Monte Rosa Therapeutics, Inc. Common Stock Study result

Andrew, you may begin. Good morning, and thank you for joining us to discuss results from GFORCE-1, a phase I study of MRT-8102, our NEK7 directed molecular glue degrader in subjects with elevated cardiovascular disease risk.

Joining me today are Markus Warmuth, Chief Executive Officer, Filip Janku, Chief Medical Officer, Hemang Kapadia, Senior Vice President, Translational Research. 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 for 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. We issued a press release this morning summarizing today's clinical data update.

A copy of today's presentation is available in the Events and Presentation section of our IR website. With that, I will turn the call over to Markus.

Thank you, Andrew, and good morning, everyone. Today, we are delighted to report the full results from our GFORCE-1 study, the part 3 of our phase I first-in-human study for our NEK7 molecular glue degrader, MRT-8102. GFORCE-1 follows on the heels of remarkable and benchmark setting data from our single ascending dose and multiple ascending dose or SAD/MAD portion of the trial. As a reminder, we reported data for that earlier portion of the trial in January this year, and that data, as well as information on the entirety of our pipeline, can be found on our corporate website. Let's turn back to today's update on MRT-8102.

MRT-8102 is a molecular glue degrader of NEK7. We have shown before in preclinical models that depleting NEK7 leads to a substantial and sustained block of the assembly of the NLRP3 inflammasome, referred to in today's update as the NEK7 NLRP3 complex. Our GFORCE-1 human data confirm now that MRT-8102 does exactly what we designed it to do. It degrades NEK7 potently. It reduces an array of key molecular drivers of plot progression and vessel wall remodeling that are fundamental in atherosclerotic cardiovascular disease or ASCVD, a complicated and multifaceted disease. It does so with a favorable safety and tolerability profile. We believe that the positive results reported today validate the power of our approach and strongly support continued development of MRT-8102 across multiple indications, including the three indications we will focus on today.

ASCVD, in particular, coronary artery disease or CAD, hidradenitis suppurativa or HS, and gout. GFORCE-1 enrolled 108 subjects with elevated cardiovascular risk randomized to MRT-8102 at 5, 20, or 40 milligrams once daily or to placebo for 4 weeks of dosing, followed by 4 weeks of safety follow-up. On safety, consistent with the data we previously reported with MRT-8102, the overall safety profile observed was highly favorable. There were no serious adverse events. The treatment emergent adverse event rate, predominantly grade 1 events, was comparable to placebo at 33% versus 30%. Importantly, we saw no evidence of increased infection risk. On target engagement, we saw robust and sustained NEK7 degradation of approximately 80%-90%, in line with what we had seen in the SAD/MAD portion of the phase I trial. Degradation was comparable across all three dose levels.

Importantly, pathogenic drivers of ASCVD, including those indicative of atherogenic and thrombogenic risk, like various DAMPs and IL-1 beta, as well as systemic inflammatory markers, were reduced to levels comparable with healthy volunteers at every dose level tested. Finally, we saw an important precision medicine signal that could be helpful for efficient future development. Carriers of NLRP3 risk alleles had higher baseline DAMP and IL-1 beta levels, which identifies a genetically defined population that potentially carries higher risk of progression and that we will consider enriching for in our development program. We do believe, and will show you data, that many, if not all, the pathogenic drivers measured in GFORCE-1, so in a CVD context, will be relevant in other indications as well, turning our GFORCE-1 results into a broadly valuable translational data package.

Taken together, our clinical data, including the safety profile across all dose levels and the wide therapeutic margin, support broad development of MRT-8102 across multiple NEK7 NLRP3-driven diseases. Now, let's spend a few minutes to go deeper into the rationale and the disease biology and why we chose to target NEK7. As seen on slide 5, multiple intrinsic and genetic factors can promote NEK7-mediated assembly of the NEK7 NLRP3 complex. NEK7 NLRP3 activation triggers pyroptosis and the release of inflammatory cytokines such as IL-1 beta and IL-18 DAMPs such as HMGB1 and calprotectin, and other disease-promoting factors. Cytokines drive multiple downstream inflammatory pathways, while DAMPs further amplify NEK7 NLRP3 activation, creating a self-sustaining cycle of pathway activation that, if left unchecked, promotes tissue injury and remodeling.

This feedforward biology is a key driver of pathology across NEK7 NLRP3-mediated diseases, but in particular in ASCVD, gout, and HS, and we refer to this broad cascade of events as the NEK7 NLRP3 pathway or signaling cascade. Because the NEK7 NLRP3 complex sits upstream of these pathogenic processes, we believe that targeted degradation of NEK7 may deliver meaningful therapeutic benefit across the already mentioned and additional NEK7 NLRP3 relevant indications. Moving to slide 6. We have mentioned our excitement of pursuing clinical development in ASCVD, gout, and HS. So let's walk through where this excitement is coming from. This slide summarizes our internal analysis of publicly available disease-centric RNA-seq data sets, asking which diseases show the most NEK7 NLRP3 activation. To do this, we performed an unbiased enrichment analysis across hundreds of diseases using an in-house curated NEK7 NLRP3 activation signature.

ASCVD, gout, and HS emerged among the highest-scoring indications. Importantly, diving deeper into the data, now on a single gene level, all three indications showed consistent upregulation of NLRP3 itself and of associated downstream cytokines and DAMPs in diseased tissue relative to healthy tissue. We believe this consistent elevation of both NLRP3 itself and its downstream pathogenic mediators suggests that the pathological consequences of NEK7 NLRP3 activation are conserved across indications spanning various organ and tissue types, and supports that learnings from one indication, and in particular from our GFORCE-1 data, can be extrapolated to other indications in the future. Collectively, we believe these data support the relevance of NEK7 NLRP3 signaling in these indications and our prioritization for future development of MRT-8102. Moving to slide 8. Let's now focus on the rationale for and our excitement around ASCVD and CAD in particular, and why we think targeting NEK7 will be superior to any other approach in the pathway.

We believe the conventional view of the NEK7 NLRP3 pathway has been oversimplified, overlooking the complex biology it drives within atherosclerotic plaques. As shown on this slide 8, NEK7 NLRP3 and its downstream effectors affect multiple aspects of plaque biology, influencing multiple cell types and processes that collectively drive atherosclerosis and atherothrombosis. NEK7 NLRP3 activation in plaque-resident monocytes and macrophages drives the release of IL-1 beta, IL-18, DAMPs, and prothrombotic mediators that collectively promote endothelial cell dysfunction, oxidized LDL retention, and foam cell formation, smooth muscle cell remodeling, vessel wall alterations, and thrombosis. Together, these changes accelerate plaque growth, instability, and atherothrombosis, eventually raising the risk of cardiovascular events.

We believe only upstream targeting of the pathway, for example, through NEK7 degradation and NEK7 NLRP3 disassembly, will be able to control this complex biology to a point where therapeutic benefit can be derived. So in the following few slides, allow me to provide clinical and scientific evidence for what we just explained. We will show you how colchicine, a drug that blocks NLRP3 signaling by acting on the NLRP3 complex, has shown positive clinical outcomes as opposed to recent results with an IL-6 antibody that acts further downstream. Interestingly, colchicine has been shown to block NLRP3 complex formation, so acts similar to MRT-8102, albeit by a quite different mechanism. It blocks the function of cytoskeletal components important for this process and hence has a much narrower therapeutic margin. We will also show you human genetic data demonstrating the superiority of upstream targeting.

Lastly, we will provide you our analysis of ASCVD risk factors, again, showing that the upregulation of many upstream ASCVD pathogenic drivers carries more significance than downstream markers like IL-6. Slide 9 shows a summary of important clinical trials completed in this space. We believe the results of these trials support targeting the upstream nodes of the NEK7 NLRP3 pathway in general and of NEK7 in particular. For example, as opposed to ziltivekimab, an antibody to IL-6 that targets the downstream acute phase response and that failed to reduce MACE compared to placebo in a clinical trial called ZEUS. Colchicine led to significant MACE reductions in two trials, the LoDoCo2 and COLCOT trials. Both trials had focused on patients with stable CAD post-myocardial infarction.