Insilico Medicine, a clinical-stage biotechnology company powered by generative artificial intelligence, said it entered an exclusive global co-development collaboration with Hygtia Therapeutics to advance ISM8969, an orally available, brain-penetrant NLRP3 inhibitor designed to treat central nervous system (CNS) diseases.

Under the deal terms, Insilico and Hygtia – incubated by Shenzhen Pengfu Fund of Fosun Health Capital and Fosun Pharma – will hold 50% worldwide rights each to research, develop, manufacture, and commercialize ISM8969. Insilico is eligible to receive up to USD 66 million in upfront and milestone payments, including an initial USD 10 million upfront fee.

Insilico is slated to lead the initial clinical development activities, including the Investigational New Drug (IND) application and Phase 1 clinical trial, with an initial focus on Parkinson’s disease. Following early clinical work, Hygtia will take responsibility for subsequent global clinical studies, regulatory filings, and commercialization.

ISM8969 was discovered and optimized using Insilico’s generative AI platform, Chemistry42, and preclinical data reportedly show robust efficacy, a favorable safety profile, and effective blood-brain barrier penetration, an important feature for CNS-targeted therapeutics.

NLRP3: the Research Context

ISM8969 targets the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome, a validated and highly attractive target for a broad range of inflammatory, neurodegenerative, metabolic, and autoimmune diseases. The NLRP3 inflammasome is a multiprotein complex critical for innate immune responses. Upon activation by diverse stimuli (e.g., pathogens, metabolic stress, crystals), NLRP3 triggers caspase-1 activation, driving IL-1β- and IL-18-mediated innate immune activation, and inducing pyroptosis (inflammatory cell death).

At least 20 biopharma are advancing over 25 distinct NRLP3 molecules, including small molecules and biologics, although no approvals have been issued to date. Preclinical and translational evidence has been generated linking NRLP3 dysregulation to pathogenesis of conditions such as gout, Parkinson’s disease, Alzheimer’s disease, type 2 diabetes, and more. Examples of small-molecule NLRP3 inhibitors under development include: Novartis’s DFV890 (formerly IFM-2427) for myeloid diseases, Ventyx Biosciences’ VTX2735 in pericarditis, Ventus Therapeutics’ systemic inhibitors partnered with Novo Nordisk for cardiometabolic indications, and NodThera’s programs targeting obesity.