean I'm trying to think of why I would recommend somebody stay on SPRAVATO. Nothing is coming to mind. I mean you can do -- get these great effects generally quicker and longer duration. I mean I have to think hard about some situations where that wouldn't be a no-brainer recommendation. And even if I didn't recommend it as soon as the patients got wind, they'd say, "Hey, are you going to be buffering this year" because I'd much rather come in once every few months.

And I would agree with that. My response to that question would be all, obviously, considering the sort of inclusion and exclusion criteria that are already a part of the trials and the REMS, but I don't see any reason why we would recommend esketamine before BPL. In fact, I'm more enthusiastic about BPL than esketamine for a number of reasons. So I think this could potentially take over as the treatment of choice.

Yes. And maybe, Jason, if I can add, too. I think we talked about the broad treatment-resistant depression population in the U.S. and penetration within that with SPRAVATO or FDA-approved TRD treatment is so small. So I think absolutely, the low-hanging fruit here is those who are not getting the clinical effect from SPRAVATO or can't deal with the weekly visits or biweekly visits. But I think there is a much larger cohort potential that could potentially benefit from BPL as well within the TRD landscape.

Very helpful. Okay. Great. Moving on to another question. And Kevin, I'll oppose this to you. For BPL, can we go into the patient visit time to check in, the time to prepare for the therapeutic session, interactions with monitors? Just can you provide some insights into the patient experience before and after being dosed with BPL?

Yes, sure. And I think we've sort of touched on this already, but I would separate out maybe what we're doing in the trial, in particular, the core trial with what we're doing in the open label and what might ultimately be how we do this in clinical practice.

So I mean, at the moment, we're taking -- we're doing certain things in the trial like collecting PK that aren't relevant and won't follow through into the clinic. So let's think about a patient who's coming in for maintenance therapy, so has had a number of doses before. What would that look like?

We would expect typically kind of an intake so that there may be a check in the day before, maybe on the day where we're checking on the patient's mental state, any major life events. So generally just checking in before we dose the participants. Then there's the dosing itself and the monitoring thereafter that.

And obviously, we're striving for a 2-hour discharge. And that's really where we're sort of aiming for, for that. And I think there would be -- in terms of sort of safety structures around that, clearly, the monitoring is going to be a key factor. And like SPRAVATO, blood pressure assessments and that sort of thing will be important as well.

The safety data that we have to hand so far suggests that there aren't any other safety interventions that are going to be required for the majority. We know the blood pressure and that sort of thing is something that we need to monitor. And we certainly, as I mentioned, offered intervention with, say, benzodiazepines for anxiety or agitation.

None of that was required in the Phase II. So I think those things are kind of in the back pocket, but it seems like the rate of their use will be low. And really, it's the quality of that monitoring and a brief intake that are going to be the most important. And I do expect that patients will become familiar with the dosing sort of logistics and time course over time. So that -- and we're trying to build that in even to our protocols to have sort of flexibility as we move into latter dosing, not to take it away entirely, but clearly, the first time you have this dose is going to be different to the fifth time you have this dose.

So I think there are going to be -- we're going to see that evolve over time. But I want to hand this also off to the clinicians. You've dosed many of these patients for our trials and you have a much more hands-on sort of experiences. So I don't know if you have anything to add to that.

Well, I think that was going to be a very comprehensive answer then. Another question here. Ryan, I'm going to pose this one to you. Can you talk a little bit about our IP estate around BPL and how it may be able to prevent other branded 5-MeO based drugs from entering the market?

Absolutely happy to, Jason. I mean, I think as a preparatory point, we're here in service to our mission, which as I mentioned before, is to transform patient outcomes by developing rapid-acting, durable and convenient mental health treatments while executing in a way that drives meaningful value for all of our stakeholders. I'd also note that the depression and broader mental health markets are massive.

In short, we don't view competition as a bad thing at all, and we root for other psychedelic developers. In a perfect world, the products reaching patients are those that can be predictably executed and which drive the best health outcomes as compared to an effective placebo. This is an area in particular where we believe that we and BPL-003 in particular, stand out.

That said, we were founded on the traditional biotech belief that a strong patent estate is absolutely critical to ensure that we can effectively finance, thereby enabling us to achieve that mission. This was a key reason that I was brought on early in the company's existence. A strong patent estate comes from having the right strategy and executing well on it. We've discussed our approach and the fruits that my talented team has produced in the form of numerous issued and Orange Book listable U.S. patents.

In my personal view, this is the type of point of question not asked enough of drug developers, particularly in the psychedelic sector. And while I'm not privy to any nonpublic information of those other developers and wouldn't comment on any specific third-party patent estates either way, I think the answers in some cases may well surprise you.

Finally, I would note that as part of the comprehensive IP strategy we undertake here at AtaiBeckley, as noted previously, in terms of our Orange Book strategy as well as securing issued U.S. patents on alternative sites -- excuse me, salts, formulations, routes of administration and use in alternative indications is to ensure that we've got a strong foundation for commercialization and potential expansion while having multiple layers of defense, all of which we believe will make it very difficult for would-be competitors to design around our patent estate.

Wonderful. Thanks, Ryan. Appreciate that. We're coming up on the hour here. So I think we have one more question for Kavita and then a final question to our clinicians on the call. Vita, what pricing bands or kind of pricing considerations are we -- are you considering for 003 at this stage? Any kind of high-level commentary there would be helpful.

Sure. And it will definitely be high level. As we know at this stage, we're not at a position to provide any specific pricing guidance. What I will say and what I shared in the presentation earlier is when you look at kind of our closest proxy, at least in the market today, SPRAVATO, and you see the actual utilization in the real world of what the average patient is the dosing frequency often monthly at the higher dose, you're in a range based on our data of 60,000, maybe even well north of that. And this is WAC pricing. Pricing is complicated. There's a lot behind that.

And so what I would say is if we truly deliver on this trifecta of benefit. So again, rapid acting, very durable compound that is convenient, this 2-hour window and convenient for patients and clinics, we believe that there is opportunity for premium pricing potential if that value is delivered. So I would just leave it at that at this point.

Perfect. All right. So I think one last question here, and I'll pose this to our clinicians on the call before handing this back to Srini to close. And just perhaps some final thoughts on the psychedelic field and what you're most excited about moving forward, just as some kind of parting thoughts before we close. I'd love to kind of hear those. So perhaps Dr. Wilkinson, you can start just because you're first on my screen here.

Yes. thanks. Well, I'm just excited that we have -- we're finally in a space where we have lots of different things with different mechanisms. For a long, long time in drug development, it was just me-too drugs. It was adding a methyl group to some SSRI or something like that. And we do owe a lot to the ketamine SPRAVATO story because that really I feel like opened up the field to really just thinking about, hey, one dose I mean a couple of times in this call, we've said SPRAVATO is not very long acting.

But from a historical perspective, it is, right? You had a drug that has a 2-hour half-life and it couldn't keep people well for a week. That was a really kind of paradigm shifting reconceptualization. So I'm excited about the short acting and the potential for long durability.

Perhaps Dr. Feifel go next.

Yes. I mean I am just excited about practicing in a field where I feel I have really powerful weapons for maybe a lack of a better term to fight this monstrosity of mental illness, which is such a surge on society and it doesn't seem like it's going to be going away anytime soon with the nature of our society. And I actually went into psychiatry.

One of the reasons I chose it was that I believe that it was on the precipice of a revolution. Neuroscience was advancing so rapidly. And I thought it's going to translate into great changes. And not many students were choosing psychiatry. I actually posted a paper about student attitudes because we couldn't fill our residency slots and about a decade ago, a little over a decade ago, things were so gloomy because companies were pulling out of R&D. In fact, there was a New York Times column by psychiatrists who talked about the innovation crisis in psychiatry. It was a really kind of gloomy time.

And I was still -- I said I'm a decade into my career, and I'm still writing prescriptions for the same -- essentially the same drugs that my mentors were writing when they were residents. They got a little fancier and so forth, but they were essentially the same mechanism of action. I was thought, wow, this is -- I may have miscalculated here. And thankfully, look, here we are.

I described this as sort of the Cambrian explosion of new treatments where we've got an embarrassment of riches of all these new and they are they are revolutionary. If you want -- if I had to precipitate down to what am I excited about, sitting across the desk from a patient that I know I've got something that will change their life where I did not feel that for.

I almost felt like I was just trying to string them along and say, well, what if we just change the dose here, we had this drug, we had this drug, but I wasn't really convinced that I was really doing something dramatically different. And now I just feel like I've got stuff. I've got -- and what's coming down the road, I'm going to really have some good stuff.

Dr. Hendricks?

There's a lot I can say about this. But let me just start by saying my interest before I knew psychedelics existed was in a concept known as quantum change and that captures this idea that sometimes people do change rather suddenly and dramatically and this change is durable. But it happens or happened so infrequently, it was fair to say that scientists didn't really understand that process. So we have fictionalized versions of it in the case of, say, Ebenezer Scrooge. I was always fascinated by the story that sometimes people can change dramatically and for good.

And when I came across the literature on psychedelics, my first thought was, well, my goodness, we can actually schedule quantum change for a time and place. Now I recognize that not everybody has that experience, right? And like any intervention ever, not everybody will respond. But I think prior to psychedelics, usually in a clinical trial, if we had a successful intervention, that intervention would, in fact, have ultimately failed less than the placebo, but was still not successful for most participants. That's demoralizing for the clinician when we know that even our best treatments won't work for most.

I think with psychedelics, the tide is turning. And as David mentioned, we're at this place now where we might be able to offer treatments that work for most people. Not only that, but they speak to a mechanism of action that can cut across diagnoses. And that's likely because potentially, these interventions are getting at the core of the mental health condition rather than only addressing the symptoms.

And personally, I think one thing that makes psychedelics quite unique is that they get at deeply held personal values and how we form meaning in life and allow people some clarification of these values and perhaps alignment of their behavior with those deeply held personal values, which is a good thing. So I'm quite excited.

I also do want to say again that I think in the case of BPL, we have a very unique psychedelic that is not just, say, psilocybin in a shorter-acting form. I think it has a number of unique properties that could make it especially amenable to a wide range of mental health conditions and in a way that is scalable to the clinic workflow.

So as this conversation has gone on, I've become more enthusiastic as we're talking about these things out loud, but it's a really exciting time to be involved in this space because I think we're on the precipice of offering a treatment that could really work for the majority of people and that the majority of people can access.

Wonderful. Thank you very much, and a special thanks to Dr. Hendricks, Dr. Wilkinson, Dr. Feifel for joining us today. Insights were just incredibly valuable, meaningful, impactful. So really appreciate you joining. And with that, Srini, I think I'll pass this back to you for some closing thoughts before we end today.

Yes. So let me start by actually reiterating what you just said, Jason, thank you so much, Dr. Feifel, Dr. Hendricks and Dr. Wilkinson, just for your time, which was significant, your enthusiasm and also for all those insights.

I want to thank the audience as well for their interest and all the great questions that we received over the course of the call. Thank you to the team for making this webinar possible, obviously, and all the hard work it took to get the company to this place.

2025 was transformative for the company. A lot of things happened, a lot of great things happen. 2026 promises to be so as well. So we've got -- we're getting this Phase III program up off the ground. We're awaiting the data for VLS-01. It's also worth mentioning, it's going to be an exciting time for the space. We've got some Phase III readouts will be coming up, have had some, and we'll have others as well. So it's really important for the patients. So stay tuned, and we look forward to continuing the discussion with all of you.

Thank you for standing by. My name is Amy, and I will be your operator for today. At this time, I would like to welcome everyone to the AtaiBeckley EMP-01 Phase IIa Topline Data Conference Call. [Operator Instructions]

I would now like to turn the call over to Jason Awe, VP of Investor Relations with AtaiBeckley. Please go ahead.

All right. Thanks, Amy. Good morning, everyone, and thank you for joining us today. We're here to discuss the positive topline results from our exploratory Phase IIa trial of EMP-01 in social anxiety disorder. Joining me on the call are Dr. Srini Rao, Chief Executive Officer and Co-Founder; and Dr. Kevin Craig, Chief Medical Officer.

Before we begin, I would like to remind everyone that during today's call, we may make certain forward-looking statements as set forth on this Page 2 of the presentation. These risks are detailed -- discussed in detail in the Risk Factors section of our most recent Form 10-K and in subsequent SEC filings. We undertake no obligation to update or revise any forward-looking statements, except as required by law.

With that, I'll turn the call over to our CEO and Co-Founder, Dr. Srini Rao, to begin with background on social anxiety disorder and the context for today's results. Srini, over to you.

Thanks, Jason, and good morning, everyone. We're very excited to share these first inpatient data for EMP-01, our oral R-MDMA candidate, with all of you today. As the first controlled clinical trial of EMP-01 in social anxiety disorder, or SAD, the study gives us an important early look at this compound with its unique pharmacological profile. In short, we're encouraged by what we've seen across feasibility, safety and initial efficacy signals.

On the next slide, I want to start with a brief overview of SAD because the scale and impact of this condition often go underappreciated. SAD is one of the most common psychiatric disorders globally, affecting hundreds of millions of people, and it remains a chronic and highly impairing condition for many.

Despite that, nearly 60% of people living with this condition received no treatment at all. Even among those who do seek care, many continue to struggle with persistent fear, avoidance and significant functional limitations in everyday life situations. Despite its prevalence and impact, there have been virtually no pharmacological innovations in this indication in over 20 years.

Today's standard pharmacotherapies, typically SSRIs or SNRIs, require daily dosing, can take months to achieve a meaningful clinical benefit and over half of patients do not respond adequately. And even for those who do, the improvement is often partial and tolerability can be a limiting factor.

So we're left with a very large, very well-characterized unmet need for treatments that act more rapidly, more robustly and ideally with intermittent dosing rather than continuous daily exposure. That's the context in which we designed this exploratory Phase IIa study of EMP-01.

Our goals for this first inpatient study were twofold. First, to understand the safety, tolerability and feasibility of 2 in-clinic administrations of this novel agent in a real-world SAD population. And second, to determine whether we can see early clinically meaningful signals on accepted regulatory endpoints, all without psychotherapy.

I'm very pleased to say that the study delivered on these -- on both objectives. The team enrolled a highly severe patient population, executed with strong adherence and achieved exceptional retention across the trial. Importantly, across the data set, we see a consistent pattern of improvement that supports further development of EMP-01 in SAD.

Kevin will now walk you through the fourth study design, safety outcomes and the key efficacy signals we observed. Kevin, over to you.

Thank you, Srini. So on the next couple of slides, I'm going to talk through a bit about the study design and the baseline characteristics to really frame the results. So moving just to the next slide, I'll talk about the study design.

As Srini mentioned, this is an exploratory Phase IIa randomized placebo-controlled study that was primarily designed to assess safety, tolerability, feasibility and efficacy of 2 doses of EMP-01 in 70 patients with social anxiety disorder. So as you can see in the graphic, participants are randomized to either EMP-01 225 milligrams or to placebo, and they received 2 doses, one at Day 1, one at Day 29. The endpoints were taken at Day 43, both the safety and efficacy, and we had a safety follow-up 2 weeks later.

Importantly, this study was not powered for statistical significance and efficacy, but rather to characterize the safety and determine whether we could detect clinically meaningful signals worth advancing in this or other indications.

On the efficacy side, the main secondary endpoint was change from baseline in the Liebowitz Social Anxiety Scale, the LSAS, total score between baseline and Day 43. And we had a number of other exploratory endpoints, including other clinical scales such as the CGI-I, the CGI improvement scale, which we'll talk about today, and others which are not part of the top line, but will come at a later date.

An important aspect of the study was the fact that we went to make sure that we used central raters for all the clinical measures, including the LSAS and CGI, and this is intentional and adds rigor and improved consistency. And as Srini mentioned, there was no psychotherapy. We had a typical psychedelic prep and in-study support as participant support, but no psychotherapy was delivered.

And in terms of enrollment, we randomized 71 participants, of which 70 received a dose and are part of our modified intention to treat analysis set. We had a very high retention rate with 69 participants completing the Day 43 rate. So I think a very high retention rate. And we're very pleased actually with the -- both the results, but also how the study was run. It was run, as Srini mentioned, kind of effectively enrolled well. We had good baseline characteristics.

So maybe on the next slide, I'll move across and talk a little bit about what the patient group looked like. So you can see here the 2 middle columns are the baseline demographics and other characteristics of the placebo group on the left and EMP-01 on the right. And you can see that it was very well balanced across the demographics in terms of age, sex, ethnicity. There was a slight imbalance in terms of the number of prior medications that people have used for their social anxiety disorder. But this is very small, and I think it didn't affect the results and it's typical of a small study of this kind.

Just to draw your attention to the middle of that, which is the baseline LSAS score, which in this case is very high. So we had a mean baseline LSAS of 108. And just to put that into context, and we'll show a slide a bit later, many of the registration trials historically have had LSASs of around 80 to 90 in -- at the baseline. So again, this represents quite an unwell group with severe disorder going into the trial.

I think in general, as I said, we're very pleased with the results and how this has balanced out. So on the next slide, we're going to talk a bit about the safety. So I think the general takeaway was that this was very tolerable. It was -- it had adverse event rates, which were kind of expected. We had, as you can see at the top line, a number of treatment emergent adverse events, both in the placebo group and the EMP group, but a slightly higher proportion of treatment-related treatment adverse events.

What I would say, though, is that we had only mild or moderate adverse events throughout the whole study with no severe adverse events and no serious adverse events. We had -- towards the bottom of that table, you can see that we had 3 participants who were withdrawn from study drug due to adverse events. Importantly, to note these were all mild or moderate, and a number of them were predefined due to vital sign.

So I think in summary, we had a very well tolerated safety profile. We had no severe or serious adverse events. There was -- we looked very carefully at suicidality, and we had no suicidal intent or behavior reported during the study. We also had -- we had a measure of the CEQ, that's the challenging experiences questionnaire, which really sort of measures how difficult the experience was, and we had very low scores here as well. So I think generally well tolerated during dosing with the expected adverse events.

And on the next slide, I'll talk you through some of those adverse events. So on the left, you can see the adverse events that occurred. These are drug-related treatment adverse events that occurred at more than 15% in the study. And we've separated these out into those that are adverse events of special interest and not typical of the psychedelic experience and those that are not part of that list.

So on the left, you can see the most common there, things like nausea, headache, fatigue, dizziness, decreased appetite, palpitations, vomiting, hyperhidrosis, bruxism and blurred vision. And again, these are very typical of the class. And then we also had a number of these more psychedelic-related adverse events such as feeling of relaxation, sensory disturbance, hallucinations, euphoric mood, anxiety and somnolence. So again, very much what we expected and what we saw in Phase I, really no surprises, very consistent across the Phase I and Phase II studies.

On the next slide. Here, I just wanted to talk a little bit about some of the difficulties in treating patients with social anxiety disorder. And Srini alluded to this a little bit as well. So the way that we measure social anxiety is twofold. One is the sort of a symptom that is the fear of the context. And the other is the -- whether or not participants or patients avoid those contexts. And so this could be anything from talking to a person that you don't know very well all the way up to speaking in public or being in a group setting in small group setting that kind of thing.

And importantly -- it's important that people have both a reduction in their fear but that then has to translate into a behavioral change. So really, we're looking for people to then go out and experience these difficult experiences, and they then need to not avoid those. So in order to get an improvement on the LSAS scale, you really have to have a reduction in fear, but also a reduction in avoidance of those stimuli.

And that does take some time. So if you look at the scale, there's something that happen very commonly like speaking to someone you don't know very well, but also there are things like holding a party, which takes a bit of time for those things and most of us don't have -- can hold parties too often.

So there really is a time factor to the sort of how quickly the treatment trajectory for this illness, which is, I think is different to some of the other conditions, which are very much based on symptoms like depression or anxiety writ large. And I do think that EMP-01 does show great potential here for changing both the experienced fear in these situations and also the behavioral change, that change in avoiding those situations and really with a dose that is really twice in 1 month, so 1 month apart rather than a daily dose, which often takes some time to achieve.

So moving on to the next slide, we'll talk a little bit about the efficacy. So on the LSAS, what we had was a least squared mean treatment difference between drug and placebo of 11.85 points, and that translated to a standardized effect size of 0.45. And this is very much in line with treatment of standard of care at the moment, both pharmacotherapies like SSRIs and SNRIs, but also for psychotherapy. So what we got here really after 2 doses and 6 weeks was a treatment effect that is in line directionally with treatments that usually take 6 to 12 weeks to have an effect.

Next slide. Just looking further into the LSAS scale, as I mentioned, there is both this fear axis and an avoidance axis. And we were very encouraged to see that both of these pretty consistently moved between baseline and the end of treatment. And in every case, they were higher in the EMP-01 arm.

So both the experience of fear in these situations and people were less avoidant of the situations because the fear was lower. And we looked at that in terms of subscales within that, like fear of social interactions, avoidance of social interactions, fear of performance -- this might be giving a speech or speaking in public even on the telephone -- and avoiding those public engagements. And again, consistently throughout, we saw greater improvements numerically in the EMP arm.

Moving on to the next slide. We also looked at the CGI-I. This is the Clinical Global Impression of Improvement. And again, people coming into this trial, as I said, a high LSAS score, they also had a high CGI severity score coming in. So we had a significant disease burden in this group.

And here, we saw some quite significant differences at Day 43 in terms of CGI-I rating. So here, really, nearly 50% of people were deemed responders in the EMP group, and that is a CGI-I score of 2 or less, as opposed to 14% in the placebo group. And this really translates to a number needed to treat of less than 3. And I think number needed to treat is one of the ways that we really want to assess the clinical meaningfulness of these scores. And this really means that in order to obtain one participant who responds and is in remission at the end of treatment, you need to treat 3 patients.

And just to put that into context, I mean, that's a very low number. So in social anxiety disorder with other pharmacotherapies, the range of number needed to treat is around 3 to 5. And again, that's quite low in comparison to other psychiatric conditions like depression, where the number needed to treat is often 8 to 10. So we had a very good response rate in this group with EMP-01.

Next slide. And just to put this in a bit more context here, you can see in the green row at the top of this table, these are the numbers that we got from our trial. Baseline LSAS, as I say, was higher than the kind of combined, if you take SSRI registrational trials as a whole and SNRI registration trials as a whole. And also we compared this to psychotherapy where there's less data, but we have some ideas about effect size.

And what you can see is that we compare very favorably both in terms of the severity of the condition, but also then the change from baseline, which is very much in line with standard of care for SSRIs and SNRIs with a number needed to treat around 3 to 4 in the case of other pharmacotherapies and about 3 in our case. And I think importantly, these trials often take 6 to 12 weeks and really does take some time on daily dosing to get there, whereas we've achieved this with 2 doses over a 6-week period.

Next slide. I also wanted to just talk a little bit about the experience of this compound relative to other psychedelics and relative to racemic MDMA. So on the left-hand side, you can see from this trial, the 5D-ASC, that's the 5 dimensions of altered states of conscious. It's a very commonly used psychedelic scale. And you can see the comparison between EMP-01 and placebo. And across the scale, we see quite high numbers for a number of these dimensions such as reduction in vigilance and oceanic boundlessness, but across the scale.

And on the right-hand side, if you compare that to the literature, and again, this is directional. I think it gives us an idea. It's difficult to compare study-to-study. But if you take this as directionally correct, what we're seeing here is psychedelic ratings that are kind of in line or similar to psilocybin and actually quite significantly higher than racemic MDMA.

And that's very much expected given the preponderance of 5-HT2A activity with R-MDMA EMP-01 relative to racemic MDMA. And again, we saw less of the monoaminergic, dopaminergic, noradrenergic effects with this. So we had less bruxism, less muscle tightness and things like that, but certainly higher rates of hallucinations, visual disturbance, et cetera. So again, I think this is a unique profile that we see with R-MDMA, but very much in line with the pharmacology that we would expect.

And with that, I'm going to hand back to Srini.

All right. Thanks, Kevin. Let me close on the next slide by stepping back just to summarize what makes these findings and EMP truly meaningful. As Kevin kind of alluded, what stands out for me is in this data set is a unique profile of EMP-01. It's a compound that delivers a predictable psychedelic like therapeutic experience without the stimulant driven liabilities racemic MDMA and with a tolerability profile that aligns well within our patient interventional use scenario. That's exactly the differentiation our advisors highlighted in the press release, and it's encouraging to see it reproduced.

At the same time, what we reviewed here are only the top line results, as Kevin indicated, for this exploratory Phase IIa study. We will still have additional analyses that are underway. We do have additional analyses and some additional data sets will be forthcoming. Those will help us -- they help inform us how we think about the next phase of development, and we want to make sure we give that process the rigor it deserves.

But overall, we're genuinely encouraged by what we've seen so far with the strong feasibility, a clean and manageable safety foundation and early but consistently positive signals of clinical benefit across multiple measures. All that gives us great confidence in the path forward for this product.

Before I close, I want to thank the patients, the investigator and the site teams who made the study possible.

Operator, I will pass it back to you for questions.

[Operator Instructions] Your first question comes from the line of Andrew Tsai with Jefferies.

Thanks for this interesting data set. Congrats.

Thank you.

So it looks like your study completely stopped at week 6, maybe no open-label follow-up. If that's true, can you maybe somehow find these patients again and maybe track their LSAS scores just to see how efficacy could be trending over time? Or is that not possible?

Yes. I mean, again, this is an early stage trial. So it's common not to do any kind of extension. We certainly talked about following up with these patients.

Kevin, I don't know if you want to jump in on that.

Yes. No, absolutely. I mean I think with the sort of data in hand, that would be great, and we had exactly that discussion. But I do think this was really framed as a very exploratory study. It's been a long time since people have studied social anxiety disorder. So I think for us, this is really about feasibility, safety in this patient population and some idea of efficacy. And certainly, in the next study, we want to look at that durability in a more focused way.

Right. And that actually goes to my second question, the next step for EMP-01. When do you think you could start like a Phase IIb or even a Phase III next? And in this next trial, what kind of time point for the efficacy primary endpoint would you be choosing? And would you be choosing also the same 225 mg dose?

Yes. No, I mean, this is really a discussion of the top line readouts. As I mentioned, we are taking these data, and we're still awaiting some additional data. We'll be doing those analyses and then come back with a more formal plan. So this is really to relay the top line results and our excitement for them, and then we will obviously have to do our own analysis to understand how we want to take this forward.

I mean I can say sort of in general, the other trials that the pivotal studies from a long time ago that Kevin alluded to did have endpoints in the 8- to 12-week range. So that seems to be fairly -- that's something that's come up previously. And of course, durability is going to be a key one here, but those are very general comments.

Your next question comes from the line of Ritu Baral with TD Cowen.

First question is around time to discharge readiness. Did you guys assess that in these patients in the 2-dosing period? And then my follow-up was on the 3 discontinuations. If you could give sort of time for resolution both for those, I think they were cardiac. And then just a little more detail on the other dropouts, please.

Yes, sure. So maybe address the first question. The patients that dropped out, starting there maybe. So we had 3 participants. We had some criteria around blood pressure, which were predefined. And we had 2 participants who had increased blood pressure, one just very marginally above the cutoff. But we were very keen, again, in this early study not to redose people who had raised blood pressure.

That the one participant had a blood pressure that just tipped the number and then came back down. Another person had more of a sustained -- I'm talking a few hours blood pressure rise. And so I think it's early on, probably most cautious to not redose those subjects. That was 2 of them. And the third subject was somebody who had some suicidal ideation that was moderate in severity a few days after dosing. This is very much in the context of premorbid pre-study suicidal ideation as well. So it was there. But again, out of the abundance of caution, we felt that it was best not to redose that subject. Those are the 3. In terms of discharge...

There was no intent certainly and no behavior. So that's the usual -- that's what is typically exclusionary in these kind of trials, including in depression. Suicidal ideation per say is not normally an exclusionary criteria. Sorry.

And days later, you said?

It was some days later, and it recovered without any hospitalization. It was -- as I say, it was sort of a resurfacing perhaps of some premorbid things. And I think it's someone who was sort of well-known and managed within the system. So not really a concern, but I think our decision was best not to redose that subject.

And maybe just then moving to time to discharge. So we don't have the discharge readiness data yet, but what we have got a sort of -- we had a sort of time course for a measure called the SIRs or the subjective intensity rating. So this really ask participants on a scale of 1 to 10, how intense is this experience right now.

And our sort of rubric is that by the time you get down to a 1 or a 2, you're kind of back down to baseline. And the average time to baseline was back to go back to baseline was less than 6 hours. So this is a longer duration compound, and we knew that relative to some of the short-acting compounds that we're more familiar with. But I think it's going to be in that 6-hour range when we do get the readiness for discharge assessment, which was conducted, but it's not part of the top line.

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

Nice to see these data. On a later stage program, do you think LSAS is the best primary endpoint at the same time points used in the trial? Or could we see a move to a public speaking test? That's my first question.

It's a really good question. I think there are difficulties with the LSAS. And as I say, part of that is that it's sort of event-driven. So a number of items on the scale, people have to have experienced those events in order for them to rate it on the scale. So it is difficult in that way. But I do think it is more valid than public speaking.

So I think in this group, actually, we actually excluded participants who only had performance anxiety. We're really looking for true social anxiety. And I think the thing about performance anxiety is that it is a very -- it's a subtype and it's a very context-specific place. So those public speaking challenges are, I think, very good for an experimental medicine studies that give you an idea. But really, if we're trying to treat this condition, our preference was to use the scale that regulators are familiar with and on which other drugs have been approved.

And just one point there, clarification. So the other companies that have been developing things for SAD or social anxiety disorder have really been focused on acute interventions, right? So they are PRN drugs for when there's a situation you're going to go into that you know is going to trigger your social anxiety.

That's the reason that they use this measure of performance anxiety, the social speaking or the social stress test. That is different than the previous approvals, which are based -- they're basically based on the totality of social anxiety disorder. And that is really what we were pursuing here. So it is a bit of an apples and oranges comparison.

Yes. Got it. And then what drove the choice of 2 doses to start with in this trial versus 1 dose?

Yes. I think we had some prior data with racemic MDMA that suggested -- and again, if you look at the treatment trajectory in PTSD that you get further improvement with doses. And in fact, the separation from placebo really begins at dose 2 and perhaps continues to dose 3. So it was a balance between an exploratory trial that was trying to get a sense of whether or not this would work. But I think one dose we felt would be less effective. And I think that's been borne out. So we were keen to give the drug the best chance that it could get while also trying to make sure that this is a fast trial that gave us a readout in short order.

Yes. I think one of the things here is because of this behavioral element to the LSAS, there's this question of whether it's time or doses, right? Do you need more time to actually have some of the symptoms start to be reflected in behaviors? Or do you need more doses to kind of work through these issues? And of course, we don't know that from this one.

But yes, going back to this trial, it was really around what's feasible, let's understand this drug a little bit better. We did change 2 variables, so to speak, with this trial. We had a compound that was unique. Again, it's got these properties that seem to split the divide of an pathogen and taxogen and a psychedelic. So that was the first new element. And the second one was the indication, right? So really, no one's looked at a psychedelic in SAD before. So those are the 2 things. We're trying -- we wanted to take a look at both, and I think we did that quite well. But that's why there are some of these questions that are sort of open here.

The next question comes from the line of Patrick Trucchio with H.C. Wainwright.

This is [ Arabella ] on for Patrick. The placebo arm showed a 16.67 LSAS reduction. And so how do you contextualize this relative to historical SAD trials? And then what design features would you consider in later studies to mitigate placebo response? And have you collected any subjective assessments or guess rates from participants or riders?

Yes, good question. So I think certainly in terms of the change from baseline in the placebo group, it's very much in line with other studies. And in some ways, the LSAS is interesting in that it has a relative to, say, major depression, it has a relatively lower placebo response rate. But I think especially in the context of psychedelic trials, we don't want to completely remove the placebo rates because I think that really questions some of the validity of the trial.

You would expect that there's an effective trial. It's just more patients get seen, they get seen by health care professionals that are coming in, and you would expect to see that. So I think the question is more about how do we separate from placebo rather than how do we have no placebo response. So I think that's the way we think about this.

And so we sort of live with that. The central raters clearly help with that. So I think the central raters are blinded to the visits that the patient is going to. And that means that we have a lower variability with central raters, and we can kind of mitigate some of those potential unblinding issues.

In terms of whether or not we would -- we certainly didn't take assessments of unblinding or expectation in the study. And I think it is difficult to really contextualize some of that data. So because we have psychedelics, we do work in this and we think about this a little bit more. But of course, most CNS drugs have some effect that help people guess, whether that's sedation or weight gain or whatever it might be. So I think it's certainly common that people taking CNS medication have some idea of what they're on. But I think, again, the separation here from placebo with a reasonable placebo response.

And we did have some patients who had quite high psychedelic rating scales, which also suggests that they were well blinded. And I think that in the context of the way that we designed the trial feels sufficient rather than specifically picking up these or asking patients to guess and then it's always a difficulty to sort of really interpret that data in light of the results.

Great. And then just one follow-up question. The baseline LSAS was quite high. How do you see this translating into more moderate severity patients?

That's a good question. And I think the way that we were thinking about the study going in was that this is a new therapy. It's quite intensive, and it's likely that genericized drugs will be first-line treatment or CBT or something like that, at least initially. And so in order to sort of think about where we are in the treatment line, which would be, say, second line, we probably want a group that is either resistant or more severe and has tried these therapies and have failed.

There aren't clear definitions for a treatment-resistant social anxiety disorder, but we can certainly think about making sure that patients both on the CGI severity and the LSAS baseline was sort of unwell enough that they are sort of effectively treated. And I think that's probably where we continue to think about positioning the treatment of the sort of second or third-line drug. So I think that is why we got to this higher baseline as a start.

Yes. And it's an interesting point. I don't think we touched on it in the core presentation, but we noted about just under 50% of folks had been on drugs previously for their social anxiety disorder. Interestingly, almost no one needed to wash off, just speaking to the lack of efficacy or the lack of tolerability or some combination thereof for this patient population of those drugs. So basically, no one was taking anything. No one needed to wash off. And again, so that's, again, speaking to this whole notion that this is probably a treatment-resistant group as Kevin was alluding to.

The higher severity is an interesting one because, again, we've been talking about the LSAS as a behavioral scale. Behaviors are hard to change. And if there are severe behaviors, there may be more entrenched. So that is something that we are thinking about and trying to work through and have some discussions or have had some discussions with the KOLs as well. So would it be -- are behaviors that maybe are less entrenched more movable? I mean, conceptually, sure. But it's something that we obviously need to think about as we plan for subsequent studies.

Yes. And maybe just to sort of follow-up on that. I think this is a condition that really begins often in the second decade in people's teens. It's very trait like. And I think the idea of taking a daily therapy for the rest of your life is a daunting prospect for many. And I think actually many people have a sort of an ecological approach to this. In other words, they -- over time, they find a way to live with the condition rather than take daily treatment for it. So I think that's one of the difficulties, in fact, is that in many cases, people have spent years or even decades managing this by avoiding certain situations, and it does take a lot of time for that to change now that they've got a different sort of fear response to the same community.

Your next question comes from the line of Elemer Piros with Lucid Capital Markets.

What I was wondering if whether you have looked at the LSAS scores between the 2 doses or after the first dose, please?

It's preliminary. So yes, I mean, this is our top line. So we will be looking at the totality of the data, including the split between the 2 in subsequent weeks and months.

Okay. And second question I had is on what were the response rates when you look at the LSAS scores?

So the response rates, I have to say, again, we're -- I'd have to go back and have an exact look, but I think they were about 50% higher in the EMP group. And so sort of really tracked, I would say, with the CGI-I. But again, the sort of definition of response with LSAS does take a bit of time. So we're still looking at that data to really understand it better.

Yes. And I think the CGI-I, the way it was represented to us as we discussed with KOLs, was that this is maybe a -- this an early warning, so to speak. The clinicians do get a sense before some of these behaviors are changing. So I think that was also interesting in terms of contextualizing these results. And there's -- I believe there's also some literature out there where the CGI was, in fact, used as a responder criteria as opposed -- like with MADRS or depression, you have a 50%, right? That's the response criteria here. I have seen some literature as well that is actually focused on the CGI as opposed to the LSAS per se.

Your next question comes from the line of Pete Stavropoulos with Cantor Fitzgerald.

Congratulations on the data. I'm not sure if I missed, but you did say 70 participants received at least one dose of study drug, 69 completed Day 43 efficacy assessment. I don't know if you can give any color on how many patients received a single dose. I'm curious to know what the level of response after the first dose and durability after Day 43. Were there any signals that would suggest a single dose would suffice for some patients?

Yes. So as you said, we had 70 dosed and 3 did not receive the second dose. So 67 went through, received the second dose. And again, those -- and remarkably, the 3 that didn't receive the second dose actually continue to the end. So again, really good retention despite not being able to be dosed, we actually got the LSAS CGI scores.

So we're still, as Srini mentioned, looking at the Day 29 versus Day 43. The difficulty here is that the scale is one that does take time. People have to go through these experiences. So it's actually difficult to disentangle the -- how rapidly the drug works versus how to change the scale because people have to go out and experience speaking to strangers, having small group meetings, speaking on the phone in public, et cetera, et cetera. So I think there is a time element to the scale, which is unique relative to some of the scales that we're more familiar with, which are very symptom based.

And unfortunately, we don't have data beyond the 6-week primary. That was consistent with the early exploratory study. So we didn't really focus on durability, and we don't have data beyond that.

Okay. And a follow-up question. You reported simultaneous improvement in both fear and avoidance subdomains. So how does standard of care affect these subdomains? And if both are improved, are they improved simultaneously? And do you view this as evidence that EMP-01 is influencing core learning or behavioral distinction mechanisms rather than simply anxiety?

Yes. So I think, again, the effect of approved pharmacotherapies are similar. And I think the idea is that the fear experience goes down first, people then experience these things, which they are typically fearful of and avoidance of, and it isn't as bad as it was before. It's less threatening. And so that they then gradually learn and they do more of those sorts of things.

And that's actually very similar to the way people think potentially SSRIs might work that the environment is less threatening and you can then go out into that environment. And gradually over time, you interact with that environment differently. So I think that's exactly what we are seeing here, and I think how we think this is going to work

People perceive the world as a less threatening place, and that changes behavior over time. But it takes time for that behavior to consolidate and people to have repeat experiences that suggest that it's actually not so bad and that you can go out and do these things again. And there are clearly within the scale, some low hurdles, as I say, like speaking on the phone or speaking to people you don't know very well. And then there are sort of higher hurdles like speaking in public, arranging parties, things like that, which I do think would take longer to really shift.

So here with this trial, I mean, again, it was a short study. Typically, with an SSRI, SNRI, you're seeing fear move first, as Kevin said, and then the behavioral stuff, the avoidance actually catches up over time. With this small study at 6 weeks, we saw both move sort of in parallel, kind of more in keeping with something like a therapy, but again, small study, something that we need to replicate.

Your next question comes from the line of Eddie Hickman with Guggenheim Securities.

Congrats on the data. Just 2 for me. How confident do you feel about this dose and dosing interval? Would you think you need to try others in the subsequent study? And given the light dose experience, how are you thinking about therapy versus no therapy in the Phase III? Have you had any preliminary FDA dialogue on this?

Thank you. So I think on the first one, the dosing interval is something that we may want to explore. I think this is a -- again, there's some strong priors with racemic MDMA that suggests this is not a bad separation, but it could potentially be expanded or contracted. It is a longer stay in the clinic. And I do think that that -- if you push it if it's every 2 weeks, there's a sort of an increased burden and scheduling issue there. So there is a sort of sweet spot to find on that. So I think that's something that we're still exploring.

And forgive me, the second part of your question, could you repeat it again?

Just given the light dose experience, how are you thinking about therapy versus no therapy in a pivotal? Have you had any preliminary FDA dialogue here?

Very good. Yes. So I think we have not had the preliminary FDA dialogue. But clearly, we are keen to think about this in a no-therapy context, if possible. And that is an access issue as well. So I think as soon as it becomes something that is bound to therapy, we are also bound to the availability of therapists.

That being said, I think it's an interesting -- with all psychedelics, I have no doubt that in the clinical setting, there will be people who are treated with both pharmacotherapy and psychotherapy, and I'm sure that there will be an additive effect there. But I think our current intent is to think about this as much as possible without a therapy component.

And there are various gradations of that. There are certainly drugs like weight loss drugs or drugs in the treatment of substance [indiscernible], which are given in the context of underlying therapy. But I wouldn't imagine that we are pairing this very intentionally with the kind of therapy as part of a trial.

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

Congrats on the progress and thanks for sharing the data. My question is just sort of a follow-up on how to think about the evolution of sort of the response over the course of the 43 days. Did you see separation after the first dose? And just based on this data, how would you think about a future trial in terms of the number of doses you would explore? Could there be benefit from additional dosing after the 2 doses here?

And then secondly, just on the statistical significance, I think you indicated it was a one-tailed p-value. Why did you pick a one-tailed test for this study? And then what would a two-tailed test have looked like?

Sure. Maybe I can address the first part about the number of doses. I mean I think the next phase would definitely require some dose ranging. And I could imagine dose ranging both in terms of the amount per dose and the number of doses. And I think we can think about those 2 axes.

And there's both a follow-up period that would -- is 3 doses better than 2. There's clearly some aim also to achieve a meaningful benefit without dosing for 6 months. So I think there's obviously some guardrails around that. But I think those are the thoughts that we're having right now about what does the dose ranging look like? Is that number of doses and/or the amount per dose. So that's the way we're thinking about that at the moment.

And again, forgive me the second part of your question?

The second part was on the p-value ones. Why did you take a one-tailed test? And how should we interpret that? And perhaps if you could tell us what a two-tailed would have looked like?

Yes. Sure. Yes. And I think we were again quite intentional here about this being an exploratory study that wasn't powered. We took the view that if it was something that was going to get worse, we would not move this forward. So hence, the choice for a one-tailed test, we're only looking for improvements really because a worsening would have clearly led to no further development of the compound. So we're really focused on that improvement tail, if you will.

And again, because it's unpowered, it was a small study without any sense of what the treatment effect might be, we chose that as a level. And again, I mean, one-sided p-value is essentially half of a two-sided p-value. So if you multiply that by 2, you would get a 2-test pitch, which was, I think, 0.07.

Yes. I think it's kind of -- let's go back to that first part of your question in terms of number of doses, et cetera. I mean, we are aware, obviously, that this has some -- this is a behavioral kind of endpoint. It's -- the question is whether it's time or doses again, right? So it's not symptomatic improvement like depression or what is measured with the MADRS, for example, where it does move quickly.

So that's something that we really do need to spend some time thinking through. And again, that kind of leads into the exploratory nature of the trial and the fact that we are only looking at improvement essentially. So not that unusual in small studies where they are unpowered because there's no real data to properly power them to do a one-sided test, particularly in that context of the time element that we weren't fully -- we didn't fully understand going into it.

Your next question comes from the line of Jay Olson with Oppenheimer.

Congrats on these impressive results. It's really exceptional to hit stat sig on such a small study and the effect size and especially the NNT is super impressive.

Yes, yes, thank you.

Yes, thank you.

We had a couple of quick questions. Was there a psychotherapy given to the patients in the study? And were any patients enrolled in the study psychedelic experienced at baseline? And then maybe a bigger picture question. Can you please remind us the differential diagnosis for SAD versus GAD? And any read across from these results in SAD to a GAD population?

Yes. Sure. And I'm going to start backwards and maybe we can kind of go from there. But clearly, there is some comorbidity. And one can make a specific diagnosis of social anxiety disorder. It typically occurs earlier. It has a very kind of social context. So it's context-specific. So it does look different to GAD. But of course, like many psychiatric conditions, there is comorbidity and people are anxious and they can have episodes of anxiety disorder. They can also have episodes of major depression. So I think the definition of the case is important here.

We certainly required medical records that were consistent with the social anxiety disorder diagnosis. But of course, it is underdiagnosed in the area. So a lot of people seldom actually make it to tertiary care with the sort of treatment seeking for social anxiety disorder. Many cases, they have an episode of something that presents and they also -- the social anxiety is discovered during that intake.

So the way that we approached that was that we required medical records and a treatment history that was consistent with SAD and we did a thorough assessment using standardized structured interviews at screening to make sure that they did indeed meet the criteria. But I think that's a key piece going forward as well is how we define this group and the evidence that we need. I think for the validity of this, we really do need some sort of documentary medical records.

Yes. And I think that going back to your point around how does it differentiate from GAD. You can think of it as -- I mean, I sort of conceptualize GAD as almost an extension of MDD, right? I mean in both cases, there's a prominent rumination component. There's particularly a negative rumination or a negative -- the self-referential thoughts

Depression, you're kind of looking backwards. Anxiety, you're kind of looking forwards. And these 2 are very comorbid. But then there's the other -- there's a whole bunch of other things that are more phobias, right? They're kind of more specific to a single thing. I mean where everybody think knows about arachnophobia or something. Yes, you can sort of live with that. I mean you avoid spiders and you're probably okay.

But this is a phobia almost against social interactions, right? That is different than GAD where it's just this unnerving kind of sensation that something bad is going to happen. This is more specific, you're avoidance of social interaction. So it's got that phobia-like element to it, but it is kind of clearly differentiated. And that's what the LSAS and all these structured interviews are also getting at. Like is it this nonspecific thing that the sense of impending doom, which is kind of GAD? Or is it you really don't want to do these things like talk to someone you don't know, interact with other people, blah, blah, blah. That's what differentiates these 2.

I know you had a question also about therapy. No, we didn't do therapy in this trial. We don't wish to it. Again, as Kevin outlined, that isn't something that we really want to touch on going forward either.

And just to elaborate, we took the standard participant support approach. So we had some preparation with participants. There was a facilitator who was in the room during dosing with the second one monitoring from outside the room. And then we had a follow-up assessment that was done after the dosing day. So it's a very standard, very focused on education support during the dosing.

And again, what we found was that this is a very different compound with a lot less of the challenging experiences. So some people were sort of more talkative. Many were quite internal in their experience, and they described it almost as dream like. So that part, in fact, was particularly easy relative to some of the other drugs that we've experienced.

Yes. I think we didn't touch upon it in the core presentation again, but there were some elements that were kind of unique around the anxiety or anxiolysis that seems to be -- that's occurring with this compound. Again, we need to do follow-up studies and particularly comparative studies to really flush this out. But feeling of relaxation is not something you normally see with other psychedelics, in my opinion. I mean that's just not something that's normally seen. It was prominent with this -- in this patient population.

Is it the patient population? Or is it the drug? That's something that we need to assess out. But that was something that was really interesting. And again, there was normally -- I mean, there was a subset of individuals that was quite talkative during this process, kind of like MDMA and not typically like a normal psychedelic. I mean people that are taking psilocybin, which is similar in duration to this compound are not normally talkative unless things are going sideways, but that wasn't necessarily the case here. So it was different in these elements.

And then there was this vigilance reduction, which I think was very prominent here. I mean, again, think about this, we have someone who has social anxiety that is stuck in a room with someone they don't really know very well, and they're comfortable with that. And some of them are actually talking to that person, which is kind of antithetical to their nature essentially.

Your next question comes from the line of Harry Gillis with Berenberg.

Congrats on the data. Could you help us contextualize the 12-point placebo-adjusted improvement in LSAS at 6 weeks, I guess, in terms of what this means for patients in the real world and perhaps how it compares to what you were hoping for heading into the trial? And then you've also clearly described this as clinically meaningful and supporting further development. Just curious what would have been the minimum threshold that you thought would have supported further development or broadly what that level might have been?

Sure. So I think in terms of the contextualizing of the clinical response, again, this sits very squarely in the -- similar to existing pharmacotherapies. And actually, I think the CGI in conjunction with the LSAS was most compelling. So both the response rates and a CGI of 2 is very much improved. It's quite a high bar. And I think that sort of gave us comfort that it wasn't just the LSAS, but these numbers are very good. I mean if you look at the numbers needed to treat for CGI relative to the existing pharmacotherapies, they are better or comparable depending on the drug in question. So I do think that together, we're sort of encouraged by that. And I think it is a clinically meaningful benefit.

I think in terms of what might be a no-go for this, it would have been twofold, and we actually had safety criteria and efficacy criteria. But clearly, something that is worse than the standard of care would have been a problem and I think would have led us to sort of stop the program. We had -- there's a range for LSAS, there's a range for CGI. And they were very focused on those things, both in terms of responders and absolute change.

And the absolute change in LSAS across the sort of pharmacotherapies is about 10 to 15 placebo subjective, so 10 to 15 points placebo subtractive difference. So we were in the middle of that quite squarely. I think if we found a 5-point difference is something that wouldn't have been viable, especially if the CGI matched that. And I think that was for us the kind of the thing that tied it up really.

And similarly for safety, we had that early Phase I study that suggested it was fairly well tolerated. It was a fairly pleasant experience, reliably psychedelic, but not aversive. But of course, in a social anxiety population, we're taking this into a very different group. So Phase I participants tend to be fairly okay with risk in general, whereas I think this group is a sort of an anxious and worried population. But again, we saw a very consistent sort of signal there that looked like the Phase I data. So I think both of those potentially could have been reasons to not regret.

Yes. And just contextualizing further, I mean, we saw a similar efficacy at 6 weeks of 2 doses, right, as opposed to 8 to 12 weeks with daily dosing. That is something that really resonated with the KOLs that we talked to. And the other element here is because it's behavior, there was a lot of conjecture what would have happened if we had run the trial out longer, right? Even if with these 2 doses, if you just left them alone afterwards, that allowed them to experience these new things. And we got anecdotes on that, like the folks are saying, Oh, this happened to me yesterday, I would not normally have been able to do it. And that kind of success builds upon itself, and it just takes time.

So there was a lot of discussion about if we had -- if we had just looked at another endpoint, not even dosing, but looked at an endpoint, say, 8 weeks or 12 weeks out, could this have continued? In other words, is this a plateau? Or is this kind of the start of something? So these are some important questions. And that's what goes along with the CGI are all reason to believe here.

And just one follow-up. I mean, one of the things that we think about in terms of the safety is really the prevalence of the side effects. So in our case, we have side effects like hallucinations, feelings of relaxation, headache, but they are limited to 2 days out of 6 weeks, whereas others may have maybe fewer nausea, weight gain, concentration difficulties, but they do persist for the duration of that 8 to 12 weeks. So I do think from a safety perspective, we see this as sort of if you look at the prevalence, how long are you going to suffer with this adverse event or side effect. We have a real differentiated here. People have mostly drug-free with no side effects in between those dosing days.

That's really clear. And could I just squeeze in one more. Just based on the data that we've seen today, do you think 225 milligrams is the highest dose you anticipate giving sort of at a single point in time? And then it's -- I know you then discussed it's about the amount per dose. Is it then lower than that? Are the other options and then the frequency? Or could you even go higher than 225? Or should we think of that as a ceiling?

Yes, that's a good question, one that we've been thinking about ourselves. I mean R-MDMA has been studied up to 300 milligrams. I think there are changes in vital signs like with all of these drugs, you get increased blood pressure. And there is a balance and especially if we want to redose. So I think 225 is approaching a limit. I mean we'll certainly think about higher doses. But I mean, we've got a good effect here. And I think that it was tolerable. So I'm not sure that we would necessarily go up higher because I think there's -- the higher you go, the more patients may not be able to receive further doses.

Our next question comes from the line of Michael Okunewitch with Maxim Group.

Congrats on what looks like really great data.

Thank you.

I think just to start off, I would like to expand a little bit on some of the prior questions on schedule. And I guess, how you're thinking about how the drug could be used in the clinic because there are quite a few considerations here. So is this something you're thinking more along the lines of an induction regimen followed by an untreated follow-up or potentially a more Spravato like schedule where there is some maintenance dosing over a study period? I'd like to get your thoughts on that.

Yes, it's a really good question. And I do think for this, we really need some durability data.

Yes.

So the next step would be, say, 2 doses and then a follow-up that goes out for 10 to 12 weeks. So we can have a look at that response trajectory, both in terms of the average. But of course, what we're really interested there is the subgroups. There's typically subgroups who get well and stay well, and subgroups who get well and then gradually begin to sort of get worse again. And that really helps us inform how frequently. I don't expect this will ever be Spravato like and that it's once every 2 weeks, even once every month, I think would be challenging.

But if this is 2 doses and then it's a quarterly follow-up, maybe a sort of second or a third dose, one dose quarterly, that I think is manageable. So to be determined once we've got some more data, but that's where -- I mean, again, looking at the other compounds in the psychedelic class, I think that's what we sort of expect to see.

I think that does lead into my follow-up question a little bit just on the clinical strategy going forward. There has been a lot of difficulty in SAD. But as you mentioned, there are still a lot of answers that you kind of want to understand. So is the strategy here more to go into a Phase IIb for a larger data set, longer follow-up and to really understand these questions rather than moving potentially faster given the unmet need in SAD?

I mean we'll provide more guidance on that. This is -- again, this is top line results and very encouraging top line results. We have some additional data sets coming from this. I mean this is -- the topline results show a subset of the -- all the analyses that need to be done. So we'll make some decisions once we have all that data in hand.

And our last question comes from the line of Justin Walsh with Jones.

This is [indiscernible] on for Justin. Congrats on today's update.

Thank you.

We have a further down the line sort of question. MDMA is a Schedule I controlled substance. So we are curious about the company's current strategy for EMP-01's scheduling and how are you preparing for it.

Yes, that's a good question. And of course, we -- it's for us, a bit of a well-trodden path now with BPL-003 and VLS-01. So all ends...

And for the specter, right, psilocybin and LSD also in development. Yes. Yes.

So I think we're approaching this at the moment by collecting adverse events of abuse potential. And you saw that list there, which is really a list that's -- although we haven't had this discussion with this compound of the regulators, we certainly have on others. And there's a clear list that I think we need to characterize the abuse potential of this drug. So currently, it's Schedule I, and that really means that there is no therapeutic potential.

But of course, should we get ourselves through pivotal trials and this goes to drug approval, it then, by definition, has a treatment or it has a therapeutic use, and it will move out of Schedule I to Schedule II or Schedule III. So I think there's no way that this drug has no abuse potential. I don't think it's realistic to say that we're going to come out with no scheduling, but it will certainly be in a reasonable scheduling along the lines of Spravato, which had a similar course to the approval process.

And that process really means that you present your dossier of abuse potential to the regulators. And in the U.S. that then following approval move to the DEA. The DEA make a decision on scheduling and you move through from there. So I think that's an approach that we will take, and we're beginning to gather that data even through the study.

Okay. For our follow-up question, the FDA stated recently that they will now require only one pivotal trial plus confirmatory evidence for new drug approvals. How does this change your late stage development plan due to EMP-01 drug category? Would you now consider only one pivotal trial for a faster path? Or would you plan to do 2 pivotals to provide a more robust MDMA package?

Yes. So this has come up a fair amount. I mean the issue typically with one trial is you still need safety data, right? You need a database in a chronic indication, right? So depression, social anxiety disorder, generalized anxiety disorder, these are all chronic indications that will require redosing as we've been discussing. So in that context, you typically do need more exposures.

For an example here, if you want to find a 1% adverse event rate, you need to dose 300 people and 300 placebos, I mean broadly speaking, to have a comparison -- a comparative data set. With acute studies, that's not -- I mean, with acute indications, that's not necessarily the case. It's a little bit different in that context. One trial approval is certainly a possibility there. And indeed, one of the other companies in this space that's looking at PPD recently announced that trial approval was a possibility for them makes sense because PPD or postpartum depression, sorry, is an acute indication. It only occurs in that postpartum period, you're treated and it's done. So that's acute.

So -- and as a corollary to this, you don't normally want to do everything in one very large study. You'd rather split it into 2 smaller studies to get different data from those 2 smaller studies. So that's a general fact that I think most of the companies have been taking. Our drugs are a little bit more different. I mean, we'd like to think of a second generation. The -- in the case of BPL and VLS, you can't really get those pharmacokinetics in any kind of normal approach. There's really no source of R-MDMA either. It's very -- it actually is very difficult to produce. You can't just entirely separate it like you normally can with other compounds. So they are different. So I could easily see the requirement for more safety database because of that.

There are no further questions at this time. On behalf of AtaiBeckley, we thank you for joining today. That concludes today's conference call. You may now disconnect.

Thank you for standing by. My name is Tina, and I will be your conference operator today. At this time, I would like to welcome everyone to the AtaiBeckley BPL-003 Phase IIb Open-Label Extension Study Data conference call. [Operator Instructions]

It is now my pleasure to turn the call over to Ashleigh Barreto, Investor Relations at AtaiBeckley. Please go ahead.

Thank you, operator, and good morning, everyone. Before we begin, I would like to remind everyone that this call will contain forward-looking statements, which are subject to risks and uncertainties. Any statements regarding future events, results or expectations are forward-looking statements. Please note that these forward-looking statements reflect our opinions only as of the date of this call. We undertake no obligation to revise or update these forward-looking statements in light of new information or future events, except as required by law. Information concerning factors that could cause actual results to differ materially from those contained in or implied by such forward-looking statements are discussed in greater detail in our recently filed 10-K available on our website or sec.gov.

I'd now like to turn the call over to the host, Dr. Srini Rao. Srini, over to you.

Good morning, everyone. I'd like to start by welcoming you to today's webcast, our very first as AtaiBeckley. I'm joined here with Dr. Kevin Craig, Atai Beckley Chief Medical Officer; and Dr. Rob Conley, our newly appointed Chief R&D Officer. On the course of the next few slides, will walk you through the results of the open-label extension of the Phase IIb trial of BPL-003 in patients with TRD.

Next slide, please. All right. This slide provides a summary of the results of the open-label extension. In summary, a second dose to 12 milligrams administered 8 weeks after the initial dose of 12 mg, 8 mg or 0.3 milligrams in the core study resulted in rapid, clinically meaningful additional antidepressant effects. These effects were sustained for upto 8 weeks and resulted in a response rate of 63% and a remission rate of 48% in those subjects to receive either 8 or 12 milligrams in the core study. The drug was well tolerated with the majority of treatment-emergent adverse events occurring on the day of dosing. Most were classified as mild or moderate and they were transient in nature.

BPL-003 has a potential to fit in to be established to our interventional psychiatry treatment paradigm as we'll see in subsequent slides. Finally, just to remind everybody, BPL-003 was recently granted Breakthrough Therapy designation by the U.S. FDA for results with treatment resistant depression. This is a recognition of its potential to deliver substantial improvement over existing therapies.

Okay, I'll now hand it off to Kevin, who will provide an overview of the results of the CORE study. Kevin?

Thank you, Srini. So I'm going to now talk a little bit about the study overview and the focus on the core study. This is a review of what we discussed previously, that is a setup for the open label discussion later on.

Next slide. So in terms of the study design, this is one of the largest -- or the largest study of [indiscernible] it was a study that was conducted globally across 6 countries. We randomized 193 participants. Those that were eligible were washed out of their medication. This is a monotherapy trial, and then they were randomized to 1 of 3 doses, either 0.3 milligrams, which is the controlled arm. This was chosen in conjunction with the regulators to have rather than a placebo, some chance of receiving a [indiscernible] drug on all 3 arms. And then the 2 active arms, the 8-milligram and the 12-milligram, these have chosen explicitly to be active and to be in the therapeutic range. So although we were expecting there to be a dose response, we very much wanted to look at 2 doses that were likely to be efficacious.

Participants were assessed after dosing on day 1, they were assessed [indiscernible] at day 2, day 8, day 29 and day 57, so an 8-week blinded follow-up period, and the primary endpoint was the 29-week [indiscernible] assessment. After completing that double-blind period, participants had the opportunity to roll over into the open-label extension, where they received a single dose of 12 milligrams and were followed up for a subsequent 8 weeks.

Next slide. So the final results on efficacy are shown here. The first thing to point out is the control arm, which we see as a fairly reasonable decrease from baseline in the control group. And I think this is very encouraging to us. This looks very similar to other psychedelic and TRD trials where we see a decrease as expected. So I think we were encouraged that there was no so effect here, and this was a robust and that this is a robust trial.

Moving on to the doses. What we saw was a rapid decrease from baseline to day 2, they really reached its maximum around day 8 and it was very sustained thereafter, 2 week. There was more numerical difference between 8 and 12 at the day 29 endpoint. But I'd point out that this is really not a statistically -- statistical difference. This is really just a numerical difference with it seeming to be slightly better than 12. But what is important is that this was really sustained all the way out to were statistically significant, really from day 2 or to week 8.

Next slide. Moving on to the responders and remitters. What we saw here on the list, the responder rates, this is patients who improved by at least 50% on their [indiscernible] dosing. We saw about 1/3 of participants by day 8 reaching responder status, and that was really sustainable the way out. And there's no difference really between the 8 and the 12 from day 8 all the way out to week 8.

On the remission rates, we saw a numerical improvement here of the 8 relative to the 12 with about 1/4 of participants meeting remission status again by day 8 and remaining fairly sustained upto week 8.

Next slide. Just moving on to a summary of the safety for the core study. What you can see here is, I think, a very well-tolerated study. We had more than 99% of treatment emergent adverse events were either mild or moderate. We had no serious adverse events throughout the trial. But what you can see here is now a beginning of a separation in terms of the doses. So here, we saw that 12 had adverse events than in 8. And for example, if you look at the anxiety rates in the 8, they were fairly low, higher in the 12. So what we see otherwise is a pretty expected list of adverse events in nausea, vomiting, headache, anxiety. We also had administration like pain and discomfort that comes with the nasal delivery of the compound. And we had an increase in blood pressure as again expected for the class.

Blood pressure increases were transient. They really were returning to normal within about an hour and the majority of these adverse events occurred on the dose dosing?

Finally, really important for our product profile was the time to discharge. So we looked at that with a specific measure. And the majority of patients were deemed ready for discharge at the 90 minutes post-dose assessment, which I think fits into our idea of making sure that these patients can be dosed and be ready for discharge within a roughly 2-hour type period.

I think looking at the safety profile, unlikely efficacy, we really do see the benefits of the 8-milligram here in terms of safety with very similar efficacy. And it is for that reason that we are proceeding with the 8-milligram dose in future trials.

Next slide. So finally, then just to talk a little bit about the study design or the setup for the open-label phase. As I mentioned, those have completed the core study were eligible to move into the open-label phase. Not all sites have the open-label phase available at the beginning of the study. Once they were available about 126 participants were completed and ready to move into the open label. And of those 107 were dosed for the second dose, and now was followed up again for another 8 weeks. The intent here was primarily to look at safety after a second dose, but also to look at the effects in terms of efficacy on a second dose.

And with that, I'm going to hand over to Rob.

Thanks very much, Kevin. Now I'd like to go over our top line findings from our open-label extension study. The next slide, please. This study, which, as Kevin mentioned, was really a subset of our core study, has very similar demographic profile. And of course, same population, more or less, somewhat female-oriented, very chronically ill, moderate to severe depression going into the overall study.

Next slide. What you see here is the change over time in our group meets. The top gray line, you can see the group that got psuedo placebo, the low dose in the first study, you see that core on the left. And then you see they improved quite a bit when they got what was to them the first dose of active medication in that second open-label study. And you can see the shape of the line is very similar to what we saw in the first administration of the active drug homes, which is somewhat reassuring of our effect size and change over time.

In the 2 active drug arms, however, we did see even more improvement after we gave the second dose. You see an improvement in the 12-milligram arm, which is the dark line. And then in the light green line, which is the 8-milligram arm quite a robust improvement over time. And importantly, with the one dose being given at the beginning of the open-label study, you see this as continued improvement out to 2 months. So we really do have 16 weeks of good follow-up with improvement in depression with just the 2 doses during that time. With all of this data in front of us, we have decided to move forward with recommending an 8-milligram dose for our Phase III studies.

The next slide. Now it just looks at our response in a somewhat different way. This looks at our responder rates. And again, response here is defined by at least a 50% loss of the initial MADRS score, the depression score. Left-hand side, again, you see our core data 1 more time. Now you see after the second dose on the right-hand side that you get this greater improvement with all of the cells going up, particularly the 8-milligram sell, you see we actually get to an 81% responder rate over time. This is this improvement of response, again, with just that 1 single second dose. So again, very encouraging for persistence as well as improving response over time.

Next slide. Next slide looks at the remission rates. Again, remission is this very high definition of response where people have a MADRS score of 10 or below. Again, on the left-hand side is our core data, which you've seen before, a good improvement over time, but that improves much more after that second dose. Again, you see all the dose cells going up. Again, particularly the 8-milligram cell getting to a 67% response rate at day 57 with the 1 redosing. So again, this does support our decision to recommend the 8 milligrams as the dose we're going to move forward into a Phase III overall.

Next slide. Now we're going to look at our side effects. Again, like before BPL-003 was generally well tolerated. The majority of our adverse events were characterized as mild or moderate. They were transient. They tended to resolve on the first day. Again, the most common side effects were mostly at site administration in the nose. We had 1 serious drug-related adverse event. This was a person who had a history of not only depression, but panic anxiety and suicidal ideation. And sometime after dosing, she had a return of those symptoms, and it was decided for that reason to briefly hospitalize her. She was hospitalized and for that reason, it became a serious adverse event. However, the side effect itself, the serious adverse event did resolve the next day. So fortunately, the subject did have a resolution [indiscernible], but it was a hospitalization and therefore, an SAE.

Overall, though, the other side effects were mild to moderate, as I said. And again, our average time to discharge like in the initial study was within about 2 hours of dosing.

The next slide. So where we are right now is the BPL-003 has demonstrated this rapid robust and durable therapeutic benefit for at least 4 months after 2 doses. In fact, again, you see this really improvement of response over the time of 4 months, and very favorable tolerability and side effect profile. So we do think that this open [indiscernible] extension does show that this redosing paradigm can be very useful for improving response in people. We have shown in these 2 dose administrations, a 2-hour timing clinic that can be expected, which is very similar to the SPRAVATO treatment paradigm.

We have been fortunate to be granted breakthrough therapy designation by the FDA in October of this year. And we do think our overall data set supports advancement of 8-milligram dosing into Phase III. So for upcoming key program events, we intend to have a meeting -- end of Phase II meeting feedback from the FDA anticipated in the first quarter of next year. And with positive feedback from the FDA, we hope to be able to initiate Phase III studies in the second quarter of next year.

With that, I'd like to turn things back over to Srini.

Thank you, Rob. Let's now talk about the commercial opportunity for BPL-003. We'll talk about this in the context of the competitive landscape, starting with a brief discussion of SPRAVATO.

Next slide, please. As many of you know, despite a slow start, SPRAVATO has become a successful key franchise for J&J. SPRAVATO achieved blockbuster status in 2024 and has already exceeded $1 billion in sales in the first 3 quarters of 2025. This product falls into the interventional psychiatry paradigm, where administration occurs in the doctor's office. Product offer administration involves a drug being delivered intranasally by the patient under medical supervision and then per label, the patient has been monitored for a period of 2 hours. At the end of that period, the patient can be discharged if and medically and psychologically stable.

There are approximately 5,000 clinics certified under the REMS to deliver SPRAVATO. Last year, approximately 50,000 patients were treated with SPRAVATO in the United States, resulting in about $930 million worth of sales. The challenge with SPRAVATO therapy is the sheer number of administrations that are needed to both induce a response and then maintain that efficacy. Induction occurs over the course of 4 weeks and involves 2 administrations per week each in the doctor's office. Maintenance follows thereafter. The first 4 weeks of the maintenance period require administration every week and then it's as needed thereafter. However, recent data suggests that most patients are getting the arms for SPRAVATO every week to 2 weeks to maintain the efficacy long term.

Next slide, please. We believe BPL-003 and secondarily VLS-01 are uniquely suited to leverage the 2-hour in-clinic paradigm established by SPRAVATO. We anticipate each visit for these 2 compounds to be very similar to the ones involving SPRAVATO, where there's a single administration and the resolution of physiological and psychological symptoms should occur in 2 hours or less. This paradigm addresses the scalability concerns that are present with longer duration products like [indiscernible] and also address the complexity of same-day multi-dose paradigms.

The benefits of the simplification included the ability for increased utilization by site and importantly, improving the quality of life for patients with TRD to the much reduced burden, including travel, et cetera.

Next slide, please. We're excited to come together as Atai Beckley with our focus on short-duration psychodelic therapies. We've been discussing BPL-003, of course, as it is the most advanced asset in the pipeline. And as noted previously, we anticipate initiating Phase III next year after an end of Phase II meeting. However, I'd like to take this opportunity to mention 2 other assets in our pipeline, namely VLS-01 and EMP-01.

VLS-01 is a buckle form of DMT [indiscernible] being developed for treatment-resistant depression. It's currently in the Phase IIb trial, and we anticipate reading out in the second half of next year. EMP-01 is an oral form of R-MDMA. It's currently being developed for social anxiety disorder. It's presently in a Phase IIa trial, and we anticipate reading -- that trial reading out in the first quarter of next year.

All right. With that, I will now open up to questions. Operator?

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

Congratulations on the data, and congrats on the overall execution this year, including the breakthrough designation. My first question is on the FDA meeting that you will have. Can you remind us the key questions that you'll be asking the agency? And more specifically, what kinds of alignment are you hoping to get as it relates to expediting the pathway. For instance, do you think you will ask if this Phase IIb can be considered a pivotal study? Or do you think you can file a rolling NDA because I think another sponsor just got to buy in for that?

Thanks, Andrew, for the question and your kind words. It has been a very eventful and very positive year. So we're very excited about that ourselves. In terms of the specific questions that we'll be asking of the FDA, of course, we're not -- we won't be divulging that. What we have committed to is in Q1 of '26 providing an update on the online plan forward, the plan that's aligned with the agency once minutes are received. There has been some discussion around a single trial approach that involves the Phase IIb. The companies and the sponsors have said as much. Let's see how that goes. I mean, I don't -- all we're not going to do is change our plan vis-a-vis a 2-dose -- I mean 2 trial approach.

So we will go ahead and kick off 2 Phase III programs. Just the detail [indiscernible] 2 Phase III trials is just the details of the trials may differ a little bit depending on some of the discussion around that. So maybe Kevin, I'll let you pick it up from there. If there's anything to add?

Yes. Thanks, Srini. I think you've covered it really. I mean as you say, there's a lot to talk about there, and you're mainly aiming to align with the plan. And as you mentioned, I think we still need to run 2 Phase III trials. And that's as much to do with the safety database, if anything else. But the further details, really, I think, got for the discussion. And although we've seen some movement in other -- from other sponsors, I think it's really certainly at that meeting that we'll get some clarity.

And my follow-up is that one case of suicidal ideation, can you describe this patient whether she had a meaningful efficacy response and which dose she was exactly on? And would you expect a suicidal ideation to happen in Phase III blinded portion with a lower 8-mg dose?

Maybe I will start. So as you know, Andrew, suicidal ideations are unfortunately part of the clinical presentation [indiscernible] depression and certainly those with more severe format depression like TRD. So this is obviously quite prevalent in other programs, particularly the SPRAVATO program. There were multiple instances of suicidal ideation actually, behavior as well. So Rob, maybe I can hand it off to you for a bit more color on the patient.

Yes, happy to. So she, as many people with TRD and as Srini just mentioned, she didn't have new suicidal ideation. In other words, this is -- unfortunately, it was part and parcel of her illness. And she actually had a -- not so much a treatment plan as a treatment outline if she was filling anxious, severely depressed, more severely depressed or suicidal. And she began to hear that she had these thoughts. And actually, contacted her clinicians, and they activated and cleared that same thing happened before in her life, which is this [indiscernible].

So for her, again, certainly [indiscernible] not backing away from that, but it wasn't a novel thing. Fortunately, she not only responded well to this intervention, she was having none of these thoughts within the day. And even when she was describing these idea, she was initiating protective action, meaning she was asking her parents to help her getting the treatment. She was not trying to harm herself, she [indiscernible] want it not to. So she did well in that regard. She actually was a responder overall. She ultimately had an improvement in her depression. She is on the higher dose, she's on the 12 milligrams. So I'm not -- so while we're analyzing this, I think it's important to now have done a lot of large studies in depression. This is part and parcel of the illness. We never want anyone to have these bad thoughts or actions, of course, but it literally does happen. So it wasn't a novel thing. It was a return to a prior thought pattern as it were. She was an overall responder, she was on the higher dose. And fortunately, everything resolved okay.

And our next question comes from Ritu Baral with TD Cowen.

Congratulations on this data. I don't -- you guys specified whether you were going to pursue redosing in the Phase III. If you are, are you going to -- given the overall AE profile, would you redose with the total? Would you redose with the 8, given what you've seen? If you could clarify how you're thinking about that in Pivotal. And then I've got a follow-up.

Thank you Ritu, and it's good to hear from you. So we have basically shelved the 12 at this point. So even if we did a redosing paradigm, it would be 8 and 8. We did present some data that involved redosing of the open-label study that also looked at 12, but these are all things basically designed prior to the Phase IIb data. So at this point, 12 is essentially shelled.

The redosing paradigm is something that we are looking at. We're certainly going to have some discussions around that. There's potential efficacy that I think one could argue we are leaving on the table by doing only a single dose, but there's just additional complexity if you do a multi-dose paradigm. So these are some of the things that we're trading off at this point. I don't know, Kevin, if you had any additional thoughts on that.

Yes. No, I mean, I think you're absolutely right. I mean the interesting -- we've seen this data, and it's the IIa open-label data and it is encouraging that we can get maybe a bigger efficacy effect with 2 doses. But as you say, we need to trade that off against the complexity of coming in, let's say, 2 or 3 weeks after your first dose. And I think ultimately, it would be good to have a label that allows for either a single or 2 dose induction and then the maintenance thereafter. So as you say, I think we're kind of -- we're sort of working through that at the moment and how exactly to implement that in our development program. But certainly, it's something that's on our mind.

Yes. I think one other follow-up to that...

Go ahead.

So just one quick follow-up to that is, of course, this is something that also is short, right? It's a 2-hour paradigm. So we're certainly open to that notion. This is different than a much longer acting compound as an example. So the whole idea here is to fit in this SPRAVATO paradigm. Obviously, folks that are taking SPRAVATO are getting 8 administrations over the course of 4 weeks, and they're getting very similar efficacy to BPL with a single dose. So we do have some flexibility in that regard.

So my follow-up is sort of a safety and commercial blended question. You mentioned that those patients were out in 90 minutes. Can you quantify for us what percentage of patients did not resolve outside of, say, that 2 hours SPRAVATO time frame or 2.5 hours because I understand that SPRAVATO is like -- SPRAVATO suites are booked for, I think, 3 hours at a time. And then the patient with the SAE, did she have any sort of adverse reaction during her first dose? I'm wondering just about intra patient reaction?

Okay. So I will let -- actually, Kevin, do you want to jump in on this?

Yes, sure. I can talk certainly the first part. I mean in terms of the proportion, I mean, the majority of -- ready for discharge quite early on. I think 2 things to say. There is -- there's a proportion of 10%, maybe 15% kind of required longer so it went beyond 2 hours. And that is dose dependent. So we did see differences between the 12 and the 8, and the 8 being better in terms of people being ready for discharge. And I think also we've maybe refine the scale that we used. We used a multifaceted scale that looked at psychiatric effects, neurological effect on pressure, and a sort of global assessment by the commission [indiscernible] discharge based on the adverse events, et cetera.

And we've seen that some of those are more sensitive than others. And I think as we go forward into the mix to the studies, we would refine that based on some of the learnings we've had from with this one. But what we do know is that some sort of structured assessment is going to be necessary. And so that's very much a topic of discussion. So I think that's -- I think we sort of pretty confident that the 8 milligrams in particular has fewer of those people at the tail who need to stay around. But it's important to remember that even in compounds like SPRAVATO, there is a tail of people who are not really at 2 hours, but the 2 hours are sort of the minimum time that people need to stay under assessment.

Yes, I think that's really good point to highlight.

Yes. Sorry about that. I was just going to say I think roughly 85% or so from the summary basis of approval, but I would need to go back on that with SPRAVATO that we're ready, so to speak, at 2 hours. So it is indeed kind of a floor. It's not by any means a number [indiscernible].

And then intra-patient safety?

Yes.

Yes. So Ron, do you want to take that or either one?

Yes, sure. I mean [indiscernible] So this particular patient, you're right, this thing happened on the second dosing. And again, I think what you're seeing is probably the effect of this one individual who unfortunately has the suicidal ideation as part of a depressive condition. Fall over the course of 4 months, 1 of these things did happen. It didn't actually happen after the first dose. She wasn't [indiscernible] she had a bad effect and then another bad effect. She actually did relatively well in the first dosing period with some response, did have more response after the second dosing that had this 1 episode.

So yes, so it wasn't -- there was not a phenomenon for doing poorly and then doing worse. It was more -- this just happened over the course of the 4-month period. Also one thing to add to everybody's earlier answer, and Kevin had touched on this is important to note because this is how we differ from some of the other sponsors. There's a lot of people who have talked about the duration of the psychedelic effect itself, which we certainly can talk about in kind of a miss or a different context, but the [indiscernible] is very short with this agent, also with the other agents we're developing in the time frankly. The [indiscernible] effect is over with in almost literally everyone within an hour. And usually, it's much shorter than that.

What we're really looking at here is a dischargeability scale that we're still working on actively with the FDA to finalize it there. The [indiscernible] effect has to be able with cardiovascular affects, blood pressure, heart rate, a neurologic exam and then a global assessment of being ready to go home. All of those things have to be in the green, shall we say for a person will be considered dischargeable. So that's where when Srini was saying, there's about 85% within that window we're talking about. It literally means they are ready to go home. It doesn't mean that the people who [indiscernible] go home are still having a psychedelic effect. That's just not the case.

In this Phase II study, we learned a lot of things. Some of it was that a lot of investigators really interpreted cardiovascular effects going away that they're going totally back to baseline. And any time you're checking with somebody's heart rate or something that can be a condition where you want to be conservative, so you want to make sure. So we've seen the people who are tailing off as it were. It was more they weren't quite considered back to baseline until -- just to let you know after the 90 minutes, the first set [indiscernible] the majority of the next check, which is at 120 minutes, people were right. There were a few people that tailed out. A few people tailed out because they didn't have a right home literally, and the most together said, well, that means they're not ready. We can't discharge them on their own. We're waiting for other person. So we remain pretty conservative about being ready to go home.

We'll work on that. We'll have that in the label. I can tell you from this early data, I feel fairly secure. We obviously have to look in Phase III, but I'm pretty secure this part of the thing will become SPRAVATO-like shall we say. So it's not that you have to keep people around for a long period of time. You can let them go when they're clear. We did look at 90 minutes in SPRAVATO, first looked at 120 minutes. We will probably continue a look like that in our studies. So we think that the overall time of the clinical be relatively short. So sorry to jump back to the first half of your question, but I wanted to put a little more detail on there.

That's awesome. Thank you so much for all the color, very helpful.

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

Congratulations on the data. First question is when you look at the responder and sort of remission rates from the core study and for those that were on the 8- and 12-milligram dose cohort, is there a consistency in terms of those that were responders or remitters on the 57 in the core study and those that were responders and remitters in the OL lease at day 57. And I'm partially asking to see if the original responders and remitters were resilient?

Yes, that's a great -- well, first of all, thank you for the question, Pete. That's a great question, whether there was sustained response. I don't remember that data specifically. Kevin, I don't know if you have seen that?

Yes, I can say a little bit, and I'm sure to say some more as well. I mean, so on average, we've looked at this and we haven't done a specific looking at people who were defined to sustained responders algorithmically. But looking at the data, we do see that those who responded after the first dose, are those indeed who have a sort of subsequent improvement after the second dose. So there's a group who I think with all drugs may not respond to the drug at all and those that do respond -- to respond to subsequent treatments as well.

Yes, this is Rob. I'll add to that. Kevin is completely right. And what we found so far, and this is a very preliminary analysis that in essence, most people did respond. The vast majority of people did respond somewhat. So first part of your question, is if you didn't make much of a responder criteria in the first dose, and you still have a pretty good chance to have some response in the second dosing, but it appeared that if anything, responds predictively response. What I mean was it if you were a relatively robust responder in the dose -- first dosing period, you really got a very good response in the second dose. That is part of what suggested as the 1 versus 2 dose induction is at least worth thinking about because of that.

So -- there are -- there were definitely some people who just don't respond to this medication like any other medication. That's fortunately a very small number. Most people did have some effect on the second dose. And if the people were a partial responder, they tended to be even a more robust responder on that second dose.

All right. And one follow-up question. Thinking about the Phase III study design, [indiscernible] will be conducted. Will they follow the current paradigm of one against placebo? And the other against a subclinical dose. And will retreatment be based on a clinical sale threshold? And are you thinking about monotherapy studies or allowing concomitant standard of care and the questions?

Yes, of course. So the more recent studies, the more recent Phase III trials have not used a subtherapeutic dose paradigm. So we're not necessarily anticipating that, but of course, this is one of those questions for the FDA. So we'll -- that's something that we'll obviously provide some color on. In terms of the open-label extension, with other sponsors, there has been -- there have been some criteria. This is something that we are looking into as well. So we'll provide more color on that as well in the first quarter.

And then what was OEM monotherapy versus [indiscernible] therapy, same kind of thing. I mean, this is kind of like Kevin was suggesting for the 1 versus 2, it'd be great to have the option of either. And the question is how to get there most efficiently in the context of 2 trials, we will take a look. I mean, do we do this in the context of these 2 trials? Do we do this in the context of an ANDA with a separate study [indiscernible].

Our next question comes from the line of Harry Gillis with Berenberg.

Congrats on the data. You've been very clear that you're going to proceed with the 8-milligram dose. But I was wondering whether there's any indication or signs you may also examine a dose below 8 milligrams given the 8 and 12 produced a similar effect? That's my first question.

Yes, it's a good question. So the agency as a general statement does like to see a dose response, right? That's one of the ways that you address concerns around functional unblinding. And the example that I give here is the COMPASS data, right? The Phase IIb, they both -- they had the subtherapeutic or [indiscernible], I should say, or 1 milligram dose, but then they had 10 and 25, both 10 and 25 were mostly psychedelic, but the 10-milligram dose did not have the same degree of efficacy and indeed did not hit that fig, whereas the 25-milligram dose did.

So I think that is an important kind of data point. We are -- it's again, another question for the agency how to proceed on something like that. Kevin, I don't want to know if you have anything to add on that point?

No, I think you've covered it, Srini. I think clearly, we -- looking at some of the other sponsors that sort of mid dose that is psychodelic, but maybe less efficacious is a consistent paradigm that we see across a number of the other companies in Phase III. And so I think that's certainly something that is likely to be on the cards. And we have really good data from Phase I. We know the sort of subjective intensity in the PK meeting from 0.3 up to 14 milligrams has been studied. So I think we are in a good place to sort of pick a dose that is intermediate between 8 and 0 or 8.3 that meets those criteria. And as you say, that's something that's going to be coming up in the conversations with the regulators.

Understood. That's really clear. And then if I could just ask, so VLS-01 obviously had some delays. I was wondering, one, how that's progressing? Obviously, you've reiterated the readout in the second half of next year. And then as we think [indiscernible] just given everything we know the FDA end of Phase II meeting, potential Phase III start first half of next year. What's your current base case in terms of FDA filing and then eventual launch if everything goes to plan from here?

So on the second point, on BPL-003 time line to launch, we don't want to provide any color on that until we have clear guidance from the agency. So stay tuned on that point once we have those -- the minutes in hand. On VLS-01, no change in guidance on that. We're looking for a readout in the second half of next year.

And our next question comes from the line of Elemer Piros with Lucid Capital Markets..

So what I'd like to ask Srini and the team is how the noncompleters were treated. I think in the first 8-week period, you identified 90% completion rate. I don't know what it was in the redosing paradigm? And how you treated those who didn't make it to the end of the 8-week period?

How we treated those? Okay. So let's see, maybe Kevin, I don't know how best to handle that one. Obviously, we have attrition as we would in any study. So normally, it's something -- in this case, it's -- we don't really model it not like the primary analysis we have in MMRM, et cetera. Here, it's more an observed case. So the data that you have is the data that you have. But I don't know, Kevin, if there's anything else you can say on that?

No, it's a very good question, and that's exactly right. So we obviously have a model we're comparing statistically 3 doses in the core study. The analysis in the open label is, as you say, observed data. So we had a similar withdrawal or dropout rate in the open label, so about 90% to the end. But the values for each of those time points or actually kind of observed data rather than putting a model to that.

Okay. Okay. And Srini, I just wanted to make sure that you are still undecided whether it's going to be in the Phase III of 1 dose or a 2-dose paradigm at this stage?

Correct. At this moment, we're not sure. I'd say that one of the big picture considerations is time line of the primary endpoint, right? So obviously, with SPRAVATO, the primary endpoint was at 4 weeks, and that's in the original Transform 2 as well as the subsequent monotherapy SMDA trial. But the other sponsors have been -- seem to have a 6-week end point. So the inclination is that if it's a longer primary endpoint, there may be utility in doing a second dose, if it's a shorter one, perhaps a single dose may supply. So that's, again, not something that we've discussed in detail yet, and we're just kind of considering these different things. And of course, we'll have that discussion with the agency.

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

It's great to see you advancing the science and all the progress [indiscernible]. Does the response on the 12 mg dose, especially on the retreatment part, have any read-throughs for frequency and time point of future dosing in terms of perhaps the ceiling effect. It's not what might explain the results in the 12 mg -- plus 12 mg dose versus the 2 other groups in the OLE? And then I have a follow-up.

Sumant, thank you very much for the question and the kind words. Yes. I mean it's an interesting one, right? So in the core study, we also highlighted that while statistically not different, the 8 and 12, there was certainly a numerical benefit to the 8 milligram. And if you look at the adverse event table that was presented a while back, there was an increased anxiety noted with the 12-milligram dose. So I'm clear, to be perfectly honest with you, whether that anxiety is adversely impacting the efficacy that seems downstream. It's certainly something that one could postulate. I mean as you know, this is a single -- well, the core study was a single administration trial. So normally, when the high dose -- a normal study where it's a daily dosing when the high dose looks worse than the mid-dose, usually [indiscernible] someone dropped out along the way or what have you. But that's not -- that wasn't the case with the core study because it was only a single dose.

So that's interesting. I don't know that it materially impacts how we're thinking about the redosing paradigm, however. As noted, we're going to go with the 8 and 8 and leave it at that. Good, robust efficacy that was seen out indeed for reasons that were interesting, I guess, or observation that was interesting is that response remission criteria tend to seem to be getting better as a function of time. I really do you need to understand that, that may just be a result of dropouts, but I'm not certain on that. So anticipating redosing and kind of the 8 to 12 weeks time frame, and that's more or less consistent with what other sponsors are doing?

And then we appreciate the actual time of psychedelic effect with BPL-003 is quite short here, limited to an hour or even less than that. But do you have or expect to have any analysis that attempt to parse out efficacy differences among patients depending on the differences in the duration of their actual psychedelic experience?

Yes, that's a great question. I mean these are all the secondary analyses that we are looking forward to doing and making public, I should say. So you can anticipate more posters as well as publications that come out of this over time.

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

Congrats on the data. The first is just on the OLE data showing a deepening antidepressant effect over time. I was just wondering what your interpretation of that progressive increase in remission through day 57 post redose, just your interpretation of that? And then as well, it sounds like -- what we're looking at is a paradigm where we have a more simplified dosing than SPRAVATO and as well perhaps as efficacious results. And so I'm just wondering, are we looking at a paradigm where we're redosing once quarterly. What is this data set kind of pointing to you as we're seeing this longer-term data mature?

Yes. I mean we certainly anticipate something -- let me take the second question first and maybe I'll hand it to Kevin on the first one, the progressive increase. But certainly, that's our conjecture, right, that this will be significantly substantially improved redosing paradigm compares to SPRAVATO. Yes. As I mentioned in the talk itself, SPRAVATO is being redosed very frequently in many patients. It's at least once every 2 weeks.

We would anticipate redosing closer to rate to 12 weeks, somewhere in that time frame with BPL. So substantially a substantial improvement in logistics for the patient and by extension, presumably quality of life as well. Kevin, do you want to take the progressive increase there, but our progressive improvement that would be 8 milligrams does?

Yes, absolutely. I mean it is interesting, and it's a slightly different pattern compared to the core study. And I mean we've had a couple of thoughts about that. I mean the one is, of course, it's worth bearing in mind that we are selecting a slightly different sample in the open label. So there were sort of 15% of people who dropped out of the core study, and we had a few more who dropped out who are eligible, but then dropped out for various reasons playing into the open label. And so that, of course, is select for maybe a group that are more prone to response. But I think there are other interesting interpretations. I mean one thing that we do here is that there is increased social connectedness, people to the [indiscernible] coming down quite significantly. And it may be that there's just a virtuous cycle filling up at that stage that they are participating more in activities with life, and that's creating its own feedback loop.

So I think certainly something to understand in more detail. But I think as we look at that, that's how [indiscernible] said actually we start getting to people into situation where they're actually over time, getting better more than getting worse.

Right. That's helpful. And then just as a follow-up, if you can talk about the safety profile a bit more, particularly as it relates to SPRAVATO and some of these other short-acting as well as longer-acting psychiodelics et cetera in development?

Yes. I mean I think -- yes, go ahead, Kevin.

Yes. I mean I think on the sort of face of it, the class looks very similar across a lot of the adverse events. So increases in blood pressure and heart rate, nausea and vomiting, we have rates that are quite similar to some of the other reported numbers out there. I think it's unique to this drug delivery is the nasal discomfort, which I think are rates that are -- when we look at sort of things like Nasacort, steroids and other, there are a few internasal things out there. I think it comes somewhat with the territory. So nasal fullmess, it's going [indiscernible] sense of irritation or itchiness, and so we sort of see some of that. The [indiscernible], I think, is something that we've been watching quite carefully. But that is in a small proportion and a very short lived [indiscernible] that pain go away, really been out of dosing.

So there hasn't been a lot that looks particularly different compared to the other [indiscernible]. It is somewhat different to the sort of associative folks like ketamine and SPRAVATO in as much as the association sort of these people getting clearly spaced out here in this case, people are having maybe a sort of an intense experience that is less sedating, shall we say. But I think that's a lot of it down to the sort of nature and the business experience. And we spend a lot of time preparing people for that, monitoring people through that and checking in on the most to make sure that they they're sort of well and back in terms of life afterwards.

So I suppose, I mean, we haven't seen anything that you're concerned about, and it seems to be very much taking that we're seeing with these kinds of drugs, except in our case, of course, the time that people experience [indiscernible] event is shorter. So in terms of the amount of discomfort that someone has, we're talking about an hour or 2 every, let's say, 8 to 12 weeks, as opposed to an hour or 2 every twice a week or once a week or 8 hours or 12 hours of the dose. So I think our sort of area under the curve for discomfort, if you will, is shorter, but otherwise no surprise.

I just want to make a quick addendum here that the patients that actually that we were discussing that have the serious adverse event actually, it was in the 0.3-milligram dose arm initially. So the -- essentially the functional placebo and then got the 12 milligrams in the open label. So just -- it is important to keep that in mind.

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

Congrats on the continued progress that you guys are making this year. It's great to see. My question is just with regards to -- I mean, clearly, this data along with the Phase IIa that you recently disclosed indicates that with an induction dose and then with also a maintenance dose, we see subsequent improvement in response, so what are some of the considerations that may prevent you from -- or sort of that you would weigh in considering kind of induction as well as the maintenance stores in Phase III. And with regards to the maintenance stores, would you consider it to be sort of a time to every 8-week redosing? Or would that be based on some other specific criteria, maybe the business score or some of the criteria for the patient? And then I've got 1 other question.

Sounds good. So yes, in terms of the redosing, this is a discussion with the agency, what they are looking to see. It seems like that the feedback that we've gotten from other discussions is that the agency does have specific or particular views on how 1 approaches redosing. So that's something that, again, we'll be talking to the agency about. In terms -- I think the way I understood your first question was around the induction approach. Currently, correct me if I am wrong, obviously, we're doing a single dose reduction now. There's certainly the notion that you're leaving some degree of efficacy on the table if you're doing only single dose and you may want to do 2 doses to see if there's more. That's something that we are going to look into [indiscernible] happens and how that looks in the Phase III program or something that [indiscernible]. Of course, there's some precedent here. Compass is doing exactly that split across 2 different trials as you, I'm sure you're aware. So there are 5 trials, a single dose, [indiscernible] a 2-dose induction.

So again, something that we're looking into, as I mentioned previously, there's going to be some impact on the primary endpoint, whether it's a 4-week or 6-week endpoint is something that we'll also take under advisement as we think about 1 or 2 those paradigms.

Understood. That's helpful. Secondly, with regards to the dispatch time lines, it sounded like there might have been some patients who weren't quite ready. So my question, what I'm trying to understand is that what might have been the reasons. I think you mentioned one example where some patients just didn't have somebody to pick them up at the end of the time frame, and so they weren't deemed the start ready. So in terms of the discussions with the FDA, what are some of the changes in the criteria or the questionnaire that you might explore changing to be able to sort of fit within the existing paradigm?

Yes, sounds good. Rob, do you want to take that one?

Yes. So the agency is interested in several different parameters. That's a good question. And one is, of course, the duration of the [indiscernible] effect. So that's one thing. The second thing is that the person is essentially physically back to normal. So that's more the physiologic characteristics like [indiscernible] and blood pressure. The third thing is the neurologic standing, a person can walk, they seem oriented time in place, different than the [indiscernible] elect, just more of like a neuromuscular effect going back to normal. And then finally, there's just a global assessment that the clinician thinks they're ready to go home, where we found a lot of variance is that ready to go home thing, and we'll define that better in our next trial. We were very open and conservative first time.

I think we found that the physiologic and the physical [indiscernible] as well as technological standpoint seem to work well. We haven't worked with the agency through this year. But we did do the study, of course, under an improved IND, and that included this readiness to discharge scale. There wasn't a preexisting [indiscernible] scale, which you can't really have because each drug is different. So SPRAVATO has one, will have one. And I think that's what we'll ultimately work on is to be able to have that home down so people know when people are ready to go home.

The final thing about that is important. It's not as if you have to watch everyone until the last person in a Phase III study design was ready to go home. This is much more how soon can you send someone come, which is like what happens is SPRAVATO in the clinic that Srini said earlier, the vast majority of people with SPRAVATO can go home within a couple of hours. There are a few people that aren't ready and then they stay longer. So that's what we're expecting in the clinic. And when we'll work and we're actively going to work on that scale with the agency.

I will now hand the call back over to Dr. Rao for closing remarks.

Thank you very much. Yes. I mean, obviously, very excited about these results, very excited also about this very first call, this very first webcast that is Atai Beckley, so as mentioned earlier, this has been a very eventful year. It's been a very good year for Atai. Overall, we've had lots of positive momentum over the course of the year. So clearly looking forward to continuing that in the next year with multiple readouts and multiple kind of important inflection points. Not the least of which is the end of Phase II meeting manage that we've been talking about, but also the EMP-01 readout, which will be in the first quarter of next year as well as [indiscernible] readout for the Phase IIb in the second half of next year.

So again, looking forward to following up with everyone as these various milestones are achieved. Thank you so much.

Thank you again for joining us today. This does conclude today's presentation. You may now disconnect.

Good morning, everyone, and welcome back to H.C. Wainwright's 27th Annual Global Investment Conference held from September 8 to September 10, 2025. My name is Patrick Trucchio. I'm a senior health care analyst at H.C. Wainwright. It's my pleasure to introduce the next company, atai Life Sciences, a clinical stage biopharmaceutical company pioneering development of highly effective mental health treatments to transform patient outcomes with a pipeline focus on short duration psychedelics aim to address the complex nature of mental health, providing commercially scalable interventional psychiatry therapies that can integrate seamlessly into health care systems.

And from the company, it's my pleasure to introduce you to Srini Rao, CEO of atai. Thank you very much again for joining us.

Thank you, Patrick.

And maybe you can start first with an overview of atai's pipeline and strategic focus over the next 12 months.

Yes, absolutely. Again, thank you, and it's great to be here. So yes, in terms of our pipeline, we have three clinical stage assets. We recently announced results of BPL-003, Phase 2b results in treatment-resistant depression. That's a formulation of 5-methoxy-DMT. We have in Phase 2b VLS-01, which is a formulation of DMT. And behind those two, we have something called EMP-01, which is our R-MDMA and oral formulation that we're developing for social anxiety disorder. We also have a discovery program consisting of both psychedelic as well as non-psychedelic or hallucinogenic compounds.

How would you define atai's leadership position within the emerging short-duration psychedelics?

I mean if you -- our philosophy when we put together VLS-01 was to have something that truly slotted into the SPRAVATO paradigm. So the idea was to really have something that could drag and drop in. So what that meant was a single administration and psychedelic experience and physiological effects that should wrap up well within 2 hours, allowing for monitoring and then discharge at the 2-hour time point, just like SPRAVATO, again, very much in keeping with that. Obviously, the piece that we wanted to improve on is the durability. So SPRAVATO is efficacious, but it requires frequent redosing. And many patients, even in the maintenance phase are getting the drug every week to every 2 weeks. This is an interventional psychiatry drug, which means you have to go into the doctor's office. And again, as I mentioned, you have to get dosed and monitored for 2 hours. You're clearly not driving home. If you're doing this every week or every 2 weeks, it's difficult to hold down a typical job. Well, I mean this is a, let's call it, half a day on a good day, right? So you have to get to the doctor's office, you got to get checked in, you got to get dosed and you got to get a ride home. So 3 hours would be kind of the very -- the minimum of that.

So we want something that could be dosed every 8 weeks, 12 weeks, ideally closer to the upper limit of that. So that's where our focus is. BPL was designed by another company called Beckley Psytech. We are merging or acquiring that company later this year. They had a very similar design philosophy. So if you put those two together, I mean, that is the entirety of the later-stage short-duration psychedelic market, I mean, development pipeline at this point.

Right. And so with BPL-003, this is the 5-MeO-DMT intranasal. Maybe you could walk us through the mechanism of action, formulation, how it's differentiated.

Yes. So -- as I mentioned, we have these two assets. BPL-003 is 5-methoxy-DMT and VLS-01 is DMT. So structurally different compounds, different APIs, pharmacologically differentiated. If you just look at serotonin, 5-methoxy-DMT, it has more potency and more activation of the 5-HT1A receptor versus DMT. Subjectively, people believe that 5-methoxy-DMT has a different kind of profile compared to the DMT. And that some of that was evidenced in our phase -- respective Phase 1 studies. We don't have a single Phase 1 that compares both compounds or any kind of trial. But in the independent Phase 1s, there do seem to be some subjective differences between these two compounds.

In terms of the products themselves, BPL-003 is using an Aptar pump kind of just like SPRAVATO. It is a dry powder that is sprayed up into the nose. VLS-01 is using an oral thin film technology that was developed with a company that's formerly called IntelGenx that's actually been acquired by -- was acquired by atai in the fall of last year. So that's -- it's like a Listerine strip that goes under the buccal surface, the internal cheek surface and gets absorbed that way. And of course, degrades and erodes away in about 10 minutes or so.

So what are the most important takeaways from the recently reported Phase 2b trial in TRD with BPL-003?

So a couple of questions that we're trying to answer with that trial were, number one, what is the impact of short psychedelic duration on magnitude of efficacy? And what is the impact of that on durability as well. So the -- obviously, the leader in this space is COMPASS, and they published their Phase 2b results of COMP360 or oral psilocybin a couple of years ago. Psilocybin has a psychedelic effect that lasts about 4 to 6 hours. So this is something that's going to be the majority of the day, right, a vast majority of the day. And the question was always out there, if you shorten that psychedelic duration, what does that do to the efficacy and durability.

In our study with BPL, the results were recently reported, we can say that there was no impact. In other words, the magnitude of efficacy that we saw was comparable to psilocybin acutely. So 3 weeks and 4 weeks data looks pretty much the same. And moreover, the durability was almost identical. The Phase 2b with BPL-003 went out to 8 weeks. The trial data -- the trial from COMPASS on COMP360 went out to 12. But nonetheless, if you look at the curves, they look pretty much the same. So that was -- those are the most important things that we learned from that trial.

That's interesting. How do you interpret the 8-milligram dose versus 12-milligram dose in terms of both efficacy and tolerability?

Yes. They were both picked as potentially efficacious doses. And the idea was to see if there was a view that the 8-milligram dose based on Phase 1 results will be better tolerated. And the question was, how would that trade-off against efficacy. And what we saw in this trial was that the 8 and 12 statistically have exactly the same level of efficacy. If you look at -- if you compare the stats on change in MADRS score, numerically, interestingly enough, the 8 was a little bit better than the 12. We don't have a very good explanation for that. There was more anxiety seen at the higher dose, unclear what to make of that at the moment. But certainly, the efficacy looks very similar, if not better.

Right. And what gives you confidence in BPL-003s scalability and fit within the interventional psychiatry model?

Yes. A lot of it is exactly what I was mentioning. I mean in the Phase 2, we looked at discharge readiness criteria. So that was subjective effects, but also blood pressure, et cetera. The majority of folks were eligible for discharge at 90 minutes and the vast majority of patients were eligible for discharge at 2 hours. So comparable to what we see with SPRAVATO in essence, if you think about dissociation in that context, but also blood pressure changes, et cetera. So I think that's a really important element. So the idea -- the concept is if a doc can administer SPRAVATO, hopefully, they can also administer this. We do have somewhat higher monitoring requirements as a psychedelic. In the case of VLS-01, you do need someone in the room. BPL actually had two people in the room. We hope that over time that, that can be scaled back further. I mean there's really no reason that SPRAVATO doesn't need someone in the room and this does. One is an anesthetic and the other one isn't. There is no therapy that occurs. I mean that's a bit of a misnomer. There are -- people do have anxiety reactions and things as they do with ketamine or as ketamine, they might need settling down. You can do that by monitoring a patient and remotely. But again, that's something that we have to generate data on.

Right. And so what does the time line look like for initiating the Phase 3 trial? And do you have an idea of what that design would look like?

Yes. I mean we haven't really guided on that. What we have said publicly at this point is that we're going to be submitting the end of Phase 2 meeting request this quarter. So that's on track. And then, of course, there's a time line to that to getting the actual meeting in place and, of course, getting the meeting minutes. But realistically, dosing towards the latter part of next year is based on what I know now, not to be held to it, but based on what I know now is not an unreasonable time line.

In terms of the trials themselves, I mean, if you look at across the various companies, they all look pretty much the same, right? So it's 1 administration or 2 administrations of a compound. It's a primary endpoint that is mostly around 6 weeks, but SPRAVATO at a 4-week endpoint. There's the total trial duration of about 12 weeks, COMPASS being the exception and then open-label extension beyond that. So I would anticipate it's pretty much going to be the same as that, but there are a lot of devils in those details, and that's what is going to be the subject to the end of Phase 3.

I think there's an open-label extension readout coming in the third quarter of this year for BPL-003. What's your expectation for that readout?

So there's actually two data sets. One is from a Phase 2a. It's a small cohort, 12 subjects. It's looking at induction dosing, so 2 doses 2 weeks apart, and then following the patients for 10 weeks post that second dose. So that's the first one. And then there's the actual open-label extension data from this trial. So I mentioned that this trial had a 4-week endpoint. So single dose, 4-week endpoint, primary endpoint. They were then followed for an additional 4 weeks, and then they were redosed in an open-label fashion at 12 milligrams and followed for another 8 weeks. So obviously, the primary objective here is to assess safety because it's open label. So efficacy is a little bit more difficult. But broadly, we have these three groups that are going to be coming in. Those have got the functional placebo or active placebo and those have got 8 and 12. And so it will be interesting to see what the changes on efficacy look like after those -- with those three groups going in.

Right. And so you talked quite a bit about VLS-01. So I'm wondering what's the status of this program? When is the next data? What are your expectations for it?

Yes. So VLS-01 again is DMT. We, back in the day, picked DMT for a couple of reasons. One was that there was a publication looking at ayahuasca in a double-blind placebo-controlled trial in treatment-resistant depression. Ayahuasca is a psychedelic brew essentially used ritualistically. So DMT itself is not orally bioavailable, but this brew contains Psychotria viridis, which is a plant that has this stuff, but it also contains other plants that provide monoamine oxidase inhibitors. So when you drink it, it actually goes become orally bioavailable. It has a very low and slow pharmacokinetic profile. So the DMT serum concentrations aren't that high, but they do -- they are protracted.

So that gave us comfort, and it was robustly positive. So that gave us comfort on DMT. Then there was a subsequent study of IV DMT by a company called Small Pharma, another double-blind, placebo-controlled trial, also small around 30 patients, 15 and 15-ish. And there, they had a much more rapid PK and showed efficacy again at 2 weeks. So our PK bracket is in between those. We have bracketing PK essentially. So that gives us confidence. We also have 2 doses. It's a 2-dose induction model. My view is that given the morbidity associated with depression and particularly tumor-resistant depression, we anticipate being able to get additional efficacy with the second dose. If we can drive the patients, the vast majority of patients truly into remission, you may not need a dose as frequently from there on out, right? You can maintain that a little bit longer. So that was the idea with the Phase 2b for VLS-01. Of course, we also knew that we have all the data from BPL, which helps, so we can try something a little bit different there. So that's what we're doing there.

Can you talk more about the significance of being discharge-ready within 90 minutes? And is there kind of a wide range? Are there some patients who are maybe beyond that their outliers? How should we think about this?

Yes. So it's -- again, you can go back to SPRAVATO, right? So SPRAVATO, I think it was around 85% of individuals had no more dissociation and no blood pressure elevations at 2 hours, roughly 85% might have been a little higher or lower. And that was the basis for the label. So the idea is that you get medically assessed at that point at 2 hours. And if everything looks good, if you look stable, then you can get discharged. Otherwise, you hang out a little bit longer. So that's the idea. So it was very similar in what we saw in the Phase 2b trial. It was about the same thing. Essentially, by 2 hours, it was about 85% of people met our criteria for discharge readiness. So again, very much in keeping with SPRAVATO.

And how do you envision moving BPL-003 and VLS-01 forward? Are there different patient groups that these drugs are relevant in? And are there different indications maybe that one would be relevant in versus the other?

So the second one is a really interesting point. Right now, we don't know, right? We do know that, again, anecdotally, the subjective effects are different. We know the pharmacology is different. We don't know how those elements will impact efficacy and whether they will be better set for different patient populations. I mean, we just don't have enough data on that. So that is -- that remains to be seen. Right now, we're pursuing both in TRD. People have brought the issue up of how are they going to cannibalize. I mean the reality is that SPRAVATO hit $1 billion in sales based on U.S. treatment of about 50,000 patients out of at least 3 million, right? So there's a huge unmet medical need. There's a huge total addressable market, which is quite substantial compared to what's being actually addressed. So that -- I mean, I haven't stressed too much about that. And I've also quipped that, that is literally the Oxford English dictionary definition of first world problem. You can use two drugs that you've gotten approved for TRD, and oh my God, they're going to interact with. They're going to cannibalize each other. It's like, okay, we'll get there when we get there.

Right. No, that makes sense. So then maybe just moving on to EMP-01. This is our R-MDMA. Maybe you can walk us through this program and the development rationale in social anxiety disorder.

Yes. So initially, when we started, we were contemplating PTSD. And this was based, of course, on some of the work that MAPS/Lykos was doing with the racemate of MDMA. So we tested our MDMA in a Phase 1 study, and we found that it had a very unique profile. Of course, we -- the reason we went with R is that, that's where a lot of the serotonergic effects were. And we thought the speculation was that, that was driving the entactogenic effects, the sort of elements that sort of are prosocial, but really more being able to kind of suppress some fear in terms of confronting things in your own past essentially, right? So it turns out the S-enantiomer of MDMA is a really potent stimulant. I mean it's very aggressive in that. It's a dopamine releasing agent or norepinephrine releasing agent. So that is what gives you all the dose-limiting tox that you get with racemic MDMA. So by stripping that out, we thought we could have a safer compound. When we tested in Phase 1, we found a very different profile for MDMA. It had psychedelic elements that, in some ways, resembled a classical psychedelic, but it also maintained these entactogenic pieces. So that was interesting. It was also -- MDMA is a much more -- is an externally kind of focused experience. That's why it's used as a drug of abuse when you take it and go to raves or something, right? It's prosocial. This turned out to be a more internally focused experience, kind of like what you get with a classical psychedelic. In the trial itself, we found some benefits on self-compassion that were persistent. There was other elements there that lined it up with -- I mean, PTSD would still be a very good indication for this, but social anxiety disorder is a huge indication that's really underserved. There was some data around MDMA, but really, we want to go out in a different direction with this. Social anxiety disorder is quite impactful for individuals. You don't hear about as much about it, but it became a little bit more prominent with COVID because a lot of people were impacted by this. It's several million people more compared to depression in terms of epidemiology, not well treated by current medications. There are several approvals. They were LCM placed from a long time ago for 2 SSRIs and SNRI, but nothing is particularly effective. And so this struck as an indication that could be very interesting for this particular compound.

And what's the next step for development?

So we have a double-blind placebo-controlled study that's ongoing now, Phase 2a using a regulatory endpoint. That will be reporting out in the first quarter of next year, and we will make some decisions about it at that point.

Will this drug have relevance in PTSD?

Absolutely. I mean there's no reason you can't go after PTSD. And that's obviously a really important indication with a huge unmet medical need unto itself. We'll have more clarity also on where things go with Lykos MAPS over the course of the next little bit. I don't anticipate them having a lot of success, but let's see.

So how should we think of any read-throughs, if any, from the MDMA-assisted therapy AdCom with Lykos in PTSD? Are there any read-throughs from that to your program? Or how should we think about it?

No, not really. I mean the CRO was actually released last week. Yes, it was last week. And I mean, there were a lot of fundamental things that weren't collected like adverse events of special interest. There was no durability data. There's a lot of issues with that particular program that just aren't relevant to us or any other company in the space that's developing psychedelics and we're all doing more traditional studies, et cetera. So no, we're not doing therapy. We're certainly not pitching this as drug-assisted therapy, right? I mean we -- in all cases, we're doing de minimis. It's not therapy per se. It is psychological support. It's an unusual experience. You do have to prepare the patients. You do have to assess psychological safety the day after because these kind of -- these drugs can surface things that the patient may have suppressed.

Right. So recently, there were some reported news on the M&A front. So we had AbbVie will acquire Gilgamesh bretisilocin program for up to $1.2 billion. So I guess my question is, what's your take on this deal? And what's the read-through to the atai's programs?

Yes. So obviously, incredibly validating for the entire space of psychedelics, but particularly validating for the short duration psychedelics, I would say. And the reason -- the reason for that statement is that they specifically called that out. Obviously, this -- there wasn't -- if I'm being honest, there wasn't a lot of strategic interest in the space for a while. Suddenly, there's a lot more because of the success of SPRAVATO, which is the $1.7 billion run rate this year. So there's been a lot more interest recently, but everybody is looking for things that are short duration. And bretisilocin is that, albeit in an IV infusion format. And so both BPL and VLS are that as well. So single administration, psychedelic experience wrapping up. And again, we are pretty unique in that space at this point. In terms of things that are in Phase 2b or going into Phase 3, there really isn't anybody else.

Right. Well, that was my follow-up question because the route is different and the stage of development is different. So how can we compare across these two programs?

I mean I think it's tough, right? Because that was a Phase 2a, it was four sites, but we use the same network actually. It's in the U.K., it's called the MAC network. They're very good. The four sites behave in many ways almost as one. So Phase 2a typically are -- you get a much bigger signal, et cetera. So these are much more experienced sites. So we'll see how that actually ultimately translates.

So we talked about the OLE data that's upcoming. What are the big sort of catalysts that investors should look forward to? And is there anything about the story that you think they're missing?

Yes, there's quite a few catalysts. I mean, again, we have these two trial readouts coming up. I think the next big one for BPL is going to be the end of Phase 2 meeting minutes and the clear plan that we hope to have alignment on with the agency for the Phase 3 program. And of course, Phase 3 initiation will be after that. In terms of value that's not really being seen. I think VLS-01 remains very interesting. It's got some of the best tolerability data that we've seen, albeit in a Phase 1, so it has to be replicated, but has very good tolerability. It's a slightly different paradigm, as I mentioned, with 2-dose induction. Obviously, people have said there's downsides to that because it may have the label that says that. On the other hand, the efficacy we anticipate being higher than it would be with the acute sort of headline efficacy being higher than it would be with one dose. And we'll see what happens there, too. So we're pretty excited about that one as well.

Terrific. Well, thank you very much. Always a pleasure to catch up, Srini, and thank you to atai for attending. Thanks, everyone else for attending. Have a great rest of your day and conference.