Monte Rosa Therapeutic (GLUE) investor relations material

Interim Phase I Study Results

• MRT-8102, a NEK7-directed molecular glue degrader, showed rapid, robust, and sustained reductions in hsCRP (up to 85%) and fibrinogen (31%) in both healthy volunteers and high CVD-risk subjects, with 112 participants dosed as of interim analysis.

• 94% of high-risk CVD subjects achieved hsCRP below 2 mg/L after four weeks; significant reductions in IL-6 (up to 55%) and IL-1β (up to 80%) were also observed.

• MRT-8102 demonstrated comparable or superior efficacy to high-dose IL-6 biologics and IL-1 inhibitors in cross-trial comparisons, with oral administration as a key differentiator.

• No evidence of increased infection risk or serious adverse events; adverse events were mild to moderate, self-resolving, and not dose-dependent.

• CNS penetration was demonstrated, with up to 75% reduction in cerebrospinal fluid IL-6 in subjects with elevated baseline levels.

Study Design and Population

• Phase I included single (SAD) and multiple ascending dose (MAD) cohorts (5–400 mg) in healthy volunteers and a proof-of-concept cohort in high CVD-risk subjects, totaling 112 participants.

• SAD (48 subjects) and MAD (40 subjects) cohorts completed; CRP PoC (24 subjects) ongoing in high-risk CVD population with obesity and elevated CRP.

• Study endpoints included safety, tolerability, pharmacokinetics, NEK7 degradation, and changes in inflammatory biomarkers (hsCRP, IL-6, IL-1β, fibrinogen).

• MRT-8102 achieved 80–90% NEK7 degradation in peripheral blood T cells at all dose levels, sustained up to four weeks.

Mechanism of Action and Differentiation

• MRT-8102 selectively and catalytically degrades NEK7, suppressing NLRP3 inflammasome activity and pyroptosis, leading to broad inhibition of disease-promoting cytokines and DAMPs.

• Proteomics confirmed high selectivity for NEK7, minimizing off-target effects.

• Upstream targeting of NEK7 may offer greater efficacy and safety than downstream IL-6 or IL-1 targeting biologics, with less risk of infection.

• MRT-8102’s oral administration and sustained pharmacodynamic effects differentiate it from other NLRP3, IL-1, and IL-6 pathway inhibitors.