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. At this time, all participants are in listen-only mode. A question-and-answer session will follow the formal presentation. 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, 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 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 & 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 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 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 mg, 20 mg, or 40 mg once daily or to placebo for four weeks of dosing, followed by four 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 five, 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 six. We have mentioned our excitement of pursuing clinical development in ASCVD, gout, and HS. 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 eight. 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 eight, 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. 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 nine 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.
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, under-reported events, and excess 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 meta-analysis of patients treated with colchicine, further reinforce the importance of upstream targeting of the NLRP3 pathway. Intriguingly, across all trials, 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 sparsely prescribed due to its significant GI and other side effects. In addition to colchicine, canakinumab, an 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, that 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 alleles variants that activate the NEK7 NLRP3 signaling cascade are associated with a 1.6 to 2.3-fold higher odds of CAD across independent cohorts. By contrast, an established IL-6 receptor protective allele has only a very modest protective benefit in all comers. The hazard ratio 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 carriers, so patients with clonal hematopoiesis of indeterminate potential, a condition that directly drives IL-6 expression.
As shown on the right, NLRP3 risk allele carriers also show 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 plaques in general. They are even more upregulated in unstable atherosclerotic plaques. 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 in plaque and 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 NLRP3 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 translational 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 and longer safety and 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- 50 mg per liter, placing them at increased risk for developing atherosclerotic cardiovascular disease. Participants were randomized to receive 5 mg, 20 mg, or 40 mg 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 hs-CRP.
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, approximately 20- 30 years younger compared to a typical fully established ASCVD population. A median BMI of approximately 34 kg per square meter, with elevated hs-CRP 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, with 80%-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 four 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 eight weeks, 408 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 emergence adverse event rates, which reflect any AEs on treatment regardless of attribution to study drug, 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 arthralgia, 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 eight weeks was comparable to placebo across the dose range evaluated. Slide 17 provides safety data in more detail. Over four weeks of dosing, followed by four weeks of additional safety observation for a total of eight 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 mg cohort, there were seven other treatment discontinuations, four in the 40 mg cohort and three in the 20 mg 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'll discuss in a few minutes when we review our phase II development plans, we will use the now defined safe dose range of 5- 40 mg 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 on pathogenic drivers of ASCVD. Manav?
Thank you, Filip. Before we take a deep dive into the clinical activity analysis, it is 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 Bungard and colleagues suggests that up to 70% of asymptomatic adults ages 40- 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 associate 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. We explored whether human genetic features, in particular activating SNPs in NLRP3, led to higher baseline levels in key pathogenic ASCVD drivers in our GFORCE-1 cohorts. With that context in mind, I will now walk you through the framework we used 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. 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 us 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. 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 design. 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 looked at whether the NLRP3 risk alleles that Markus had referenced during his intro are associated with those elevations. As discussed, NLRP3 gain-of-function SNPs are significantly associated with higher odds of coronary artery disease, as supported by multiple independent datasets. 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 one in three subjects carry the highest risk genotype, and more than half carry the moderate risk genotype. Importantly, in GFORCE-1, these 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 supports 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 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 plaques 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-triggered pyroptosis. 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 marked reduction by week four, 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%-60%, with levels at week four 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 four 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-resident 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 axis.
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 four, 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 the 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 are 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. 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, in those with upper quartile baseline levels, there was a significant treatment-induced reduction of 37% by week four, 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 effectors, 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 four 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 drivers, 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 assessed the baseline and therapy-induced changes in the IL-6/CRP axis. 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 toward healthy volunteer levels.
Notably, 88% of subjects achieved reductions of CRP to below 2 mg 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 share 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 are very excited about the opportunities presented by MRT-8102.
With that, I will 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 a 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 with stable 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 will confirm the impact of NLRP3 risk alleles on NEK7 NLRP3 pathway activation, the impact on baseline upregulation of pathogenic drivers of ASCVD, response of dose to MRT-8102, and any FAI changes. Slide 36 lays out the trial schematic. GFORCE-2 is a phase II-B study in approximately 160 patients with stable coronary artery disease and residual inflammation. Patients will be randomized across three MRT-8102 dose levels, 5 mg, 10 mg and 15 mg or placebo, and treated for six 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 a six-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 MRT-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 flares, with endpoints 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 HiSCR 75 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 in plaques is not adequately addressed.
A 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 conducted, 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 in 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 DAMPs and IL-1 beta, validates 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 patient-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 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 first-in-human study later this year. Finally, on slide 42, I'll add just a few additional highlights on the rest of our pipeline. We were pleased to see our collaborator, Novartis, activate two large phase II-A/B 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 AR-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?
Thank you. To ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Edward Tenthoff with Piper Sandler. Your line is now open.
Great. Thank you very much. I am 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 II-B 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.
Thank you, Ted. Our plan, as you 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 II-B with the six-month administration, it is unlikely, even in the population of patients with coronary artery disease, it is 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 II-B and GFORCE-2 is we actually can connect the plaque morphology through the imaging with 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.
That actually will ultimately allow us to have more efficient clinical trial design, the subsequent phase III design, which is expected to show the difference in outcomes.
You would potentially look for genetic drivers, or other factors to focus the population for a potential phase III trial.
Potentially, yes. I mean, the expectation from the GFORCE-2 is that we will understand how these factors all connect together and how they potentially relate to the local plaque biology, as well as to some other markers associated with the local and systemic inflammation.
Great. Excellent. Thank you so very much, and thanks for the thorough update.
Thank you. Our next question comes from the line of Michael Schmidt with Guggenheim. Your line is now open.
Oh, hey, good morning. Thanks for taking my questions. I am trying to better understand the predictability of the DAMP reductions that you have highlighted. Maybe talk a bit more about how meaningful this 50% reduction is. How strong is that correlative data, or is it just about normalizing levels of those DAMPs?
I mean, obviously, we view normalization, so 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 because you are now basically at the status of a healthy one on T from a risk point of view. Obviously, the rest of your immune system and host defense can still appropriately respond. In particular, we are of course sure this would also go through some of the other inflammasomes. Ultimately, of course, the next step here, as [audio distortion] Filip has pointed out, is to now connect the normalization of DAMPs and IL-1 beta as a critical cytokine correlated to plaque morphology and inflammation status by imaging.
I think if we can build that connection, then again, as Filip referred to, connect both of the two genetic features, I think we should have a lot of evidence. Of course, also 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 per pilot cost.
Okay. How do you interpret the IL-1 beta reduction seen in a GFORCE-1 study, perhaps in terms of translation to some of the more IL-1 beta-driven conditions like gout? Have you looked at IL-18 as well? Just curious.
Yeah. Obviously, I am super excited about those results. IL-1 beta, and you have pointed this out, Mike, in some of our previous conversations, super hard to measure in the blood. I think there are very few companies that present IL-1 beta blood data. We were fortunate to be able to establish an assay that is sensitive enough. If you looked at the Y-axis, though, I mean, we are talking sample grams here. 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.
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.
Okay. Just last question, just going back to the possible patient selection strategy in phase III. 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?
Again, it depends. Obviously, if imaging perfectly correlates with an NLRP3 SNPs you would likely prefer imaging because that is a more established modality in ASCVD to characterize baseline inflammation. I have to say, the level of biomarker increase we are seeing here is very convincing. At the end of the day, the frequency of homozygous TG is already 30%, and if you count in the TC, 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 suggests that there will be a population at higher risk, but still modifiable. It could, as I said, allow us to run a more efficient, smaller, faster phase III trial at the end of the day.
Okay, thank you.
Thank you. Our next question comes from the line of Tyler Van Buren with TD Cowen. Your line is now open.
This is Ikenna on for Tyler. Thank you guys for the very interesting presentation. It is 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. Which ones provide the strongest evidence that 8102 is affecting plaque biology rather than only the systemic inflammation. I had a follow-up to that.
It is a little bit the favorite child question, right. I definitely think HMGB1, IL-1 beta as an axis is absolutely crucial. I would go as far as if you are not modulating these two, it is going to be hard to see meaningful MACE activity, obviously. We wish, the colchicine trials would have looked at these markers. Obviously, they did not. There is 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. These are the two we will definitely look at. I think calprotectin, obviously, a little bit easier to measure, I think would be another great surrogate.
At the end of the day, if you look at the aggregate data, we didn't want to complete things today with the heat maps and all sorts of fancy analysis, but on treatment, these markers all start to correlate with each other. 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 four weeks on treatment between those different terms is really quite striking.
Thank you. For the other indications, HS and gout, are the same biomarkers relevant, or are they different from ASCVD?
Definitely very similar. We were trying to make the point in one of our intro slides. If you look at existing data sets across these three indications, the pattern are strikingly different. 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. Again, we really believe that what we're seeing in GFORCE-1, because of that similarity, isn't just 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 help us to also pick the appropriate doses per indication.
Thank you.
Thank you. Our next question comes from the line of Derek Archila with Wells Fargo. Your line is now open.
Hey, good morning, and congrats on the update. Thanks for all the info this morning. Just a couple of questions for us. On the GEMINI-1 trial, I guess this seems like this is going to be run without placebo. What background rate of new flare should be assumed in the enrolled population?
Yeah, 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 you have to allow the patients to actually use some rescue medications since to large extent, it's not really acceptable to have the patient with 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. I think from that standpoint, it didn't really make much sense.
The study also has a, that's about the acute flares, right? 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. In this one, I think you might make a case a little bit for placebo, but the expected effect size is actually quite large. If you look at the historical data from 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 be probably somewhere in the 45% range. While the expectation is that on the 8102, the expected flare rate will be actually much lower than that.
The effect size is actually quite sizable. I think this trial actually is for the phase II setting of the proof of concept appropriate.
Very helpful. On hidradenitis, I just want to get a better understanding on the translation here. 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. I think the data which we have from GFORCE-1 and subsequently we will have them obviously from the GFORCE-2 as well, are super relevant. MRT-8102 is a small molecule with the expected good penetration to the target issues. Actually, I think what we see now in the GFORCE-1 setting is very relevant to the other indications as well.
Got it. Thank you, guys.
Thank you. Our next question comes from the line of Faisal Khurshid with Jefferies. Your line is now open.
Hey, guys. 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? I have another question as well. Thank you.
No, great question, actually. I love it because it is very complementary in regards to sort of the approaches. 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. But it is not a secret that urate-lowering drugs initially because they do mobilize urate and urate crystals, have flares within at least the first 6- 12 months. Long story short, we actually think of this as an opportunity for us more than competition. As these hopefully come through in their clinical trials and hit the market, combining with something like 8102, great concept, 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.
Definitely something on our radar as a potential development path on top of just the flare prevention approach in sort of the more regular, typical patient population.
Got it. Super interesting. I just wanted to ask for clarification on the safety profile. I saw that at 40 mgs, it looks like you had three, you said asymptomatic non-QTc Grade 1 electrocardiogram changes. Can you just explain what those were and whether those are believed to be drug-related or not?
We are not concerned by these findings at all. These changes were all Grade 1, incidental, and completely asymptomatic. That is important to point out. These were kind of picked up on the regular, quite frequent EKGs, which are done as a part of the phase I study. They were kind of associated with the change in the pattern of the T wave on the EKG. We have done appropriate workup and ruled out any ischemia or any other organic heart pathology which might potentially explain them. They are essentially changes which are not associated with any underlying organic cause, which we can point out. It is also important to point out that we do not see any signals which would be related to QTc-related changes or anything like that.
Overall, again, I would just explain that we are not concerned, and looking at the overall symptom totality on all AEs, the frequency of the AEs in MRT-8102 and placebo is nearly identical, with 33% versus 30%.
That is helpful. Thank you.
Thank you. Our next question comes from the line of Brian Cheng with J.P. Morgan. Your line is now open.
Hi, guys. This is Sarah on for Brian. Thanks for taking our questions here this morning. The degradation of NEK7 and downstream impact, it really looks pretty similar across the 5 mg, 20 mg, and 40 mg. What is driving the dose selection for phase II if the pharmacodynamic profile seems largely saturated at this lowest dose? Do you expect a dose response that can be easily observable over the treatment course of six months in your GFORCE-2 trial? Then we have a follow-up after.
It is a great question. Obviously, we disclosed today that we are going to go forward with 5 mg, 10 mg and 15 mg in GFORCE-2. We had a discussion whether we should go even lower. At the end of the day, obviously, we are trying to optimize GFORCE-2 for the maximum chance to see that correlation of our imaging versus, the plaque markers we are super interested in and the genetics. We did not really want to play around anymore with doses. In particular, in light of the safety that we are seeing here, I do not think you would have many other molecules in this pathway that carve out such an impressive safety margin.
Long story short, no, for now, we are not expecting to see a dose response. But in a longer-term setting, this will be six months, obviously, not four weeks. You never know until you eventually analyze the event.
Great. That helps. When you think about the other indications that are fundamentally different than heart disease, is there a need to tweak the dosing, just given the differences in tissues that you are aiming for, especially like the diseases in gout and HS?
Another great question. Let me maybe start by just making a point here that we really like this lineup of indications. It is sort of probing the same pathway. 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. There is the chronic inflammation in ASCVD, kind of a pure play, NLRP3, NEK7 NLRP3 signaling cascade disease. You have gout with an acute component, at least in that initial trial induced by crystals. Then we are sort of more on augmenting side of the pathway with HS which gets me to your actual question. Yes, we are considering different dose levels. Part of it is getting into different organs.
Part of it is also the acuteness of the disease. I think you probably want to go higher in gout when you are starting in an acute flare situation. If you were in a preventative setting, so where you are just trying to prevent future flares, maybe it could be lower. Again, really great that we have this very wide window now. We are talking, just to keep it simple, roughly a tenfold window, and it could even be higher because again, who knows how we continue to be safe even above 40 mg, because there is a lot of opportunity to play around with a dose per indication and obviously, also in regards to then future commercialization and labels.
Great. Thanks, guys.
Thank you. Our next question comes from the line of Oliver McCammon with LifeSci Capital. Your line is now open.
Congrats on the data, and thanks for taking my questions. Just given today's update, I am curious in your level of confidence in an infection signal not emerging with 8102, particularly with longer dosing. What would you need to see from GFORCE-2 in order to pursue a registrational strategy in ASCVD? Thanks again.
Confidence on infections is very high for two reasons. We believe that colchicine and the lack of an infection risk tells the story. 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 to infection risk bias for both IL-1 beta and IL-6 really relates to just taking these cytokines out more or less completely, where these 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. Even if there was a residual role 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 is definitely some level of response to infections left. In a nutshell, at this point, very confident that we can avoid them.
Got it. What you want to see from GFORCE-2 in order to pursue a future registrational strategy in ASCVD.
Yeah. Again, we are lining this up, definitely, as you have 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 is more efficient in regards to number of patients, length of the trial. At the end of the day, of course, also magnitude of the mean effect, which obviously are all interrelated. That is really the goal of GFORCE-2. Again, we are very confident that GFORCE-2 will give us the information that we need, but we need to run the trial first, of course.
Very helpful. Thank you.
Thank you. Our next question comes from the line of Robert Driscoll with Wedbush. Your line is now open.
Hello, can you hear me? Sorry.
Yes. At least I can hear you. Yes.
Sorry. Excellent. Let's carry on. Great. Just wanted to congrats on the comprehensive data here. 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 timeframe. Then second question, just wondered if you'd looked at how the level of NLRP3 pathway inhibition compares maybe pre-clinically to colchicine, just given the clinical validation there. Thank you.
Yeah, I can take the pre-clinical question. MRT-8102 actually is better inhibiting the pathway in our assays. Admittedly, colchicine is a bit of a complicated molecule to handle in vitro, but we are convinced that 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 the overall cardiovascular health of a population. You can see by our GFORCE-1 population how there's still a lot of silent and known as effect, but for us it was silent ASCVD out there.
Filip, do you want to address the imaging question?
Yeah. 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. It has been historically done with using the technology with contrast, but now it looks like that it can be done even on non-contrast CT, which would actually make it even more simple and easy to do in the clinical practice routinely. But we already know that actually the FAI index can be associated with really strong prognostic significance for the future MACE and cardiovascular mortality, showing that the cardiovascular mortality, and we mentioned it during presentation, can be actually increased 30-fold.
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 to at least to some extent, although not in that massive number of patients, as the prognostic significance that the FAI can actually change on therapies. If you have a therapy which targets atherosclerotic plaques and which modulates atherosclerotic plaques, you can actually see it in FAI in a relatively short-term perspective. There are actually 15 weeks data out there.
It was one of the reasons why we actually changed the study duration from three months to six months because we believe that with the data which is out there from the prior prospective studies, that the six months data is the adequate time window where we can see the FAI changes.
Got it. Super helpful. Thank you, guys.
Thank you. Our next question comes from the line of Mitchell Kapoor with H.C. Wainwright. Your line is now open.
Hi, this is Yi on [audio distortion] sitting in for Mitchell Kapoor. Thanks for taking my question and congratulations. On slide 17, it shows that you have no adverse event related discontinuations at 5 mg versus three at 20 mg and five at 40 mg. Would you be able to characterize the asymptomatic non-QTc ECG changes and skin reactions and explain how those findings inform the planned phase II dose range?
Yeah, absolutely. I think one thing which I would point out, we are not really concerned about it. There is one thing which is 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. This was a population which was of participants in the cardiovascular risk who, however, were volunteers, not the patients. The threshold for stopping or discontinuing 8102 or therapy in general was actually quite low. I think I am 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 events which were asymptomatic. The appropriate workup did not identify any underlying organic cause which can explain them. No organic pathology related to ischemia or anything else cardiac-wise. What they exactly were associated with, they were some modulation in the T wave pattern. Again, I would like to emphasize that there were no QTc-related changes, which is obviously something which would be potentially source of bigger concern. When it comes to the skin events, we have seen skin events in the study. They were present in both placebo and active drug, and overall we did not see any significant or statistically significant difference between placebo and MRT-8102.
Got it. Thank you so much.
Thank you. I am 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.