Monte Rosa Therapeutics Inc Aktie

Greetings, and welcome to the Monte Rosa Therapeutics conference call to discuss the company's clinical results from the GFORCE-1 Phase I study of MRT-8102. [Operator Instructions] As a reminder, this conference is being recorded. It is now my pleasure to introduce Andrew Funderburk, Chief Investor Relations and Strategy Officer at Monte Rosa. 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; and Manav Korpal, 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 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. 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 Presentations 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 three 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 the 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. And 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 confirmed now that MRT-8102 does exactly what we designed 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, and 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 over 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 and 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% to 90% in line with what we had seen in the SAD/MAD portion of the Phase I trial and 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 CBD 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.

The feed forward biology is a key driver of pathology across NEK7/NLRP3 mediated diseases, but in particular, in ASCVD, gout and HS can be referred to this broad cascade of events as the NEK7/NLRP3 pathway or signaling cascade. Because NEK7/NLRP3 complex sits upstream of these pathogenic processes, we believe the targeted degradation of NEK7 may deliver meaningful therapeutic benefit across the already mentioned and additional NEK7/NLRP3 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 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 higher 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 disease tissue relative to healthy tissue. We believe this consistent elevation of both NLRP3 itself and its downstream pathogenic mediator suggest that the pathological consequences of NEK7/NLRP3 activation are conserved across indications, spanning various organ and tissue types, and support the 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 after thrombosis eventually raising the risk of cardiovascular events. We believe only upstream targeting of the pathway, for example, through NEK7 degradation and NEK7/NLRP3 disassembly, we'll 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 act 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 human genetic data demonstrating the superiority of upstream targeting. And 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. So for example, as opposed to ziltivekimab, an antibody to IL-6 that targets the downstream acute phase response and that fail to reduce MACE compared to placebo in a clinical trial called ZEUS. Colchicine led to significant MACE reductions in two trials, LoDoCo2 and COLCOT trials. Both trials had focused on patients with stable CAD post-myocardial infraction. Not shown on this slide, in addition to these trials, colchicine was also tested in a more acute setting within 72 hours of a myocardial infarction in the CLEAR SYNERGY trial. Although CLEAR SYNERGY was ultimately neutral, patients enrolled before the COVID-19 pandemic and those on the original twice-daily colchicine regimen showed MACE reduction. The trial was then substantially affected by the COVID-19 pandemic, leading to disrupted dosing schedules, underreported events and access non-cardiovascular deaths as well as a protocol amendment that lowered the colchicine dose.

Beyond these landmark trials, we believe broader clinical evidence, including several matter analysis of patients treated with colchicine further reinforce the importance of upstream targeting of the NLRP3 pathway. [indiscernible] which is no increased infection risk was seen in treated patients. While colchicine is approved to reduce MACE in patients with established atherosclerotic disease and patients with multiple risk factors for cardiovascular disease, it is only partly prescribed due to its significant GI and other side effects. In addition to colchicine, canakinumab and IL-1 beta targeting antibody also led to positive MACE effects with a hazard ratio of 0.85. However, due to the broader role of IL-1 beta across multiple inflammasomes and in other immune pathways, the drug showed an increased rate of severe and lethal infections and we understand that, that was the reason why the drug did not make it to an approval.

Human genetic data are also very supportive of the NEK7/NLRP3 complex as a target for upstream ASCVD. Indeed, there are two known activating SNPs in NLRP3 that have been studied extensively. The graph on the left of Slide 10 shows that the NLRP3 TT risk allele variants that activate the NEK7/NLRP3 signaling cascade are associated with the 1.6 to 2.3-fold higher odds of CAD across independent cohorts. By contrast, an established IL-6 receptor protective allele is only a very modest protective benefit in all comers. The hazard ratio for that for that protective allele, while statistically significant is 0.97 and it required analysis of hundreds of thousands of patients to gain certainty about its impact. A benefit for the IL-6 receptor allele is only obvious in the small subset of CHIP associations with clonal hematopoiesis of indeterminate potential, a condition that directly drives IL-6 expression. As shown on the right, NLRP3 risk on new carriers also show a markedly elevated NLRP3 dependent expression of key pathogenic drivers of ASCVD, including for IL-1 beta. Something we have also looked at in GFORCE-1 as you will see soon.

Finally, as shown on Slide 11, many upstream pathogenic ACV drivers, including DAMPs like calprotectin, S100A12, and the thrombogenic factor SAA and cytokines like IL-1 beta are not just upregulated in human atherosclerotic clots in general, they are even more upregulated in unstable atherosclerotic clots, so it's no surprise, and this is what is shown on the right, that all these key ASCVD pathogenic drivers are independently associated with higher CV risk and they appear to be linked to significantly higher risk than IL-6 or LP(a) as a comparison. Taken together, we believe that the human genetic association of NLRP3 risk alleles with CVD, the past clinical trial results with colchicine and canakinumab and the dominant role of IL-1 beta and DAMPs and plaque in vessel biology and as independent CVD risk factors provide strong support for targeting the NEK7/NLRP3 pathway as far upstream as possible.

At points in the cascade where intervention has the potential to modulate a broader network of pathogenic drivers and cellular processes contributing to plaque initiation, progression and instability. Furthermore, we believe that NEK7 is the optimal target for such upstream intervention.

With that, I will hand it over to Filip and then Manav to describe how our GFORCE-1 data further support and validate our hypothesis. Filip will start by walking you through the study design and pharmacodynamic and safety results. Manav will then present data from our unique transitional approach with a focus on determining MRT-8102's impact on key molecular drivers of atherosclerotic plaque formation, progression, instability and rupture including many of the DAMPs mentioned before as well as IL-1 beta.

Thank you, Markus. Slide 13 outlines the GFORCE-1 study design. As Markus mentioned, given the promising activity and safety data we generated for MRT-8102 in our SAD/MAD study, which we disclosed earlier this year, we advanced MRT-8102 into a randomized double-blinded placebo-controlled dose exploration study to obtain additional activity data while also enrolling subjects with increased risk for developing atherosclerotic cardiovascular disease. To this end, our GFORCE-1 study was designed to enroll obese participants with elevated CRP levels ranging from 3 to 50 milligrams per liter, placing them at increased risk for developing atherosclerotic cardiovascular disease.

Participants were randomized to receive 5, 20 or 40 milligrams of MRT-8102 or placebo once daily for 28 days, followed by a 28-day safety follow-up. Primary endpoints included safety and tolerability, while secondary endpoints included changes in pharmacokinetics and hsCRP. Exploratory endpoints assessed NEK7 expression levels, inflammatory and atherogenic DAMPs, cytokines, lipids, lipoproteins and other pathogenic factors relevant to the development of atherosclerosis.

Slide 14 details baseline characteristics of our study participants, which were generally well balanced across the treatment groups. Participants had a median age of 41 years, so approximately 20 to 30 years younger compared to a typical, fully established ASCVD population. And the median BMI of approximately 34 kilograms per square meter with elevated hsCRP consistent with an inflammatory cardiovascular risk population. Importantly, there were no meaningful baseline differences across groups that would be expected to impact interpretation of the study results.

Turning to Slide 15. MRT-8102 demonstrated robust degradation of NEK7 across all three dose levels tested, this 80% to 90% degradation noted in peripheral blood T cells and no apparent dose dependency. The level of degradation in GFORCE-1 was comparable to the marked degradation noted after both single and multiple administrations in the SAD/MAD healthy volunteers portion of the study. In summary, these data demonstrated rapid, robust and sustained degradation with continued dosing of up to 4 weeks.

Turning now to our study results. We will begin with a review of our unblinded safety data, which we are happy to report demonstrated favorable safety profile. Slide 16 details unblinded safety data for participants enrolled in GFORCE-1. Safety data were collected over 8 weeks for 108 participants, of which 81 were treated with MRT-8102 across three dose levels, and 27 were treated with placebo. No serious adverse events were reported. Treatment-emergent adverse event rates, which reflect any AEs on treatment regardless of attribution to drug, they were similar between MRT-8102 and placebo with rates of 33% and 30%, respectively. 86% of events were grade 1, with the most common events being headaches and otalgia, both occurring at similar rates between MRT-8102 and placebo. As we previously disclosed, there was one episode of grade 3 elevation of liver enzymes in a participant with an incidental finding of asymptomatic hepatitis A. There was also one episode of grade 3 shoulder pain in a patient with accidental shoulder dislocation. No serious infections were reported and overall infection rates were similar at 7% in both groups.

In summary, overall safety over 8 weeks was comparable to placebo across the dose range evaluated. Slide 17 provides safety data in more detail. Over 4 weeks of dosing, followed by 4 weeks of additional safety observation for a total of 8 weeks. MRT-8102 was generally well tolerated with no serious adverse events. No adverse events of neutropenia or thrombocytopenia were observed across any dose group. In addition, to the above-referenced hepatitis A case in the 40-milligram cohort, there were seven other treatment discontinuations, four in the 40-milligram cohort and three in the 20-milligram cohort, mostly related to grade 1 events. Importantly, and as mentioned, infection rates were balanced across all groups, including placebo, with no serious infections reported. Overall, these data support a favorable safety profile and establish a wide, safe dose range to move forward with our three prioritized indications. As we will discuss in a few minutes when we review our Phase II development plans, we will use the now defined safe dose range of 5 to 40-milligram to determine an optimal dose range for each indication.

I'll now hand the call over to Manav to review our data on the clinical activity of MRT-8102 and pathogenic drivers of ASCVD. Manav?

Thank you, Filip. Before we take a deep dive into the clinical activity analysis, it's important to understand the GFORCE-1 population as detailed on Slide 19. These were subjects with obesity and elevated cardiovascular risk but without a requirement for established ASCVD. Interestingly, a large prospective study published this year by Bundgaard and colleagues suggests that up to 70% of asymptomatic adults aged 40 to 49, which is comparable to the median age of our GFORCE-1 cohorts, had detectable atherosclerosis. This study, coupled with another published by Yang and colleagues in 2013, highlighting that CRP and BMI independently associated with vascular inflammation strongly suggests our GFORCE-1 population is likely enriched for participants bearing vascular inflammation and or plaque burden.

Consistent with this, the baseline profile of our GFORCE-1 subjects showed the expected elevations in ASCVD associated drivers and broadly tracked with patterns reported in established ASCVD. Although the magnitude of elevation may not necessarily be equivalent. We used the healthy volunteer cohort from the SAD/MAD portion of our trial as a real world reference for normal physiological levels of local pathogenic drivers of ASCVD and systemic biomarkers, and we explored whether human genetic features, in particular, activating SNPs and NLRP3 led to higher baseline levels in key pathogenic ASCVD drivers in our GFORCE-1 cohort.

With that context in mind, I'll now walk you through the framework we use to interrogate key pathogenic drivers contributing to ASCVD. As shown in Slide 20, directly downstream of NEK7/NLRP3 activation, we looked at proximal markers that might inform on atherogenic and vascular processes, including IL-1 beta, DAMPs and thrombogenic factors. These markers can inform on vascular remodeling status, and they have well-characterized roles across multiple aspects of plaque biology, including plaque initiation, progression, destabilization and thrombosis. Further downstream, we assess IL-6 and CRP, which reflect the systemic acute phase response. So overall, this framework allows us to examine the entirety of the pathological cascade from proximal plaque and vascular biology to the downstream systemic response.

Now let's turn to data from our study. Slide 21 shows the baseline levels of the aforementioned proximal and a few distal or systemic markers in our GFORCE-1 population compared to what we saw in our healthy volunteer reference population. In brief, and importantly, we see coordinated elevation across the above delineated cascade of both proximal and distal ASCVD drivers and markers. So even without confirmed ASCVD, as mentioned, it appears the pathogenic biology relevant to cardiovascular disease is engaged in a subset of subjects that reinforces the strength of our study designs.

Moving to Slide 22. Having seen elevated baseline levels of various ASCVD relevant drivers we want to take things a little further, and we next look at whether the NLRP3 risk alleles that Markus had referenced during his intro are associated with those elevations. As discussed, and NLRP3 gain of function SNPs are significantly associated with higher odds of coronary artery disease as supported by multiple independent data sets. These moderate to high-risk genotypes are not uncommon. In fact, our analysis shows that activating NLRP3 SNPs are highly prevalent in the GFORCE-1 population. Nearly 1 in 3 subjects carried the highest risk genotype and more than half carried a moderate risk genotype.

Importantly, in GFORCE-1, the underlying genetics were compellingly associated with higher levels of DAMPs, IL-1 beta and acute phase response proteins at baseline extending literature findings to DAMPs. This provides evidence of increased pathway activity in NLRP3 risk gene carriers and support the potential use of NLRP3 genetic profiling to enrich for patients more likely to bear NLRP3-driven CV risk.

Now let's discuss the impact of MRT-8102 treatment on proximal pathogenic markers, like DAMPs and IL-1 beta. All known to play a significant role in plaque and vascular biology and atherogenic progression.

Slide 24 dives deeper into the biology of DAMPs, pathogenic drivers that have long been underestimated in their significance in ASCVD. Indeed, a substantial body of evidence indicates that DAMPs function as potent amplifiers of inflammation across various diseases creating a feed forward loop that reinforces NEK7/NLRP3 activation and propagates pathogenic signaling. They also, as shown before, tend to be more meaningful ASCVD risk factors than downstream cytokines like IL-6. As an example, calprotectin is a well-studied DAMP implicated in ASCVD. As we discussed, calprotectin is significantly enriched in unstable plaque and is independently associated with increased cardiovascular risk. Consistent with this, and as shown on the right side, circulating calprotectin levels correlate with greater plaque burden while plaque calprotectin expression is enriched in atherosclerotic lesions and closely associated with features of plaque instability. Similar data also exists for other DAMPs that are released by NEK7/NLRP3 trigger keratosis.

Moving to Slide 25. In cell-based assays, we functionally confirmed MRT-8102 potently inhibits pyroptosis and hence, release of IL-1 beta and multiple DAMPs, including calprotectin. By contrast, IL-1 and IL-6 biologics fail to inhibit pyroptosis, do not block the release of DAMPs and only neutralize IL-1 or IL-6, respectively. This is a critical mechanistic distinction that functionally supports the therapeutic potential of upstream targeting in this crucial signaling cascade.

Let's now turn to the clinical data demonstrating these effects in humans. Slide 26 shows our data on how treatment with MRT-8102 affects levels of calprotectin. At baseline, calprotectin levels were elevated versus healthy volunteers, as shown on the left. Following treatment with MRT-8102, calprotectin declined rapidly with a market reduction by week 4, moving down to levels equivalent to what was measured in healthy volunteers. This analysis is across the three treatment cohorts grouped together.

Breaking this out by dose level, Slide 27 illustrates consistent reduction in calprotectin across all three dose cohorts. At all doses, calprotectin was reduced by approximately 50% to 60% and with levels at week 4 returning to the range observed in healthy volunteers. This consistency across doses is also aligned with the NEK7 degradation profile shared earlier. Given the consistent activity across the dose levels in the next set of analyses for simplicity, we'll group all three dose levels together. Slide 28 presents an analysis for two additional pathogenically relevant DAMPs, S100A12 and SAA. Although the magnitude of elevation in GFORCE-1 was more modest as compared to calprotectin, we did observe a significant reduction in both after 4 weeks of dosing. As with calprotectin, these reductions brought levels back to those observed in healthy volunteers.

Now let's turn to two additional significant local ASCVD drivers, HMGB1 and IL-1 beta, both of which have been shown to work in concert to drive plaque formation, progression and rupture in ASCVD. As a matter of fact, if you remember the earlier analysis of ASCVD risk factors, these are the two highest ranking risk factors, and modulation of these will be key for successfully improving MACE outcomes.

Slide 29 focuses on the role of HMGB1 and IL-1 beta and how they work together. After being released from monocytes and macrophages following NEK7/NLRP3 activation, HMGB1 acts across multiple plaque residue cell types, promoting endothelial cell activation and vascular smooth muscle cell remodeling. HMGB1 itself can further trigger NEK7/NLRP3 dependent IL-1 beta production and vice versa, IL-1 beta itself can further amplify HMGB1 release and contribute to local inflammation and matrix remodeling. Consistent with this biological crosstalk, HMGB1 and IL-1 beta show a strong correlation at baseline in our GFORCE-1 population supporting coordinated modulation of this proximal disease driving access.

Moving on to Slide 30. We now take a look into whether both HMGB1 and IL-1 beta are elevated in our GFORCE-1 population and are similarly impacted by MRT-8102 treatment. Indeed, as shown on the left, HMGB1 was elevated at baseline in at least a subset of GFORCE-1 subjects relative to healthy volunteers, although not as dramatically as calprotectin. Importantly, among participants with baseline HMGB1 levels above 4.7 nanograms per milliliter, representing the upper quartile in the study population, MRT-8102 treatment reduced HMGB1 levels by 40% by week 4, bringing levels closer to those observed in healthy volunteers and to the median of the group.

We next examined endogenous baseline and treatment-induced levels of a highly inflammatory cytokine IL-1 beta as shown on the right. Importantly, these data reflect endogenous circulating plasma levels of IL-1 beta, so they're not derived from artificial ex vivo stimulation experiments as typically shown by others. Also keep in mind that circulating levels of IL-1 beta are usually difficult to detect as IL-1 beta is mostly tissue resident, so we applied a high sensitivity assay to reliably quantify the extremely low levels that are circulating in plasma. In healthy volunteers, IL-1 beta values cluster tightly, which is expected for a cytokine this potent and active. That said, a significant elevation of baseline IL-1 beta levels was observed in GFORCE-1 subjects, further confirming the enhanced inflammatory state of this cohort. Finally, similar to HMGB1 and those with upper quartile baseline levels, there was a significant treatment-induced reduction of 37% by week 4, bringing them closer to healthy volunteer levels.

Taken together with the data shown before, the overall pattern of down modulating DAMPs is consistent with selectively lowering elevated key pathogenic drivers of ASCVD toward physiological levels and validates NEK7 degradation by MRT-8102 as a potential path to controlling plaque and vessel wall resident pathological changes in ASCVD.

Building on the data for upstream drivers of plaque progression in ASCVD, we next turn to proximal thrombotic factors as shown on Slide 31. While tissue factor and fibronectin were not elevated at baseline, fibrinogen levels were clearly increased in GFORCE-1 subjects compared to healthy volunteers. Over 4 weeks of treatment with MRT-8102, median fibrinogen decreased by about 28%, returning to levels observed in healthy volunteers while placebo showed no meaningful change.

Having established consistent modulation of proximal NEK7/NLRP3 associated [ levers ], we next move downstream to markers of systemic inflammation and the acute phase response. While these markers are further removed from the NLRP3 complex and potentially not as significant in driving ASCVD, they do provide an important readout of whether proximal pathway modulation translates into broader systemic effects. To this end, we assess the baseline and therapy-induced changes in the IL-6 CRP access.

As shown on Slide 33, MRT-8102 produced a rapid and sustained reduction in CRP across all dose levels, normalizing from elevated GFORCE-1 baseline towards healthy volunteer levels. Notably, 88% of subjects achieved reductions of CRP to below 2 milligrams per liter, a threshold associated with lower cardiovascular risk as defined by the CANTOS trial. As expected, IL-6, the cytokine that induces release of CRP from the liver showed a similar normalization to a lower risk healthy volunteer range.

In summary, NEK7 degradation and inhibition of the NEK7/NLRP3 signaling cascade appears to translate meaningfully into reduction of systemic inflammation. Collectively then, the comprehensive analysis we shared today demonstrates that MRT-8102 can optimally reduce pathologic levels of multiple drivers that are relevant to plaque formation, progression and rupture as well as vessel wall remodeling back to normal physiological levels that are equivalent to the levels we found in our healthy volunteer population.

Based on these findings, we're very excited about the opportunities presented by MRT-8102. With that, I'll turn the call back to Filip to provide an update on our clinical development plans for MRT-8102. Filip?

Thank you, Manav. Slide 35 discusses our differentiated approach to a Phase II study of MRT-8102 in CAD, a subset of ASCVD. Our goal is to inform an innovative and efficient design of a future Phase III study focused on a patient population in [ this liable ] disease and the highest need for intervention. We plan to build on the learnings from prior anti-inflammatory cardiovascular trials that showed MACE benefit in stable CAD populations, supporting intervention during the chronic phase when residual inflammatory risk persists.

While we continue to refine our dose exploration and build our safety data set in a chronic disease setting, we will use GFORCE-2 to optimize our strategy for imaging, biomarker and genetics-based enrichment of high-risk patients with potential for more significant MACE benefit in a future Phase III trial. We will use coronary artery imaging, including fat attenuation index or FAI as a means of assessing plaque inflammation at baseline and during the course of treatment. We will evaluate the modulation of upstream pathogenic drivers of atherosclerosis and thrombosis, including DAMPs, cytokines and thrombogenic factors. Finally, we'll confirm the impact of NLRP3 risk alleles for NEK7/NLRP3 pathway activation, the impact on baseline of regulation of pathogenic drivers of ASCVD, responsive dose to MRT-8102 and any FAI changes.

Slide 36 lays out the trial schematic. GFORCE-2 is a Phase IIb study in approximately 160 patients with stable coronary artery disease and residual inflammation. Patients will be randomized across three MRP-8102 dose levels, 5 milligram, 10-milligram and 15-milligram or placebo and treated for 6 months. The study is designed to provide proof of concept by assessing changes in plaque biology through cardiac imaging and investigating changes to levels of key molecular drivers of ASCVD as well as systemic biomarkers, thrombogenic factors and lipids and lipoproteins. We will also confirm frequency of the NLRP3 moderate and high-risk genotypes, along with pharmacogenomic correlations, liver inflammation and any impact on anemia. We believe the 6-month treatment period will be important to fully evaluate imaging and analysis of plaque inflammation through FAI. With these extensive changes from our original design, study initiation is now planned for the first half of 2027.

Now I'd like to briefly discuss two additional Phase II studies we are planning for MRP-8102 shown on Slide 37. Our GEMINI-1 study will seek to establish proof-of-concept for the prevention of flare recurrence after management of an acute gout flare with study initiation expected in Q4 2026 or Q1 2027 with a data update expected in the second half of 2027. We expect to enroll around 60 patients with recurrent gout flare with end points, including reduction in pain score at 72 hours and frequency of new flares over 12 weeks of treatment. Our Phase II GALAXY-1 study, detailed on the right, will evaluate efficacy and safety in moderate to severe HS. We plan to enroll around 160 patients randomized to MRT-8102 or placebo, with the primary efficacy outcome being HiSCR75 after 16 weeks of treatment. Trial initiation is expected in the first half of 2027.

I'll now hand the call back to Markus to wrap up.

Thank you, Filip. Let's now turn to the big picture on the CAD opportunity. As shown on Slide 39, CAD remains a very large market with around 14 million patients in the U.S. Current ASCVD therapies address important individual drivers of disease but substantial residual inflammatory and thrombotic risk remains. Even patients who reach LDL targets can continue to experience cardiovascular events in part because chronic NEK7/NLRP3 driven inflammation and plaque is not adequately addressed.

The recent very large study showed that patients with plaque inflammation measured by FAI scores have strikingly up to nearly 30x greater risk of cardiac mortality. MRT-8102 is designed to target this NLRP3-mediated inflammatory risk with an oral therapy that could offer a favorable safety and tolerability profile and fit naturally alongside current standard of care treatments.

Slide 40 highlights the compelling opportunities presented by the three indications we're pursuing with MRT-8102. Looking beyond the CAD opportunity I just spoke about, we see a large opportunity in gout and in HS. Gout is a canonical NEK7/NLRP3 pathway disease. As is well documented in literature, MSU crystals trigger NEK7-mediated, NLRP3 assembly, driving IL-1 beta release and flare pathology. Breakthrough flares are common in gout patients despite standard of care therapy and flare prophylaxis is a major unmet need. It's notable that in a large physician survey, we conduct an over 55% of gout treating physicians indicated they were unsatisfied with current prophylaxis options.

Turning to HS. HS has the highest NLRP3 pathway activity scores of any indication we studied with consistent upregulation of NLRP3, IL-1 beta and DAMPs and lesional tissue. A large portion of patients are poorly managed with standard of care, and IL-1 antibodies provide a promising proof of concept for this approach in HS. Remarkably to date, no targeted oral immunomodulatory therapy has been approved for HS. We believe our NEK7 directed molecular glue degrader approach, has the potential to deliver a differentiated therapy for each of these indications and that the data presented today compels the continued development of MRT-8102 across CAD, gout and HS.

Moving to Slide 41. We believe that the remarkable data from GFORCE-1, especially the impact we are seeing on proximal disease drivers, including TAMs and IL-1 beta, validate NEK7 degradation using MRT-8102 as a differentiated broadly applicable approach to NEK7/NLRP3 driven diseases. The study demonstrated a favorable safety profile across all doses with no SAEs and no infection signal. We achieved robust sustained degradation of NEK7 at all dose levels. We saw broad clinical activity on local pathogenic drivers of ASCVD as well as systemic inflammatory biomarkers with all these reduced to healthy volunteer levels at all dose levels tested.

Finally, we identified patients carrying NLRP3 risk alleles as a potential genetically enrichable population with the further potential to correlate it with imaging-based plaque inflammation and morphology in future studies. We look forward to the launch of multiple Phase II studies to explore the potential of MRT-8102 in NEK7 and NLRP3-driven diseases, starting with our GEMINI-1 gout study initiating in Q4 this year or Q1 next year, followed shortly after by our GFORCE-2 CAD study and GALAXY-1 HS study in the first half of 2027. Moreover, our next-generation NEK7 degrader MRT-9347 will enter a first in-human study later this year.

Finally, on Slide 42, I'll have just a few additional highlights on the rest of our pipeline. We were pleased to see our collaborator Novartis activate two large Phase IIb studies for our VAV1-directed MGD, MRT-6160. Both the study in Sjögren's disease and the psoriatic arthritis study are now enrolling patients. We look forward to additional Phase II initiations to continue to broadly explore the potential of MRT-6160, across multiple immune-mediated diseases.

For our GSPT1 directed MGD, MRT-2359, we plan to present an update on our Phase I study in castration-resistant prostate cancer where we combine MRT-2359 with enzalutamide later this year. The confirmatory Phase II study of MRT-2359 in combination with apalutamide in ER mutant castration-resistant prostate cancer is now also actively enrolling, and we look forward to providing a clinical update in 2027. We also expect IND submissions for our CDK2 and cyclin E1 directed MGDs in 2027. In summary, with now three programs currently in or quickly approaching Phase II studies and multiple additional assets moving through IND-enabling studies, there has never been a more exciting time for Monte Rosa.

With that, I'll open the call for questions. Operator?

[Operator Instructions] Our first question comes from the line of Edward Tenthoff with Piper Sandler.

And I just blown away by the thoroughness of this data update and all the different markers and information it provided, really incredibly thorough, incredibly helpful. My question has to do with GFORCE-2 and the Phase IIb study. Appreciating that the outcome markers are going to be both imaging and pathogenic ASCVD drivers. Ultimately, I would anticipate this might require a cardiovascular outcome study. How is that data going to strengthen your understanding of what you might be able to show in terms of MACE or other outcome measures?

Thank you for that. Yes. So our plan, as you kind of correctly pointed out, is to use the GFORCE-2 to find the higher risk, but at the same time, modifiable subpopulations which then can be actually tested in the subsequent outcome study because in the Phase IIb with the 6 months administration, it's unlikely even in the population of patients with coronary artery disease, it's unlikely actually to see the outcome difference because the total number of the potential events actually will be quite low. But what we can do in the Phase IIb in GFORCE-2 is we actually can connect the plaque morphology through the imaging as the modulation of the critical disease drivers and how these relate to potential genetic features, as Markus just pointed out, particularly the SNPs in the NLRP3, the activating SNPs in the NLRP3. And that actually will ultimately allow us to have more efficient clinical trial design, the subsequent Phase III design, which will potentially -- which is expected to show the difference in outcome.

So you would potentially look for genetic drivers to -- or other factors to focus the population for a potential Phase III trial?

Potentially, yes. And I mean the expectation of the GFORCE-2 is that we will understand how these factors kind of all connect together and how they potentially relate to the local plaque biology, which as well as to some other markers associated with the [indiscernible] and systemic inflammation.

Our next question comes from the line of Michael Schmidt with Guggenheim.

I'm trying to better understand the predictability of the DAMP reductions that you sort of highlighted. And yes, maybe talk a bit more about how meaningful this sort of 50% reduction is. How strong is that sort of correlative data? Or is it just about normalizing levels of those DAMPs?.

Obviously, we view normalization as the way to go, I think, in previous meetings, we always emphasized it like taking a downstream cytokine out completely probably will lead to an infection risk because these cytokines are typically also important elsewhere, bringing local factors back to physiological levels in that context makes a ton of sense, right? Because you're now basically at the status of a healthy volunteer from a risk point of view. But obviously, the rest of your immune system in host defense can still appropriately respond. In particular, we're, of course, sure this would also go through some of the other inflammasomes.

Ultimately, of course, the next step here, as [indiscernible] has pointed out, is to now connect the normalization of DAMPs and IL-1 beta as a critical cytokine correlated to a plaque morphology and inflammation status by imaging. I think if we can build that connection, and then again, as Filip referred to connect both of the two genetic features, I think we should have a lot of evidence and, of course, also like a lot of confidence to move into an outcomes trial that hopefully would be run more efficiently which means fewer patients, faster and, of course far less cost.

And how do you interpret the IL-1 beta reduction seen in the GFORCE-1 study, perhaps in terms of translation to some of the more IL-1 beta-driven conditions like gout? And have you looked at IL-18 as well? Just curious.

Yes. Obviously, I'm super excited about those results. IL-1 beta, and we've pointed this out, Michael, in some of our previous conversations, super hard to measure in the blood. I think there's very few companies that present IL-1 beta blood data. We were fortunate to be able to establish an assay that's sensitive enough. If you looked at the Y axis, I mean, you're talking sample grams here, right? So these are low levels, IL-1 beta, just like HMGB1 tends to not go into the system. These are more tissue resident which will not be very different in gout and HS. And so seeing that and seeing that level of reduction we find super encouraging, hence obviously, super confident as we move into gout first and then together with GFORCE-2 also into HS.

And then just last question, just going back to the possible patient selection strategy in Phase III. I mean are you considering using genetic factors like an NLRP3, SNPs as a possible selection criterion or will it be more likely focused on specific clinical features?

Well, again, it depends, right? I mean obviously, if imaging, like perfectly correlates with NLRP3 SNPs, you would likely prefer imaging because that's a more established modality in ASCVD to characterize baseline inflammation. But I have to say, like the level of biomarker increase we're seeing here is very convincing. And so at the end of the day, the frequency of homozygous GGs already is 30%. And if you count in the [ GGs ], the ability to get over 50%, at the end, this becomes quite feasible even from a genetic selection point of view. Definitely, all the data we have for now suggest that there will be a population at higher risk, but still modifiable, and so it could, as I said, allow us to run a more efficient, smaller, faster Phase III trial at the end of the day.

Our next question comes from the line of Tyler Van Buren with TD Cowen.

This is Ikenna on for Tyler. It's great to see the updated, robust data. I had a question, what biomarkers or pathogenic drivers do you believe are most validated for predicting plaque progression? And which ones provide the strongest evidence that 8102 is affecting plaque biology rather than only the systemic inflammation? And I had a follow-up to that.

That's a bit the favorite child question. But I definitely think HMGB1 1, IL-1 beta as an access is absolutely crucial, I would go as far as if you're not modulating these two, it's going to be hard to see meaningful MACE activity. Obviously, we wish like the colchicine trials would have looked at these markets. Obviously, they didn't but like nice evidence obviously out there that even the lipid-lowering drugs like the statins, have an impact on HMGB1 expression, actually a quite significant impact. And so these are the two we will definitely look at.

I think, calprotectin obviously a little bit easier to measure, I think, would be another grade surrogate. At the end of the day, I mean, if you look at the aggregate data, and we didn't want to complicate things today with the heat maps and all sorts of fancy analysis, but on treatment, and these markets all start to correlate each other, right? So as you bring down HMGB1 and IL-1 beta, actually, your calprotectin also go down. Or maybe it's the other way around, we don't know. But the correlation at 4 weeks on treatment between those different DAMPs is really quite striking.

And for the other indications, HS and gout, are the same biomarkers relevant? Or are they different from ASCVD?

Definitely very, very similar, right? And we were trying to make the point in one of our intro slides. I mean if you look at existing data sets across these three indications, the pattern are strikingly different. I mean, if you would put that in front of me without a label for each of these diseases, I would have a hard time to assign the disease to the actual plots for those biomarkers. And so again, we really believe that what we're seeing in GFORCE-1 because of that similarity isn't just like sort of good data -- actually terrific data for ASCVD or CAD but also gives us a lot of guidance around gout and HS. And obviously, will really, really help us to also pick the appropriate doses per indication.

Our next question comes from the line of Derek Archila with Wells Fargo.

Congrats on the update. So just a couple of questions for us. So on the GEMINI-1 trial, I guess, this seems like this is going to be run without placebo, so what background rate of new flare should be assumed in the enrolled population?

Yes, Derek, it's a good question, this study will enroll patients with the acute flare and the incorporation of the placebo would not necessarily gain you much because like you have to allow the patients actually to use some rescue medications and like to a large extent, it's not really acceptable to have the patients with the acute flare to be on placebo. So in the reality, you wouldn't really have the placebo control, but you would have a very noisy rescue medications, which will be used in these patients. So I think from that standpoint, it doesn't really make much sense. The study also has a -- that's about acute flares, right? I mean the study also has another important goal, which is to look at what is the frequency of the flare recurrence during the 12 weeks of dosing. And in this one, I think you might make a case a little bit for placebo, but the expected effect size is actually quite large.

I mean, if you look at the historical data from a variety of trials, the frequency of the flares in this population, which will be the target population for the GEMINI-1, the expected flare rate is actually up to 60%. If you even find the most favorable data set, you will probably be somewhere in the 45% range while the expectation is that on the 8102, the expected flare rate will be actually much lower than that, so the effect size is actually quite sizable. So I think this trial actually is for the Phase II setting of the proof of concept appropriate.

And then on hidradenitis, I just want to get a better understanding on the translation here. Just for the doses that you're starting to evaluate, I guess, should we expect sufficient skin exposure to reproduce that direct IL-1 beta neutralization?

Yes, I think so. Yes, I think the data which we had from like a GFORCE-1, and subsequently, we will have them obviously from the GFORCE-2 as well. I mean, super relevant. I mean the MRT-8102 is a small molecule with the expected good penetration to the target issues. So actually, I think what we see now in the GFORCE-1 setting is very relevant to the other indications as well.

Our next question comes from the line of Faisal Khurshid with Jefferies.

Thank you so much for the really detailed presentation, felt like I was in grad school. I wanted to ask on the gout hypothesis, could you just explain to us how the NEK7 thesis compares to that of the URAT1 inhibitors? And I have another question as well.

Great question, actually. I love it because it is very complementary in regards to sort of the approaches, right? I mean, sure, URAT1 inhibitors will lower urate. Interestingly, this will likely still lead to quite a few flares, and it will be interesting to see how that actually impacts compliance with those drugs, right? But it's not a secret that urate-lowering drugs initially because they do mobilize urate and urate crystals have flares within at least the first 6 to 12 months. So long story short, we actually think that as an opportunity for us more than competition, right? As these hopefully come through in their clinical trials and hit the market, combining with something like 8102, great concept, right? Because then eventually, if you avoid flares in patients that are beginning to be on urate lowering drugs, you will definitely increase the compliance for both. So definitely, something on our radar as a potential development path on top of just the flare preventional approach in sort of the more regular, typical patient population.

And then I just wanted to ask for a clarification on the safety profile. I saw that 40 mg, it looks like you had three -- you said asymptomatic non-QVC grade 1 electrocardiogram changes. Can you just explain like what those were? And whether those are believed to be drug-related or not?

So we are not concerned by these findings at all, right? I mean, these changes were all grade 1 incidental and completely symptomatic, that's important to point out. These were kind of picked up on the regular frequent EKG so that -- which are done as a part of the Phase I study. And they were kind of associated with the change in the pattern of the T-a from the EKG and the -- so we've done appropriate workup and ruled out any ischemia or other organic heart pathology, which might potentially explain to them. So they are essentially changes which are not associated with any underlying organic cause which we can point out. It's also important to point out that we don't see any signals which will be related to QTc-related changes or anything like that. So overall, again, I would just explain that we are not concerned. And the -- looking at the overall totality on all AEs, the frequency of the AEs and MRT-8102 and placebo is nearly identical, it's 33% versus 30%.

Our next question comes from the line of Brian Cheng with JPMorgan.

This is Sarah on for Brian. The degradation of NEK7 and downstream impact, it really looks pretty similar across the 5, 20 and 40 milligram. What's driving dose selection for Phase II? So the pharmacodynamic profile seems largely saturated at the lowest dose. Can you expect a dose response that can be easily observable over the treatment course of 6 months in the GFORCE-2 trial? And then we have a follow-up after.

It's a great question. Obviously, we disclosed today that we're going to go forward with 5, 10 and 15 in GFORCE-2. We had a discussion whether we should go even lower. At the end of the day, obviously, we're trying to optimize GFORCE-2 for the maximum chance to see the correlation of imaging versus the plaque markets we're super interested in, and their genetics, and so we didn't really want to play around anymore with doses. In particular, in light of the safety that we're seeing here, I don't think you have many other molecules in this pathway that carve out such an impressive safety margin. So long story short, no, we're not expecting to see a dose response. But in the longer term setting, this will be 6 months, obviously, not 4 weeks. You never know until you eventually analyze the [indiscernible]

When you think about the other indications that are fundamentally different than heart disease, is there a need to treat the dosing just given the differences in tissues that you're aiming for? Especially like the diseases in gout and HS?

Another great question. Let me maybe start by just sort of making a point here that we really like this lineup of indications, right? I mean it's sort of proving the same pathway. And again, we made the point that the pathway overlaps very nicely, literally down to the actual disease drivers downstream that you want to measure, but they have different aspects, right, just like the chronic inflammation in ASCVD kind of a pure play NLRP3 or NEK7/NLRP3 signaling cascade disease. You have gout with an acute component, at least in that initial trial induced by crystals and then we sort of augmenting side of the pathway with HS, which gets to your actual question, yes, we are considering different dose levels. Part of it is sort of like getting into different organs. Part of it is also the acuteness of the disease.

I think you probably want to go higher in gout than you are starting in an acute situation, if you were in a preventative setting, so where you're just like trying to prevent future flares, maybe it could be lower. Again, really great that we have this very wide window now. I mean we're talking, just to keep it simple, roughly a 10-fold window and it could even be higher because, again, like who knows how we continue to be safe even above 40-milligram because there's a lot of opportunity to play around with a dose per indication and obviously, also in regards to the future commercialization and labels.

Our next question comes from the line of Oliver McCammon with LifeSci Capital.

Congrats on the data. Just given today's update, I'm curious in your level of confidence in an infection signal not emerging with 8102, particularly with longer dosing? And then separately, what would you need to see from GFORCE-2 in order to pursue a registrational strategy in ASCVD?

Confidence on infections is very high for two reasons, right? A, we believe that colchicine and the lack of an infection risk tells the story, right, like going after the NLRP3 pathway upstream sparing all other inflammasomes and other immune pathways really does the trick. I think what we have seen in regards through infection risk bias for both IL-1 beta and IL-6 really relates to just like taking these types of kinds out more or less completely where we at least have a broad function, not just in NEK7/NLRP3 signaling, and that sort of gets us back into the normalization versus wiping out message here, right, even if there was a residual rule for the NEK7/NLRP3 inflammasome in host defense by bringing things back to normal physiological levels rather than wiping out the downstream pathway altogether, we think there's definitely some level of response to infections left. So in a nutshell, at this point, very confident that we can avoid them.

And then just what you want to see from GFORCE-2 in order to pursue a future registrational strategy in ASCVD?

Yes. I mean, again, sure, I mean, we're aligning this up. Definitely, as you've seen a bit more complicated study than the average Phase II CVD study out there. The idea really is to see if we can use plaque imaging, the more relevant upstream pathogenic markers and potentially NLRP3 genetics to come up with a Phase III design that's more efficient in regards to a number of patients on length of the trial. And at the end of the day, of course, also magnitude of the MACE effect, which obviously are all intercorrelated, but that's really the goal of GFORCE-2. Again, we're very confident that GFORCE-2 will give us the information that we need, but we need to run the trial first, of course.

Our next question comes from the line of Robert Driscoll with Wedbush.

So just wanted to congrats on the comprehensive data here. So I wondered if you could talk more a little about the cardiac imaging endpoint for GFORCE-2 and what you might expect to see in this time frame? And then second question, just wondered if you'd look at how the level of NLRP3 pathway inhibition compares maybe preclinically to colchicine, just kind of given the clinical validation there.

I can take the preclinical question and the MRT-8102 actually is better inhibiting the pathway in our assays. Admittedly colchicine has a bit of a complicated molecule to handle in vitro. We are convinced that, I mean, if colchicine here leads the way, then we should at least be able to achieve equal results. Obviously, we'll be running those trials at a different point in time for sort of the overall cardiovascular health of a population. So you can see by our GFORCE-1 population on how there's still a lot of silent and known as an effect. But for us, it was silent ASCVD out there. Filip, do you want to address the imaging question?

Yes. The imaging is something which is really emerging over the last few years as something which is extremely promising, right? We already know and it has been, I would say, fully validated that the FAI index, which is actually quite easy to obtain because all you need is actually the CT, coronary imaging, I mean it has been historically done with using the technology with contact, but now it looks like that it can be done even on noncontact CT, which will actually make it even more simple and easy to do in the clinical practice routinely. But I mean we already know that actually the FAI index can be associated is really strong prognostic significance for the future MACE and cardiovascular mortality showing that the cardiovascular mortality, and we mentioned that during the presentation, can be actually increased 30-fold. So that's -- if you kind of put it to any other marker, which is out there, these numbers are pretty stunning.

What we also know it's a little bit more emerging evidence, but it has been also prospectively validated already, at least to some extent, although not in that massive number of patients as the prognostic significance. The FAI can actually change on therapies. If you have a therapy which targets atherosclerotic plaques and which modulates atherosclerotic plaques, you can see it in FAI in relatively short-term perspective, there are actually 15 weeks data out there. That was one of the reasons why we actually changed study duration from 3 months to 6 months because we believe that with the data which is out there from the prior prospective studies that the 6 months data is adequate time window where we can see the FAI changes.

Our next question comes from the line of Mitchell Kapoor with H.C. Wainwright.

This is [indiscernible], I'm sitting in for Mitchell Kapoor. Congratulations. So on Slide 17, it shows that you have no adverse event related to continuation of 5 milligrams versus three at 20 milligrams in five and 40 milligrams. Will you be able to characterize the asymptomatic non-PTC EPG changes and skin reactions and explain how those findings inform the planned Phase II dose trend?

Yes, absolutely. So I think one thing which I would point out we are not really concerned about it. There is one thing which is kind of important to understand that these were mostly grade 1 events. And in the therapeutic setting, these would be unlikely to lead to the treatment discontinuation, right? This was a population which was -- of participants in the cardiovascular risk, however, were volunteers not the patient. So the threshold for stopping the -- or discontinuing 8102 or therapy in general, was actually quite low. So I think I'm pretty confident that in the therapeutic trial when you have more motivated patient population, that vast majority, if not nearly all of these events would not actually lead to treatment discontinuation.

When it comes to these ECG events, I already commented on that. These were even which were asymptomatic, the appropriate work up did not identify any underlying organic cause which can explain them. So no organic pathology related to ischemia or anything else cardiac-wise. So what they exactly were associated with, there were some modulation in the T-a pattern. And again, I would like to emphasize that there were no QTc-related changes, which is obviously something -- which would be potentially a source of bigger concern. When it comes to the skin events, I mean we have seen a skin events in the study. They were present in both placebo and active drug overall, we didn't see in a significant or statistically significant difference between placebo and MRT-8102.

Thank you. And I'm currently showing no further questions at this time. This does conclude today's conference call. Thank you all for your participation. You may now disconnect.