JANX011 Phase 1 Healthy Volunteer Data and Autoimmune Development Strategy - JANUX THERAPEUTICS INC

Welcome to the GenX Therapeutics GenX 011 Phase 1 Healthy Volunteer Data and Autoimmune Development Strategy Call. All participants will be in a listen-only mode. Later, we will conduct a question-and-answer session. I would now like to turn the conference over to Chad Rubin, Investor Relations for GenX Therapeutrics. Mr. Rubin. You may begin. Good morning, everyone, and thank you for joining us. Earlier today, Janix issued a press release announcing initial Phase 1 clinical data for Janix 011 and 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. 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 uncertainty can be found on JANX's 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. JANIX 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 JANX. Good morning, and thanks for joining us. Today, we're presenting the first human data from JANICS 011, our CD19-targeted armed 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 five subjects with a single subcutaneous dose and no step-up dosing. Most achieved greater than 90% B-cell depletion, and two of the five reached undetectable peripheral B-cel levels. CRS was grade one only. For us, these results do two things. First, they established Janix 011 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 GenX portfolio. Then I'll walk through the human data, our development strategy, and the milestones ahead. GenX now has three precision platforms, and we think they create complementary value drivers across oncology and autoimmune disease. Tractor 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. Tractor & 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 Janux 011 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 five subjects with a single subcutaneous dose. Most achieved greater than 90% B cell depletion, and two of the five 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, depletions persisting through day 42, and T cell activation concentrated in the intended TRVV6 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. And when we put those pieces together, we believe Janix 011 has now demonstrated the human pharmacology, tolerabilty, 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, lymphodepletions, specialized treatment centers, and management of toxicities like CRS and ICANNs. At the other end, antibody-based therapies have attractive safety and convenience profiles, typically with intermittent outpatient dosing. They've 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 have helped validate the importance of deep B-cell depletions, but achieving and maintaining that depletION is 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 depletation 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 was 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 receptors 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, in which there are approximately 30 different beta chains in our T cell repertoire. We then looked across a number of naturally occurring V-beta populations. We focused on three 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 Janix 011. TRBv6 represents approximately 10% of circulating T-Cells, so by design, the majority of the T-Sell 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, JanXL11 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. the pharmacology we want while limiting the breadth of immune activation, and Janix 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 TRBV6 positive subset, providing evidence that the molecule is behaving as designed. The Healthy Volunteers 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 were trying to determine whether Janux 011 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 five subjects dosed at 3,000 micrograms. Most achieved greater than 90% peripheral B-cell depletions with two 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, 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 continued to see depletion through day 42. But again, I wouldn't look at the depletions results in isolation. What matters is the context. One 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-cel depletion in humans without broadly recruiting the T-cel compartment through CD3. On the previous slide, we showed that Janix 011 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 depletation? Looking first at CRS, there were no events among the 16 subjects treated from 30 to 300 micrograms. At 1,000 microgram, one of four subjects experience grade 1 CRS, and at 3,000 micrograms, 4 or 5 experience 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 Janix 011, what matters to me is the severity of CRS in the context of the pharmacology we're getting. CRS 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 depletions 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 was no grade two or higher CRS events, no ICANNs, infections, or hypogammaglobulinemia reported. Most treatment-related adverse events were grade one and transient, and the CRS event resolved rapidly with acetaminophen. As you can see in the table, we did have one 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 innovations 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 at doses where we saw profound B-cell depletion. The next question is whether that overall profile ties back to the way we designed the molecule, and that's what we'll look at on the next slide. As we discussed earlier, GenX 011 is designed to selectively recruit the TRBV6 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. And 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 ranged 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 Janix 011 actually activates that population selectivity, 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 TRBB6 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 Janix 011 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 JANIX-011 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 firsthuman evidence supportingthe arm design thesis. Now, I want to put that starting profile in context with the other CD19 T-cell engaging approaches shown here. is 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, Janix 011 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 one only CRS. In contrast, the conventional CD19 T-cell engager program shown here have 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 two or grade three CRS events. And to put that starting profile in perspective, I'm not aware of another T-cel engager that has achieved that depth of B-cell depletion with a single dose and grade one only CRS. For us, that's the important point. Janix 011 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 for the first dose. dosing to potentially deepen or extend depletion. So, the way I think about this slide is pretty straightforward. We're starting with deep depletation, grade one 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 GenX 011 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 GenX011 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, GENX 011 falls well within the range of approved subcutaneus biologics with respect to concentration and injection volume, supporting the potential for practical outpatient delivery. The key point here is that GenXO111 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 three 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 GenX011 into autoimmune patient studies, while also strengthening the broader arm platform opportunity. Up to this point, we've mostly been talking about GenX 011 as a product candidate. This is where the story starts to extend beyond GenXO11 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 GENXL11 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 CD 19 to begin building on that opportunity. Second is platform leverage. Clinical, translational, manufacturing, and regulatory learnings from Janux 011 can all inform the programs that follow. That leverage should become increasingly value 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 HEMOC, 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 Janix 011, 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 Volunteers 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 Janix 011 Healthy Volunteer Study established three important foundations, deep B-cell depletion, a favorable initial tolerability profile, and validation of the YARN 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 support further investment. More broadly, every patient study has the potential to create value at two levels. First, by advancing GenX 011 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, then systematically expand the opportunity where the clinical data support additional investment. The important point here is that the Healthy Volunteers Study gave us a strong starting profile, with patient development giving us the opportunity to optimize from there. And remember that starting profile, deep B-cell depletion, including undetectable levels in some patients, with grade one 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 GRA1-CRS, deepen or extend B-cell depletion, and ultimately improve the clinical response? If a single dose gives us the response we want, great. If step-up dosing can improve tolerability or repeat dosing and 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 achieve 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 can we 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 Janix 011 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 GENX 011 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 GenX 011 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. GenX 011 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 GenX011 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 Gen X 007, 014, and 013, with important clinical catalysts across tractor 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 adds 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 Janix now has multiple opportunities to create value across three 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 depletions, 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 accomplish two important things. First, they support advancing GenX011 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 a 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 GenX 011 and how broadly ARM can ultimately be applied. And that's really the broader opportunity. GenX011 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 GenXO11 into patient studies and sharing additional data as the program progresses. And with that, I'm happy to take your questions. If you would like to ask a question, please press star 1 on your telephone keypad now. You will be placed into the queue in the order received. Please be prepared to ask your question when prompted. Once again, if you would ask a questions, please press star one on your phone now. And we'll give about 30 seconds for questions to queue up. we'll take our first question from Matthew Phipps of William Blair. Hey, good morning, David. Definitely intriguing initial data. Thanks for the presentation. Curious if you have any evidence that the beta V6 T cell subset, you know, is present at sites of inflamed tissues or lymph nodes, or you think it can traffic there. You know, there's been some data looking at these in oncology settings showing the clones and tumors. I just want to confirm there was no CRS prophylaxis used in any of these cohorts? Thank you. Yes. With respect to TRBV6, you know, we'll reference what's in the public domain. You know, one is our number is 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 a healthy volunteer, cancer patient, or autoimmune patient. 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 to a step beyond that. You know, 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, mid-year update, we demonstrated that the pharmacology is primarily being driven from the naive and early memory T cell populations rather than the effector populations. And if you think about what that means, the naive and memory populations primarily reside in the lymph node, the effector populations less so. The effector populations are out and about in the tissues. So as you think about a subcube lymphatic uptake through the lymphatic system coupled with our drug functioning through naives and memory population primarily, 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, when you reference a little bit of what's in the public domain, a little bits of building on the science that we've shared, and that's how we're thinking about the ability to deplete both in the periphery as well as in tissues of interest. Thanks. Then any CRS prophylaxis? Oh, 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 TOSI being used to modulate CRS profiles. So when a patient to have a grade 1 CRS, for instance, we only would give them acetaminophen. So there was some prophylactic, but there was no DEX or TOSI used to modulate a grade one CRS event. Thanks. And then maybe just quickly on the next studies, do you think you'd be able to start at that three milligram dose and go up from there, or do you Think you'll need to start a bit lower as well just moving into patients thank you great question as you could imagine we're in the middle of regulatory dialogue around that we expect to be able to start it's not at 3 and minus 1 with one of those two doses probably is where we expect to start but final the final determination will be based upon interactions with the regulatory groups but we're expecting to be able to start either at three or one. Great. Thanks, David. Congrats. And our next question comes from Josh Shimmer of Cantor Fitzgerald. Great. Thank you for the work and 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 two, versus more methodically exploring the optimal dose and delivery profile, and has the experience with 07 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 three, how should we anticipate your communication strategy around future updates for this one program? Thank you. Oh, hopefully, Josh, I can remember all three 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 dose and regimen. So the way that we're focusing on that are other geographies that have a history of being able to enrollment more rapidly than what we might expect in a U.S. setting. The next question, Josh, you just want to run through question number two again for me? Yeah, you bet. That's the capital formation or partnering strategy question for all your programs and platforms. You know, I would say all of this is going to be data and value-driven discussions. Fast 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 COSTIM, we see a great opportunity in the prostate cancer franchises arm. We have early data right now. It looks very promising and healthy volunteers. We really need to generate value-creating data in autoimmune disease patients. So similar to what our plans are for clinical developments on the other side, I would say the discussion about partnering is really going to be what is the value of that partnering dialogue? Does it make sense based upon the data, the capital required to get to a next value inflection point, and the risk in that next value infliction point. So, you know, just sharing with you the considerations that would go into that. Capital-wise, our last update press release was 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 does 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? Yeah, is communication strategy around 011 will be similar to 07, where you provide updates once you've addressed certain answers that you've hoped 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 1B or 1A 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, you know, I'm just going to go back to the slide we shared at the very top level. I know there's a few TBAs in here that are, but we're thinking about alternative strategies for the 011 program. Okay, thank you very much. And our next question comes from Jonathan Miller of Evercore ISI. Hello. This is for John and congrats on the initial data and thanks for taking our question. I have a few questions as well. So first, do you mind sharing what color on the patient was elevated liver signal, so was it associated with CRS? And the second question is, as you explore, you know, higher dose and potential dosing, other dosing regimen in patient settings, how do you expect CRS and safety signal to evolve? Because it does seem like there's some dose-dependent CRS signal with the healthy volunteer data. And then last question, maybe the first two questions. Yeah, first. Yeah, thanks. Thank you for limiting me to two. So the ALT patients and correlating with CRS. CRS was grade one 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 DEX modulates the response. So as we think about the ALT levels in this particular patient. ALT, AST elevations, they were transient, asymptomatic, and we and others experienced them in 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 one, 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 HEMOC, that we expect to apply here. So that's how we're thinking about that. I do want to reinforce, you were asking about dose escalations. Keep in mind what we're talking about here. A single dose, full B cell depletion with grade one CRS. I haven't seen a program with that starting point. Now, if we apply on top of that step dosing, 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 produce the percentage of patients to having a grade one CRS. So, you know, there's two ways to look at that. Yes, we will be looking at increased doses. We want all the patients to respond, achieve deep B-cell depletion. How we do that, step dosing, repeat, are going to be tools available to us. We think those tools not only give us an opportunity to deplete B-cel depletions fully in patients, potentially extend durability, but also modulate any cytokine release-mediated AE profiles. Our next question comes from Tara Bancroft of TD Cowan. Hi. This is Ekenna on for Tara. You know, you guys showed the data after 42 days. I was wondering if you had any thoughts on what do you expect the depletion to be, the duration of depletation to be? And then a second one, how representative do you think the peripheral B-cell depletions 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 in my earlier, so I'd refer 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 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. You know 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 you know on the slide, earlier slide, where we showed our dose response. You saw they maintained B-cell depletion quite well out to day 42 and beyond with that single dose. So, we think there's 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 depletation to occur, you know, 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 doing on in the underlying memory subsets of the B cell compartment. We'll be tracking on 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 three months or so, you start seeing rebound around two to three months in the periphery. The goal there is that then what rebounds is primarily naive. We think this early data set with a single dose rolling depletions out through day 42 is a very good start because remember, we haven't even done repeat dosing yet. You know, tried-and-true method, FCRNs, the CD19, CD20 antibodies, other T-cell engages are typically using repeat dosage in order to drive a deeper, more durable response. And so, all of those tools are available to us. I would just reinforce, this is a starting point. We now have additional levers with step-up with repeat dosaging to address durability, to address and further reduce CRS-mediated AE profiles. Our next question comes from Jeffrey LaRosa of LeeRink Partners. Awesome. Thanks, David. Thanks for addressing the data and taking the questions. I got two. I'll just start with the first one first. So, you mentioned that you think there's an advantage on infection risk, given the, you know, kind of narrow subset of T-cells that you kind of expand. But if, you Know, if most of the infection risk is driven by B-cell aplasia with B-cel depleting therapies, do you just sort of characterize the T-cel component and where you think you have an advantage? Yeah. You know, on the B-celeplasia, you know, 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 Lincito, we've got teclistamide, talquidamide. 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. You know, there's at our barrier functions, our first line of defense at our lung, GI tract, liver, are 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 percent of the T cells are going be fully active because we're not interacting with them with our drug. As you start looking at infections, especially in active drugs that have durable responses. What I would be looking at are some of the viral infections, some of fungal infections that you start seeing that are delayed onset. Those are 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 at the barrier function, as well as long-term protection against virus and fungal infections. We've got the significant majority of the T-cel population unperturbed, still able to do those activities. Our next question comes from Michael Schmidt of Guggenheim Securities. Hi, this is Sarah on for Michael. Thanks so much for taking my question. 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 TRBV6 positive? Like is the 5% to 7% fairly consistent, or do you think there's any chance that, you know, some testing may be necessary? Thank you. The data that we reported in this update today is in the patient, 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 looked at individual patients within those groups, it varied between 8% to 12%. So, we're not seeing broad variability. The 8% to 12%, which is small, it's not surprising, did not correlate with responses. So, we don't view this as 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 percent 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 LifeSide Capital. Congrats on the data and thanks for taking my questions. Just looking for some additional details on how you're thinking about the dosing strategy going forward, 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 on the patients who are dosed at three megs 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? Thanks again. Starting with the last question. So we had two 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% cutoff. The one patient in blue on the slide that 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 did not resemble ADA. It really looked like that patient got about half the dose that they should have based on exposure. I'm not saying they only received half the dosage. We would just say that the sub-Q 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 number of doses you're thinking about testing the patients moving forward? Yeah. Put that in context of the competition. Other competing approaches. FCRNs, you get four weekly doses every three months or so. CD19, CD20 antibodies, you gets two doses every six months. T-cell engagers are all over the place. probably some of the better are four doses, four weekly doses, TBD, how often they need to be repeated. So within that context, you know, whether it's one dose, two doses, four doses we don't really see that as a critical differentiator between the programs. It's really going to be, what is the combination of your B-cell depletion, tolerability? Hello? Go ahead, Dr. Campbell. Okay. So, it's really going to be the combination convenience, tolerabilty, and efficacy that's going to be important. We actually, like I said in the presentation, if step-up dosing allows us to take 80, 90% of the patients having a grade one CRS to less than 50%, we'd certainly want to use that. If repeat dosing allow 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 Dye of UBS. Great. Thanks for taking my questions and congrats on the data. So David, just want to kind of, you know, double-click on the memory B-cell reset hypothesis that you mentioned. What are you seeing across healthy volunteers in terms of naive memory of the B-Cell subset So far, you know, do the two subjects with B-cells, the load detection show quantity of different B-cel, memory B-Cell profile compared to others that support the new RISA 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, you know, 99%. So, the answer for those patients is 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 is just too early to tell because we still have that full B-cel depletation in those patients out through day 42. Our next question comes from Supwat Thongtip of Truist Securities. Congrats on the data team. Really exciting. Maybe two questions for me. What evidence from the ITP and RS studies will get expansion into the broader autoimmune portfolio? And just based on the current profile in the low-volume sub-Q formulation, a potential for previous divided series if self-administration could be part of the target profile um or would the crs monitoring you know keep it in more of an outpatient setting thanks so much okay um on itp and and rheumatoid arthritis the two that that we've selected um 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 two to four weeks to B-cell depletion really provides us that quantitative link between dosing and response. You know, 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 is absolutely critical to understand exactly the benefit that we're getting with this drug. Rheumatoid arthritis, another validated approach with CD19 targets, CAR-T, T-cell engagers, large patient population ability to rapidly, more rapidly enroll. So really those are the ones, that's why we prioritize those two. On that slide, we listed a number of additional expansions, but you could have added another five or six just based on other publications. So that's how we're thinking about the setting. As you think about outpatient setting, really, if we look what's going on in the field right now, you know, people are doing outpatients even with grade two. As we look at this drug, you truly do have a grade one only profile, and they're not progressing towards grade two, and these patients weren't. we look at hypoxia, we look at blood pressure. Those are the next two 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 were not using DEX to treat this, all they got was acetaminophen. So really as you think about, it is going to be about the severity of the CRS profile that you are generating, With the profile that I've just described, patients not moving on to grade 2, we need to do much more work to flush 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, it's a sub-Q at this point in time, and that also supports that. But as we get into our patient studies and we feather in step-up and 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 Wolf Research. Hey, thanks for taking the question. This is Guggen on for CalPIT. Why do we see significant variability between patients in the 3000 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 depletation and CRS LFTs? Thank you so much. The variability, if we think about T-cell engagers that we've seen in the public domain, until you select a dose that drives everybody to full B-cell depletion, which probably means you're overdosing some of the patients or giving them additional drug, that the drug level that you're giving some of those patients to drive full B cell depletions, once you once you start achieving that, that's when you get reduced variability. The variability that we're really seeing here is what 90%, you know, four of the patients were 89% and 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 one. Can we reduce the percentage of patients that have grade one? 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