Monte Rosa Therapeutic - Earnings Call - Q4 2024

Executive Summary

• Q4 2024 delivered collaboration revenue of $60.6M and net income of $13.4M, reflecting a step-change vs no collaboration revenue and a $33.3M net loss in Q4 2023; cash, cash equivalents, restricted cash, and marketable securities ended at $377M, extending runway into 2028.
• Clinical updates were the principal catalysts: MRT-6160 Phase 1 SAD/MAD showed >90% VAV1 degradation with strong T/B-cell functional inhibition and favorable safety; MRT-2359 showed an early confirmed RECIST PR (-57%) and two SDs in CRPC patients on the enzalutamide combo.
• Strategic focus shifts: deprioritization of lung and neuroendocrine MRT-2359 expansions due to lower-than-expected L/N-MYC biomarker positivity; concentration on CRPC cohort with potential expansion to 20–30 patients in H2 2025.
• Near-term events: MRT-8102 IND submission (H1 2025) and additional MRT-2359 CRPC/breast data in H2 2025; MRT-6160 Phase 2 planning with Novartis and anticipated U.S. P&L sharing in later stages.

What Went Well and What Went Wrong

What Went Well

• MRT-6160 achieved sustained, dose-dependent VAV1 degradation >90% in T and B cells with marked cytokine suppression (IL-2, IFN-γ, IL-17A up to 99%) and was generally well-tolerated without SAEs; “highly encouraging” per CEO.
• MRT-2359 in CRPC: early efficacy with one confirmed PR (-57%) and two SDs among first three evaluable patients; PSA -90% in the PR case; safety favorable in combination with enzalutamide.
• Balance sheet strengthened: Q4 collaboration revenue recognition and Novartis upfront payment drove cash to $377M, enabling funding into 2028 through multiple proof-of-concept readouts.

What Went Wrong

• Lower-than-expected L/N-MYC biomarker positivity in NSCLC/SCLC/NE tumors constrained MRT-2359 expansion potential, prompting deprioritization of those cohorts.
• MRT-2359 higher doses above MTD due to thrombocytopenia (DLT) under certain schedules; RP2D set at 0.5 mg 21/7 to balance tolerability and PD effect.
• Early dataset size is small in CRPC and breast cohorts; paired biopsies in prostate were not yet obtained, limiting PD-efficacy correlation analyses.

Transcript

Operator (participant)

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 Monte Rosa Therapeutics. Thank you, Andrew. You may begin.

Andrew Funderburk (SVP of Investor Relations and Strategic Finance)

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 Warmuth, Chief Executive Officer; Filip Janku, Chief Medical Officer; Sharon Townson, 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.

Markus Warmuth (CEO)

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 MRT-6160, which very clearly supports a path into broad phase II development of this asset. Filip will discuss these results in a minute, but heads up, we really strengthen our conviction in the potential of MRT-6160 as a broadly applied novel treatment approach for immune-mediated diseases. We will then briefly touch on our next NEK7 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. As sort of a last contribution from the I&I side, I will show you a few slides on how we're using our QuEEN platform to expand our portfolio of oral I&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. Now, let's turn to the I&I program, starting with MRT-6160, our VAV1-directed molecular glue degrader. As you can see on Slide 5, VAV1 is a signaling molecule critical in both T- and B-cell receptor signaling. VAV1 regulates the secretion of key immunemodulatory cytokines, including IL-2, IL-17, interferon gamma, and IL-6.

By doing so, VAV1 is really critical for the interplay of T-cells, in particular Th17 cells with B cells in immune-mediated diseases, where there is clear evidence that VAV1 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 alternative to many of these therapies. We believe 6160, as mentioned before, could have very broad potential applications in immune-mediated diseases. We have designed 6160 as a highly selective MGD-targeting VAV1, 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 I&I space, with a company that has an outstanding clinical development organization, we believe we can accelerate and broaden the scope of potential development for MRT-6160 while retaining substantial value for Monte Rosa. With that, I'm pleased to turn the call over to Filip, our Chief Medical Officer, to review the actual data we have from our phase I study.

Filip Janku (Chief Medical Officer)

Thank you, Marcus, and thanks, everyone, for joining. We are really pleased with the data from our phase I SAD and MAD study of MRT-6160 in healthy volunteers. As shown on Slide 8, MRT-6160 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 VAV1 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 MRT-6160 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, 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, MRT-6160 achieved dose-dependent VAV1 degradation in peripheral blood T cells, which exceeded 90% after single and multiple dose administrations, except for dose level one 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, VAV1 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 MRT-6160 on the functional inhibition of T and B cells as measured across several well-characterized immune markers. In our clinical study, VAV1 degradation by MRT-6160 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, MRT-6160 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, MRT-6160 substantially attenuated interleukin-6 at the higher dose levels.

Collectively, our pharmacokinetic 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 the duration of these functional effects post-dosing. Interestingly, administration of MRT-6160 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, MRT-6160 demonstrated a sustained effect on BCR-mediated cytokine production following single and multiple dose administrations and ex vivo TCR stimulation. MRT-6160 treatment significantly and deeply inhibited interleukin-2, interferon gamma, and interleukin-17A secretion, consistent with what we have shown you earlier.

Just as for CD69 suppression, the effects were sustained into the post-treatment period. In summary, the effects of MRT-6160 on both CD69 activation as well as cytokine production provide further evidence for the impact of VAV1 degradation on downstream T and B cell biology. Moving on to the safety summary on Slide 15, we are pleased to report that MRT-6160 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 MRT-6160 included pain from blood draws, headaches, and other AEs, as detailed on the slide. Overall, the frequency of treatment emergent adverse events was similar between MRT-6160 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 VAV1. Degradation of VAV1 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 inflammasome space, focused on NEK7 and its role in the NLRP3 inflammasome.

On this slide, let's begin with a quick overview why we see NEK7 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 NEK7. In this context, NEK7 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 NEK7 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 a NEK7 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-1β and the subsequent elevation of CRP. Importantly, IL-1 and the NLRP3 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. The existing data with IL-1 targeting agents out there, and to some degree, the emerging data from first-generation NLRP3 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 SAD/MAD phase I 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 MRT-8102'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 NEK7 program. Sharon?

Sharon Townson (Chief Scientific Officer)

Thanks, Filip. Shown on Slide 22, we believe the potency, selectivity, and long-lasting PD profile of MRT-8102 creates potential differentiation from competitive approaches. We have demonstrated potent and monoselective degradation of NEK7, including no degradation of any of the other NEK family members. Our data also demonstrate that drug exposure results in a prolonged PD effect, which we think distinguishes our NEK7 degrader from NLRP3 inhibitors. Preclinical profile of MRT-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 cynos, in vivo NEK7 degradation leads to near-complete inhibition of caspase-1 activity and IL-1β release in ex vivo stimulation assays. Moreover, the preclinical GLP toxicology study suggests a considerable safety margin for MRT-8102.

The no-observed adverse effect level was the highest dose tested in both rats and cynos, with a greater than 200-fold exposure margin over the projected human efficacious dose in both species. Importantly, there were no MRT-8102-related clinical signs, no changes in immunophenotyping, and no gross or clinical pathology findings at any dose level. We also studied 8102 in a rabbit-gout model to better characterize its effect on inflammatory diseases. As shown on Slide 24, daily oral dosing of 8102 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 8102 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 NEK7 program and the optimization of our NEK7 degraders for CNS penetration.

Given the large therapeutic potential we see for NEK7, we've been advancing MGDs specifically optimized for CNS penetration. Just to show you a few highlights on Slide 26, we're achieving very compelling levels of NEK7 degradation in PBMCs, similar to those shown for MRT-8102, which corresponds to near-complete suppression of IL-1β following ex vivo stimulation, as shown on the right. As you can see in the middle, we also see deep reduction of NEK7 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.

To wrap up the I&I part of this presentation, I'd like to now briefly discuss the opportunity we see more generally across the I&I space. Based on everything we've learned today, we believe our MGDs are uniquely suited to address key unmet needs in I&I 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 our VAV1 and NEK7 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&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, we believe our MGDs have broad therapeutic potential across the I&I 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.

Markus Warmuth (CEO)

Thank you, Sharon. Just to recap the I&I 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%+ degradation of VAV1 and cytokine modulation of 82%-99%. Very encouraging data, as I said, and mapping a clear path into phase II trials. We are also looking at an IND in the first half of this year for our next NEK7 degrader MRT-8102, targeting a pathway, the NLRP3 inflammasome, that is getting more and more attention. Then we talked about creating more opportunities for us to utilize, clean our discovery engine to build a highly differentiated portfolio of oral I&I drugs. 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 MYC on top of AR, of course. We will discuss why we decided to prioritize this indication over other expansion cohorts. 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 Cyclin E1, two very, very interesting programs, highly validated targets, and provide you a quick update on our path to an IND submission in 2026. With that, I'll hand it back over to Filip to lead you through our updates on MRT-2359.

Filip Janku (Chief Medical Officer)

Thank you, Marcus. I'll start off with a brief recap for our therapeutic hypothesis for the GSPT1 program. GSPT1 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 MYC-driven cells compared to other cells, resulting in impaired protein translation, synthetic lethality, and ultimately reduced MYC expression. Therefore, GSPT1 degradation offers a potential therapeutic modality to drug-MYC-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 MRT-2359. These include both small cell lung cancer, non-small cell lung cancer driven by N-MYC or L-MYC, high-grade neuroendocrine tumors, and androgen receptor-positive prostate cancer, as well as hormone receptor-positive breast cancer driven by c-MYC.

Based on our most recent data, we started to focus on tumors that are primarily known to be MYC-driven, which has the added benefit of not requiring biomarker-based selection of patients. One of these tumor types is prostate cancer, in which MYC overexpression drives androgen receptor dependence and therapeutic resistance in castration-resistant prostate cancer. Our Phase 1/2 study of MRT-2359 was designed to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of MRT-2359 in patients with previously treated selected solid tumors. Our monotherapy dose escalation cohorts focused on selected MYC-driven tumors, such as non-small cell lung cancer, small cell lung cancer, high-grade neuroendocrine tumors, and tumors with L-MYC and N-MYC 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 mg dose level would be our recommended phase II 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 a heavily pretreated population. On Slide 36, we outlined the adverse event profile observed for each four 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 events, 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 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 N-MYC biomarker analysis. Remember, our trial was not designed to enroll only biomarker-positive patients, but rather enroll patients with the tumor types expected to be enriched for the presence of high L- and N-MYC expression. Instead, we performed a retrospective biomarker assessment in patients treated on the trial where biopsies or archival tissues were available. The graph on the left depicts the frequency of L- and N-MYC 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 N-MYC, 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 N-MYC amplification, even if tissue was not available to assess expression. Of these 48 patients, 37 patients were available for response as per RECIST 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 a disease control rate of 38%. Of the 24 biomarker-negative patients, there was one unconfirmed partial response and three patients with stable disease for a disease control rate of 17%. Moving to Slide 39, as I mentioned earlier, we have also initiated two combination arms studying MRT-2359 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 castration-resistant prostate cancer cohort, again a patient group where we believe MYC 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 RECIST 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 assessments were available for two patients showing one PSA response of 90% in the patient with a confirmed RECIST PR. The safety profile observed has been favorable. We are continuing to enroll and evaluate patients with castration-resistant prostate cancer with the potential to expand enrollment to 20-30 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 the second half of 2025.

Here on Slide 40, we have, as a vignette, a heavily pretreated patient with castration-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 MRT-2359 and enzalutamide, the patient developed a rapid and deep response, with PSA dropping by 85% after cycle one and by 90% by cycle four. More importantly, the RECIST imaging demonstrated a partial response of 46% after cycle two and 57% after cycle four, and the patient continues on treatment on cycle five. 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 castration-resistant prostate cancer patients with androgen receptor alterations associated with resistance to androgen receptor inhibitors.

We see MRT-2359's activity in castration-resistant prostate cancer as an exciting opportunity in a large, high unmet need population. c-MYC 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 castration-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-2359. Considering our other opportunities, in particular castration-resistant prostate cancer, we believe the low biomarker positivity in these small L- and N-MYC indications does not 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 Cyclin E1 programs. Sharon?

Sharon Townson (Chief Scientific Officer)

Thanks, Filip. 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 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 effect of our CDK2 degrader 51443 in combinations 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 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?

Markus Warmuth (CEO)

Thanks, Sharon and Filip, for sharing these exciting updates with us this morning. 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. 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. Today, we shared encouraging clinical data with you on MRT-6160. These 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 pretreated castration-resistant prostate cancer patients. It's a small sample size, but given how heavily pretreated these patients are, certainly encouraging. In light of that, we made the strategic decision to focus on that 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 NEK7, we also look forward to an IND submission for MRT-8102, and that's going to happen in the first half of this year, and then a potential IND for our CNS-optimized NEK7 program next year. Our cell 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 QuEEN platform, in particular in the I&I space, in the context of more oral I&I drugs in the relatively near future. 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. With that, I would like to open up the call for any questions you have, operator.

Operator (participant)

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. The first question comes from Kelly Shi with Jefferies. Your line is open.

Kelly Shi (SVP and Senior Research Analyst)

Good morning, Sharon, the progress, and thank you for taking my questions. On VAV1, given that it is involved in multiple signaling pathways, how do you decide, and also with your partner, the most promising IND indications to pursue based on now available panel of biomarker profiling data? I also have a follow-up. Thank you.

Markus Warmuth (CEO)

A great question, Kelly. Obviously, you can tell we're still preparing for those phase II studies, and 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 T B cells combined. 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, we're at this stage, of course, this 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.

Kelly Shi (SVP and Senior Research Analyst)

Thank you very much. Also, a well-follow-up is we see pretty good biomarker inhibition by using this ex vivo stimulation approach. Curious, how does it differ from the direct in vivo measurement to represent the treatment impact, and what level of in vivo biomarker reduction could we expect in I&I patients based on this result? Thanks.

Markus Warmuth (CEO)

Yeah, I mean, honestly, hard to put a number out on what % 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 thought important benchmark Healthy Volunteer Trials were, we're matching up very, very well in regards to depth of cytokine secretion or, as a matter of 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. Again, the exact %, 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.

Kelly Shi (SVP and Senior Research Analyst)

Congrats again. Thank you.

Operator (participant)

The next question comes from Edward Tenthoff with Piper Sandler. Your line is open.

Edward Tenthoff (Analyst)

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 mutational 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.

Filip Janku (Chief Medical Officer)

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

Edward Tenthoff (Analyst)

Would you envision combination trials in the future? Thanks.

Filip Janku (Chief Medical Officer)

The combination trials beyond the combination with enzalutamide, it's certainly a possibility. I mean, there doesn't seem to be any significant addition of toxicity by combining these two drugs together. I think it's definitely combineable. 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 a combination of androgen receptor inhibitor with chemotherapy.

Edward Tenthoff (Analyst)

Great. Thanks, Filip.

Operator (participant)

Our next question will come from Marc Frahm with TD Cowen, and your line is open.

Marc Frahm (Managing Director and Senior Research Analyst)

Hi, thanks for taking my questions, and thanks for the very comprehensive presentation. Maybe on VAV1, just the kind of cytokine changes that you're able to show in the ex vivo stimulation. 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 kind of single cytokine mechanisms? Just to kind of put the context of this broad inhibition, what are you achieving on each side of the equation? Also with the dosing, just the PK and the MAD dosing, it looks like you're getting very sustained suppression of VAV1. 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?

Markus Warmuth (CEO)

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. 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, 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. Again, I think we compare very favorably 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. 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.

Marc Frahm (Managing Director and Senior Research Analyst)

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

Markus Warmuth (CEO)

Yeah, I mean, it's assignment stage too, would you sign. There is an interim efficacy readout. Again, admittedly, yeah, this is early, but as we said, super encouraging with that response with the stable diseases. It has clearly helped us, obviously, to gain excitement and momentum on enrollment. There is an interim efficacy criteria that we look at for full expansion to 20-30. Of course, it is 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. 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 EZH2 inhibitor. To throw it out, I think our patient population here is more heavily pretreated.

Everyone, not just the ones where we have efficacy assessment, the ones that have been enrolled since have some form of a mutation in the androgen receptor pathway. Obviously, we have to put that into the equation as well. I'm sure there was a lengthy answer to a relatively short question, and the short answer is here. There's an interim efficacy assessment to then go to the full 20-30.

Marc Frahm (Managing Director and Senior Research Analyst)

Okay. Thank you.

Operator (participant)

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

Robert Driscoll (Research Analyst)

Thanks, 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? 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.

Markus Warmuth (CEO)

Yeah. Let's start with breast, right? We look at breast in a very similar way as we look at prostate, right? Our preclinical data, admittedly in cell lines and in PDXs, suggest that MYC high expression is very widespread. We do not think we need to home in on a particular subpopulation, just like for CRPC, no need to have a companion diagnostic in that setting. Just like we have alluded to this interplay between MYC and AR, we see this for MYC as well. Again, this cohort lags a little bit behind, and we do not really have any data yet from that cohort to share. In regards to biomarker positivity, sure, I mean, you always scratch your head right when you see it.

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 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. We're using a different assay. We try to make sure that these assays somehow match up. It's not completely off, but like small cell, 70-80% 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 standard of cares in that population have changed.

Certainly, your now current study population isn't any easier to treat. I think that's our best explanation. 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.

Robert Driscoll (Research Analyst)

Perfect. Thank you.

Operator (participant)

The next question will come from Michael Schmidt with Guggenheim. Your line is open. Michael, your line is now open.

Michael Schmidt (Senior Biotech Analyst)

Thanks for taking my questions. Question on VAV1. Obviously, the safety profile looked very clean as you've 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?

Markus Warmuth (CEO)

You were breaking up a bit, but I tried to answer based on what I thought I understood. On-target, potential on-target toxicities, I would say really none based on the preclinical data we have. Obviously, 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. We have margins here of 500-fold and above based on calculating this off either rat or cynos. All the information we have, I mean, we did immunephenotyping in cynos and suggested it is immunomodulatory and not immunosuppressive. Can you absolutely exclude infection risk? I'd say no. I think no one in this field, no one in I&I can actually confidently do this. I think it's obviously there as a risk. Again, based on everything we've seen so far, we're not concerned at all.

Obviously, we do 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.

Michael Schmidt (Senior Biotech Analyst)

Okay. Great. Thanks. A question on the GSPT1 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 patients so far? 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 patients.

Markus Warmuth (CEO)

Yeah. The PR that we saw in the biomarker-positive patients during dose escalation, there was a neuroendocrine bladder characterized by extremely high expression of N-MYC. Almost a, let's call it a signature patient for the setting, but again, failed to say, and we've discussed it, that sort of high N-MYC population, sadly, was rare, not as frequent as we had hoped, even in neuroendocrine tumors. Certainly, a patient that gives us confidence that the drug works. Of course, in the patient, we saw the 60-some % degradation of GSPT1 in totality, although it's not many patients, as you can tell. In the biomarker positives, we've seen very decent levels of degradation, 60-70% 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 were not able to get the paired biopsies, right? These are not trivial things to get. We are always happy when we get the screening biopsies, and I think we have 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 are not getting that on everyone. Sadly, for prostate, we have not gotten the paired samples yet.

Michael Schmidt (Senior Biotech Analyst)

Thank you.

Operator (participant)

The next question comes from Eric Joseph with JPMorgan. Your line is open.

Eric Joseph (Analyst)

Thanks for taking the questions. Good morning. Maybe just one question on the VAV1 program. Anything you can share at this point in terms of how Novartis might be thinking about duration of an initial phase II trial? I wonder 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 I-B type trial before moving into a longer randomized phase II program? On the GSPT1 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? Whether there's any, I guess, variation as patients are more heavily pretreated? Thanks.

Markus Warmuth (CEO)

Yeah. I start on the VAV1 question. I think, again, the best answer I can give here is work in progress. Trial 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. Of course, the upside here is, as you were able to see in the presentation, VAV1 levels stay down for an additional seven days. From a safety assessment, with the additional one week of collecting safety observations, right, we've essentially recorded two weeks of low VAV1 with a total of three weeks observation. I think whatever the lengths of the phase II-A's are, we're in reasonably good shape here.

I've said it multiple times, might sound like a broken record, but this really gives us a clear path into these phase II-A trials. On 2359 and c-MYC, again, and that's why we are so excited about it, we've seen c-MYC up and correlating to AR really throughout, say, the life cycle of prostate cancer is kind of a weird name term. I think that makes it a lot easier, as I said, as some of these smaller L-MYC and N-MYC indications, right? 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 upfront and, again, early, right? So far, the data we're seeing in many ways sort of confirms them.

Eric Joseph (Analyst)

Okay. Thanks for taking the questions.

Operator (participant)

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 NEK7. First, can you remind us of the level of degradation that you'd like to see here to be potentially supportive of efficacy? Then second, can you elaborate a bit on the decision to plan the phase I proof of concept in the pericarditis population versus some other options? Thank you.

Markus Warmuth (CEO)

Yeah. I mean, I'll start with the expected degradation level. 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 give us pretty much 100% inhibition of secretion of IL-1β. 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, right? I think what we have in this presentation is based on Westerns.

As we go into the clinic, obviously, we will switch over to flow cytometry because that has proven very robust in our VAV1 trial, definitely less noisy than with Westerns or even targeted mass spec, which we had actually used for GSPT1 and are still using. Filip, do you want to address the pericarditis question?

Filip Janku (Chief Medical Officer)

Yeah. Pericarditis is obviously one of the indications, but I mean, for NEK7, the indication, even in the cardioimmunology space, is actually 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. No, that's helpful. Thank you.

Operator (participant)

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. First, on the VAV1 program, kind of what are the gatekeeping steps remaining to initiate the phase studies? Have you shared if there are any specific milestones triggered by the initiation of the studies? On the GSPT1 program, just how much data should we expect in the second half of the year update for the prostate cancer cohort? Thanks.

Markus Warmuth (CEO)

On VAV1, I mean, you saw the clinical data, right? Everything we need to know from the SAD/MAD, including safety, of course, which looks very favorable, is here. There's a couple of bridging studies that are being done around formulation, to get to something that's more scalable for larger trials or even for later commercialization. The typical things that need to be done, protocols need to be written and presented to the FDA. Again, I think most of the work's done, clear path into phase II-A studies now. Can you repeat the 2359 question?

Filip Janku (Chief Medical Officer)

Just on the milestones.

Markus Warmuth (CEO)

Oh, actually, sorry. Back to VAV1 milestones. Yes, there are phase II initiation milestones in our agreement.

Thanks. The GSPT1 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, right? I think we can expand here based on pre-specified criteria into 20-30 patients. I think the excitement from the investigators is there. I think there's going to be a sizable upgrade by the second half of the year in regards to the number of patients we will have treated. Again, I'm hesitant to give you a specific patient number.

Thanks.

Operator (participant)

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

Markus Warmuth (CEO)

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

Operator (participant)

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