Monte Rosa Therapeutics, Inc. Price & Performance (GLUE)

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 Janku, 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 are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Please refer to our annual report 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'll 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 I healthy volunteer study of MRT6160. Which very clearly support a path into broad phase two development of this asset. Philip will discuss these results in a minute, but heads up, we really strengthen our conviction in the potential of MRT-six thousand one hundred sixty 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. I'm 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 I and I 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 WAF1 directed molecular boot degrader.

I mean, so as you can see on slide five, Bef1 is a signaling molecule critical in both T and B cell receptor signaling. Therefore, it regulates secretion of key immunomodulatory cytokines including IL-two, IL-seventeen interferon gamma, and IL-six And by doing so, WAF1 is really critical for the interplay of T cells, in particular, cells with B cells in immune mediated diseases. And where there's a clear evidence that VAP1 is critical for hyperactivation of these pathways. Most importantly, with the overlap of MRT 6160's mode of action with those known for approved biologics we think this could be an exciting all alternative to many of these therapies. And so, we believe 6,160 as mentioned before, could have very broad potential applications in immune mediated diseases. We've designed 6,160 as a highly selective MGD targeting WAF1, 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 MRT6 by retaining substantial value for montirosin.

So with that, I'm pleased to turn the call over Philip, our Chief Medical Officer, to review the actual data we have from our Phase I study. Thank you, Marcus, and thanks everyone for joining. We are really pleased with the data from our Phase I SAD and MAD studies, of MRT6160 in healthy volunteers. As shown on slide eight, MRT-six thousand one hundred sixty 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 BUN BUN 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 nine, 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 twofold increase in exposure at steady state, and no food effects were observed. As shown on slide 10, Fab one 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, cytokine secretion measured by immunoassays.

As we show on slide 11, MRD6160 achieved dose dependence above degradation in peripheral blood T cells, which exceeded 90% after single and multiple dose administrations except for dose level one of SAD, 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, BAP1 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, VAP1 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-two, interferon gamma, and interleukin 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 six at the higher dose levels.

Collectively, our pharmacokinetic and pharmacodynamic assessments in the clinic are in line with preclinical studies, suggest that robust functional effects on cytokine production is 80% and higher degradation of VAP1, 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 a marked and sustained suppression of T cell mediated CD69 activation. Results were observed in peripheral blood B cells following BCR stimulation. With regard to cytokine secretion, as shown on slide 14, MRT6160 demonstrated a sustained effect DCR mediated cytokine production, following single and multiple dose administrations and ex vivo PCR stimulation. MRT6160 treatment and deeply inhibited interleukin-two, interferon gamma, and interleukin 17A secretion, consistent with what we have shown you earlier. And just as for CD69 the effects were sustained into the post treatment period. In summary, the effects of MRT-six thousand one on both CD69 activation as well as cytokine production, provide further evidence for the impact of FUN1 degradation on downstream T and T 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 MRT6160 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 sixty. And placebo. In summary, we were extremely pleased to see our pharmacodynamic and functional ex vivo studies [indiscernible] significant effect 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 one 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 next seven, its role in the NLRP3 inflammasome. On this slide, let's begin with a quick overview why we see Next7 as a highly relevant and 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, an activation of the NLRP3 inflammasome critically depends on NAC7. In this context, that facilitates assembly of the active NLRT 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 [indiscernible] and the NLRPC inflammasome are clinical for the production of interleukin-one beta. Resulting in elevated CRP levels. CRP is a known, among other things, as a key long term predictor cardiovascular risk. Several anti IL-one and other NLRT C inhibitors have shown promising reductions of CRP levels in clinical trials. Therefore, we think an exome 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-one beta and the subsequent elevation of CRP. Importantly, IL-one and the NLRP3 signaling pathway are clinically validated extensive clinical data exists to support its relevance to multiple diseases therapeutic area spanning cardioimmunology, rheumatology, and neurology, as we detail on slide 20. The existing data with IL-one 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 21, we have outlined our proposed development path forward. Following a planned [indiscernible] we plan to pursue trials to establish clinical proof of concept initially in individuals with high levels of CRP, 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, demonstrates MRT-eight thousand one hundred two's excellent duct 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 NEXT seven program. Sharon?

Thanks, Phyllis.

Shown on slide 22, we believe the potency selectivity and long lasting PD profile of 82,102 create potential differentiation from competitive approaches. We have demonstrated potent and mono selective degradation of NEX-seven including no degradation of any of the other neck family members. Our data also demonstrates that dreg exposure results in a prolonged PD effect which we think distinguishes our Nex7 degrader from NLRP3 inhibitors. Preclinical profile of AT102 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 NEX-seven degradation leads to near complete inhibition caspase one activity and IL-one beta release in ex vivo stimulation assays. Moreover, the preclinical GLP toxicology study suggests a considerable safety margin for MRT AT102 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 MRT AT102 related clinical signs no changes in immunophenotyping, and no growth or clinical pathology findings at any dose level. We also studied AT102 in a rabbit gout model to better characterize its effect on inflammatory diseases.

As shown on slide 24, daily oral dosing of AT-one hundred two at fifty mgs 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 AT-one hundred two. And look forward to filing an IND in the first half of this year.

This now breaks us to the potential for expansion of our Next seven program and the optimization of our NEXT seven degraders for CNS penetration. Given the large therapeutic potential we see for NEXT seven, 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 next seven degradation in PBMCs. Similar to those shown for MRT81 and two. Which corresponds to near complete suppression of IL-one beta following x vivo stimulation as shown on the right. As you can see in the middle, we also see deep reduction of next seven 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 I and I part of this presentation, I'd like to now briefly discuss the opportunity we see more generally across the I and I space. Based on everything we've learned today, we believe our MGDs are unique suited to address key unmet needs in I and I indications. As shown on slide 28. The high expression of sarablon in immune cells enables robust target degradation, when combined with the exquisite selectivity of our oral MGDs, allows for a high therapeutic index. A key potential advantage demonstrated in both our BAG1 and next 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 I and I 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, believe our MGD's 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 I and I part of today's call, we just showed you very encouraging data for sixty thousand one hundred and sixty in our healthy volunteer trial. And we really got to the 80% plus degradation of RAF1 and cytokine modulation of 82% to 99% Very encouraging data set and 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 degrader MRT AT102. Targeting a pathway, the NLRP to inflammasome that's getting more and more attention. And then we talked about creating more opportunities for us to utilize and clean our discovery engine and to build a highly differentiated differentiated portfolio of oral I and I drugs And so now let's turn to our programs, equally exciting. In the second half of the call, we will provide you an update on our MRT2359 development program. And we will show you some really encouraging data in castration with cancer, a tumor type characterized by widespread expression of C MYC 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 MRT2359 moving forward with the added benefits of not having to develop companion diagnostic in that setting. Towards the end, we will then also touch base on CDK2 and Cyclin E1. To very, very interesting programs on highly validated targets and provide you a quick update on our path to an IND submission in twenty twenty six. So, that, I'll hand it back over to Philip to lead you through our updates on MRT 2359. Thank you, Marcos. I'll start off with a brief recap for our therapeutic high hypothesis for the GSPT1 program. So GSPT1 a translation termination factor, which has an important role in termination of the protein translation. Often tests, we discovered that molecular glue degrader induced GSPT1 degradation is deeper and faster MYC driven cells compared to other cells, resulting in impaired protein translation synthetic vitality, and ultimately reduced MYC expression. Therefore, GSPT1 degradation of offers a potential therapeutic modality to drug MEG driven cancers. The three different MYC family members are involved in multi cancers, including ones which are listed here on Slide 33 and which we explored in our Phase III study of MRT2359.

These include both small cell lung cancer, non small cell lung driven by MYC or L MYC, high grade tumors, and androgen receptor positive prostate cancer, as well as hormone receptor positive breast cancer driven by c MEG. Based on our most recent data, we started to focus on tumors that are primarily known to be c MEG driven, which has the added benefit of not requiring biomarker based selection of patients. One of these tumor types is prostate cancer in which cMACO expression [indiscernible] and therapeutic resistance and castration resistant prostate cancer. Our Phase onetwo study of MRT2359 was designed to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of MRT-two thousand three hundred fifty nine in patients with previously treated selected solid tumors. Monotherapy dose escalation cohorts focused on selected megtremium tumors such as non small cell lung cancer, small cell lung cancer, high grade neuroendocrine tumors, tumors with L and L MYC amplifications. We dosed patients at multiple dose levels using a five days on, nine days off [indiscernible] As well as a twenty one days on, seven days off schedule. Late last year, we announced that the schedule of twenty one days on, seven days off, at the zero point five milligram dose level would be our recommended Phase II dose.

Slide 35 shows you the patient demographics of the study population I believe the most important takeaways here are that we were able to nicely balance recruitment between different tumor types. Also that we were dealing with a heavily pretreated population. On slide 36, we outline the adverse infant profile observed for each of the dose levels and their respective frequencies. Doses of zero point five milligram and one milligram per day in the five nine schedule and doses of zero point five milligram and zero point seven five milligram in the twenty oneseven schedule, were well tolerated with mostly low grade adverse events. While doses of one point five milligram or higher were above the maximum tolerated dose with thrombocytopenia being a dose limiting toxicity. Most importantly, dose limiting toxicities reported with non selective competitive 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 anemic 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 present of high [indiscernible] and MYC expression.

Instead, we performed a retrospective biomarker assessment in a patient treated on the trial where biopsies or archival tissues available.

The graph on the left depicts the frequency of L and NMIG high expression in forty patients with available tumor tissue To keep it brief, we saw considerably lower than expected frequency tumors with high L or MYC, especially in non small cell lung cancer cell lung cancer as compared to preclinical data we had obtained. Pleasingly, in that biomarker positive population, where we had paired tumor biopsies, we saw optimal target GSP T1 protein degradation of approximately percent, which was consistent with our preclinical data.

Slide 38 summarizes the clinical response data into dose escalation cohorts. There were forty eight patients where expression in tumor tissue was obtained at baseline, we also included patients with known L or N MEG amplification even if tissue was not available to assess expression. Of these forty eight patients, thirty seven patients were available for response, as per the resist 1.1. From this group, thirteen patients saw about one third were determined to be biomarker positive. Of these thirteen patients, there was one confirmed partial response, and four patients with stable disease. Resulting in disease control rate of thirty eight percent. Of the twenty four biomarker negative patients, there was one unconfirmed partial response and three patients with stable disease. For a disease control rate of seventeen percent. Moving to slide thirty nine, as I mentioned earlier, we have also initiated two combination arm studying MRT2359 with enzalutamide in castration resistant prostate cancer, with fulvestrant in hormone receptor positive breast cancer. On this slide, we summarize initial data in the castrate resistant prostate cancer cohort, again, a group where we believe c MYC overexpression is critical in driving androgen receptor dependence therapeutic resistance, and where there is a significant unmet need for new safe oral therapies.

As of 03/10/2025, we have a 1.1 assessment available for three patients and very encouragingly, among them we saw one confirmed partial response 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 for expression of AIB7 transcript. PSA response assessment were available for two patients showing one PSA response of ninety percent in the patient with a confirmed RECIST PR. The safety profile observed has been favorable, We are continuing to enroll and evaluate patients with castrate resistant prostate cancer, the potential to expand enrollment to 20 to thirty 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 twenty twenty five.

Here on slide 40, we have, as a vignette, a heavily pretreated patient with castrate prostate cancer and androgen receptor H875Y mutation. Which is typically associated with resistance to androgen receptor inhibitor 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 one by 90% by cycle four, More importantly, the research imaging demonstrated a partial response of 46% after cycle two, 57% after cycle four, and the patient continues on treatment on cycle five. 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 allergen receptor alterations associated with resistance to androgen receptor inhibitors. We see MRT2359's activity in castrate resistant prostate cancer as an opportunity in a large high unmet need population. CMIC expression in this population is widespread, 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 MRT-two thousand three fifty nine considering our other opportunities.

In particular, castrate resistant prostate cancer, we believe the low biomarker positiveness in these small L and MYC 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 Cyclin E1 programs. Sharon?

Thanks, Philip. I'm excited to now share some promising preclinical data from both our cyclin E1 and CDK2 programs. As many of you know, cyclin E1 and CDK2 are 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 probe program. Where we assessed our selective degrader 50,969, 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 51,443 in combination with a standard of care regimen of ribociclib and fulvestrant 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 pre 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 to over to Marcus for a summary and concluding remarks. Before we open up the call to Q and A. Marcus? Thanks, Sharon and Phillip, for sharing these exciting updates. 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. 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 MRT-six thousand one hundred sixty. These data are mapping a clear path, as mentioned before, to phase two studies. While I can't give you guidance on exact timing for the phase two initiations, I can say that we are working with our collaborators at Novartis to advance 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 pretreated castrate resistant prostate cancer patients. It's a small sample size when given how heavily treated these patients are, 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 AT102, and that's going to happen first half of this year. And then a potential IND for our CNS optimized NEX-seven program that year. Our cell cycle programs are projected to have an IND in 2026 as well and we will share more on the exciting work coming from our clean platform, in particular in the I and I space, in the context of more oral INI drugs in relatively near future. And so lastly, as stated on this 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. Star one one on your telephone and wait for your name to be announced. And the first question comes from Kelly Shee with Jefferies. Your line is open.

Congrats on the progress. And thank you for taking my questions. So on vibe one, given that it is involved in multiple signaling pathways, how do you decided and also with your partner the most promising and eye indications to pursue? Based on now available panel of biomarker profiling data. Also have follow-up. Thank you.

Great question, Kelly. And so, 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, I 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 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 inhibition by using this ex vivo simulation approach Curious, how does it differ from the directing vivo measurement to represent the treatment impact and what level of in vivo biomarker reduction could we expect in INI patients? Based on this result? Thanks.

Yeah, I mean, honestly, to put a number out on what percentage to expect 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 saw an important benchmark volunteer trials were matching up very, very well in regards to deaths cytokine secretion or, as a result, inhibition of them. And so I think from here I'm fairly confident that this molecule can hit the mark 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 Congrats, again. Thank you.

And the next question comes from Edward Tenthoff 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 their mutation burden changes, where do you think the ideal application is for two three five nine? And what kind of combinations do you think are worth exploring? Thank you.

Yeah, thank you, Todd. That's a It's a great question. I think, logically, I think starting off starting off with the second line and the combination with drugs like enzalutamide, so essentially androgen receptor inhibitors, is a is probably a good starting point. But I think the potential applications are definitely beyond that. So essentially, in a way, 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 actually quite broad. And would you envision combination trials in the future? Thanks. The combination trials beyond beyond the combination with enzalutamide The It's certainly a possibility. I mean, there doesn't seem to be doesn't seem to any significant additional toxicity by combining these two drugs together. So I think it's definitely combinable. 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's is a possibility that we potentially replace combination of androgen receptor inhibitor with chemotherapy Great, thanks, Filip.

And our next question will come from Mark Fromm with TD Cowen. Your line is open.

Hi, thanks for taking my questions and thanks for the [indiscernible] very comprehensive presentation. Maybe on [indiscernible] the [indiscernible] changes that you're able to show in the ex vivo simulation and [indiscernible] 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 site IL-seventeen inhibitors and other single cytokine mechanisms just to kind of put the context of this broad inhibition kind of what are you achieving on each side of the equation? And then also with the with the dosing, just the PK, you know, in the MAD dosing, it looks like you're getting very sustained suppression of AV1. 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'd start with your second question. I think high level short statement here is yeah, I think what you saw in today's presentation, of course, creates a lot of functionalities in regards to [indiscernible] I think that's certainly a strength of molecular degraders in general, obviously the catalytic mechanism Of course, a little bit on sort of what the resynthesis rate of a protein is, you know, daily dosing is not the only option you have, and I think that can create interesting opportunities [indiscernible] how we compare to other molecules. I would say really bad, right? I mean, sure, we looked at what does a BTK inhibitor do at clinical doses, What are the IL-seventeen and the IO-twenty three antagonists doing. And again, I think the 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 gamma aller. Because that seems to be the one everyone looks at. And I would say we clearly hit the mark here with up to 99% in addition. 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 best for your indication.

Okay, that's very helpful. Then maybe just on the prostate cancer expansion cohort.

You know, recognize it's up to 20 to 30. Are there kind of any interim gating factors that we should think about in terms of enrollment through the rest of the year?

Yeah, I mean, it's assignment stage two design, so there's an interim efficacy readout Again, admittedly, this is early but as we said, super encouraging. With that response with the stable diseases [indiscernible] clearly you have just obviously to gain and momentum on enrollment. And so, there's an interim efficacy criteria that we look at for full expansion to 20 to thirty But of course, not as simple as looking at a response rate, right, 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 one data from Pfizer and the combination with the EDH2 inhibitor and to throw it out, I think our patient population here is more heavily pretreated. Everyone, not just the ones we have efficacy 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 that was a lengthy answer to a short question. And the short answer is, yeah, there's an interim efficacy assessment. To then go to before twenty to thirty.

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. [indiscernible] couple of questions. On 2359 for the breast cancer cohort, how are you thinking about the MYC biomarker there? I guess the potential patient population And then second question, just any extended thoughts on why there appears to be discrepancy between the preclinical data and the clinical data for the MIG biomarker and the other cancer cohorts? Thanks.

Let's start with breast. We look at breast very in a very similar way as we look at the prostate, right? Like our preclinical data, immediately in cell lines and PD access, suggest that c MYC 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 alluded to this interplay between CMIC and AR, we see this for CMIC and ER as well. But again, this cohort lags a little bit behind in so we don't really have any data yet from that cohort to share. In regards to biomarker positivity, sure, I mean, you obviously your head right when you see Nguyen. Spent a lot of time looking at real world data sets not just cell line or PDX data, even real 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, and it's not completely off point, but sure, like small cell seventy percent to eighty percent 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, truer standard of care in that population has changed and certainly current study population any easier to treat I think that's our best explanation. And again, sure part of 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 BAF one Obviously, safety profile looked very clean. And you know, as [indiscernible] are there any expected on target side effects that you're paying attention to, for example, in [indiscernible] or or other things that are that are interesting?

So you were breaking up a bit, but I 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 GLP tox study showed nothing. No test article related findings, and we dosed extremely high We talked about this data a while ago and we have margins here of 500 fold and above. Based on calculating this off either red or signals. All the information we have, I mean, did immunophenotyping and signals, such as this is immunomodulatory and not immune suppressive. Can you absolutely exclude infection risk I'd say no. I think no one in this field, no one in I and I 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 have longer term tox 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 tox data we now have gives us a lot of confidence and that's a clear path Okay, great, thanks.

And then, a question on the GSPD1 program, just sort of reconciling some of the data that was presented today. Have you looked at correlating GSPT1 degradation with clinical activity in the patient so far and I don't know if you disclosed [indiscernible] tumor type that one responder in the biomarker positive patients was the lung cancer patient or neuroendocrine, and then same for the unconfirmed. Response.

Number one.

Yeah, so PR that we saw [indiscernible] biomarker positive patient during dose escalation. There was neuroendocrine bladder characterized by extremely high expression of [indiscernible] Almost let's call it a signature patient for the setting. But again, fair to say, and we've discussed it, that sort of high end MYC population sadly was [indiscernible] Not as frequent as we had hoped, even in neuroendocrine tumors. But again, certainly again, a patient that gives us confidence that the the drug works. And of course, in the patient we saw the sixty some percent degradation of TSP21 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 These are not trivial things, again. We're obviously happy that we get the screening biopsies, and I think we've done really well. We are getting second biopsy. Again, have a very decent success rate. With about a third of the patients, but 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 JPMorgan. Your line is open.

Thanks for taking the questions. Good morning. Maybe just one question on the VAL-one program. Anything you can share at this point in terms of how Novartis might be thinking about of the initial Phase two trial? And I wonder here, just given the seven day mad portion of this study, is there any chance of [indiscernible] on the safety side, whether you expected a sort of intermediate length phase Ib type trial before moving into a longer randomized phase two program. And then on the GSPT-one program, just having focused in prostate cancer going forward. Can you just talk a little bit about your sense of how MYC expression tracks with line of treatment? What is it? There's any guess variation as a patient are more heavily pretreated Thanks.

Yes, I'll start on the [indiscernible] question. And I think, again, the best answer I can give you is work in progress. Try designs, are being worked on. No details disclosed. I think the best assumption here is pretty much going to be standard designs. I think 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, VAC one levels stay down for an additional seven days. So from a safety assessment, we see additional one week of collecting safety observation right, we've essentially recorded two weeks of low RAF1 with a total of three weeks observation. And so I think we're whatever the lengths of the phase two ASRs, we're in reasonably good shape here. And so, again, I've said it multiple times, but sound like a broken record, but this really gives us a clear path into these phase 2a trials. On 02/1959 in CMIC, again, and that's why we are so excited about it. We've seen CMIC up and correlating to AR really throughout [indiscernible] the life cycle of prostate cancer. Kind of a weird name firm. And so I think that makes it a lot easier as some of these smaller LNN MYC indications, because as soon as you have an AR driven cancer, c MYC seems to be quite relevant and almost there, so no need to go in and define expression levels up from an again, early, right?

But so far, the data we're seeing in many ways sort of confirms then 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 and our question. A couple on NEXT seven. 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 decision to plan the Phase one proof of concept in the pericarditis population versus some other options? Thank you. [indiscernible] started with the expected degradation, and I know that's always a favorite question.

From folks. I'd say again, if you just look at the data we have in this stack and previous stacks, 80% degradation at least in the ex vivo stimulation assay. Can can give us pretty much 100% inhibition of secretion of IL-one beta. And so I'd say 80% is probably what we're aiming for. [indiscernible] single and multiple ascending dose studies. As always, I throw out sort of the precautionary. This will also depend a little bit on assay Orion. Think what we have in this presentation is based on Western's As we go into the clinic, obviously we will switch over to flow cytometry because that has proven very robust in our VAP1 trial, definitely less noise given with targeted mass spec, which we had actually used for for GSPT1 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, at the NEX-seven indication even in the cardioimmunology space is actually much much broader than that. But it's actually nice about pericarditis is that the the development pathway is actually relatively well defined. And definitely scalable. Does that answer your question, or did I leave something out?

Yeah, no, that's helpful. Thank you.

The next question will come from Derek Archila 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 VAB-one program, kind of like, what are the gatekeeping steps remaining to initiate the phase two studies? Have you shared, are there any specific milestones trigger by the initiation of the studies? And on the GSPT-one program, just how much data should we expect in the second half of the year update for the prostate cancer cohort.

Thanks. So, on RAF one, [indiscernible] the clinical data, right? So everything we need to know from the FADMAT 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. Again, I think like most of the work's done, clear path into Phase 2a studies now. Can you repeat the two thousand hundred and fifty nine on the mild Oh, actually, sorry, back to RAV4 milestones. Yes, there are phase two initiation milestones in our agreement.

Thanks. And the GSPT-one question was how much data should we expect in the second half of the year updates for the prostate cancer cohort?

Yeah, I mean, again, hesitant to give you a specific patient number. Beyond we said, right? 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 that'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. Yes, thanks. Just like a brief thank you to everyone for dialing in today. And obviously, look forward to presenting more and updating you in the course of this year.

Everyone.

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