Monte Rosa Therapeutics announced that the U.S. Food and Drug Administration has cleared its Investigational New Drug application for MRT-8102, a NEK7-directed molecular glue degrader designed to treat inflammatory diseases driven by the NLRP3 inflammasome and IL-1β. The clinical-stage biotechnology company plans to initiate a Phase 1 study in the coming weeks, with initial results expected in the first half of 2026.
MRT-8102 represents the first clinical-stage molecular glue degrader that selectively targets NEK7, positioning it to address multiple inflammatory conditions including cardio-immunology, rheumatology, and respiratory indications. According to CEO Markus Warmuth, M.D., the compound could provide "a highly differentiated clinical profile compared to IL-1 antibodies and NLRP3 inhibitors in development based on its potency, selectivity, and long-lasting pharmacodynamics."
Preclinical Efficacy and Safety Profile
Preclinical studies demonstrated MRT-8102's nanomolar-level degradation of NEK7 in vitro with no observed off-target activity, including against related NEK family proteins. In non-human primate studies, oral administration resulted in near-complete inhibition of downstream inflammatory markers in ex vivo stimulation assays and improvements in pathological measures in inflammatory disease models.
The compound showed therapeutic potential in a rabbit gout model, where daily oral dosing reduced pathogenic effects including joint swelling and histopathology scores. Preclinical GLP toxicology studies revealed a considerable safety margin, with greater than 200-fold exposure margin over the projected human efficacious dose in both rats and non-human primates.
Clinical Development Strategy
The upcoming Phase 1 study will evaluate safety, pharmacokinetics, NEK7 protein degradation, and key downstream pharmacodynamic markers in healthy volunteers. As part of the study design, Monte Rosa plans to establish initial proof-of-concept for cardio-immunology indications by evaluating changes in C-reactive protein and other inflammatory markers in subjects with elevated CRP levels.
NEK7 as a Therapeutic Target
NEK7 has been shown to be required for NLRP3 inflammasome assembly, activation, and IL-1β release both in vitro and in vivo. Aberrant NLRP3 inflammasome activation and subsequent release of active IL-1β and interleukin-18 has been implicated in multiple inflammatory disorders, including cardiovascular disease, gout, osteoarthritis, neurologic disorders such as Parkinson's and Alzheimer's diseases, and metabolic disorders.
In non-human primate models, MRT-8102 demonstrated potent, selective, and durable NEK7 degradation, resulting in near-complete reductions of IL-1β and caspase-1 following ex vivo stimulation of whole blood.
Pipeline Expansion
Beyond MRT-8102, Monte Rosa is advancing a second-generation NEK7 program with enhanced central nervous system penetration, with an IND submission expected in 2026. The company retains full worldwide rights to MRT-8102 and its second-generation CNS-optimized NEK7 molecular glue degraders.
This IND clearance marks Monte Rosa's second inflammatory and immunology indication following MRT-6160, a VAV1-directed molecular glue degrader, expanding the company's clinical portfolio in this therapeutic area.
