Monte Rosa's MRT-8102 Shows Biomarker Gains in GFORCE-1 Study

Key Points

• MRT-8102 demonstrated strong target engagement and biomarker improvements in the Phase I GFORCE-1 study, with 80%–90% NEK7 degradation and reductions in calprotectin, IL-1 beta, HMGB1, fibrinogen, IL-6 and CRP after four weeks.
• The treatment’s safety profile was comparable with placebo: no serious adverse events were reported, and most treatment-emergent events were mild, though some discontinuations and isolated Grade 3 events occurred.
• Monte Rosa plans to advance MRT-8102 into the Phase IIb GFORCE-2 cardiovascular study in the first half of 2027, while also preparing Phase II trials in gout and hidradenitis suppurativa; the biomarker data do not yet prove a reduction in cardiovascular events.

Monte Rosa Therapeutics NASDAQ: GLUE reported results from GFORCE-1, a Phase I study of its NEK7-directed molecular glue degrader MRT-8102 in participants with elevated cardiovascular risk. The company said the four-week dosing study showed sustained degradation of NEK7, reductions in inflammatory and atherogenic biomarkers, and a safety profile comparable with placebo.

GFORCE-1 enrolled 108 obese participants with elevated high-sensitivity C-reactive protein, or hs-CRP, levels, a population the company said was at increased risk of developing atherosclerotic cardiovascular disease, or ASCVD. Participants received 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.

Safety and Target Engagement

Chief Medical Officer Filip Janku said MRT-8102 achieved approximately 80% to 90% degradation of NEK7 in peripheral blood T-cells across all three dose levels, without an apparent dose-dependent effect. The results were consistent with earlier single- and multiple-ascending-dose data in healthy volunteers, according to the company.

No serious adverse events were reported. Treatment-emergent adverse events occurred in 33% of MRT-8102-treated participants and 30% of placebo recipients, with 86% of events categorized as Grade 1. Headache and arthralgia were among the most common events and occurred at similar rates in the treatment and placebo groups.

Monte Rosa reported one Grade 3 liver-enzyme elevation in a participant later found to have asymptomatic hepatitis A and one Grade 3 shoulder-pain event associated with an accidental shoulder dislocation. The company said infection rates were 7% in both the MRT-8102 and placebo groups, with no serious infections, neutropenia or thrombocytopenia reported.

Janku said there were treatment discontinuations in the 20 mg and 40 mg cohorts, largely involving Grade 1 events. During the question-and-answer session, he said several electrocardiogram findings were asymptomatic Grade 1 changes in T-wave patterns, with no QTc-related signal or identified underlying cardiac pathology.

Biomarker Results

The company positioned MRT-8102 as an upstream inhibitor of the NEK7-NLRP3 inflammatory pathway. According to Chief Executive Officer Markus Warmuth, degradation of NEK7 is intended to disrupt formation of the NLRP3 inflammasome, which is associated with release of inflammatory cytokines, damage-associated molecular patterns, or DAMPs, and prothrombotic factors.

Monte Rosa said GFORCE-1 participants had elevated baseline levels of several ASCVD-associated markers compared with the company’s healthy-volunteer reference group. After four weeks of treatment, the company reported reductions in calprotectin of roughly 50% to 60% across dose cohorts, reaching a range comparable with healthy volunteers.

The company also reported reductions in S100A12, serum amyloid A, fibrinogen, IL-6 and CRP. In participants with elevated baseline HMGB1 or IL-1 beta levels, MRT-8102 reduced HMGB1 by 40% and IL-1 beta by 37%, respectively, by week four, according to the presentation. Median fibrinogen declined about 28%, while 88% of treated participants achieved CRP levels below 2 mg per liter.

Manav Korpal, senior vice president of translational research, said participants carrying activating NLRP3 genetic variants had higher baseline levels of DAMPs, IL-1 beta and acute-phase-response proteins. Monte Rosa said the findings could support using NLRP3 genetic profiling to identify patients with greater pathway activity in future studies.

Company executives emphasized that the biomarker findings are intended to guide future development and do not yet establish an effect on major adverse cardiovascular events, or MACE. Janku said a later outcomes study would be needed to evaluate clinical-event differences.

Phase II Development Plans

Monte Rosa plans a Phase IIb study, GFORCE-2, in approximately 160 patients with stable coronary artery disease and residual inflammation. The trial is expected to randomize patients to 5 mg, 10 mg or 15 mg of MRT-8102 or placebo for six months.

The company said GFORCE-2 will use coronary imaging, including fat attenuation index imaging, to assess plaque inflammation, alongside measurements of inflammatory biomarkers, thrombogenic factors and NLRP3 genetic variants. Trial initiation is planned for the first half of 2027, later than the company’s original design timeline following revisions to incorporate imaging and genetic-enrichment strategies.

Monte Rosa also outlined two additional planned Phase II studies:

• GEMINI-1 in gout: Expected to begin in the fourth quarter of 2026 or first quarter of 2027. The study is planned to enroll about 60 patients with recurrent gout flares and evaluate pain reduction at 72 hours and the frequency of new flares over 12 weeks.
• GALAXY-1 in hidradenitis suppurativa: Expected to begin in the first half of 2027. The company plans to enroll about 160 patients with moderate-to-severe disease, with HiSCR 75 at week 16 as the primary efficacy outcome.

Warmuth said the company also expects its next-generation NEK7 degrader, MRT-9347, to enter a first-in-human study later in the year. Separately, he noted that Novartis has activated Phase II studies of Monte Rosa’s VAV1-directed molecular glue degrader MRT-6160 in Sjögren’s disease and psoriatic arthritis.

About Monte Rosa Therapeutics (NASDAQ:GLUE)

Monte Rosa Therapeutics, Inc is a clinical-stage biotechnology company focused on developing medicines that selectively eliminate disease-causing proteins. The company uses its proprietary molecular glue degrader platform to identify small molecules that recruit targeted proteins to the cell's natural protein-disposal machinery, potentially addressing proteins that have been difficult to treat with conventional drugs.

Monte Rosa's pipeline is centered primarily on autoimmune and inflammatory diseases, as well as other serious conditions.

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