Janux Therapeutics Inc Stock

Welcome to Janux Therapeutics Janux011 Phase I Healthy Volunteer Data and Autoimmune Development Strategy Call.

[Operator Instructions]

I would now like to turn the conference over to Chad Rubin, Investor Relations for Janux Therapeutics. Mr. Rubin, you may begin.

Good morning, everyone, and thank you for joining us. Earlier today, Janux issued a press release announcing initial Phase I clinical data for Janux011 in healthy volunteers.

The press release, today's webcast, and the accompanying presentation slides are available on our Investor Relations website.

Before we begin, I'd like to remind everyone that certain statements made during today's presentation and question-and-answer session may constitute forward-looking statements.

These statements are based on current information, assumptions, and expectations and involve risks and uncertainties that could cause actual results to differ materially from those expressed or implied.

Additional information regarding these risks and uncertainties can be found on Janux' periodic filings with the Securities and Exchange Commission.

We caution you not to place undue reliance on these forward-looking statements, which speak only as of today. Janux undertakes no obligation to update these statements, except as required by law.

With that, I'd like to turn the presentation over to Dr. David Campbell, President and Chief Executive Officer of Janux.

Good morning, and thanks for joining us. Today, we're presenting the first human data from Janux011, our CD19-targeted ARM product candidate following completion of the healthy volunteer study.

Before diving into the details, I thought it would be helpful to set the stage for today's presentation. At 3,000 micrograms, we dosed 5 subjects with a single subcutaneous dose and no step-up dosing.

Most achieved greater than 90% B-cell depletion, and 2 of the 5 reached undetectable peripheral B-cell levels. CRS was grade 1 only. For us, these results do 2 things. First, they established Janux011 as a clinical-stage autoimmune asset.

And second, they provide the first human validation of the ARM platform. Today, I'll start by putting ARM into the context of the broader Janux portfolio. Then I'll walk through the human data, our development strategy, and the milestones ahead.

Janux now has 3 PRECISION platforms, and we think they create complementary value drivers across oncology and autoimmune disease. TRACTr remains our oncology foundation, and TRACER builds on that foundation through localized CD28 co-stimulation with the potential to deepen and extend responses.

ARM extends our precision T cell engagement strategy into autoimmune disease, where the objective is to deplete disease-driving immune cells with an off-the-shelf biologic.

I also want to point out an important distinction with ARM. Unlike tractor and TRACER, ARM does not rely on masking or proteolytic activation. It is a bispecific antibody that achieves selectivity by engaging a different site on the T cell receptor rather than CD3.

Strategically, we think that's important. TRACTr and TRACER expand what we can do in oncology, while ARM gives us the opportunity to build an autoimmune franchise using many of the same scientific, clinical, and manufacturing capabilities.

We view ARM as more than a single product opportunity. It has the potential to become another long-term growth platform for Janux. With that context, let me turn to Janux011 and the first human data.

I want to start with a top-level view of the Janux011 clinical profile, and then we'll go through each of these findings in more detail over the next several slides.

As I noted during the introduction, at 3,000 micrograms, we dosed 5 subjects with a single subcutaneous dose. Most achieved greater than 90% B-cell depletion, and 2 of the 5 reached undetectable peripheral B-cell levels.

There was no priming dose or step-up dosing, and CRS was grade 1 only. We also saw a clear dose response, depletion persisting through day 42 and T cell activation concentrated in the intended TRBV6 positive population.

However, I would not focus on any one of those readouts in isolation. It's how the activity, tolerability, and dosing profiles come together. Ultimately, the question is whether that overall profile can support broad use in autoimmune patients.

When we put those pieces together, we believe Janux011 has now demonstrated the human pharmacology, tolerability, and intended mechanism needed to provide the clinical foundation for moving into autoimmune development.

If you step back and look at the autoimmune treatment landscape, we think there's a pretty clear opportunity. At one end, CAR-T has shown the potential for deep and durable responses, but it also comes with complicated manufacturing, lymphodepletion, specialized treatment centers, and management of toxicities like CRS and ICANS.

At the other end, antibody-based therapies have attractive safety and convenience profiles, typically with intermittent outpatient dosing.

They have transformed treatment across a number of autoimmune diseases, but generally have not shown the same depth of immune cell depletion and response associated with cellular therapy.

Conventional T cell engagers sit somewhere in between. They've helped validate the importance of deep B-cell depletion, but achieving and maintaining that depletion often required step-up dosing and frequent repeat dosing, adding a treatment burden and CRS-related safety considerations.

That's really the opportunity we designed ARM to address, combining the depth of T cell-directed depletion with the practicality of an off-the-shelf biologic.

The goal is meaningful depletion with a scalable and convenient treatment approach that can fit into traditional clinical settings. The healthy volunteer data provide an encouraging initial profile with an activity, tolerability, and dosing profile consistent with the strategic position we designed ARM to occupy.

ARM came out of a relatively simple question. How many T cells do you actually need to engage in order to get the biology that you want? CD3 T cell engagers have clearly shown that redirecting T cells can generate very meaningful biology.

The question we asked is whether you really needed to broadly recruit the T cell compartment to get that biology. Once we thought we might not need to recruit every T cell, we investigated a number of different T cell receptor binding regions.

We were looking for a population that could give us the activity we wanted with limited cytokine release. At the highest level, the T cell receptor is the antigen recognition machinery on a T cell.

You have alpha and beta chains that make up the T cell receptor itself, which is associated with the CD3 signaling complex. The important distinction is that CD3 is broadly shared across T cells, whereas different T cells express different alpha and beta chains.

This work led us to the beta chain binders, of which there are approximately 30 different beta chains in our T cell repertoire. We then looked across a number of naturally occurring beta populations.

We focused on 3 things: the proportion of circulating T cells they represent, limited expression on barrier T cells that are important for antimicrobial protection, and limited representation in autoimmune disease.

Based on that overall profile, we selected TRBV6 for Janux011. TRBV6 represents approximately 10% of circulating T cells. So by design, the majority of the T cell compartment remains outside the directly targeted population.

We believe preserving that broader T cell repertoire has the potential to be important for maintaining host immunity over time. On the target side, Janux011 binds CD19, providing broad B cell coverage to support the objective of deep depletion across relevant B-cell populations.

And importantly, we're not limited by that 10% starting point. The biology is intended to be adaptive. We've shown that as target cells are encountered, the selected T cell population can expand and differentiate into the effector cells needed for depletion.

As the target is eliminated, the stimulus falls away, and the population can contract. This is similar to our own normal adaptive immune response.

It's important to note that expansion is not the objective. The objective is engaging enough of the right T cells to do the job. That's really the arm thesis: generate the pharmacology we want while limiting the breadth of immune activation, and Janux is our first clinical test of that thesis.

Later in the presentation, we'll show first human data demonstrating that T cell activation was indeed concentrated within the intended TRBV6p-positive subset, providing evidence that the molecule is behaving as designed.

The healthy volunteer study gave us the first opportunity to test that thesis in humans. And I'd emphasize one thing upfront. This study was designed to establish a starting profile, not the final clinical regimen.

We evaluated single subcutaneous doses ranging from 30 to 3,000 micrograms in order to understand the human pharmacology and activity tolerability relationship well enough to design the patient studies.

Importantly, the study incorporated a predefined healthy volunteer B-cell depletion ceiling of approximately 95% in order to minimize infection risk, reflecting the risk-benefit considerations appropriate for this population.

So we weren't trying to establish the maximum achievable biological effect. We're trying to determine whether Janux011 behaved the way we designed it and whether the data gave us a clear path into patients. And that's what I'll show you next.

You've already seen the overall profile. Here, I want to focus specifically on the depletion pharmacology. On the left, you can see a clear dose-dependent response following a single subcutaneous administration and interesting durability profiles even at the less active doses.

And on the right, you can see the 5 subjects dosed at 3,000 micrograms. Most achieved greater than 90% peripheral B-cell depletion, with 2 reaching undetectable levels.

I do want to point out the one patient who didn't have as deep a response; we've now determined that was due to suboptimal PK levels and exposure levels in that patient.

So it was well defined why that patient had a lower response than the others. Importantly, this wasn't simply an early effect. We continue to see depletion through day 42.

But again, I wouldn't look at the depletion results in isolation. What matters is the context: subcutaneous dose, no step-up dosing, and only grade 1 CRS, including in both of those subjects who reached undetectable B-cell levels.

For us, that's an important answer. Selective T cell recruitment was able to generate deep B-cell depletion in humans without broadly recruiting the T cell compartment through CD3.

On the previous slide, we showed that Janux011 can drive deep B-cell depletion following a single dose.

The next question is the other side of the design thesis. What was the inflammatory response associated with achieving that level of depletion?

Looking first at CRS, there were no events among the 16 subjects treated from 30 to 300 micrograms. At 1,000 micrograms, 1 of 4 subjects experienced Grade 1 CRS, and at 3,000 micrograms, 4 or 5 experienced Grade 1 CRS.

The way I think about CRS is that it's more a severity question than an incidence question. Grade 1 is generally manageable. Typically, it's a fever treated with acetaminophen.

Depending on the activity you're getting, limited Grade 2 may also be acceptable. What becomes much more consequential is Grade 3 or higher CRS because that's where you can really begin to limit the development opportunity.

So for Janux011, what matters to me is the severity of CRS in the context of the pharmacology we're getting. CRS Grade did not exceed Grade 1 at any dose level, including in those subjects who achieved undetectable B-cell levels.

The cytokine data helps put that profile into context. Across IL-6, TNF alpha, interferon gamma, and IL-2, we saw some low-level cytokine induction, but it remained relatively controlled and did not translate into higher-grade CRS.

When you put the depletion and inflammatory data together, this is where the arm design thesis really starts to come together: deep B-cell depletion without the higher-grade inflammatory toxicity that can constrain T cell-directed approaches.

Of course, this was a healthy volunteer study, so patient data will ultimately determine the activity-tolerability relationship, but we think this gives us an encouraging starting position.

The prior slide focused on CRS and cytokines. Here, I want to broaden the lens and look at the overall safety profile. No serious adverse events or dose-limiting toxicities were observed.

There were no grade 2 or higher CRS events, no ICANS, infections, or hypogammaglobulinemia reported. Most treatment-related adverse events were Grade 1 and transient, and the CRS events resolved rapidly with acetaminophen.

As you can see in the table, we did have 1 Grade 3 ALT elevation in the 3,000-microgram cohort, along with Grade 2 ALT and AST elevations at that dose.

I think the important context is that these transaminase elevations were transient, asymptomatic, and did not require treatment. Transaminase elevations are often seen with T cell engagers.

So this is a finding we're familiar with and have approaches to potentially mitigate as we optimize the regimen in patients. For us, the conclusion is pretty straightforward.

The overall safety profile supports moving forward, including the doses where we saw profound B-cell depletion. The next question is whether that overall profile ties back to the way we design the molecule, and that's what we'll look at on the next slide.

As we discussed earlier, Janux011 is designed to selectively recruit the TRBV6p-positive T cell subset rather than broadly engaging T cells through CD3.

Before getting to the activation data, I want to spend a minute on the left side of the slide. Across the healthy volunteers in our study, the TRBV6-positive subset was consistently around 10% of circulating T cells.

When we looked at PBMC samples from patients with autoimmune disease, we saw essentially the same thing. Across all of these groups, individual patient TRBV6 levels range from approximately 8% to 12%, and the levels did not correlate with responses.

So the population we're targeting appears to be relatively consistent across both healthy volunteers and the autoimmune patient samples we've evaluated.

I think that's important as we move into autoimmune patients because it suggests we're not starting with a highly variable target T cell population.

The next question is whether Janux011 actually activates that population selectively, and that's what we saw.

Across both CD4 and CD8 T cells, CD25, which we're using here as a measure of T cell activation, increased in a dose-dependent manner within the TRBV6-positive population, while activation remained limited in the TRBV6-negative population.

To me, this is where the design really comes together. We selected a defined T cell population. That population is consistently represented across the samples we've evaluated, and Janux011 selectively activates that population we intended to recruit.

That's really the premise behind ARM: recruit enough of the right T cells to get the biology we want without broadly activating the T cell compartment. And when you put that together with the prior slides, the takeaway is pretty simple.

Selective T cell recruitment led to selective T cell activation while still achieving deep B-cell depletion and a favorable initial tolerability profile.

We think that's important validation of the ARM design thesis and supports moving Janux011 into autoimmune patients, while also providing the first human evidence supporting the broader potential of the ARM platform.

At this point, we've shown the first human evidence supporting the ARM design thesis. Now I want to put that starting profile in context with the other CD19 T cell engaging approaches shown here.

To be clear, these are cross-trial observations and not head-to-head comparisons. With that caveat, I think one thing stands out: regimen intensity. In our healthy volunteer studies, Janux011 achieved greater than 90% B-cell depletion, including some subjects with undetectable levels.

That profile was achieved with a single subcutaneous dose without step-up or repeat dosing in Grade 1 only CRS. In contrast, the conventional CD19 T cell engager program shown here has generally used more intensive exposure strategies, including continuous IV infusion, step-up dosing, frequent repeat administration, or combinations of those approaches while still reporting Grade 2 or Grade 3 CRS events.

To put that starting profile in perspective, I'm not aware of another T cell engager that has achieved that depth of B-cell depletion with a single dose in Grade 1 only CRS.

For us, that's the important point. Janux011 enters autoimmune development from a differentiated point of entry into patient development.

Before we've even used many of the regimen optimization tools available to us. As we move into patients, those tools include step-up dosing to potentially improve first-dose tolerability and repeat dosing to potentially deepen or extend depletion.

So the way I think about this slide is pretty straightforward. We're starting with deep depletion, Grade 1-only CRS, and a relatively simple dosing profile, with multiple opportunities still available to optimize from here.

Having discussed the clinical profile, the next question is whether Janux011 also has the product and manufacturing attributes needed to support broad development and commercialization.

The manufacturing process has already been demonstrated at 500-liter scale and utilizes well-established monoclonal antibody manufacturing and purification processes.

We've also formulated Janux011 to support both IV and subcutaneous administration, which gives us flexibility as we optimize the development strategy.

The subcutaneous formulation is particularly relevant for autoimmune disease, where simplicity, convenience, and outpatient administration become increasingly important for broad application across the autoimmune disease landscape.

As shown in the benchmark comparison, Janux011 falls well within the range of approved subcutaneous biologics with respect to concentration and injection volume, supporting the potential for practical outpatient delivery.

The key point here is that Janux011 isn't just interesting biology. We have a product candidate with a manufacturing process and formulation that can support the development path we're laying out.

Taken together, we now have 3 important elements in place. First, a differentiated biological mechanism designed to balance depth of depletion with tolerability.

Second, encouraging first-in-human pharmacology and safety data that support advancement into autoimmune patient studies; and third, a manufacturing and formulation strategy designed to support scalable development and potential commercialization.

We believe this combination creates a strong foundation for advancing Janux011 into autoimmune patient studies while also strengthening the broader ARM platform opportunity.

Up to this point, we've mostly been talking about Janux011 as a product candidate. This is where the story starts to extend beyond Janux011 itself.

From the beginning, ARM was designed as a platform, not as a one-product idea. The concept is to selectively recruit defined T cell populations against disease-driving targets with the goal of achieving deep target cell depletion while limiting the breadth of immune activation.

What changed with the Janux011 healthy volunteer study is that we now have the first human evidence supporting that design thesis. So what does that potentially unlock?

First, additional targets and programs. The ARM architecture can extend beyond CD19 to other disease-driving targets and multi-specific approaches.

We are already advancing additional ARM assets beyond CD19 to begin building on that opportunity. Second is platform leverage. Clinical, translational, manufacturing, and regulatory learnings from Janux011 can all inform the programs that follow.

That leverage should become increasingly valued as the platform matures. And third, the opportunity to build a broader autoimmune franchise.

We think deep selective immune cell depletion may have utility across multiple autoimmune diseases where there continues to be a need for more durable and convenient treatment approaches.

The way I think about expansion is fairly straightforward: go where selective T cell recruitment gives us the greatest potential advantage.

Autoimmune disease is clearly our first focus. We also see potential opportunities in hem/onc, particularly as treatment moves into earlier lines where safety and convenience become increasingly more important.

Solid tumors are a longer-term opportunity. I think about this sequentially: establish the biology with Janux011, expand where ARM offers a clear advantage, and let the clinical data tell us how broadly to take that platform. That's really the significance of the healthy volunteer study.

ARM is no longer just a preclinical hypothesis. We now have the first human evidence supporting the platform and a disciplined path for determining where it can create the most value.

At this point, we've answered the first question. The biology can work in humans. Now it's about how we create the most value from that. And our approach here is going to be disciplined and driven by the data.

The Janux011 healthy volunteer study established 3 important foundations: B-cell depletion, a favorable initial tolerability profile, and validation of the arm design thesis in humans.

The next step is to translate those findings into autoimmune patient studies and determine how that biology performs in the clinical setting.

We intend to start in indications that have clinical evidence that targeting CD3 is beneficial to patients and that let us efficiently evaluate the relationship between depletion, durability, safety, and clinical benefit.

ITP has been selected because it offers a clear and interpretable efficacy readout through platelet response and provides an efficient path to understanding whether the depletion profile we're observing can translate into meaningful patient outcomes.

We also intend to pursue rheumatoid arthritis, which provides an opportunity to evaluate the platform in a large established autoimmune setting while further optimizing dose, schedule, and durability.

Importantly, this is a strategy built around generating the highest quality clinical evidence as efficiently as possible and expanding where the data further support further investment.

More broadly, every patient study has the potential to create value at 2 levels. First, by advancing Janux011 as a product candidate; second, by expanding our understanding of the broader ARM platform and informing future programs.

The goal is straightforward: translate the first human validation of ARM into patient proof of concept and systematically expand the opportunity where the clinical data support additional investment.

The important point here is that the healthy volunteer study gave us a strong starting profile, with patient development giving us the opportunity to optimize from there.

Remember that starting profile: deep B-cell depletion, including undetectable levels in some patients with Grade 1 only CRS after a single subcutaneous dose.

Ultimately, as we move into patients, we want the flexibility to optimize the overall profile. Can we further reduce the incidence of Grade 1 CRS, deepen or extend B-cell depletion, and ultimately improve the clinical response?

If a single dose gives us the response we want, great. Step-up dosing can improve tolerability, or repeat dosing can deepen the response or extend durability; we want those options available as well.

The goal is to let the patient data determine the regimen rather than locking ourselves into one approach based on the healthy volunteer study.

Importantly, we achieved the profile you've seen today before using any of those optimization tools. That's why I think the right way to view the healthy volunteer data is as a strong differentiated starting position and not the ceiling.

From here, the question is how we can build on that starting profile in patients and whether further optimization can translate into meaningful clinical benefit and differentiation.

That's where the next phase of value creation begins, both for Janux011 and the broader ARM platform.

The next slide focuses on how we think about that value creation opportunity. Up to this point, we've talked about why we believe the ARM design works, how we plan to develop it, and why we view the healthy volunteer results as a starting position rather than an endpoint.

This slide is really about what creates value from here. Near term, the priorities for Janux011 are straightforward: initiate autoimmune patient studies, optimize the clinical regimen, and establish patient proof of concept.

Each step answers a progressively more important question. First, how does the pharmacology translate from healthy volunteers into patients?

Second, how much can we optimize the overall profile through dose and regimen? And ultimately, does that biology translate into meaningful clinical benefit?

At the same time, what we learned from Janux011 has value beyond the individual program. Clinical, translational, manufacturing, and regulatory learnings will all inform future Arm programs and help us determine where that platform has the greatest potential.

So I don't think about this as a single binary value creation event. Janux011 can create value as a product candidate while also building the clinical foundation for the broader ARM platform. That's the leverage we see in the platform.

As Janux011 advances and we answer these questions in patients, we have the potential to reduce uncertainty at the asset level while increasing what we know about where ARM can be applied more broadly.

The next slide puts that into specific milestones investors can follow across both the autoimmune disease and oncology. We spent today going from the design to the human data and then what we do next.

Looking ahead, we have multiple ways to create value across both autoimmune disease and oncology. For ARM, the next major milestones are straightforward: start the autoimmune patient studies, optimize dose and regimen, and ultimately establish patient proof of concept.

At the same time, the oncology portfolio continues to move forward through Janux007, 014, and 013 with important clinical catalysts across TRACTr and TRACER programs. And I want to be clear on one point.

Today's update expands the portfolio. It does not change our commitment to prostate cancer or the broader oncology platform. ARM has a new opportunity in autoimmune disease, while prostate cancer and the broader oncology portfolio remain major drivers of long-term value creation.

The takeaway is that Janux now has multiple opportunities to create value across 3 complementary platforms with meaningful clinical milestones ahead in both autoimmune disease and oncology.

Let me close with the way I think about what this healthy volunteer data means. We started today with a simple question. Can selective T cell recruitment give us deep depletion with a tolerability profile that could work well in autoimmune disease?

The healthy volunteer study was our first opportunity to test that idea in humans, and the results give us the first evidence that the profile we designed for can be achieved clinically.

We saw deep B-cell depletion, including undetectable levels in some patients, together with Grade 1 only CRS and controlled cytokine induction with selective activation of the intended TRBV6-positive T cell subset.

For us, these data accomplished 2 important things. First, they support advancing Janux011 into autoimmune patient studies. The focus now shifts to optimizing the regimen and determining whether this biology translates into meaningful clinical benefit.

Second, they provide the first human validation of ARM and give us the foundation to expand the platform where the data support it.

The next step is patient proof of concept. As we generate those data, we'll learn both how to optimize Janux011 and how broadly ARM can ultimately be applied. And that's really the broader opportunity.

Janux011 can create value as a product candidate, while at the same time, establishing the clinical foundation for the broader ARM platform.

Thanks again for joining us. We look forward to advancing Janux011 into patient studies and sharing additional data as the program progresses.

And with that, I'm happy to take your questions.

[Operator Instructions]

And we'll take our first question from Matthew Phipps of William Blair.

Definitely intriguing initial data. Curious if you have any evidence that the TRBV6 T cell subset is present at sites of inflamed tissues or lymph nodes, or if you think it can traffic there?

There's been some data looking at these in the oncology setting, showing the clinical impact in tumors. And I just want to confirm there was no CRS prophylaxis used in any of these cohorts.

Yes. With respect to TRBV6, we'll reference what's in the public domain. One is our numbers around 10% in the literature; you'll typically see 5% to 7% levels of TRBV6 in patients.

And this is irrespective of whether they're healthy volunteers, cancer patients, or autoimmune patients, based on what's been published. With respect to tissue distribution, probably the best data that I've seen would be in oncology, where people have looked at, in a few studies, differences between what's in the periphery and in the tumor, and you don't see significant differences there either.

So I think all of those come together to argue about TRBV6 presence. Now, as we think about taking that a step beyond that, lymph nodes and other tissues, but right now, for the sake of this dialogue, I'm going to focus on lymph nodes.

If we think about what we've shown here, but more importantly, probably last year's midyear update, we demonstrated that the pharmacology is primarily being driven by the naive and early memory T cell populations rather than the effector populations.

If you think about what that means, the naive and memory populations primarily reside in the lymph node. The effector population is less so. The effector populations are out and about in the tissues.

So as you think about a subcutaneous lymphatic uptake through the lymphatic system, coupled with our drug functioning primarily through the naive and memory populations, you could make a reasonable scientific argument that, hey, in some of the tissues of interest, you may actually expect to see an improved profile with a memory-early naive-type targeted agent.

So as we think about that data set, Matt, I referenced a little bit of what's in the public domain, a little bit of building on the science that we've shared.

And that's how we're thinking about the ability to compete both in the periphery as well as in tissues of interest.

And any CRS prophylaxis use?

Sure. Yes. Out of an abundance of caution, we utilized some prophylactic Dex in these patients. I do want to point out that post-dose, there was no dex or Tax being used to modulate the CRS profile.

So when a patient had a grade 1 CRS, for instance, we would only give them acetaminophen. So there was some prophylaxis, but there was no dex or Tax used to modulate a Grade 1 CRS event.

And then maybe just quickly on the next study, do you think you'll be able to start at that 3-milligram dose and go up from there? Or do you think you'll need to start a little bit lower as well, just moving into patients?

Great question. As you could imagine, we're in the middle of regulatory dialogue around that.

We expect to be able to start, if not at 3 and minus 1, with one of those 2 doses probably is where we expect to start, but final determination will be based upon interactions with the regulatory groups.

But we're expecting to be able to start either at 3 or 1.

And our next question comes from Josh Schimmer of Cantor Fitzgerald.

Thank you for sharing these remarkable results. I have a few questions. First, how do you balance the need for speed, since other modalities are advancing quickly too, versus more methodically exploring the optimal dosing delivery profile?

And has the experience with 007 helped you move faster with 011?

Second, given how much work there is ahead across the platforms, what is your capital formation or partnering strategy to move this all forward as comprehensively as you can?

And then, third, how should we anticipate your communication strategy around future updates for this one program?

Hopefully, Josh, I can remember all 3 of those. You're pushing the bounds of my short-term memory. I'm here to remind you.

The first question: speed. We are evaluating a number of geographies right now and interacting with regulatory groups in a number of different geographies in order to be able to enroll rapidly to understand the right dosing regimen.

So the way that we're focusing on that is other geographies that have a history of being able to enroll more rapidly than what we might expect in the U.S. setting.

The next question, Josh, do you just want to run through question #2 again for me?

Yes. You bet. That's the capital formation part strategy question for all your programs and platforms.

I would say all of this is going to be a data- and value-driven discussion path forward. As you can appreciate, with an emerging prostate cancer franchise, and I'm sure we're all aware of the J&J data that came out with Kim, we see a great opportunity in the prostate cancer franchise arm.

We have early data right now. It looks very promising in healthy volunteers. We really need to generate value creating in autoimmune disease patients.

So, similar to what our plans are for clinical development on the other side, I would say the discussion about partnering is really going to be about the value of that partnering dialogue.

Does it make sense based on the data, the capital required to get to the next value inflection point, and the risk in that next value inflection point?

So just sharing with you the considerations that would go into that. Capital-wise, our last update press release, we're probably around $950 million, plus or minus.

So we're well capitalized to fully assess the opportunity in prostate cancer trials with 007, 013, 014, as well as the autoimmune disease.

At that point, once we have that data set, where we focus our capital going forward, once again, it's going to be based on what the clinical data tell us that the greatest value creation opportunity is, and that's where we would then apply our existing capital at that point.

And then the third question, Josh?

Yes, is the communication strategy around 011 will it be similar to 007 where you provide updates once you've addressed certain answers that you hope to address? Or will it be a different cadence?

I don't have a clear answer at this point. I would say we are perfectly willing to consider more, given the enrollment rates that you oftentimes see in autoimmune disease; maybe waiting for a fully baked Ib or a trial to be complete doesn't make as much sense.

So I'd say all of that's up in the air. I think what we want to do at this point going forward is, if we have meaningful data for investors and the public, we would consider a different path forward on our strategy.

But having said that, Josh, we haven't I'm just going to go back to the slide we shared at the very top level. I know there are a few TBAs in here, but we're thinking about alternative strategies for the 011 program.

And our next question comes from Jonathan Miller of Evercore ISI.

This is [indiscernible] on for John. Congrats on the initial data. I have a few questions as well. So first, do you mind sharing more color on the patients with elevated liver signal, especially with CRS?

And the second question is: as you explore higher doses and potential dosing in other regimens in patient settings, how do you expect CRS and safety signals to evolve?

Because it does seem like there's some dose-dependent CRS signal with the healthy volunteer data? And then maybe the first 2 questions.

Thank you for limiting me to 2. So, the ALT patients correlating with CRS had CRS grade 1, and it was a fever. And we treated those patients with acetaminophen, and the fever broke.

Typically, what one does in T cell engagers is you'd probably be treating emerging CRS profile with Dex. And that modulates the response. So, as we think about the ALT levels in this particular patient, ALT/AST elevations were transient and asymptomatic.

And we and others experienced them with T cell engagers. It's a known secondary effect. We believe as we move forward in patients utilizing Dex, which we didn't step dosing, repeat dosing, all of which are known to modulate cytokine release and CRS risk, we believe are tools available to us to further improve both the CRS profile, even though right now, it's grade 1 as well as the ALT elevations that we've shown here.

That's a tried and true method with other T cell engagers, especially in hem/onc, that we expect to apply here. So that's how we're thinking about that.

I do want to reinforce that you were asking about dose escalations. Keep in mind what we're talking about here: single dose, full B-cell depletion with Grade 1 CRS.

I haven't seen a program with that starting point. Now, if we apply, on top of that step dosing, a tried-and-true method to further reduce. As we think about going forward, we actually think we have an opportunity with this starting point using step dosing.

Our goal will be to further reduce the percentage of patients having a grade 1 CRS. So there's 2 ways to look at that. Yes, we will be looking at increased doses.

We want all the patients to respond and achieve deep B-cell depletion. How we do that: step dosing and repeat are going to be tools available to us. We think those tools not only give us an opportunity to deplete B cells fully in patients, potentially extend durability, but also modulate any cytokine release-mediated AE profiles.

Our next question comes from Tara Bancroft of TD Cowen.

This is [Etana] on for Tara. You guys showed the data out to 42 days. I was wondering if you had any thoughts on what you expect the duration of depletion to be?

And then a second one: how representative do you think the peripheral B-cell depletion is of depletion in the disease-relevant compartments?

Well, I'm going to start with the disease-relevant compartments. We spoke a bit about that earlier, so I referred to that with respect to lymph nodes.

We think there's a real positive to targeting TRBV6 the way that we're doing it with respect to some of the tissues. We don't see any significant reasons why we'd have a deficit in tissues. We think there's actually potential upside.

Coming back to step dosing, repeat dosing, higher single dosing, all opportunities to further deplete B cells in the tissue. We actually look at the early durability data as a positive.

A lot of times, when you see T cell engagers, if you don't get full B-cell depletion in patients, they rebound very rapidly. We're actually even on the earlier slide where we showed our dose response; we saw they maintained B-cell depletion quite well out to day 42 and beyond with that single dose.

So we think there are some good indicators here. Of course, we don't have any tissue data to reinforce that. The question you asked about increased durability or how long we expect depletion to occur.

This is a presentation where the data we had was day 42. I'm probably as interested in you not only in what's going on in that depletion, but what's going on in the underlying memory subsets of the B cell compartment.

We'll be tracking that over time. I would say, looking at this data right now, if we just come back to CAR-T, you look at CAR-T, you dose, you get peripheral B cell depletion. I'm just going to focus on that, probably around 3 months or so.

You start seeing rebound around 2 to 3 months in the periphery. The goal there is that what rebounds is primarily naive. We think this early data set with a single dose, rolling depletion out through day 42, is a very good start because remember, we haven't even done repeat dosing yet.

We've tried, and true method FcRns, the CD19, CD20 antibodies, and other T cell engagers are typically using repeat dosing in order to drive deeper, more durable responses.

So all of those tools are available to us. I would just reinforce that this is a starting point. We now have additional levers with step-up repeat dosing to address durability to address and further reduce CRS-mediated AE profiles.

Our next question comes from Jeffrey LaRosa of Leerink Partners.

I got 2. I'll just start with the first one first. So you mentioned that you think there's an advantage in infection risk given the narrower subset of T cells that you expand.

But if most of the infection risk is driven by B-cell aplasia with B-cell depleting therapies, can you just sort of characterize the T cell component and where you think you have an advantage?

Yes. On the B-cell aplasia, the lack of hypogammaglobulinemia is what separates the CD19s from BCMA with respect to that.

But coming back to your question around the 90% of T cells that we're not interacting with. We know from publications from J&J, from Amgen with LINCYO, we've got teclistamab.

Treatment with those drugs leads to reduced function in the T cell compartment. And when you're doing CD3, by definition, you're reducing the T cell function of all your T cell engagers.

The TRBV6, we're not interacting with 90% of those. Those 90% are still available to perform their immune functions, which are also very critical roles.

At our barrier functions- our first line of defense at our lung, GI tract, liver, our Mate cells, gamma delta cells, and variant NKT cells- 90% of those, and more because we don't interact with gamma delta at all, are going to be available.

So our first line of defense: we're not modulating their function. As we think about what that might mean systemically, same story. 90% of the T cells are going to be fully active because we're not interacting with them with our drug.

As you start looking at infections, especially active drugs that have durable responses, what I would be looking at are some of the viral infections, some of the fungal infections that you start seeing that are delayed onset.

Those probably more than likely have an aspect of T cell function. So as we think about the opportunity for improved infection profiles, you're right, the B-cell depletion is going to have an impact.

The question that the area that we're focusing on is, well, T cell engagers also play a significant role in barrier function as well as long-term protection against viral and fungal infections.

We've got the significant majority of the T cell population unprocured, still able to do those activities.

Our next question comes from Michael Schmidt of Guggenheim Securities.

This is Sarah on for Michael. I wanted to ask, so I guess, how much variability is there from person to person in the proportion of their T cells that are CRBV6 positive?

Like, is the 5% to 7% fairly consistent? Or do you think there's any chance that some testing may be necessary?

The data that we reported in this update today is in the healthy volunteer patient blood samples that we evaluated, as well as PBMC samples from autoimmune disease; we typically see 10% across all of these groups.

As we look at individual patients within those groups, it varied between 8% and 12%. So we're not seeing broad variability. The 8% to 12%, which is small, is not surprising and did not correlate with responses.

So we don't view this as something we're going to need to pretest. This is not an HLA-02, HLA-01 sort of a program. The TRBV6 is there. It's going to be there around 10%, plus or minus 8% to 12%, based on our initial data is not going to require testing to identify patients to treat with our drug.

Our next question comes from Oliver McCammon of LifeSci Capital.

Just looking for some additional details on how you're thinking about the dosing strategy going forward, and to what extent you'd explore higher doses?

And then, to what extent, how long that -- or a number of doses patients could be receiving? And then, for the patients who are dosed at 3 mg and who did not achieve greater than 90% B-cell depletion, are there any commonalities between these patients in terms of PK exposure or T cell biology?

Starting with the last question. So we had 2 patients that did not achieve 90%. One was at about 89%. So, for all intents and purposes, we would consider that a high responder. It just didn't make the 90% cut.

The one patient in blue in the slide didn't have that deep. We noted that the PK exposure in that patient was lower than all of the other subjects. The PK exposure in that patient did not resemble ADA.

It really looked like that patient got about half the dose that they should have based on exposure, not saying they only received half the dose. We would just say that with the subcutaneous dosing, there's some variability in that patient; their PK exposure was significantly lower, and that's what correlated with their poor response.

And then what was your first question again?

Just additional details on the dosing strategy going forward and the number of doses you're thinking about testing in patients moving forward.

Yes. Put that in the context of the competition, other competing approaches. FcRns: you get 4 weekly doses every 3 months or so. CD19, CD20 antibodies: you get 2 doses every 6 months.

T cell engagers are all over the place; probably some of the better ones are 4 doses, 4 weekly doses. TBD how often they need to be repeated.

So within that context, whether it's 1 dose, 2 doses, 4 doses, we don't really see that as a critical differentiator between the programs. It's really going to be the combination of your B cell depletion and tolerability.

Okay. So it's really going to be the combination of convenience, tolerability, and efficacy that's going to be important. We actually, as I said in the presentation, the step-up dosing allows us to take 80%, 90% of the patients having a grade 1 CRS to less than 50%; we certainly want to use that.

If repeat dosing allows us to achieve greater durability, we're certainly excited to use that opportunity also. So that will all be part of the study that we'll be conducting in patients, and we'll provide updates over time as we understand those different levers better.

Our next question comes from David Dai of UBS.

So David, I just want to double-click on the memory B cell hypothesis that you mentioned. What are you seeing across healthy volunteers in terms of naive memory and other B cell subsets so far?

Do the 2 subjects with B-cell low detection show a different quantity of B-cell memory compared to others that support the new hypothesis?

It's a great question. And of course, the ones that are going to be most informative are those with the deepest B-cell depletion.

And as you can see, the latest data that we had came out last week, I believe, was at day 42. B-cell depletion was still 99%. So the answer for those patients is that it's too early. Right now, naive and memory are still fully depleted.

So we're going to need to track those patients over time. It's a key metric. It's just too early to tell because we still have that full deep B-cell depletion in those patients out through day 42.

Our next question comes from Subwaongtip of Truist Securities.

Congrats on the data team, really exciting. Maybe 2 questions for me. What evidence from the ITP and IS studies will support expansion into the broader autoimmune portfolio?

And just based on the current profile, the low-volume subcu formulation, potential for, just curious if self-administration could be part of the target profile?

Or would the CRS monitoring keep it in more of an outpatient setting?

Okay. On ITP and rheumatoid arthritis, the 2 that we've selected, there are many autoimmune disease settings that we could have selected.

If you look at the validation that has been achieved for CD19 as a target with CAR-Ts, as well as early T cell engager studies, there's a large swath of validated approaches, including ITP and RA.

We selected ITP, as we said, having a quantitative blood-borne measure of activity that can be platelets that one would expect to respond in 2 to 4 weeks to B-cell depletion, really provides us that quantitative link between dosing and response.

We did not want to be in a position where we're discussing with the public that this reduction in autoantibodies was going to lead to some impact.

So we really liked ITP because we're going to have an immediate readout, quantitative blood-borne measure of activity that we see as absolutely critical to understand exactly the benefit that we're getting with this drug.

Rheumatoid arthritis: another validated approach for CD19 targets CAR-T, T cell engagers. Large patient population, ability to enroll more rapidly. So really, those are the ones that's why we prioritize those 2.

On that slide, we listed a number of additional expansions, but you could have added another 5 or 6 just based on other publications. So that's how we're thinking about the setting.

As you think about the outpatient setting, really, if we look at what's going on in the field right now, people are doing outpatient even with Grade 2. As we look at this drug, if you truly do have a Grade 1-only profile, and they're not progressing towards Grade 2, and these patients weren't.

We look at hypoxia. We look at blood pressure. Those are the next 2 metrics that lead to a Grade 2. We weren't seeing oxygen levels decreasing. We weren't seeing drops in blood pressure.

So clearly not on the path to grade 2. And keep in mind, we weren't using Dex to treat this. All they got was acetaminophen.

So really, it's going to be about the severity of the CRS profile that you're generating with the profile that I've just described; patients not moving on to grade 2, we need to do much more work to flesh this out, of course.

But with this starting point right now, the CRS profile right now clearly would be consistent with an outpatient. The reason we're excited to subcu at this point in time, and that also supports that.

As we get into our patient studies and we feather in step-up in repeat dosing, that Grade 1 CRS profile percentage may even be further reduced. So our starting point is very consistent with potential for outpatient.

And as we use the other levers, we think we have an opportunity to further improve this profile.

And we have time for one more question from Kalpit Patel of Wolfe Research.

This is [indiscernible] on for Kalpit. Why do we see significant variability between patients in the 3,000 microgram cohort? And do you expect that to continue moving forward?

And what can we expect on B-cell depletion when moving from healthy volunteers to patients? And lastly, what's the bar moving forward on B-cell depletion and CRS LFTs?

The variability -- if we think about T cell engagers that we've seen in the public domain, until you select the dose that drives everybody to full B-cell depletion, which probably means you're overdosing some of the patients or giving them additional drug.

The drug level that you're giving some of those patients to drive full B-cell depletion. Once you start achieving that, that's when you get reduced variability.

The variability that we're really seeing here is that 4 of the patients were 89% or better. The only one that had variability was due to PK exposure. So we don't see this as a significant issue with variability.

CRS profile: I think we already spoke about as we go forward, the tools we have available to us step-up dosing is known to reduce CRS. Keep in mind, what we're talking about reducing is Grade 1.

Can we reduce the percentage of patients that have Grade 1? We would expect those approaches to also modulate the ALT-AST levels that we've described here.

So all of those, we see as opportunities to further improve this initial starting point as we move into our patient studies.

And that concludes our Q&A session. This concludes today's conference call. Thank you all for attending.

Good afternoon. My name is Jenny, and I will be your conference operator today. I would like to welcome you to the Janux Therapeutics Clinical Data Update webcast. [Operator Instructions] I would now like to turn the conference call over to Chad Rubin, Head of Investor Relations for Janux. You may begin your conference.

Thank you, [indiscernible], and good afternoon, everyone. Today, Janux issued a press release announcing interim clinical data for the company's JANX007 clinical program. This press release, today's webcast and corresponding slides are available on our website.

Before we begin our prepared remarks, we would like to remind everyone that certain comments made by Janux management on this call will include forward-looking statements. These forward-looking statements are based on current information, assumptions and expectations that are subject to change and involve a number of risks and uncertainties that may cause actual results to differ materially from those contained in such statements. These and other risks and uncertainties are described in our periodic filings made with the SEC.

You are cautioned not to place undue reliance on our forward-looking statements and the company disclaims any obligation to update those statements. With that, I would like to turn the call over to David Campbell, President and CEO of Janux.

Thank you, Chad, and thank you, everybody, for joining today. And as we present our clinical update, Phase I data sets for JANX007 for the treatment of prostate cancer. I'd like to start on this slide to speak to the areas that we've been guiding to our focus for development of 007 going forward.

We're primarily focusing in the area of early line [indiscernible] patients, this is one of the most rapidly growing segments in the MCRPC space given treatment changes. Historically, as recent as 2018, when the first RP was approved in hormone-sensitive. It used to be RPs were the standard androgen receptor inhibitors, [indiscernible] with standard MCRPC treatments.

At this point, in the United States, more than 50% of patients already received an RP in hormone sensitive. So now when they show up in MCRPC, that the main state therapies have already been used. The choices for the experience of these patients are typically attacking [indiscernible] or an RP switch that doesn't work very well. Our view is that this is a ripe opportunity for a compound like JANX007 with a differentiated safety profile and a compelling efficacy profile.

So with that, I'm now going to walk through a little bit of background, JANX007, first-in-class, first-in-human tumor-activated T-cell engager targeting PSMA. Today, what I'm going to share with you is we've achieved durable responses and radiographic progression-free survival with a manageable safety profile that compares favorably to both approved as well as investigational therapeutics in this space also share with you early results supporting a patient-friendly every other week dosing schedule.

And we've been guiding to early data sets, PSA reduction, CRS profiles and a handful of patients in our ongoing taxane Phase Ib expansion study. And then at the end, I'm going to share with you some disease burden analysis that we've been performing that suggests JANX007 has demonstrated improved efficacy in lower tumor burden patients guiding us to our belief of improved efficacy option moving forward into this early taxane-naive patient population.

PSMA itself is a clinically validated prostate cancer cell surface antigen. It's highly expressed in bone, lymph node as well as visceral metastases. There have been a number of T cell engagers that bispecifics targeting PSMA that have demonstrated antitumor activity in multiple clinical trials. However, all of them listed below. There's 6 that we show here. There's been a couple of others, have all been terminated, typically due to safety limitations, lack of efficacy or combinations thereof. So we designed JANX007 to overcome some of these safety limitations in order to meet the needs of prostate cancer patients.

On this slide, I just wanted to share with you -- get us on the same page, how we're approaching this. And on the upper left-hand side, you can see a tractor. These incorporate the bispecific 1 side binds to the tumor, one side binds to the T cell. We identified peptide [indiscernible] to those domains block their ability to interact with Target we connect those peptide mass to the bispecific with a peptide linker that incorporates a cleavable linker that's cleaved in the tumor environment.

Importantly, in order to support longer intervals of dosing. You can see we also have in blue, a half-life extender. This binds to albumin takes advantage of this clinically validated approach to extend the lifetime of this drug when we dose it. Now upon entry into healthy tissue, the masks remain in place. There's no proteases to cleave those cleavable linkers. With the masks in place, they don't bind a healthy tissue or T cell blocking that interaction, you're not triggering any pharmacology or any biogene healthy tissue to spare the healthy tissue any adverse events.

Upon entry into the tumor, tumor proteases close linkers release both the red and the purple masks. Importantly, you can see with the purple mass also releases the half-life extended, and that's going to be important in a minute. So in the tumor environment now, we have the highly potent bispecific. It's able to form a complex between the T cell and the tumor cell. That triggers activation of the T cell triggers elimination of the tumor cells. Importantly, we do not want to have accumulation of this highly active species in healthy tissue.

So when this day after spaces T cell engager escapes from the tumor, because it no longer has a half-life extending domain, which is clean during activation, it's rapidly cleared. This is allowing us to maintain very low levels of T cell engager in healthy tissue. Even when we drive significant concentrations of the tractor, and we believe this is what's contributing to our safety profile that has allowed us to develop this drug moving forward.

On the next slide, what I want to break down are the 5 different areas that I'm going to focus on today. We've been guiding for a while that today, we're going to give an update. Overall update on the Phase II patients, we've now dosed a bit over 100 patients there. We provide safety and efficacy data in that expanded set. We've been asking a number of dosing regimen questions so that we could begin triggering our pivotal studies. What is the appropriate Cerus mitigation that's easy to follow a protocol that maintains the Grade 1, Grade 2 CRS profile we shared in December. What is the target dose that maximizes efficacy and safety to support optimist in our Phase Ib studies as well as dosing interval.

We know we can dose once weekly, do we have an opportunity for every other week, which would be a very significant add to this program. And then finally, an early update on taxane-naive patients, looking at early signs of activity and CRS profiles. So I'm going to begin with an overview of the Phase Ia MCRPC patient studies that have been progressed to this point. On this slide, I'm sharing with you the baseline subject characteristics. In the middle, you can see we provide the December 2024 subjects.

We had 16 that we reported on -- on the right, you can see now we're going to be talking about 109 patients. We put those both here so that -- you can see, in general, these are very, very closely aligned end-stage MCRPC patients, typically seeing similar prior systemic therapy similar profiles with respect to bone metastases as well as lymph node and [indiscernible]. So very comparable patient populations. However, now we're going to be able to report on a significantly larger patient subset as we go forward. Beginning on this slide, what we've done on this slide is a swim plot a couple of things.

The subjects highlighted in the box. These are all subjects that have received at least the 2 mg target dose, and there's 92 patients out of the 109 that have received great of an equal to 2 mg target dose. These include a number of different regimens from different target doses, different step doses, different step dose timing, once weekly, every other week when to start Q2W and different CRS mitigation procedures. So you can appreciate there's a lot of underlying questions going into here, but we can still garner some learnings from this swim plot.

First, as you look at the swim blood, the swim lanes are blue. If that patient had a soft tissue met that could be evaluated by RECIST and gray, if it was bone-only disease. What you can see as you look at this have a number of patients with significant responses, 6, 8, 10, even greater than 12 to 14 months, both in both subjects with soft tissue mets as well as those with bone only. What you can also notice as you look at these clinical benefit has persisted beyond the RECIST-defined progression in some of these patients. if you start looking at some of these different lanes and you look at the red area -- red arrow where there was a progressive disease, you can see a number of these patients that continued on drug for significant number of months.

You can see the top patient was out another half a year. This is being driven by the PI makes the decision that the patient is continuing to drive benefit clinical benefit beyond the RECIST-defined progression in some of these patients. The way to think about this is in the scans, a number of different lesions are evaluated.

While the primary lesion, you may have lost control, the other lesions are either under control or actually continuing to be maintained. Quality of life scans is really what goes into the PI, making the decision to continue dosing drug even after progression. We're going to circle back to that as we start talking about how to think about our trials coming down the road. What you also noticed on the far left is we put the best best PSA response or best PSA reduction color coated in those boxes. And what you can see is durability at the top is enriched in subjects that have achieved a PSA 50, 90 or 99, reinforcing to us that the early PSA measure is a clear indicator of what to expect in these patients with really this durability enrichment in the subgroup. So as we look at the swim plot, you can see we've got a number of patients still on drug. We've had a number of patients that have had quite durable responses. We also have patients to continue to garner benefit from treatment 007 even after they've had RECIST mediated progression.

On the next slide, we took a look at radiographic progression-free survival in these studies. In the upper table, we start on the left-hand side with all subjects. You can see in all subjects, the median RPFS it comes in at 7.3 months. We also give Kaplan-Meier estimates at 3 and 6 months. The May 2025 QW and of 9 patients that was the press release that we provided back in May, where we provided an update on the December patients that reported a median RPFS of 7.9 going to the right now, we've expanded that group from 9 patients up to 29 patients. You can see that the median radiographic progression-free survival has been maintained at 7.9 months. the Kaplan-Meier estimates at 3 and 6 months are also still looking positive. On the far right, using the same subjects now looking at patients who received every other week dosing, we have 19 evaluable patients here. The RPFS was maintained at 8.9 months. You can see our Kaplan-Meier estimates coming in at $76 and $54 million. On the lower right-hand side, just for comparison purposes, we've got [indiscernible], which is a commercial dose.

The other 2 T cell engagers, the steep the [indiscernible] at their recommended Phase II dose. You can see that our blended groups still compare favorably both in RPFS as well as progression-free survival estimate of 6 months. What I do want to point out on this is that the subjects. The expansion groups use the December and May criteria, which is radioligand treatment naive on 6 and 9 mg target doses that allows you to compare that -- those 2 expansion groups to what we shared with you back in December and May. The overall treatment-related adverse events are summarized on this slide. We made the contact greater than or equal to 15%.

You can see a fairly well-behaved profile here. What we did, you can see we noted a few of these are CRS associated [indiscernible] this is based upon a publication from Amgen back in 2023 using that definition. You can see the vast majority of these are secondary to cytokine release, primarily limited to cycle 1 and a little bit in cycle [indiscernible]

we have a few other observations looking at dry mouth, discus hypoacusis or 3, 1 would be interested as you think about PSMA. The dry math will get back to the grade 3. That was at a dose we're not going forward with -- all the others are reversible and do not require dose reductions or terminations at this point in time. So overall, a manageable treatment-related adverse event profile continues to support moving this drug forward into earlier lines of therapy.

On this slide, we wanted to share with you the overall best PSA reductions on the left and RECIST responses on the right. Keep in mind that this includes all patients the numbers are provided there includes patients less than 2 treatment cycles and those dose under less optimal dosing regimens and/or CRS mitigation strategies.

In a couple of slides, you'll see exactly what we mean when we get into some of the CRS mitigation strategies that we use and the impact it had on PSA reductions. But overall, in this large expanded group. Anybody who's received a target dose greater than or equal to 2 mgs, you can see very nice reductions. On the right-hand side, reductions were only observed when we had a target dose of 2 mgs or greater. That's why they're all dark blue. So you can see RECIST profiles right now, RECIST responses are running at about 30%.

The next section that I wanted to go into is addressing the different questions that we were asking about dosing regimen. The first was CRS mitigation. As you remember back in December, we were using a procedure that allowed wide flexibility to the PIs. We were trying to learn about this new drug modality. So it's critical to give the PIs maximum flexibility. When CRS was observed in their clinical site. Now that we've learned a lot more about this drug, we've evaluated a number of specific new protocols that were easy to follow, [indiscernible] was to maintain the G1, G2 CRS profile and the early safety and efficacy data that we shared previously.

With that, I'm going to go to the slide where we summarize some of these efforts. On this slide, what you can see on we're sharing CRS profiles, coupled with early PSA reductions. On the far left is the December 2024 data that has already been shared. You can see it was primarily Grade 1, Grade 2 CRS we did have that 1 Grade 3 in a patient who had rabies out in cycle 5. PSA reductions, PSA 50 and 90 were looking very strong at 163%.

An example in the middle panel of a CRS mitigation procedure that was not effective. You can see in this particular subset of patients, we had a number of grade 3 CRS events cycle 1, day 1, day 15 as well is even out cycle 2 day clearly did not meet our -- was inferior to the December 2024. In addition, if you look at the PSA 50 and 90, you can see it also had an adverse impact on best PSA reductions, significant reductions both in PSA 50 and 90. So as you think about overall waterfall plot, keep in mind, we asked a number of questions like this that had adverse impacts.

On the far right, [indiscernible] is indeed a profile that we're moving forward with -- you can see the CRS profile is maintained, if not improved, compared to December of 2024, while it maintained PSA reduction similar to what we reported back in December. See primarily limited to cycle 1. The vast majority of these are Grade 1 CRS. As we look at the PSA 50 and 90, you can see we've got a good PSA50 profile, 12 out of 14 patients have achieved that. PSA, the denominator change to 13. I just want to spend the notes here.

This was a patient who came in with a low PSA value. when they achieved a PSA 50, they became undetectable. We took the conservative route. You could go either way on this. We took the conservative route and just changed the denominator. Other other way to do this would have been to say it was 8 out of 14.

But either way, we're talking about 55% PSA 90. And we have a few patients that are still, as you can see, undergoing dosing in cycle 2 and a little bit into early cycle 3. So these overall PSA reductions may improve as we go forward, especially some of the GSA 50s and numbers. So at this point, we think we've got a profile CRSP 2 that we're going to go forward with. CRSP 1 is an example, just to share with you a little bit of detail on that one. That was actually a [indiscernible] and it just didn't work well in our hands. The other evaluations that we looked at was how much Dex, the timing of Dexus TOS or Debi itself, et cetera. So we're very pleased with the CRSP 2 profile. We clearly see [indiscernible] explains some of the Grade 3 CRS issues that we had with this program. And then for comparison purposes in the light blue box, we provide PSA50 for [indiscernible] program in the J&J and you can see our PSA reductions with CRSB 2 are similar to December 2024 and compare favorably to our competition.

I do want to point out this is important as we think about continued development of this drug. CRS onset and duration continues to be resolved within 1 day. So onset typically between 8 and 12 hours, you treat with CRSP 2, it's resolved by 24 hours. So as we think about down the road, outpatient opportunities, certainly having a well-defined 24-hour window is going to be a benefit with this drug. If you look at most of the other drugs in the [indiscernible], typically have variable day of onset from day 1 to day 3 or 4 typical duration from 1 day to multiple days of CRS. So we think this is another differentiator for our molecule moving forward. On the next slide, I want to spend a little bit of time talking about target dose and dosing interval. And as you could imagine, these are tightly integrated.

So I'm first going to start talking about QW and then I'm going to talk about Q2W in the next couple of slides. What we've done is we evaluate QW on this slide and Q2W on the next slide is we want to focus on durability as measured by as well as Kaplan-Meier estimates and treatment-related adverse events that are due to the target dose. In order to make sure that we're looking at TRAs that are due to the target dose we're requiring patients to have been dosed in cycle 3. So these are the treatment-related adverse events in cycle 3 and beyond. That gets around reducing the signal because remember, the majority of our AEs occur in cycle 1 and cycle 2, which would reduce the discrimination that we have here as well as really giving us that information in this particular is really allows us to compare these target doses without other confounding events. Looking at efficacy and durability on the top, you can see 3 mg, 6, 9, 12 million essentially, they're all within line of sight of each other. We've got different RPFS in some of these groups, you can see are pretty darn small as we look at the radiographic PFS. But looking at Kaplan-Meier estimates of 3 to 6 months, you could say you could go forward with any 1 of these 4 doses.

As we looked into safety on the bottom, you can see looking at grade 3, we're running about 30% to 40% out here, a very manageable profile. -- with the 3, 6 and 9 mg QW. Once we get out to the 12 mg, you can see that's up to 5 out of the 5 patients had a grade 3 adverse event out in cycle 3 or beyond. Based upon that, we prioritize 3, 6 and 9 target doses as our preferred doses going forward. early study. We're looking at 6 mg QW and our taxane naive, the next cohort, we'll talk about on the next page. So based on this, we've prioritized 3, 6 and 9. Our preference right now is probably at 6, but we're leaving a little bit of flexibility there as we go forward in taxane-naive patients, and we'll talk about why in a few slides. On this slide is an evaluation looking at QW versus Q2. Once again, we're evaluating radiographic PFS and Kaplan-Meier curves to compare Q versus Q we're focusing on cycle 3 and beyond treatment-related adverse events.

That's when Q2W starts to also minimize the CRS of confounders like we said on the previous and the subjects continue to be as they have been from our early radioligand naive patients, same as the expansion group that I shared with you earlier that have received at least 1 target dose in cycle 3. So based on this, looking at the Kaplan-Meier evaluations, -- you can see what we had to do here is we had to combine 6 and 9 just so we had enough subjects to be able to evaluate via Kaplan-Meier. From that evaluation, you can see our RPFS is maintained when we went from 7.9% at QW to $8.1 million at Q2W.

Our Kaplan-Meier estimates at 3 months compare favorably. At 6 months, you can see a little bit of a loss. What we've noted is once we get these patients out to there, the Q2W, they have very nice durable responses. So that's why you could see a little bit of a loss at 6 months and still maintain a very favorable media and rPFS. As we look at safety, once again, looking at cycle 3 and beyond, comparable overall adverse event profiles, but you can see that there's a reduction in the grade 3 AE profile is 35% down to 21%. So based on this, these initial results, support a patient-friendly Q2W dosing schedule. As I pointed out, the first cohort in our taxane-naive is a target dose of 6 mg and it's to weekly. We started that before we had this data set. The next cohort will be Q2W, presumably at 6 mg target dose. And then finally, I wanted to share with you some of the early data that we've generated in our taxane-naive patients. We've been guiding that this is going to be a handful of patients small number early data looking at PSA reductions in CRS. On this slide, shares with you the best PSA reduction to date as well as CRS profiles in these patients. the asteric on the PSA reduction, just to note that dosing is ongoing.

Subjects are still in early dosing cycles. Those PSA reductions may improve as we go forward. But to provide you with a snapshot of where we're at on these 4 patients at this point. You can see very nice you got a patient at PSA 90. A couple have already achieved a PSA and they've all done this with 3 out of the 4 have a grade 1 CRS profile. On the right-hand side, looking at CRS, you can see once again primarily limited to dose 1 beyond dose 1 at this point, still early data. We're looking at fevers in some of the patients a couple of the patients in cycle 1 and cycle 2.

So early in PSA reductions, coupled with a manageable CRS profile, we think is encouraging as we start thinking about our opportunities in taxane-naive patients moving forward. This also is early data to reinforce CRSP 2 is behaving as we would hope it would in these patients. On this slide, I want to shift gears slightly as we now have enough patients, and we started breaking down the patients into different subsets looking at their radiographic PFS and primarily looking at disease burden. So what we've done on the left-hand side, you can see we've got 63 patients. And these patients our radioligand naive, same as the expansion groups contained 3, 6 and 9 mg target doses as well as QW and Q2W. So we've now got 63 patients. You can see the Kaplan-Meier and Gray, very nice RPFS at 7.9 months. We then evaluate -- we're evaluating a number of different models. They're all directionally pointing the same way where we can use different criteria for a high tumor burden versus a low tumor burden. As we break these out, the high disease burden patients in red have a reduced RPFS stand about 7.3 months, a meaningful number of patients here at 39. Interestingly, -- but I think what 1 would expect based on the T cell engager space. As we look at the low tumor burden patients, you can see we've improved that out to 10.5 months. So very encouraging profile as we think about moving to earlier lines of therapy. And what we've done on the right-hand side is using these clinical marker surrogates, we've provided the breakdown of low versus high in the different subsets we've evaluated, the all patient population today, the December taxane exposed versus the Phase Ib taxing naive. And when we look at the sum total of this data, it suggests a potential for an improved PFS as we move into earlier lines of patients with a lower tumor burden, especially looking at these Phase Ib taxane naive patients. So as you think about the likelihood of GenX having a desired RPS in these patients. We think this data suggests the opportunity that as we move into these earlier lines of patients we are going to continue to see improved PFS profiles. And I would argue that this is consistent with what we've seen with a number of T cell engagers.

And the way to think about that as patients have a better functioning immune system. They have a lower tumor burden, lower tumor growth rate, all of those can aspire to improve the responses in low tumor burden patients. So in summary, I just want to highlight we've identified our doses and regimens moving forward based upon our overall MCRPC patients, a study we have identified an easy-to-follow protocol that is maintained the grade 1 to CR safety profile also maintained our PSA reductions. We have identified and prioritized a 6 and 9 mg target doses as the best combination of safety and efficacy.

We've also evaluated and have selected could go forward with QW, but importantly, also with Q2W looking at 6 and 9 mg which demonstrate the best combination of safety and efficacy in the Q2W setting. And then in taxane naive, our early Phase Ib has demonstrated rapid and deep PSA reductions with primarily Grade 1 CRS. Based upon this, the data we generate continues to compare favorably to historical data in this heavily treated pretreated mCRPC patient setting. In the next section, I'd like to walk you through a couple of slides how we're thinking about clinical development to JANX007 going forward. I shared with you in my first slide, why we're focusing because of the landscape changing, we're really focusing on that taxane-naive earlier line patient subset.

Our clinical plans continue to be what we shared with you since last year. We're evaluating GNX 007 in monotherapy as well as in combination with darolutamide in taxane-naive pre-pluvicto and CRPC patients. We and others are learning as we went through this with KOLs and our clinicians. This is the largest and growing MCRPC setting. If we think about, I believe enzalutamide is going to go generic next year, we expect that's going to drive even additional uptake of these androgen receptor inhibitors in hormone-sensitive really creating an opportunity if we can differentiate from right now, the drugs that they have available to them are pretty much not differentiated, and we'll talk about that a little bit taxane.

If we could come in with a differentiated safety and efficacy profile. We see that as an outstanding opportunity, and we continue to focus our efforts in that area. We've also noticed that we're going to evaluate JANX007 in PARP inhibitor refractory patients. Right now, there are no approved therapies for these patients once they no longer respond to the PARP inhibitors, that may provide an opportunity for an expedited approval in this setting. Considerations we need and we'll continue to evaluate Pruvict uptake new clinical data with that in both the taxane-naive setting as well as the hormone-sensitive setting, and we'll adjust our plans accordingly. We're fully aware of the recent approval of taxane and PSMA.

That's with an RP switch. A couple of data sets that came out at recent at ESMO. There was a Canadian study that evaluated or compared in taxane-naive patients that we're targeting also taxane as a control compared to [indiscernible] they demonstrated that lube had no demonstrated RPFS time to deterioration differences and essentially had the same overall survival as taxane actually with taxane maybe having a slightly better overall survival. So we're aware of that study. And then there was also the PSMA addition study in hormone sensitive demonstrating while there was an improved RPFS there wasn't an improved overall survival. There was a lower quality of life, coupled with a slight increase in secondary malignancies and kidney events with a 2-year follow-up. So based on these recent studies that have been reported, we think these support and actually strengthen our rationale for why we're focused on this taxane-naive pre-Pluvicto patients.

On the next slide, I wanted to highlight something that others have noted, and we think is important as you think about the opportunities for T cell engagers going forward. What we're doing here is we're comparing radiographic PFS with overall survival. And in the upper panel, we've got Kim track, altabalatamab in 2 different lines of setting for small cell loan. And what others have noted and we're noting here is if you look at the RPFS compared to the control, the T cell engagers had a minimal improvement in improved PFS. 0.4 to 1 month compared to the control. However, there was a significant improvement and outsized improvement as you went from PFS to overall survival. You can see it went from 0.4% to 5.7%, 5.3% in 13 months. So it looks like early data set, 2 different T cell engagers, but while they may not have a significant impact on RPFS and we've seen this with other immuno-oncology drugs, you can see an outsized improvement in overall survival.

Now let's compare that with Pluvicto. We've got a couple of different studies. We've got the third line. We've got the taxane where the PFS compared to control is significant. It's 3.7, 5.3 months, but you get much less of an overall survival improvement. And what we've done on the bottom is looking at taxanes that Canadian study, we just reversed the order prostate cancer. You can see taxane even while it has an RPFS a 2.1 improvement compared to control, you can see once again an outsized -- slightly outsized, not as good as what you see with the T cell engagers improvement in overall survival. So assuming this sort of relationship holds as you think about our early RPFS around 7.9 months in end-stage patients. This provides a rationale, which allows us to think about why that might improve as we go into earlier lines of patients and remembering in prostate cancer approval is typically based on your overall survival. We think it's a positive that the T cell engagers, early data sets, clinical data sets are showing us outsized overall survival improvement. On this slide is my final slide, I just want to wrap up a few things here.

Conclusions. We've achieved durable responses, good RPS manageable safety profile compares favorably to the other T cell engagers and approved therapeutics. We have durable responses in patients with both bone-only disease as well as subjects with soft tissue mets. Some of our competitors are focusing on bone-only disease due to lack of activity in soft tissue met, we think having the ability to do both will be an important differentiator for our compound. Initial results clearly support moving forward with the Q2W dosing schedule, which we're very excited about.

That also may open up additional opportunities as we think about continued development to 0. And then favorable activity in taxane-naive Phase Ib expansion study has also been shared with you today. And I want to wrap up. This is as we think about why JANX007, why we think it may be successful as as we move forward into these earlier lines of therapy right now focusing on taxane naive, maybe focusing in other areas down the road. We shared with you lower disease burden we have an improved RPFS with 007.

That's exactly what you have as you move into earlier lines of therapy. PFS and overall survival trends from [indiscernible] and tarlanimab suggests T cell engagers may deliver greater overall survival benefit relative to their PFS and coming back to the swim plots. Evidence of clinical benefit in some of our patients treated PI choice to treat beyond RECIST-defined progression because they were still garnering benefit reinforces these observations. So based on all of this, we are full speed ahead developing JANX007, both in our monotherapy and our combination studies going forward. So with that, I wanted to leave plenty of time for questions, and I will hand off and open up the line to questions from the different people.

[Operator Instructions] Your first question comes from the line of Josh Schimmer with Cantor.

I have a couple but hopefully, they're quite quick. First, were there any differences in the rates of CRS or ADAs in the Q2 week versus the Q1 week regimen was the Grade 5 adverse event a first cycle event or subsequent? And then can you frame the market size for the PARP-inhibitor prostate cancer indication -- refractory prostate cancer indication?

All right. So rates of CRS are going to be identical. Keep in mind that when we -- the first 2 cycles whether it's QW or Q2W or once weekly. What we've learned from evaluating when to start Q2W dosing. We started after cycle 1, we started after cycle 2. we've learned that it's important with 007 to drive maximum PSA reduction in those first 2 cycles. The best way to do that is with once-weekly dosing as CRS is primarily a cycle 1, cycle 2, you'll understand why there's no different rates of CRS between Q2W versus QW. Josh, you asked a slew of questions. I would say, pick another 1 and I'll write that 1 also.

All right. The market size for PARP inhibitor refractory prostate [indiscernible]

Yes. Right now, we've got that pencil at a bit over $500 million and growing as the PARP inhibitor evaluations, genetic evaluations are being used more and more in hormone-sensitive prostate cancer, that's only increasing this patient subset over time or better identifying patients who actually will be receiving the PARP inhibitors. SP1 Your next question comes from the line of Brad Camino with Guggenheim.

And thanks for the comprehensive update, David. One of the questions I continue to hear with these data is that since 007 has clearly the best-in-class PSA. Why is it RPFS equivalent to other TCEs and Pruvict and shouldn't it be better than that?

So a 2-parter for me. First, it would just be good to hear how you respond to this question now with so much data out there for this program? And then second, what do you think are the implications of these equivalent late-line durability data as you strategize to bring 007 forward into the early lines of therapy in prostate cancer. A couple of good points, and you asked me to compare it to Pluvicto. I think this slide is how we think about that. Pluvicto is shown outsized RPFS and a reduced overall survival improvement and contrasted that with the T cell engagers, which the exact opposite. So we're looking right now, if we hold a similar relationship, one could expect an outsize overall survival. The other way to think about that is -- our RPFS in 7.9 months right now is in a blended evaluation, where we're evaluating mixing Q2W, suboptimal doses, suboptimal CRS regimens, they're all in there. That's a blended number. And we're comparing it right now to Pluvicta on a commercial dose. So I think that there is an opportunity just simply by once we start looking at and defining our recommended Phase II dose, I would expect the numbers to get slightly better. More importantly, I think as we move into earlier lines of therapy because as we're looking on this particular slide, you can see the PFS is 8.7% to 9.3 months, let's say, 9 months. And that's in a first line to third line patient population. We're in a fourth line, fifth line simply moving into earlier, we would expect our 7.9% PFS to get better. So I think all of those conspire to why we believe that our overall reductions right now, it's just a function we have a blended. We're in end stage. As we move into earlier, we expect our numbers to get better. coupled with the expectation T cell engagers are showing this interesting outsized overall survival response relative to their PFS.

Your next question comes from the line of Marc Frahm from with TD Cowen.

Maybe one, just on the RECIST responses to start, can you confirm who was able to actually confirm -- and how many of those are maybe still unconfirmed, but there may be ongoing or unfortunately are not ongoing on treatment, still?

Yes. We haven't broken that down other than to say this was a mix of confirmed and unconfirmed. SP-8 I don't know the percentages off the top of my head.

Okay. And then -- maybe just on the idea of this PARP refractory population kind of at a potentially rapid path to approval. Obviously, this is prostate cancer, in general, is a very IRA exposed population. Just maybe can you talk through the strategic rationale there versus potentially waiting for a broader approval before you kind of start the IRA clock.

Keep in mind, by generating the data, the IRA clock doesn't start until you actually file for registration that would be a decision that we would make later. The way to think about this is if we have an opportunity for an expedited path to approval that financially makes sense, we will evaluate how far away we are our combo or monotherapy with 007. So that's a decision that we'll make later will be based upon market opportunity size where we're at on that taxane-naive study. How far away are we from registrational data there. So Mark, we don't have to make that decision today. all we're doing today is triggering the study, generate the data, then we'll talk with the FDA, see if there's even an expedited path. So the way that I think about it is we're putting together a data set, we don't have to trigger that [indiscernible] until or unless we decide that's the right thing to do. And that's a few years down the road.

Okay. That's helpful. And maybe if I can squeeze in just on the CRS mitigation strategies you presented the kind of December versus Strategy 1, strategy 2. Can you just mostly the 2 versus December. Just kind of give us a sense of the magnitude of the difference of the kind of days on therapy or dose of steroids that those patients are getting?

We haven't provided the details on P2. -- the amount of time that they remain on CRS mitigation is comparable between all of these. It's really just what was done. The timing and size of the dose is really all the barriers here. And at this point in time, other than sharing CRSP 1 was to prophylaxis. We're not sharing what P2 was. We've got a number of people in this space close to us. So we're just going to keep that as competitive information for a little bit longer.

Your next question comes from the line of Matt Phipps with William Blair.

Providing a lot more data than [indiscernible] was expecting. Josh tried to ask about some details on that grade 5 cardiac arrest. So maybe I'll just follow up with that. And then I guess just how many dosing regimens and cohorts do you think you ultimately need to evaluate in the Phase Ib? I know you can do Myriad a 6 and 9 target dose in Q2 week. But just curious if you'll evaluate all of those, I guess.

No. We've mapped out our expectation is to then it's going to be -- has to be to because we're deciding what to take into project optimists and we want to make wise choices. So we -- our expectation is it will be too different the QW versus the Q2W, if we find something surprising, then it would only require 1 more. But we expect to get in and out on 2, and that will give us a data set we need to talk with the FDA about project optimists.

And then just any additional details on that cardiac arrest patient was that during the initial step-up with CRS or anything like that?

No, it was not related to CRS. It was a cardiac arrest in a patient with a pre-existing history of DIC, which we note here. I can decide even went back and forth whether or not to attribute it to drug to be conservative and careful in the end, it's been attributed to drug, even though we could find no direct reason why that should be the case.

Okay. If I can ask 1 more. How did you define tumor burden as being low or high in Slide 20? And I guess just confidence that a pre-texane patient population would really in general have that low to burden or you might doctors see this data and want to put patients with, I guess, more aggressive higher tumor burden disease on the trial? Sorry about that. For some reason, it looks like I lost can you hear me?

Yes, I can. Okay. Here we are. So on this particular slide, thank you. So I had some technical difficulties. So we have a number of different models. You can look at different clinical markers of bone disease of soft tissue nets you could add on top [indiscernible] mutations. There's a number of these models that different groups have used. We've used variations of all of them. They all directionally point in the same direction. As we look at our own data granted, it's very, very small for patients at this point in time. Keep in mind, over time what these patients are going to be looking like more and more matches, they're going to be coming off of hormone-sensitive prostate cancer treatment. And this will be their first foray into MCRPC. So if you look at the low versus high already, just looking at historical data, you can say first-line patients have a lower tumor burden than second and third. So that's certainly going to hold, but we also think the landscape treatment trends here what we're talking about is what is going to be the first treatment in MCRPC following hormone-sensitive, those patients are typically going to be in the low stage.

Your next question comes from the line of [indiscernible] with Truist.

So you show the CRS profile improved in early line patients with [indiscernible] CRS compared to later line patients. Could this potentially support use in the outpatient setting?

Yes. So yes, when we look at the CRSP 2 profile right now, where the vast majority of patients are grade 1, which is a fever outpatient right now. If you look what's going on in CAR T and hematology with the T cell engagers, it's typically stay close to the unit with a drug like ours and that particular profile, we think that would be very supportive of an outpatient treatment paradigm going forward.

Okay. And I have one more question. In patients with the decided to treat beyond progression. What do you know about the target lesions that were enlarging. Could this be a potential impact of T cells?

Yes, I think what you're asking is a pseudo inflammation based upon inflammatory environment that a T-cell engager, I would not say that. I would say, especially as we're looking at those patients in the swim plot. We've got about around 7, 8 months where they progressed I would not consider that nor would the radiographer consider that to be an inflammatory. That looks to us like it is actually progression is the primary lesion. However, as we pointed out in order for the PI to keep that patient on drug, and you can see we've got at least 1 or 2 for another half a year or so. That's because the other lesions that aren't part of the RECIST evaluation either went away, were reduced. We certainly weren't growing. So their quality of coupled with their quality of life improvements. So it's really a PI call. I would not try to say that that's due to pseudo inflammation at this point.

Your next question comes from the line of Jeff LaRosa with Leerink Partners.

A little bit on the Q2W dosing schedule. I guess high level, would you say the facility of the data supports Q2W over once weekly. And could you maybe dig a little bit more into the -- why the 6-month RPSS dropped relative to what you're seeing once weekly patient sufficient have not sufficient follow-up beyond 6 months to sort of evaluate that? And on that safety, I know you look at CRS and totality, but anything else with liver enzymes, increases, salary tox or anything else that looks different in that schedule.

When we've evaluated the Kaplan-Meier curves, what we've noted is once these patients make it out to around 6 months, they have a nice durable response. And you could start thinking about different -- we've lost the high tumor burden patients and these are the low tumor burden patients. And this study went on we've noted an increase in high-burden patients as the drug appeared to work. PIs are using it more. But in the end, what we would say is if they make it out that far, they have a nice durable response, and that's what's driving the RPFS even though we're at 60%. That basically means that line stayed flat for quite a while before for another close to 3 months before it breached the 50% line. That just gives you an idea of how prolonged the response is out there. Now with respect to safety, you noted CRS, I want to come back and the safety that we're summarizing on this slide is cycle 3 and beyond. There is no difference in CRS as on Josh's question, the first 2 weeks dosing QW versus Q2W is the same. So for all intents and purposes, those first 2 weeks look the same. What this is painting is when we start the Q2W, which is cycle what does the safety profile look like from there on out? And you can -- these are small numbers, but at least it's pointing in the right direction as we look at the Grade 3 adverse event profile, which would not be CRS at this point. You can see an improvement as we went to Q2W, which is which 1 probably could expect given the exposure levels are reduced over time as you do Q2W versus QW.

And would you say you prefer the Q2W over QW at this point?

Yes. We are very excited about the Q2W and we're looking forward to starting that cohort as rapidly as we can. Before given the different growth rates as you move into earlier lines of therapy, we're also excited about -- if we're able to do this in a rapidly growing fairly high tumor burden compared to a first-line patient with a Q2W. We think we have an even better chance of having at least as good a profile as we move into those early line taxane-naive patients.

Your next question comes from the line of Jonathan Miller with Evercore ISI.

And thanks for all the great granular data. I would love to get a little bit deeper into some of the drivers of -- I guess, the difference is in [indiscernible] maybe Obviously, you're going forward with the 6 mg doses you , but I'm curious, when you say, David, really, you could have developed any of those middle doses. Can you talk a little bit about what you were seeing at 9 megahertz 3 mg that. Are those differences in [indiscernible] has real differences in RBFS given the patient numbers that you have? And what was driving 6 months? And I guess the same question really about the tumor burden result. I guess it's probably been surprise any of us that low tumor burden patients do better. Do you really see materially better than expected PFS on the T cell engager versus just seeing better RPFS because they have less tumor so 2 parts

So I've got the QW slide up here. And John, happy to take your question. I want to point out my view of the efficacy is -- the 4 of these were comparable. To your point, the not enough numbers here, look more at the Kaplan-Meier estimates, and they're all within a line of sight each other. So on efficacy, durability, there wasn't a clear differentiator here, which is you could have gone forward with 36,912. It was more as we got into the safety, looking at the adverse events and cycle 3 and beyond where you see you went from about 30% to 40% up to about 100% of Grade 3s. It was really that number, John, that drove us a way to deprioritize the 12 mg dose. The next question was around the RPFS I have I agree. There's nothing here that is overly surprising. It's just -- it's good to see the data. It's very interesting to see an RPFS now in a low tumor burden patients of about 24 patients, which is about 10.5 months. which if you then extrapolate over taxane naive, say, okay, we have an opportunity to look like that and then you go back to and that particular patient population has an RPFS ranging from 8.6 to 9.3. If we do indeed come in at 10.5% or thereabouts would be a positive. And on this slide, we have the opportunity that appears to be unique to the immuno-oncology and the T cell engagers to have an even greater impact on overall survival than RPF. So we put all of that together, John, is why we view this as a directionally important and positive data set.

Ladies and gentlemen, due to time constraints, that concludes today's call. Thank you all for joining. You may now disconnect.