image: Powered by Insilico’s proprietary Pharma.AI platform, the BBB (blood-brain barrier) penetrable molecule was designed as a potential treatment of various inflammation-related diseases, including gout flare, asthma, Crohn’s disease, Alzheimer’s disease and epilepsy.
Credit: Insilico Medicine
As the first line against microbial infections or endogenous cellular damage in our body, the innate immune system utilizes NLRs (NOD-like receptors) to sense the molecules triggering microbial infection and damage, thus ensuring the proper immune response function. In the NLRs family, NLRP3 is the most characterized member, and its overactivation can lead to excessive production of pro-inflammatory cytokines and chemokines, driving pathological processes in various inflammatory diseases.
CAMBRIDGE, Mass., Dec 10, 2024 --- Insilico Medicine (“Insilico”), a clinical-stage generative artificial intelligence (AI)-driven drug discovery company, today announced the nomination of ISM8969, an orally available NLRP3 inhibitor as pre-clinical candidate. Powered by Insilico’s proprietary Pharma.AI platform, the BBB (blood-brain barrier) penetrable molecule was designed as a potential treatment of various inflammation-related diseases, including gout flare, asthma, Crohn’s disease, Alzheimer’s disease and epilepsy.
NLRP3 (NOD-like receptor family pyrin domain containing 3) is essential for identifying microbial infections and damage, which forms a multimolecular complex known as the inflammasome to trigger an innate immune cascade upon activation. By inhibiting NLRP3, it is possible to modulate the inflammatory response, so as to prevent tissue damage, leading to the suppression of IL-1β and IL-18 release, as well as a reduction in pyroptotic cell death. However, no current FDA-approved drugs specifically target NLRP3, calling for further research in the area.
“The need of patients has been driving our portfolio management decisions, and chronic diseases including inflammation-related disorders have attracted our attention with the massive population worldwide,” says Feng Ren, PhD, Co-CEO and Chief Scientific Officer of Insilico Medicine. “We are thrilled to take another step forward in the area of inflammation disease intervention. Leveraging our AI-driven platform has already demonstrated promising results, and we look forward to utilizing AI better for the benefit of patients.”
In preclinical evaluation studies, ISM8969 exhibited a balanced druggability profile, with promising in vitro activity and safety, favorable in vivo PK/PD (pharmacokinetic/pharmacodynamic) profile, as well as efficacy against inflammation in multiple mouse disease models, including acute inflammatory disease and chronic disease models.
Unlike certain peripheral-restricted candidates currently in the clinical stage also targeting NLRP3, ISM8969 has a desired BBB penetrable property, enabling the drug candidate to cross the natural protective membrane between CNS (central nervous system) and the blood stream, and providing the possibility to treat neuroinflammation-related diseases. The Insilico research and development team is working on the evaluation of ISM8969 in various neurological disease models.
“Chronic inflammation is closely linked to aging and a host of other serious health conditions, attaching even more importance to the fight against it,” says Alex Zhavoronkov, PhD, founder and CEO of Insilico Medicine. “It is exciting to see that AI has been accelerating the R&D process, giving more opportunities for a better shot at high-quality drugs. At Insilico, indication expansion research is ongoing for ISM8969, and we hope to see more proof-of-concept cases coming with the power of AI.”
In 2016, Insilico first described the concept of using generative AI for the design of novel molecules in a peer-reviewed journal, which laid the foundation for the commercially available Pharma.AI platform. Since then, Insilico keeps integrating technical breakthroughs into Pharma.AI platform, which is currently a generative AI-powered solution spanning across biology, chemistry, medicine development and science research. Powered by Pharma.AI, Insilico has nominated 21 preclinical candidates in its comprehensive portfolio of over 30 assets since 2021 and has received IND clearance for 10 molecules.
In early 2024, Insilico published a Nature Biotechnology paper presenting the entire R&D journey from AI algorithms to Phase II clinical trials of ISM001-055, the company's lead drug pipeline with AI-discovered target and AI-designed structure. Following that, Insilico has recently announced positive preliminary results from a Phase IIa trial (NCT05938920), where ISM001-055 showed favorable safety and tolerability across all dose levels, as well as dose-dependent response in forced vital capacity (FVC), after only 12 weeks of dosage.
About Insilico Medicine
Insilico Medicine, a global clinical stage biotechnology company powered by generative AI, is connecting biology, chemistry and clinical trials analysis using next-generation AI systems. The company has developed AI platforms that utilize deep generative models, reinforcement learning, transformers and other modern machine learning techniques for novel target discovery and the generation of novel molecular structures with desired properties. Insilico Medicine is developing breakthrough solutions to discover and develop innovative drugs for cancer, fibrosis, immunity, central nervous system diseases, infectious diseases, autoimmune diseases, and aging-related diseases.