Monte Rosa Therapeutic (GLUE) Study result summary

Study design and population

• GFORCE-1 was a randomized, double-blind, placebo-controlled phase I study evaluating MRT-8102 in 108 obese subjects with elevated cardiovascular risk, using 5 mg, 20 mg, or 40 mg daily for 4 weeks, followed by 4 weeks of safety follow-up.

• Participants had a median age of 41 and median BMI of 34, with elevated hs-CRP, and were well-balanced across groups.

• The study evaluated safety, tolerability, and multiple pharmacodynamic markers to inform dose selection for further development in NLRP3-driven diseases.

• Primary endpoints were safety and tolerability; secondary endpoints included pharmacokinetics and hs-CRP changes, with exploratory endpoints assessing NEK7 expression, DAMPs, cytokines, and other ASCVD drivers.

• MRT-8102 is a NEK7-directed molecular glue degrader targeting inflammatory diseases linked to NLRP3/IL-1 dysregulation.

Key efficacy and biomarker findings

• MRT-8102 achieved robust, sustained NEK7 degradation (80%-90%) across all dose levels, with no dose dependency.

• Significant reductions in pathogenic ASCVD drivers (DAMPs, IL-1 beta, HMGB1, S100A12, SAA, fibrinogen, calprotectin) were observed, normalizing to healthy volunteer levels.

• CRP and IL-6 were rapidly and consistently reduced, with 88% of subjects achieving CRP <2 mg/L, and hsCRP reduced by 85%.

• Lipoprotein(a) reduced by 24%, comparable to PCSK9 inhibitors, with no increase in LDL-C or triglycerides.

• Biomarker reductions were similar across all three dose levels.

Safety and tolerability

• No serious adverse events were reported; overall adverse event rates were similar between MRT-8102 (33%) and placebo (30%), with most events being Grade 1.

• No increased infection risk or serious infections were observed; infection rates were balanced at 7% in both groups.

• Grade 3 events were unrelated to study drug (asymptomatic hepatitis A, accidental shoulder dislocation); no neutropenia or thrombocytopenia occurred.

• Asymptomatic, non-QTc ECG changes and skin events were infrequent, Grade 1, and not considered clinically significant.

• MRT-8102 was safe and well tolerated over four weeks of dosing and follow-up.