MRT-8102 therapy for inflammatory diseases enters preclinical studies
Monte Rosa plans to seek FDA clearance for human trials in spring 2025
Monte Rosa Therapeutics is running preclinical studies testing MRT-8102, an orally available molecular glue degrader that targets NEK7, a protein needed to set off a type of inflammatory response involved in diseases including Parkinson’s.
The studies are a key step in the process of seeking approval for clinical studies in humans. The company said it plans to file an investigational new drug application with the U.S. Food and Drug Administration for MRT-8102, the first candidate from its NEK7 development program, in the first quarter of 2025. If the FDA accepts the application, the company will be cleared to start human trials.
“NEK7 is an essential component of the NLRP3 inflammasome pathway that has been implicated in many serious diseases, and we are excited to advance MRT-8102 toward clinical development,” Markus Warmuth, MD, CEO of Monte Rosa, said in a company press release.
Molecular glue degraders bring their targets closer to ubiquitin ligase, an enzyme that tags proteins for disposal, opening opportunities to clear up disease-causing proteins that are considered undruggable by other approaches, according to Monte Rosa.
Targeting overactive protein complex
NEK7 is needed for the activation of the NLRP3 inflammasome, a group of proteins that together set off a response against potential threats, in part by amplifying the production of pro-inflammatory IL-1beta.
Evidence suggests alpha-synuclein, the protein that builds into toxic clumps in brain cells of people with Parkinson’s, may cause the NLRP3 inflammasome to become overactive and prime cells like microglia, the brain-resident immune cells, to produce IL-1beta. The resulting inflammation may cause damage to nerve cells and contribute to Parkinson’s symptoms.
MRT-8102 can enter the brain, so it has the potential to be used in neurodegenerative diseases like Parkinson’s and Alzheimer’s. An overactive NLRP3 inflammasome has been implicated in multiple other inflammatory diseases, including gout, heart disease, liver disease, and diabetes.
In non-human primates, MRT-8102 resulted in long-lasting elimination of NEK7 and near-complete reductions of IL-1beta. Toxicology studies have shown MRT-8102 may have a favorable safety profile.
“In preclinical, non-human primate studies, MRT-8102 has demonstrated potent and selective degradation of NEK7, reducing downstream IL-1[beta].” Warmuth said. “We believe MRT-8102 has the potential to be developed in multiple inflammatory diseases.”
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