Monte Rosa Therapeutics Q4 2024 Earnings Call Transcript

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Provided by Quartr
March 20, 2025

There are 12 speakers on the call.

Operator

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. As a reminder, this conference call is being recorded. It is now my pleasure to introduce Andrew Funderburk, Senior Vice President, Investor Relations and Strategic Finance at Monterosa. Thank you, Andrew.

Operator

You may begin.

Speaker 1

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 Warmoth, Chief Executive Officer Philip Yanku, Chief Medical Officer Sharon Townsend, Chief Scientific Officer and Phil Nixon, Chief Business and Legal Officer. Before we begin, I would like to remind everyone that any statements we make or information presented on this call that are not historical facts are forward looking statements that are based on our current beliefs, plans and expectations and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Please refer to our annual report and other filings we make with the SEC for our risk factors and other information.

Speaker 1

With that, I'll turn the call over to Marcus.

Speaker 2

Thank you, Andrew, and thanks everyone for joining us this morning. It's 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 one healthy volunteer study of MRT-six thousand one hundred and sixty, which very clearly support our 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 and sixty as a broadly applied novel treatment approach for immune mediated disease.

Speaker 2

We will then briefly touch on our Next7 program, which is on track for an IND submission in the first half of this year. We're also going to provide some details today on the IND enabling studies and some results there as well as our thoughts on clinical development for this program. And then as sort of a last contribution from the INI side, I'm going to show you a few slides on how we're using our CLEAN platform to expand our portfolio of oral INI drugs. Lastly, of course, we'll also get into our oncology programs, but I'll talk about some of those details later in this presentation. So now let's turn to the INI program starting with MRT-six 160, our VAV1 directed molecular booty grader.

Speaker 2

So as you can see on Slide five, VAV1 is a signaling molecule critical in both T and B cell receptor signaling. VAV1 regulates secretion of key immune modulatory cytokines, including IL-two, IL-seventeen interferon gamma and IL-six. And 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's a clear evidence that VAV1 is critical for hyperactivation of these pathways. Most importantly, with the overlap of MRT-six thousand one hundred and sixty SMO2VXion with those known for approved biologics, we think this could be an exciting alternative to many of these therapies. And so we believe six thousand one hundred and sixty, as mentioned before, could have very broad potential applications in immune mediated diseases.

Speaker 3

We've designed six thousand one hundred

Speaker 2

and sixty as a highly selective MGD targeting VAP1, and we moved it into a Phase I healthy volunteer study last year in August. In October, seeing the broad potential for this target across the new 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 an outstanding clinical development organization, we believe we can accelerate and broaden the scope of potential development for MRT-six thousand one hundred and sixty while retaining substantial value for montirocin. So with that, I'm pleased to turn the call over to Philip, our Chief Medical Officer, to review the actual data we have from our Phase one study.

Speaker 3

Thank you, Marcus, and thanks, everyone, for joining. We are really pleased with the data from our Phase one SART and MAST study of MRT-six thousand one hundred and sixty in healthy volunteers. As shown on Slide eight, MRT-six thousand one hundred and 60 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 BAP1 degradation levels in T and B cells as well as assessment of ex vivo response to T cell and B cell receptor stimulation.

Speaker 3

Here on Slide nine, you can see the analysis of plasma concentration of MRT6160A 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, Vapman 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, MRD-six thousand one hundred and 60 achieved dose dependent VAP1 degradation in peripheral VAP B cells, which exceeded 90% after single and multiple dose administrations except for dose level one of SAD where we get to 80% degradation.

Speaker 3

We were very pleased to see this level of potency consistent with our preclinical studies and matching our target profile. In addition, VAB1 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 MR T-six thousand one hundred and sixty on the functional inhibition of T and B cells as measured across several well characterized immune markers. In our clinical study, VAP1 degradation by MRD-six thousand one hundred and sixty resulted in significant functional inhibition of T and B cells following ex vivo stimulation of whole blood.

Speaker 3

For example, following T cell PCR stimulation, we observed significant attenuation of CD69 upregulation, a key marker of T and B cell activation indicating functional inhibition. Furthermore, MRD-six thousand one hundred and sixty treatment significantly inhibited secretion of the inflammatory cytokines, interleukin-two, 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, MRD-six thousand one hundred and sixty substantially attenuated interlocutin-six 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 duration of these functional effects post dosing.

Speaker 3

Interestingly, administration of MRD-six thousand one hundred and sixty resulted in a marked and sustained suppression of T cell receptor mediated CD69 activation. Similar results were observed in peripheral blood B cells following BCR stimulations. With regards to cytokine secretion as shown on Slide 14, MRT-six thousand one hundred and 60 demonstrated a sustained effect on TCR mediated cytokine production following single and multiple dose administrations and ex vivo TCR stimulation. MRT-six thousand one hundred and sixty treatment significantly and deeply inhibited interleukin-two, interferon gamma and interlocutin-17a secretion, consistent with what we have shown you earlier. And just as for CD69 suppression, the effects were sustained into the post treatment period.

Speaker 3

In summary, the effects of MRD-six thousand one hundred and sixty on both CD69 activation as well as cytokine production provide further evidence for the impact of VAV1 degradation on downstream TMT cell biology. Moving on to the safety summary on Slide 15, we are pleased to report that MRD-six thousand one hundred and sixty was well tolerated with no reported serious adverse events. Observe 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 MRD-six thousand one hundred and sixty included pain from blood draws, headaches and other AEs as detailed on the slide. Overall, frequency of treatment emergent adverse events was similar between MRD-six thousand one hundred and sixty and placebo.

Speaker 3

In summary, we were extremely pleased to see our pharmacodynamic and functional ex vivo studies suggesting significant effect on cytokine production after marked and sustained degradation of VAP1. The graduation of VAP1 was consistent with levels required to induce efficacy in pre clinical 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 growth potential applications in multiple immune mediated diseases. I'll now turn to our next program in the INI space focused on NK7 and its role in the NLRP3 inflammasomes. On this slide, let's begin with a quick overview why we see NK7 as a highly relevant therapeutic target in this space.

Speaker 3

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 NK7. In this context, NK7 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 MEG7 and the NLRP inflammasome are clinical for the production of interleukin-one beta, resulting in elevated CRP levels. CRP is known, among other things, as a key long term predictor of cardiovascular risk. Several anti IL-one and other NLRP inhibitors have shown promising reductions of CRP levels in clinical trials.

Speaker 3

Therefore, we think an exome degradable 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 and extensive clinical data exists to support its relevance to multiple diseases in therapeutic ARR spanning cardiomyology, rheumatology and neurology as we detail on Slide 20. So 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 first half of this year. And on Slide 21, we have outlined our proposed development path forward.

Speaker 3

Following a planned SADMAD Phase I study at 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, pseudo gout and osteoarthritis. Our preclinical toxicology and pharmacodynamic data, which Sharon will review in a moment, demonstrate MRT8102's excellent DAK like properties and favorable safety profile, which give us confidence as we look to move forward into clinical development. With that, let me turn the call over to Sharon to review our preclinical work for the Next7 program. Sharon?

Speaker 4

Thanks, Philip. Sean, 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 NEG7, including no degradation of any of the other NEG family members. Our data also demonstrates that drug exposure results in a prolonged PD effect, which we think distinguishes our NEC7 degrader from NLRP3 inhibitors. Preclinical profile of 8,102 has been highly favorable and supportive of continued development as shown on Slide 23.

Speaker 4

In the left panel, we show after five days of dosing in SYNOS, in vivo Next7 degradation leads to near complete inhibition of 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 MRT8102. 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 eight thousand one hundred and two related clinical signs, no changes in immunophenotyping and no growth or clinical pathology findings at any dose level. We also studied eight thousand one hundred and two in a rabbit gout model to better characterize its effect on inflammatory diseases.

Speaker 4

As shown on Slide 24, daily oral dosing of eight thousand one hundred and two at fifty mgkg reduced pathogenic effects associated with gout, including reduction in joint swelling and histopathology scores. Overall, we are highly encouraged by the preclinical profile of AT132 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 NEG7 program and the optimization of our NEG7 degraders for CNS penetration. Given the large therapeutic potential we see for NEG7, 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 NEG7 degradation in PBMCs, similar to those shown for MRT8102, which corresponds to near complete suppression of IL-one beta following ex vivo stimulation as shown on the right.

Speaker 4

As you can see in the middle, we also see deep reduction of NextE7 protein in the CSF, suggesting significant exposure with our MGD in the brain. Going forward, we believe having a CNS optimized molecule creates a lot of optionality for us and the opportunity to address indications with both peripheral and central components on top of the peripheral inflammatory indications we mentioned earlier. So to wrap up the INI part of this presentation, I'd like to now briefly discuss the opportunity we see more generally across the INI space. Based on everything we've learned to date, we believe our MGDs are uniquely suited to address key unmet needs in INI indications as shown on Slide 28. The high expression of cereblon in immune cells enables robust target degradation, which when combined with the exquisite selectivity of our oral MGDs allows for a high therapeutic index, a key potential advantage demonstrated in both our BAP1 and NEC7 programs.

Speaker 4

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 ionized drug, I'll highlight a few exciting areas in immunology that we are homing in on. While we are not yet disclosing specific targets, we see compelling opportunities and pathways critical to B cell modulation and autoantibody production, in inflammation as well as in key pathways relevant to asthma and allergies. Consequently, we believe our MGDs have broad therapeutic potential across the INI space and we are excited to share future progress as our early stage programs advance. With that, I'll turn the call back over to Marcus.

Speaker 2

Thank you, Sean. So just a recap the I and I part of today's call, we just showed you very encouraging data for 06/1960 in our healthy volunteer trial. And we really got to the eighty percent plus degradation of RAF1 and cytokine modulation of eighty two percent to ninety nine percent. Very encouraging data, I said, 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 seven degrader MRT eight thousand one hundred and two targeting a pathway, the NLRP2 inflammasome that's getting more and more attention.

Speaker 2

And then we talked about creating more opportunities for us to utilize and clean our discovery engine and to build a highly differentiated portfolio of oral I and I drugs. And so now let's turn to our oncology programs equally exciting. In the second half of the call, we will provide you an update on our MRT2359 development program. And we will show you some really encouraging data, in castration resistant prostate 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.

Speaker 2

But bottom line, we see this as a hugely exciting opportunity for MRT2359 moving forward with the added benefits of not having to develop a companion diagnostic in that setting. Towards the end, we will now also touch base on CDK2 and Cyclin E1, two very, very interesting programs on highly validated targets and provide you a quick update on our path to an IND submission in 2026. And so with that, I'll hand it back over to Philip to lead you through our updates on MRT2359.

Speaker 3

Thank you, Markus. I'll start off with a brief recap for our therapeutic hypothesis for the GSPT1 program. So 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 MIG 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.

Speaker 3

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 III study of MRT2359. This includes both small cell lung cancer, non small cell lung cancer driven by M 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 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 TMAKO over expression drives under gen receptor dependence, intrauteric resistance and castration resistant prostate cancer. Our Phase III study of MRD2359 was designed to assess safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary clinical activity of MRD2359 in patients with previously treated selected solid tumors.

Speaker 3

Our moderate dose escalation cohorts focused on selected MIG driven tumors such such as non small cell lung cancer, small cell lung cancer, high grade neuroendocrine tumors and tumors with L and MEC amplifications. We dosed patients at multiple dose levels using a five days on, nine days off schedule 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, 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 bleached population. On Slide 36, we outlined the adverse eating profile observed for each of the dose levels and their respective frequencies.

Speaker 3

Doses of zero point five milligram and one milligram per day in the fivenine schedule and doses of zero point five milligram and zero point seven five milligram in the 2017 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 toxicity is reported with non selective competitive GSPT1 degraders such as hypocalcemia, hypotension and cytokine release syndrome were not reported in our study of MRT2359. Now let's talk about what we saw with regards to the L and MIG biomarker analysis. Remember, our trial was not designed to enroll only biomarker positive patients, but rather enrolled patients with the tumor types expected to be enriched for the presence of high L and MYC expression. Instead, we performed a retrospective biomarker assessment in a patient treated on the trial where biopsies or archival tissues were available.

Speaker 3

The graph on the left depicts the frequency of L and MIG high expression in forty six patients with available tumor tissue. To keep it brief, we saw considerably lower than expected frequencies of tumors with high L or NMIG, especially in non small cell lung cancer and flu cell lung cancer as compared to preclinical data we had obtained. Pleasingly, in that biomarker positive population where we had first 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 forty eight patients where expression in tumor tissue was obtained at baseline, and we also included patients with known L or N MEG amplification even if tissue was not available to assess expression.

Speaker 3

Of these forty eight patients, thirty seven patients were available for response as peroresis 1.1. From this group, thirteen patients, so 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 39.

Speaker 3

As I mentioned earlier, we have also initiated two combination arms studying MRP two thousand three hundred and fifty nine with enzalutamide in castration resistant prostate cancer and with fluvestrans in hormone receptor positive breast cancer. On this slide, we summarize initial data in the castrate resistant prostate cancer cohort, again, a patient group where we believe CMake 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 03/10/2025, we have a RESIST one point one 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 for expression of AR V7 transcript.

Speaker 3

PSA response assessment were available for two patients showing one PSA response of 90% in the patient with a confirmed RASIS PR. The safety profile observed has been favorable. We are continuing to enroll and evaluate patients with castrate resistant prostate cancer with the potential to expand enrollment to twenty 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 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 MRTPH2 thousand three hundred and fifty nine and enzalutamide, the patient developed a rapid and deep response with PSA dropping by 85% after cycle one and by 90% by cycle four.

Speaker 3

More importantly, the Rhesus 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 castrate resistant prostate cancer patients with androgen receptor alterations associated with resistance to androgen receptor inhibitors. We see MRT2359's activity in castrate resistant prostate cancer as an exciting opportunity in a large, high unmet need population. Chemic expression in this population is widespread, so this indication will not require patient selection upfront, simplifying our further clinical development.

Speaker 3

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 MRT2359, considering our other opportunities, in particular catheteride resistant prostate cancer, we believe the low biomarker positivity in these small L and MEC indications doesn't support expansion cohorts in these populations. I'll now hand the call back over to Sharon to walk you through some updates to our CDK2 and cycling E1 programs. Sharon?

Speaker 4

Thanks, Philip. I'm excited to now share some promising preclinical data from both our Cycline E1 and CDK2 programs. As many of you know, Cycline E1 and CDK2 are key drivers of cancers caused by changes in the CDK pathway. However, for both targets, there have been challenges for conventional inhibitor approaches. And we believe our highly selective MGDs could have key advantages here.

Speaker 4

Slide 44 highlights some of our in vivo findings for our Cyclin E1 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 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.

Speaker 4

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 and A. Marcus?

Speaker 2

Thanks, Jan and Philip for sharing these exciting updates with us this morning. So in summary, I'd like to state we're very, very proud of the progress we've made throughout 2024 and as a matter of fact, in the first quarter of this year, with a number of significant milestones, of course, still coming up throughout this year next. So let me just quickly summarize on this slide what you've seen today and also give you some guidance on what to expect moving forward. So today, we share encouraging clinical data with you on MRT-six thousand one hundred and sixty. These data are mapping a clear path, as mentioned before, to Phase II studies.

Speaker 2

While I can't give you guidance on exact timing for the Phase II initiation, 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 castrate resistant prostate cancer patients. It's a small sample size, but given how heavily pretreated these patients are, certainly encouraging. And so in light of that, we made the strategic decision to focus on the cohort, not open any other cohorts at this point for all the reasons we've discussed. We expect additional data for this program in the second half of this year.

Speaker 2

As to next level, we also look forward to an IND submission for MRT-eight thousand one hundred and two and that's going to happen in the first half of this year. And then a potential IND for our CNS optimized Next7 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 clean platform, in particular in the INI space in the context of more oral INI drugs in relatively near future. And so lastly, as stated on 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.

Speaker 2

Operator?

Operator

Thank And the first question comes from Kelly Hsieh with Jefferies. Your line is open.

Speaker 5

Congrats on the progress and thank you for taking my questions. So on VIVE1, given that it is involved in multiple signaling pathways, how do you decided and also with your partner the most promising indications to pursue based on now available panel of biomarker profiling data? Also have follow-up. Thank you.

Speaker 2

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, you might remember lots of preclinical data that we have generated in the past two, three years. I mean, 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 a very strong data on preclinical data in UC, very interesting data in rheumatoid arthritis.

Speaker 2

I think there's related diseases you could think about. And I think the data we show today from the healthy volunteer trial, of course, in that context is very informative because again, where this data of course is ex vivo stimulation, not in vivo data from patients. Nevertheless, I think it gives us clear indications that we are hitting the cytokines we want to hit and we can sort of modulate how deep we want to go in regards to inhibiting their secretion.

Speaker 5

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 direct in 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.

Speaker 2

Yes. I mean, honestly, hard 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 thought important benchmark healthy volunteer trials were matching up very, very well in regards to depth of cytokine secretion or as a fact inhibition of that. And so I think from here, I'm fairly confident that this molecule can hit the mark in vivo in patients as well. But again, the exact percentage of course will really depend on sort of the actual disease you're treating and the tissue where you're measuring cytokine secretion or levels or inhibition thereof.

Speaker 5

And

Operator

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

Speaker 6

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.

Speaker 6

Where do you think the ideal application is for 02/1959? And what kind of combinations do you think are worth exploring? Thank you.

Speaker 3

Thank you, Todd. It's a great question. I think logically, I think starting off with the second line and the combination with drugs like enzalutamide essentially under genocetra and inhibitors is probably a good starting point. But I think the potential applications are definitely beyond that. So essentially, in a way, I mean, your target might be ended up with the coverage of the same population as indolutamide currently covers, which is actually both castrate resistant prostate cancer as well as the castrate sensitive prostate cancer.

Speaker 3

So actually I think the ultimate patient population you can target with this is actually quite broad.

Speaker 6

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

Speaker 3

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

Speaker 6

Great. Thanks, Philippe.

Operator

And our next question will come from Mark Fromm with TV Cohen. Your line is open.

Speaker 7

Thanks for taking my questions and thanks for the very comprehensive presentation. Maybe on VAV1, just the cytokine changes that you're able to show in the ex vivo simulation and

Speaker 3

can you put

Speaker 7

us 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 CYR17 inhibitors and other kind of 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 dosing, just the PK, the MAD dosing, it looks like you're getting very sustained suppression of VAVALON. 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?

Speaker 2

Yes. I mean, I'll start with your second question. I think the high level short statement here is, yes, I think what you saw in today's presentation, of course, creates a lot of optionalities in regards to those regiments. 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.

Speaker 2

On how we compare to other molecules, I would say really well, right? I mean, sure, I mean, we looked at what does a BTK inhibitor do at clinical doses, what are the IL-seventeen and the IL-twenty three antagonists doing. And again, I think the company are 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 Enterferon gamma a lot because that seems to be the one everyone looks at.

Speaker 2

And I would say we clearly hit the mark here with up to 99% inhibition. Again, it doesn't mean that we need to get to 99%, but I think it's great to have that to see that and then obviously adjust the dose as you want to get to whatever and ever you think is best for your indication.

Speaker 7

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

Speaker 2

Yes, I mean, it's a Simon Stage two design. So there's an interim efficacy readout. Again, admittedly, yes, this is early, but as we said, super encouraging with that response with the stable diseases. And still you have just obviously to gain excitement and momentum on enrollment. And so there's an interim efficacy criteria that we look at for full expansion to twenty twenty to 30.

Speaker 2

But of course, it's not as simple as looking at a response rate, Rob, because I think you also need to look at how heavily are these being pretreated. Of course, needless to say, we've been looking at the early data, not the recently released data, the early Phase one data from Pfizer and the combination with the EZH2 inhibitor. And to throw it out, I think our patient population here is more heavily pretreated. Everyone, not just the ones where we have equity assessment, the ones that have been enrolled since have some form of a mutation in the androgen receptor pathway. And so obviously, we have to put that into the equation.

Speaker 2

As well, I'm sure there was a lengthy answer to a relatively short question. And the short answer is yes, there's an interim efficacy assessment to then go to before twenty to thirty.

Speaker 8

Okay. Thank you.

Operator

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

Speaker 6

Thanks. Good morning guys. Congrats on all the progress here. Just a couple of questions. On 02/1959 for the breast cancer cohort, how are you thinking about the MYC biomarker there and I guess the potential patient population?

Speaker 6

And then second question, just any extended thoughts on why there appears to be this discrepancy between the preclinical data and the clinical data for the MYC biomarker in the other cancer cohorts? Thanks.

Speaker 2

Yes. So let's start with breast, right? So we look at breast in a very similar way as we look at APPROXYCU, right? Like our preclinical data immediately in satellites and in PDXs suggest that C Myc high expression is very widespread. So we don't think we need to hone in on a particular subpopulation, just like for CRPC, no need to have a companion diagnostic in that setting.

Speaker 2

And just like we've alluded to this interplay between C Mic and AR, we see this for C Mic and ER as well. But again, this cohort lags a little bit behind and so we don't really have any data yet from that cohort to share. In regards to biomarker positivity, sure, I mean, you always scratch your head, Roy, when you see Yuan. We spent a lot of time looking at real world data sets, not just cell line or PDX data, even real world data sets, I'm sure. I think you're probably looking at a situation where our clinical trial population is more heavily pretreated than what you typically get in these real world datasets, not mentioning the companies we got the data from, but definitely more heavily pretreated.

Speaker 2

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 80% as predicted versus thirty percent. 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, Schroder standard of cares in that population have changed. And certainly, you're now current study population isn't any easier to treat.

Speaker 2

I think that's our best explanation. And again, sure part of the now focusing with all the data we have, the totality of the data we have on prostate cancer makes a ton of sense.

Speaker 6

Perfect. Thank you.

Operator

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

Speaker 9

Thanks for taking my questions. Question on VAS1, obviously the safety profile looked very clean as you described it. Are there any expected on target side effects that you're paying attention to, for example, infections or other things that are interesting?

Speaker 2

So you were breaking up a bit, but I tried to answer based on what I thought I understood. So on target potential on target toxicities, I would say really none based on the preclinical data we have. Obviously, 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 margin T of 500 fold and above based on calculating this off either red or signals. All the information we have, I mean, we did immune phenotyping in signals such as this is immune modulatory and not immune suppressive.

Speaker 2

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 there as a risk. But again, based on everything we've seen so far, we're not concerned at all.

Speaker 2

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 that we now have gives us a lot of confidence and that's a clear path.

Speaker 9

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 patients so far? And I don't know if you disclosed the tumor type that one responder in the biomarker positive patients was the lung cancer patient or neuroendocrine and then same for the unconfirmed response in that

Speaker 2

one? Yes. So the PR that we saw in the biomarker positive patient during dose escalation, there was a neuroendocrine bladder characterized by extremely high expression of NNIC, almost a let's call it a signature patient for the setting, but again, fair to say and we've discussed it, that sort of high end MYC population sadly was like rare, not as frequent as we had hoped even in neuroendocrine tumors. But again, certainly a patient that gives us confidence that the drug works. And of course, in the patient we saw the sixty some percent degradation of TSPT1.

Speaker 2

In totality, although it's not many patients, as you can tell, in the biomarker positives, we've seen very decent levels of degradation, sixty percent 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 always happy when we get the screening biopsies and I think we've done really well. We are getting that second biopsy.

Speaker 2

Again, we have a very decent success rate with about a third of the patients, but we're not getting that on everyone. And sadly for prostate, we haven't gotten the payout samples yet.

Speaker 9

Thank you.

Operator

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

Speaker 8

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 the initial Phase two trial? And I wonder, here just given the seven day mad portion of this study, is there any chance of I guess, masking around comfort on the safety side, whether you expect any sort of intermediate length Phase 1b type trial before moving into a longer randomized Phase two program?

Speaker 8

And then on the GSPT1 program, just having focused in prostate cancer going forward, can you just talk a little bit about your sense of how MYC expression tracks with line of treatment? What is it that any, I guess, variation as patients are more heavily pretreated? Thanks.

Speaker 2

Yes. So I start on the YOVAC1 question. And I think again, best answer I can give you is work in progress. Trial designs are being worked on. No details disclosed.

Speaker 2

I think the best assumption here is pretty much going to be standard designs. I think with regards to the length of the treatment in MAD, yes, it's seven doses. But of course, the upside here is as you were able to see in the presentation, VAV1 levels stay down for an additional seven days. So 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. And so I think we're for whatever the lengths of the Phase IIAs are, we're in reasonably good shape here.

Speaker 2

And so again, I've said it multiple times, might sound like a broken record, but this really gives us a clear path into these Phase IIa trials. On 02/1959 and C Mic again, and that's why we are so excited about it. We've seen C Mic up and correlating to ARM really throughout the life cycle of prostate cancer. It's kind of a weird name for the firm. And so I think that makes it a lot easier as some of the smaller L and M MYC indications, because as soon as you have an AR driven cancer, C Myc seems to be quite relevant and almost there.

Speaker 2

So no need to go in and define expression levels upfront. And again, early, right? But so far, the data we're seeing in many ways sort of confirms them.

Speaker 8

Okay. Thanks for taking the questions.

Operator

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

Speaker 10

Hi. This is Jasmine on for Ellie. Thanks for the update in our question. A couple on, NEXX-seven. First, can you remind us of the level of degradation that you'd like to see here to be potentially supportive of efficacy?

Speaker 10

And then second, can you elaborate a bit on the decision to plan Phase I proof of concept in the pericarditis population versus some other options? Thank you.

Speaker 2

I'll start with the expected degradation level. I know that's always a favorite question from folks. And I'd say, again, if you just look at the data we have in this stack and in previous stacks, 80% degradation, at least in the ex vivo stimulation assay 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 in single and multiple ascending dose studies. As obvious, I throw out sort of the precautionary, this will also depend a little bit on assay Orion.

Speaker 2

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 VAP1 trial, definitely less noise than with Western Oregon targeted mass spec, which we had actually used for GSD1 and are still using. Filip, do you want to address the pericarditis question?

Speaker 3

Yes. So pericarditis is obviously like one of the indications, but I mean, as for next seven, the indication even in the cardiomyology space is actually much broader than that. What's 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?

Speaker 10

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

Speaker 4

The

Operator

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

Speaker 11

Good morning. This is Avan for Derek. Thanks for taking our questions. A couple from us. So first on the VAB1 program, kind of like what are the gatekeeping steps remaining to initiate the Phase two studies?

Speaker 11

Have you shared is there any specific milestones trigger by the initiation of the studies? And 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.

Speaker 2

So on RAV1, I mean, you saw 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, profit calls need to be written and presented to the FDA. So again, I think like most of the work is done, clear path into Phase IIa studies now.

Speaker 2

Can you repeat the 02/1959

Speaker 3

question? Just in the milestones.

Speaker 2

Oh, actually, sorry, back to RAV4 on milestones. Yes, there are Phase II initiation milestones in our agreement.

Speaker 11

Thanks. And the GSPC1 question was how much data should we expect in the second prostate cancer cohort?

Speaker 2

Yes. 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 twenty to thirty year patients. I think the excitement from the investigators is there. And so I think there's going to be a sizable upgrade by the second half of the year in regards to number of patients we will have treated.

Speaker 2

But again, I'm hesitant to give you a specific patient number. Thanks.

Operator

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

Speaker 2

That's great. Thanks, Ian. 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. Thanks, everyone.

Operator

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

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Earnings Conference Call
Monte Rosa Therapeutics Q4 2024
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