Monte Rosa Therapeutics, Inc.

Greetings and welcome to Monte Rosa Therapeutics conference call to discuss the company's pipeline updates and clinical results. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentation. As a reminder, this conference call is being recorded. It is now my pleasure to introduce Andrew Funderburk, Senior Vice President, Investor Relations, and Strategic Finance at Monterosa. Thank you, Andrew. You may begin.

Thank you.

Good morning, everyone, and thank you for joining our conference call to discuss the clinical and preclinical updates across our pipeline. With us on today's call are Marcus Wormuth, Chief Executive Officer, Philip Iancu, Chief Medical Officer, Sharon Townsend, Chief Scientific Officer, and Phil Nixon, Chief Business and Legal Officer. Before we begin, I would like to remind everyone that any statements we make or information presented on this call that are not historical facts are forward-looking statements that are based on our current beliefs, plans, and expectations and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Please refer to our annual report and other filings we make with the SEC for our risk factors and other information. With that, I'll turn the call over to Marcus.

Thank you, Andrew, and thanks, everyone, for joining us this morning. It's a real pleasure to provide today exciting updates across our clinical and preclinical programs. I kick it off by just outlining some of the highlights we will go through in this call today. First, we'll talk about results from our Phase 1 Healthy Volunteer Study of MRT6160, which very clearly support a path into broad Phase 2 development of this asset. Phillip will discuss these results in a minute, but heads up, we really strengthen our conviction in the potential of MRT6160 as a broadly applied novel treatment approach for immune-mediated diseases. We will then briefly touch on our next seven program, which is on track for an IND submission in the first half of this year. We're also going to provide some details today on the IND-enabling studies and some results there, as well as our thoughts on clinical development for this program. And then as sort of a last contribution from the INI side, I will show you a few slides on how we're using our CLEAN platform to expand our portfolio of oral INI drugs. Lastly, of course, we'll also get into our oncology programs, but I'll talk about some of those details later in this presentation. So now let's turn to the INI program, starting with MRT6160, our VEF1-directed molecular blue degrader. So as you can see on slide five, VEF1 is a signaling molecule critical in both T and beta receptor signaling. VEF1 regulates secretion of key immunomodulatory cytokines, including IL-2, IL-17 interferon gamma, and IL-6. And by doing so, VAF1 is really critical for the interplay of T cells, in particular TH17 cells, with B cells in immune-mediated diseases, where there's a clear evidence that VAF1 is critical for hyperactivation of these pathways. Most importantly, with the overlap of MRT6160's mode of action with those known for approved biologics, We think this could be an exciting alternative to many of these therapies, and so we believe 6160, as mentioned before, could have very broad potential applications in immune-mediated diseases. We've designed 6160 as a highly selective MGD targeting VAP1, and we moved it into a Phase I Healthy Volunteer Study last year in August. In October, seeing the broad potential for this target across immune-mediated diseases, we were very pleased to announce our exclusive strategic development agreement with Novartis. By collaborating with a key player in the INI space, with a company that has outstanding clinical development organization, we believe we can accelerate and broaden the scope of potential development for MRT6160 by retaining substantial value for Monterosin. So with that, I'm pleased to turn the call over to Philip, our Chief Medical Officer, to review the actual data we have from our Phase I study.

Thank you, Markus, and thanks, everyone, for joining. We are really pleased with the data from our Phase I SAT and MAT studies of MRT6160 in Healthy Volunteers. As shown on slide 8, MRT6160 was dosed in five single ascending dose cohorts and three multiple ascending dose cohorts. The primary endpoints of the study were safety and tolerability. Other endpoints included pharmacokinetic, pharmacodynamic, which included PAP1 degradation levels in T and B cells, as well as assessment of ex vivo response to T cell and B cell receptor stimulation. Here on slide 9, you can see the analysis of plasma concentration of MRT6160 over time, which in healthy volunteers demonstrated a dose-dependent pharmacokinetic profile. Multiple ascending doses resulted in an approximately two-fold increase in exposure at steady state, and no food effects were observed. As shown on slide 10, VAV1 degradation was assessed by flow cytometry of CD3 T cells and CD19 B cells. In addition, ex vivo stimulation of whole blood was performed to assess T and B cell functions, including CD69 upregulation measured by flow cytometry, and cytokine secretion measured by immunoassays. As we show on slide 11, MRT6160 achieved dose-dependent VAP1 degradation in peripheral blood T cells, which exceeded 90% after single and multiple-dose administrations, except for dose level 1 of SAD, where we get to 80% degradation. We were very pleased to see this level of potency consistent with our preclinical studies and matching our target profile. In addition, WAF1 protein reduction was sustained into the post-treatment period with dose-dependent recovery following treatment. Similar results were observed in B cells. Next, we evaluated the impact of MRT6160 on the functional inhibition of T and B cells as measured across several well-characterized immune markers. In our clinical study, WAF1 Degradation by MRT6160 resulted in significant functional inhibition of T and B cells following ex vivo stimulation of whole blood. For example, following TCR stimulation, we observed significant attenuation of CD69 upregulation, a key marker of T and B cell activation indicating functional inhibition. Furthermore, MRT6160 treatment significantly inhibited secretion of the inflammatory cytokines interleukin 2, interferon gamma, and interleukin 17A from whole blood derived T cells following ex vivo stimulation of the T cell receptor, demonstrating reductions up to 99% from the pre-dose levels. Also following B cell stimulation, MRT6160 substantially attenuated interleukin 6 at the higher dose levels. Collectively, our pharmacokerating and pharmacodynamic assessments in the clinic are in line with preclinical studies that suggested robust functional effects on cytokine production with 80% and higher degradation of Vav1, which we have clearly achieved with the doses tested in this trial. Moving to slide 13, we were of course also looking into duration of these functional effects post-dosing. Interestingly, administration of MRT6160 resulted in marked and sustained suppression of T cell receptor-mediated CD69 activation. Similar results were observed in peripheral blood B cells following BCR stimulation. With regards to cytokine secretion as shown on slide 14, MRT6160 demonstrated a sustained effect of PCR-mediated cytokine production following single and multiple dose administrations and ex vivo PCR stimulation. MRT6160 treatment significantly and deeply inhibited interleukin II, interferon gamma, and interleukin 17A secretion, consistent with what we have shown you earlier, and just as for CD69 suppression, the effects were sustained into the post-treatment period. In summary, the effects of MRT6160 on both CD69 activation as well as cytokine production provide further evidence for the impact of 1,1-degradation on downstream T and B cell biology. Moving on to the safety summary on slide 15, We are pleased to report that MRD6160 was well tolerated with no reported serious adverse events. Observed treatment emergent adverse events, which included combined treatment-related and unrelated adverse events, were predominantly mild and self-limiting. Treatment emergent adverse events observed in two or more subjects treated with MRD6160 included pain from blood draws, headaches, and other AEs as detailed on the slide. Overall, frequency of treatment emergent adverse events was similar between MRT6160 and placebo. In summary, we were extremely pleased to see our pharmacodynamic and functional ex vivo studies suggesting significant effects on cytokine production after marked and sustained degradation of VAP1. Degradation of VAP1 was consistent with levels required to induce efficacy in preclinical models. And the functional impact on cytokine production was consistent with levels predicted to achieve efficacy in humans based on benchmark clinical data from other drugs targeting related pathways. We saw a highly favorable safety profile, and we believe the Phase I data we have presented, in addition to the chronic toxicology package, support a clear path into Phase II studies and broad potential applications in multiple immune-mediated diseases. I'll now turn to our next program in the INI space focused on NEX7 and its role in the NLRP3 inflammasome. On this slide, let's begin with a quick overview why we see NEX7 as a highly relevant therapeutic target in this space. The NLRP3 inflammasome is a key pathway activated in many inflammatory conditions, some shown at the bottom of this slide, and activation of the NLRP3 inflammasome critically depends on NEX7. In this context, NEX7 functions as a scaffolding protein that facilitates assembly of the active NLRP3 inflammasome complex in a kinase-independent manner. As illustrated on slide 19, it's been widely shown and also demonstrated by our own in vitro and in vivo work that NEX7 and the NLRP3 inflammasome are critical for the production of interleukin-1 beta, resulting in elevated CRP levels. CRP is known, among other things, as a key long-term predictor of cardiovascular risk. Several anti-IL-1 and other NLRP3 inhibitors have shown promising reductions of CRP levels in clinical trials. Therefore, we think an X7 degrader offers a unique opportunity to block the assembly of NLRP3 inflammasome, offering a new potential oral treatment modality for a variety of inflammatory diseases linked to IL-1 beta and the subsequent elevation of CRP. Importantly, IL-1 and the NLRPC signaling pathway are clinically validated, and extensive clinical data exists to support its relevance to multiple diseases in therapeutic areas spanning cardioimmunology, rheumatology, and neurology, as we detail on slide 20. So the existing data with IL-1 targeting agents out there, and to some degree, the emerging data from first-generation NLRPC inhibitors, give us great information where to focus clinically moving forward. Our team is on track to file IND in the first half of this year, and on slide 21, we have outlined our proposed development path forward. Following a planned phase one study in Healthy Volunteers, we plan to pursue trials to establish clinical proof of concept, initially in individuals with high levels of CRP, and then in additional cardioimmunology indications. We are also evaluating proof of concept studies in gout, pseudogout, and osteoarthritis. Our preclinical toxicology and pharmacodynamic data, which Sharon will review in a moment, demonstrate MRT8102's excellent drug-like properties and favorable safety profile, which give us confidence as we look to move forward into clinical development. With that, let me turn the call over to Sharon to review our preclinical work for the Next7 program. Sharon?

Thanks, Philip. Shown on slide 22. We believe the potency, selectivity, and long-lasting PD profile of 82102 creates potential differentiation from competitive approaches. We have demonstrated potent and monoselective degradation of NEC7, including no degradation of any of the other NEC family members. Our data also demonstrates that drug exposure results in a prolonged PD effect, which we think distinguishes our NEC7 degrader from NLR-P3 inhibitors. Preclinical profile of 8102 has been highly favorable and supportive of continued development, as shown on slide 23. In the left panel, we show after five days of dosing in synos, in vivo NEXT7 degradation leads to near-complete inhibition of caspase 1 activity and IL-1 beta release in ex vivo stimulation assays. Moreover, the preclinical GLP toxicology study suggests a considerable safety margin for MRT8102. The no observed adverse effect level was the highest dose tested in both rats and cinnos with a greater than 200-fold exposure margin over the projected human efficacious dose in both species. Importantly, there were no MRT8102-related clinical signs, no changes in immunophenotyping, and no gross or clinical pathology findings at any dose level. We also studied 82102 in a rabbit-gout model to better characterize its effect on inflammatory diseases. As shown on slide 24, daily oral dosing of 82102 at 50 mg per kg reduced pathogenic effects associated with gout, including reduction in joint swelling and histopathology scores. Overall, we are highly encouraged by the preclinical profile of 82102 and look forward to filing an IND in the first half of this year. This now brings us to the potential for expansion of our NEXT7 program and the optimization of our NEXT7 degraders for CNS penetration. Given the large therapeutic potential we see for NEXT7, we've been advancing MGD specifically optimized for CNS penetration. Just to show you a few highlights on slide 26, we're achieving very compelling levels of NEXT7 degradation in PBMCs, similar to those shown for MRT81M2. which corresponds to near complete suppression of IL-1 beta following ex vivo stimulation as shown on the right. As you can see in the middle, we also see deep reduction of NEX7 protein in the CSF, suggesting significant exposure with our MGD in the brain. Going forward, we believe having a CNS optimized molecule creates a lot of optionality for us and the opportunity to address indications with both peripheral and central components on top of the peripheral inflammatory indications we mentioned earlier. So to wrap up the INI part of this presentation, I'd like to now briefly discuss the opportunity we see more generally across the INI space. Based on everything we've learned today, we believe our MGDs are uniquely suited to address key or met needs in INI indications, as shown on slide 28. The high expression of cereblon in immune cells enables robust target degradation, which, when combined with the exquisite selectivity of our oral MGDs, allows for a high therapeutic index, a key potential advantage demonstrated in both RVAG1 and NEXT7 programs. Furthermore, the catalytic mechanism of action drives sustained pathway modulation, reinforcing the strong therapeutic rationale seen in these programs. As we continue to build our portfolio of oral INI drugs, I'll highlight a few exciting areas in immunology that we are honing in on. While we are not yet disclosing specific targets, we see compelling opportunities in pathways critical to B-cell modulation and autoantibody production in inflammation, as well as in key pathways relevant to asthma and allergies. Consequently, we believe our MGDs have broad therapeutic potential across the INI space, and we are excited to share future progress as our early-stage programs advance. With that, I'll turn the call back over to Marcus.

Thank you, Sharon. So just to recap the INI part of today's call, we just showed you very encouraging data for 6160 in our Healthy Volunteer trial. We really got to the 80% plus degradation of RAF1 and cytokine modulation of 82% to 99%. Very encouraging data, as I said, in mapping a clear path into Phase II trials. We're also looking at an IND in the first half of this year for our next seven, the greater MRT8102, targeting a pathway, the NLRP2 inflammasome, that's getting more and more attention. And then we talked about creating more opportunities for us to utilize and create our discovery engine to build a highly differentiated portfolio of oral INI drugs. And so now let's turn to our oncology programs, equally exciting. In the second half of the call, we will provide you an update on our MRT 2359 development program. And we will show you some really encouraging data in castration-resistant prostate cancer, a tumor type characterized by widespread expression of CMIC on top of AR, of course. And we will discuss why we decided to prioritize this indication over other expansion cohorts. But bottom line, we see this as a hugely exciting opportunity for MRT 2359 moving forward with the added benefit of not having to develop a companion diagnostic in that setting. Towards the end, we will then also touch base on CDK2 and Cycline E1, two very, very interesting programs, highly validated targets. and we'll provide you a quick update on our path to an IND submission in 2026. And so with that, I'll hand it back over to Filip to lead you through our updates on MRT 2359.

Thank you, Markus. I'll start off with a brief recap for our therapeutic hypothesis for the GSPT-1 program. So GSPT-1 is a translation termination factor, which has an important role in termination of the protein translation. Of interest, we discovered that molecular glue degrader-induced GSPT1 degradation is deeper and faster in MEK-driven cells compared to other cells, resulting in impaired protein translation, synthetic lethality, and ultimately reduced MEK expression. Therefore, GSPT1 degradation offers a potential therapeutic modality to drug MEK-driven cancers. The three different MYC family members are involved in multiple cancers, including ones which are listed here on slide 33 and which we explored in our Phase 1-2 study of MRT2359. These include both small cell lung cancer, non-small cell lung cancer driven by NMIC or LMIC, high-grade neuroendocrine tumors, and androgen receptor-positive prostate cancer, as well as hormone receptor-positive breast cancer driven by CMIC. Based on our most recent data, we started to focus on tumors that are primarily known to be CMYK-driven, which has the added benefit of not requiring biomarker-based selection of patients. One of these tumor types is prostate cancer, in which CMYK overexpression drives androgen receptor dependence and therapeutic resistance in castration-resistant prostate cancer. Our Phase I-II study of MRT 2359 was designed to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of MRT2359 in patients with previously treated selected solid tumors. Our monotherapy dose escalation cohorts focused on selected MEK-driven tumors, such as known small cell lung cancer, small cell lung cancer, high-grade neuroendocrine tumors, and tumors with L and NMEK amplifications. We dosed patients at multiple dose levels using a five days on, nine days off schedule, as well as a 21 days on, seven days off schedule. Late last year, we announced that the schedule of 21 days on, seven days off at the 0.5 milligram dose level would be our recommended phase two dose. Slide 35 shows you the patient demographics of the study population, and I believe the most important takeaways here are that we were able to nicely balance recruitment between different tumor types, and also that we were dealing with population. On slide 36, we outlined the adverse eating profile observed for each of the dose levels and their respective frequencies. Doses of 0.5 mg and 1 mg per day in the 5-9 schedule and doses of 0.5 mg and 0.75 mg in the 21-7 schedule were well tolerated with mostly low-grade adverse eatings, while doses of 1.5 mg or higher were above the maximum tolerated dose with thrombocytopenia being a dose-limiting toxicity. Most importantly, dose-limiting toxicities reported with non-selective competitor GSPT1 degraders, such as hypocalcemia, hypotension, and cytokine release syndrome, were not reported in our study of MRT 2359. Now let's talk about what we saw with regards to the L and NMIC biomarker analysis. Remember, our trial was not designed to enroll only biomarker-positive patients. but rather enrolled patients with the tumor types expected to be enriched for the presence of high L and NMIC expression. Instead, we performed a retrospective biomarker assessment in a patient treated on the trial where biopsies or archival tissues were available. The graph on the left depicts the frequency of L and NMIC high expression in 46 patients with available tumor tissue. To keep it brief, we saw considerably lower than expected frequencies of tumors with high L or NMIC especially in non-small cell lung cancer and small cell lung cancer, as compared to preclinical data we had obtained. Pleasingly, in the biomarker-positive population, where we had paired tumor biopsies, we saw optimal target GSPT1 protein degradation of approximately 60%, which was consistent with our preclinical data. Slide 38 summarizes the clinical response data in the dose escalation cohorts. There were 48 patients where expression in tumor tissue was obtained at baseline, and we also included patients with known L or NMIC amplification, even if tissue was not available to assess expression. Of these 48 patients, 37 patients were available for response as per Resist 1.1. From this group, 13 patients, so about one-third, were determined to be biomarker positive. Of these 13 patients, there was one confirmed partial response, and four patients with stable disease, resulting in disease control rate of 38%. Of the 24 biomarker-negative patients, there was one unconfirmed partial response and three patients with stable disease, with a disease control rate of 17%. Moving to slide 39, as I mentioned earlier, we have also initiated two combination arms studying MRT2359 with enzalutamide in castration-resistant prostate cancer, and with Fulvestrant in hormone receptor-positive breast cancer. On this slide, we summarize initial data in the castrate-resistant prostate cancer cohort, again, a patient group where we believe semic overexpression is critical in driving androgen receptor dependence and therapeutic resistance, and where there is a significant unmet need for new, safe oral therapies. As of March 10, 2025, we have a Resist 1.1 assessment available for three patients, And very encouragingly, among them, we saw one confirmed partial response and two stable diseases. Notably, all three patients were heavily pretreated and had mutations typically associated with resistance to androgen receptor antagonists, such as enzalutamide, including mutations in the androgen receptor ligand binding site or expression of ARV7 transcript. PSA response assessment were available for two patients showing one PSA response of 90% in the patient with a confirmed resist PR. The safety profile observed has been favorable. We are continuing to enroll and evaluate patients with castrate resistant prostate cancer with the potential to expand enrollment to 20 to 30 patients if we continue to observe a positive efficacy signal. And we expect to present additional results along with the data from the hormone receptor positive breast cancer cohort in second half of 2025. Here on slide 40, we have, as a vignette, a heavily pretreated patient with castrate-resistant prostate cancer and androgen receptor H875Y mutation, which is typically associated with resistance to androgen receptor inhibitors, such as enzalutamide. After initiation of therapy with MRT2359 and enzalutamide, the patient developed a rapid and deep response, with PSA dropping by 85% after cycle 1 and by 90% by cycle 4, More importantly, the recent imaging demonstrated a partial response of 46% after cycle 2 and 57% after cycle 4, and the patient continues on treatment on cycle 5. We are particularly encouraged to see this early response in a heavily pretreated patient. To summarize, we are encouraged by the early signs of clinical response in heavily pretreated castrate-resistant prostate cancer patients with androgen receptor alterations associated with resistance to androgen receptor inhibitors. We see MRT2359's activity in castrate-resistant prostate cancer as an exciting opportunity in a large, high unmet need population. Schemic expression in this population is widespread, so this indication will not require patient selection upfront, simplifying our further clinical development. We look forward to presenting additional data in the second half of this year. In light of the promising data in castrate-resistant prostate cancer and the data we have seen from our dose escalation cohorts, we have made a strategic decision not to open expansion cohorts in lung cancer and high-grade neuroendocrine tumors. While we believe our results in these cohorts, particularly in the biomarker-positive subset, are supportive of the clinical activity of MRT2059, considering our other opportunities, in particular castrate-resistant prostate cancer, We believe the low biomarker positivity in these small LNNMIC indications doesn't support expansion cohorts in these populations. I'll now hand the call back over to Sharon to walk you through some updates to our CDK2 and Cycline E1 programs. Sharon?

Thanks, Philip. I'm excited to now share some promising preclinical data from both our Cycline E1 and CDK2 programs. As many of you know, Cycline E1 and CDK2 are key drivers of cancers. caused by changes in the CDK pathway. However, for both targets, there have been challenges for conventional inhibitor approaches. And we believe our highly selective MGDs could have key advantages here. Slide 44 highlights some of our in vivo findings for our cyclin E1 program, where we assessed our selective degrader 50969 in cyclin E1 amplified gastric cancer and breast cancer models. In both instances, we're seeing quite potent monotherapy effects in these difficult-to-treat tumors, including near-complete tumor regression in the cyclin E1 amplified breast cancer model. Moving to our CDK2 program on slide 45, we assess the therapeutic effects of our CDK2 degrader 51443 in combinations with a standard of care regimen of ribociclib and fulvestrin, in two ER-positive breast cancer models. In both models, the results demonstrated profound tumor regression for the triple combination relative to standard of care treatment. In summary, we're very excited with the strong preclinical results we're seeing from both our cell cycle programs. Our focus going forward is on benchmarking our MGDs for both CDK2 and cyclin E1 to determine the optimal molecule to advance to an expected IND submission in 2026. With that, I'm happy to turn the call back over to Marcus for a summary and concluding remarks before we open up the call to Q&A. Marcus?

Thanks Sharon and Philip for sharing these exciting updates with us this morning. So, in summary, I'd like to state we're very, very proud of the progress we've made throughout 2024 and, as a matter of fact, in the first quarter of this year. with a number of significant milestones, of course, still coming up throughout this year next. So let me just quickly summarize on this slide what you've seen today and also give you some guidance on what to expect moving forward. So today we share encouraging clinical data with you on MRT6160. This data are mapping a clear path, as mentioned before, to Phase II studies. While I can't give you guidance on exact timing for the Phase II initiations, I can say that we are working with our collaborators at Novartis to advance this program as efficiently as possible, building on the promising data we shared with you today. As discussed, we're also quite encouraged with what we see early on for our cohort of heavily pre-treated castrate-resistant prostate cancer patients. It's a small sample size, given how heavily pretreated these patients are, certainly encouraging. And so in light of that, we made the strategic decision to focus on the cohort, not open any other cohorts at this point for all the reasons we've discussed. We expect additional data for this program in the second half of this year. As to next seven, we also look forward to an IND submission for MRT8102, and that's going to happen first half of this year. and then a potential IND for our CNS-optimized NEC7 program next year. Our sales cycle programs are projected to have an IND in 2026 as well, and we hope to share more on the exciting work coming from our community platform, in particular in the INI space, in the context of more oral INI drugs in relatively near future. And so lastly, as stated on the slide, Importantly, we do think we are well positioned to advance these programs with a very strong balance sheet and providing cash runway anticipated into 2028. And so with that, I would like to open up the call for any questions you have, operator.

Thank you. To ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. And the first question comes from Kelly Shee with Jefferies. Your line is open.

Congrats on the progress, and thank you for taking my question. So VIVE-1, given that it is involved in multiple signaling pathways, how do you decide, and also with your partner, the most promising and eye indications to pursue based on now available panel of biomarker profiling data? Thank you.

A great question, Kelly. And so, you know, obviously, you can tell we're still preparing for those Phase II studies, and so final decisions haven't been made. That said, as you know, you might remember lots of preclinical data that we have generated in the past two, three years. In particular, in indications that are driven by either T cells, in particular TH17 cells, or TB cells combined. And so, if you remember, we had very strong data on preclinical data in UC, very interesting data in rheumatoid arthritis. I think there's related diseases you could think about, and I think the data we showed today from the Healthy Volunteer Trial, of course, in that context is very informative because, again, where this data, of course, is ex vivo stimulation, not in vivo data from patients, nevertheless, I think it gives us clear indications that we are hitting the cytokines we want to hit and we can sort of modulate how deep we want to go in regards to inhibiting their secretion.

Thank you very much. And also, one follow-up is we see pretty good biomarker inhibitions by using this X-vivo simulation approach. Curious how does it differ from the directing they will Merriman to represent the treatment impact and what level of but you know biomarker reduction could we expect in I and I patients based on this result? Thanks.

Yeah, I mean honestly hard to put a number out on what percentage to. Expect in in patients because that will actually depend on the type of disease you're targeting. I think what we find encouraging here is for a healthy volunteer trial, where we looked at what we thought an important benchmark healthy volunteer trials were, were matching up very, very well in regards to depth of cytokine secretion or, in fact, inhibition of them. I think from here, I'm fairly confident that this molecule can hit the mark in vivo in patients as well. But again, the exact percentage, of course, will really depend on sort of the actual disease you're treating and the tissue where you're measuring cytokine secretion or levels or inhibition thereof.

Congratulations. Thank you.

And the next question comes from Edward Tenthalt with Piper Sandler. Your line is open.

Great. Thanks. Good morning, and thanks for the very thorough and extensive update today. My question has to do with the prostate cancer, the focus on prostate cancer, which makes a lot of sense. Obviously, as men go through multiple cycles, including androgen deprivation therapy and enzalutamide and abiraterone, the mutation burden changes. Where do you think the ideal application is for 2359, and what kind of combinations do you think are worth exploring? Thank you.

Thank you, Tata.

It's a great question. I think, logically, I think starting off with the second line and the combination with drugs like enzalutamide, so essentially androgen receptor inhibitors, is probably a good starting point. But I think the potential applications are definitely beyond that. In a way, I mean, your target might be ended up with the coverage of the same population as enzalutamide currently covers, which is actually both castrate-resistant prostate cancer as well as the castrate-sensitive prostate cancer. So I actually think the ultimate patient population you can target with this is actually quite broad.

And would you envision combination trials in the future? Thanks.

The combination trials beyond the combination with enzalutamide, it's certainly a possibility. I mean, there doesn't seem to be any significant additional toxicity by combining these two drugs together, so I think it's definitely combinable. I think the first step would be to develop this as a combination of this androgen receptor agent and potentially, again, either in the second line or even in the first line when there is a possibility to potentially replace combination of androgenic receptor inhibitor with chemotherapy.

Great. Thanks, Philippe.

And our next question will come from Mark Fromm with TVCO, and your line is open.

Hi. Thanks for taking my questions, and thanks for the very comprehensive presentation. Maybe on VAV1, just the cytokine changes that you're able to show in the ex vivo simulation, can you put this into context of maybe what's been achieved with maybe a B-cell directed therapy like a BTK or on the T-cell side with more of the T-cell specific therapies like the IL-17 inhibitors and other single cytokine mechanisms, just to kind of put the context of this broad inhibition, what are you achieving on each side of the equation? And then also with the dosing, just the PK and the MAD dosing, it looks like you're getting very sustained suppression of Avalon. Should we think about extended dosing beyond once daily to maybe test out weekly or anything like that in some of these trials that are to come?

Yeah, I mean, I'll start with your second question. I think the high-level short statement here is, yeah, I think what you saw in today's presentation, of course, creates a lot of optionalities in regards to those regimens. I think that's certainly a strength of molecular glue degraders in general, right, with the catalytic mechanism. Of course, depending a little bit on sort of what the resynthesis rate of the protein is, you know, daily dosing is not the only option you have, and I think that can create interesting opportunities. On how we compare to other molecules, I would say really very wide. I mean, you know, sure, I mean, we looked at what does a BTK inhibitor do At clinical doses, what are the IL-17 and the IL-23 antagonists doing? And again, I think we compare very favorable here. Obviously, not every healthy volunteer trial in that space has been reported out, and not every assay protocol is the same. We've used interferon gamma a lot because that seems to be the one everyone looks at. And I would say we clearly hit the mark here with up to 99% inhibition. Again, it doesn't mean that we need to get to 99%, but I think it's great to have that, to see that, and then obviously adjust the dose as you want to get to whatever level you think is best for your indication.

Okay, that's very helpful. Then maybe just on the prostate cancer expansion cohort, you know, I recognize it's up to 20 to 30. Are there kind of any interim kind of gating factors that we should think about in terms of the enrollment through the rest of the year?

Yeah, I mean, it's assignment stage 2 design, so there's an interim efficacy readout. Again, admittedly, this is early, But as we said, super, super encouraging with that response with the disabled diseases. And, you know, it's clearly helped us obviously to gain excitement and momentum on enrollment. And so there's an interim efficacy criteria that, you know, we look at for full expansion to 20 to 30, but of course, It's not as simple as looking at a response rate, Rob, because I think you also need to look at how heavily are these being pretreated. Of course, needless to say, we've been looking at the early data, not the recently released data, the early Phase I data from Pfizer and the combination with the ETH2 inhibitor and To throw it out, I think our patient population here is more heavily pre-treated. Everyone, not just the ones where we have equity assessment, the ones that have been enrolled since have some form of a mutation in the androgen receptor pathway. And so obviously we have to put that into the equation. I'm sure there was a lengthy answer to a relatively short question, and the short answer is, yeah, there's an interim efficacy assessment to then go to the full 2230. Okay.

Thank you.

And our next question comes from Robert Driscoll with Wedbush. Your line is open.

Thanks. Good morning, guys. Congrats on all the progress here. Just a couple of questions. On 2359 for the breast cancer cohort, how are you thinking about the MYC biomarker there and I guess the potential patient population? And then second question, just any extended thoughts on why there appears to be this discrepancy between the preclinical data and the clinical data for the MYC biomarker and the other cancer cohorts?

Thanks.

Yeah, so let's start with breast, right? So we look at breast in a very similar way as we look at prostate, right? Like our preclinical data in cell lines and PDXs suggest that CMIC high expression is very widespread. We don't think we need to home in on a particular subpopulation, just like for CRPC. no need to have a companion diagnostic in that setting. And just like we've alluded to this interplay between CMIC and AR, we see this for CMIC and ER as well. But, you know, again, this cohort lags a little bit behind, and so we don't really have any data yet from that cohort this year. In regards to biomarker positivity, sure, I mean, you always scratch your head right when you see one. We spent a lot of time looking at real-world data sets, not just cell line or PDX data, even real-world data sets, I'm sure. I think you're probably looking at a situation where our clinical trial population is more heavily pretreated than what you typically get in these real-world data sets, not mentioning the companies we got the data from, but definitely more heavily pretreated. And we're using a different assay, and again, sure, we try to make sure that these assays somehow match up. It's not completely off by, but sure, like small cell, 70 to 80% as predicted versus 30%. That is a huge difference and obviously made small cell lung cancer for us a lot more less attractive on top of the fact that, again, sure, standard of cares in that population have changed and certainly your now current study population isn't any easier to treat. I think that's our best explanation. And again, sure, part of the now focusing with all the data we have, the totality of the data we have on prostate cancer makes a ton of sense.

Perfect. Thank you.

And the next question will come from Michael Schmidt with Guggenheim.

Your line is open. Michael, your line is now open.

Thanks for taking my questions. Question on BAF1, obviously the safety profile is very clean, as you described it. Are there any expected on target side effects that you're paying attention to, for example, infections or other things that are interesting?

So you were breaking up a bit, but I tried to answer based on what I thought I understood. So on target, potential on target toxicities, I would say really none based on the preclinical data we have. Obviously a four-week GOP talk study. showed nothing, no test article-related findings, and we dosed extremely high. We talked about this data a while ago. We have margins here of 500-fold and above based on calculating this off either RET or Synos. All the information we have, I mean, we did immunophenotyping in Synos and suggested this immune-modulatory and not immune-suppressive. Can you absolutely exclude infection risk? I'd say no. I think no one in this field, no one in INI can actually confidently do this. I think it's obvious here as a risk, but again, based on everything we've seen so far, we're not concerned at all. Obviously, we do have long-term talk studies in hand as well, and we haven't disclosed any details there, but I think we did make a statement in today's presentation that clinical data combined with the long-term talks data we now have gives us a lot of confidence and maps a clear path.

Okay, great. Thanks. And then a question on the GSBD-1 program, just sort of reconciling some of the data that was presented today. Have you looked at correlating with clinical activity in the patients so far, and I don't know if you disclosed the tumor type that one responder in the biomarker-positive patients was the lung cancer patient or neuroendocrine, and then same for the unconfirmed response in the biomarker-positive?

Yeah, so the PR that we saw in the biomarker-positive patient during dose escalation, there was a neuroendocrine bladder characterized by extremely high expression of NMIC. Almost a, let's call it a signature patient for the setting, but again, fair to say, and we've discussed it, that sort of high NMIC population sadly was like rare. not as frequent as we had hoped, even in endocrine tumors. But again, certainly a patient that gives us confidence that the drug works. And of course, in the patient, we saw the 60-some percent degradation of TSPT1. In totality, although it's not many patients, as you can tell, In the biomarker positives, we've seen very decent levels of degradation, 60 to 70% in line with the preclinical data and expectation. We have not received yet any data from prostate, mostly because, not just mostly, simply because we weren't able to get the paired biopsies run. These are not Trivial, thanks again. We're always happy when we get the screening biopsies, and I think we've done really well there getting that second biopsy. Again, we have a very decent success rate there with about a third of the patients, but we're not getting that on everyone, and sadly for prostate, we haven't gotten the paired samples yet.

Thank you. The next question comes from Eric. Joseph with JP Morgan. Your line is open.

Thanks for taking the questions. Good morning. Maybe just one question on the valve one program. Anything you can share at this point in terms of how Novartis might be thinking about duration of the initial phase two trial. And I wonder, you know, if you're just given the seven day mad portion of this study, is there any chance of I guess I'm asking around comfort on the safety side, whether you expect any sort of intermediate length phase 1B type trial before moving into a longer randomized phase 2 program. And then on the GSPT1 program, just having focused in prostate cancer going forward, can you just talk a little bit about your sense of how make expression tracks with line of treatment whether there's any, I guess, variation as patients are more heavily pretreated. Thanks.

Yeah, so I'll start on the U of F1 question. And I think, again, best answer I can give you is work in progress. Triad designs are being worked on. No details disclosed. I think the best assumption here is pretty much going to be standard designs. I think with regards to the length of the treatment in MAD, yes, it's seven doses. But of course, the upside here is, as you were able to see in the presentation, RAC1 levels stay down for an additional seven days from a safety assessment. With the additional one week of collecting safety observations, we've essentially recorded two weeks of low Vaf1 with a total of three weeks observation. And so I think for whatever the lengths of the Phase IIas are, we're in reasonably good shape here. And so again, I've said it multiple times. sound like a broken record, but this really gives us a clear path into these Phase IIa trials. On 2359 and CMIC again, and that's why we are so excited about it, we've seen CMIC up and correlating to AR really throughout, say, the the life cycle of prostate cancer is kind of a weird name for the term. And so I think that makes it a lot easier, I said, as some of these smaller LNN indications, because as soon as you have an AR-driven cancer, CMIC seems to be quite relevant and almost there, so no need to go in and define expression levels up for them. And again, but so far the data we're seeing in many ways sort of confirms them.

Okay.

Thanks for taking the questions.

The next question comes from Ellie Merle with UBS. Your line is open.

Hi. This is Jasmine on for Ellie. Thanks for the update in our question. A couple on Next 7. First, can you remind us of the level of degradation that you'd like to see here to be potentially supportive of efficacy? And then second, can you elaborate a bit on the decision to plan the phase one proof of concept in the pericarditis population versus some other options? Thank you.

I stopped with the... expected degradation, and I know that's always a favorite question from folks. And I'd say, again, if you just look at the data we have in this deck and previous decks, 80% degradation, at least in the ex vivo stimulation assay, can give us pretty much 100% inhibition of secretion of IL-1 betam. And so I'd say 80% is probably what we're aiming for in single and multiple ascending dose studies. As always, I throw out sort of the precautionary. This will also depend a little bit on assay line. I think what we have in this presentation is based on vestibular. As we go into the clinic, obviously we will switch over to flow cytometry because that has proven very robust in our VEF1 trial, definitely less noise here than with Western or even targeted mass spec, which we had actually used for GSBT-1 and are still using. Philip, do you want to address the pericarditis question?

Yeah, so pericarditis is obviously like one of the indications, but I mean, for NEC7, the indication even in the cardioimmunology space is actually much, much, much broader than that. What is actually nice about pericarditis is that the development pathway is actually relatively well-defined and definitely scalable. Does that answer your question or did I leave something out?

Yeah, another couple. Thank you.

The next question will come from Derek Archilla. with Wells Fargo. Your line is open.

Good morning. This is Yvonne for Derek. Thanks for taking our questions. A couple from us. So, first on the VAP1 program, kind of like what are the gatekeeping steps remaining to initiate the Phase II studies, and have you shared there any specific milestones triggered by the initiation of these studies? And on the GSPT-1 program, just how much data should we expect in the second half of the year update for the prostate cancer cohort?

Thanks.

So on that one, I mean, you saw the clinical data, right? So everything we need to know from the FADMAD, including safety, of course, which looks very favorable is here. There's a couple of bridging studies that are being done around formulation, so to get to something that's more scalable for larger trials or even for later commercialization. And then the typical things that need to be done, protocols need to be written and presented to the FDA. like most of the works done, clear path into Phase IIa studies now. Can you repeat the 2359 question? Oh, actually, sorry, back to RAC1 milestones. Yes, there are Phase II initiation milestones in our agreement.

Thanks. And the GFPT-1 question was, how much data should we expect in the second half of the year update for the prostate cancer cohort?

Yeah, I mean, again, hesitant to give you a specific patient number beyond what we said. I think we can expand here based on pre-specified criteria into 20 to 30 patients. I think the excitement from the investigators is there, and so I think there's going to be a sizable upgrade by the second half of the year in regards to number of patients we will have treated. But again, I'm hesitant to give you a specific patient number. Thanks.

I show no further questions at this time. I would now like to turn the call back over to Marcus for closing remarks.

That's great. Yeah, thanks.

I'd just like to thank you to everyone for dialing in today. And I obviously look forward to presenting more and updating you in the course of this year. Thanks, everyone.

This does conclude today's conference call. Thank you for participating. You may now disconnect.