Insilico Medicine's pan-TEAD inhibitor ISM6331 receives FDA IND clearance for mesothelioma treatment

Insilico Medicine ("Insilico"), a clinical-stage generative artificial intelligence (AI)-driven biotechnology company, today announced ISM6331, potential best-in-class pan-TEAD inhibitor, has received the U.S. Food and Drug Administration (FDA) Investigational New Drug (IND) clearance for the treatment of mesothelioma, following the grant of Orphan Drug Designation (ODD) in June 2024. It brings the total number of IND-approved molecules of Insilico to nine.

Mesothelioma is a type of cancer that affects the mesothelium, a thin layer of tissue that covers most of the internal organs, primarily caused by exposure to asbestos. As an aggressive and fatal disease, Mesothelioma tends to spread along surfaces, nerves, and blood vessels inside the body, the median survival of the disease after diagnosis is only 9 to 12 months. Traditional treatments, including surgery and radiotherapy, often fail to provide long-term benefits, highlighting the urgent need for innovative treatment options.

We are thrilled to receive the FDA's ODD designation and approval to initiate clinical evaluation of ISM6331. The preclinical development of ISM6331 not only demonstrates the AI-driven approach to innovative drug discovery and development, but also showcases the best-in-class capabilities of Insilico's R&D team. We will move forward with patient enrollment in the US as soon as possible and look forward to advancing ISM6331 for patients in high unmet medical needs with mesothelioma and other Hippo pathway related tumors."

Sujata Rao, MD, Chief Medical Officer of Insilico Medicine

ISM6331 is a potent non-covalent small molecule inhibitor with a novel scaffold targeting the transcriptional enhanced associate domain (TEAD) protein family, which are considered to be key regulators of the Hippo pathway, and play an important role in tumor progression, metastasis, cancer metabolism, immunity and drug resistance. 

The development of ISM6331 was significantly accelerated by AI, where Chemistry42, Insilico's generative chemistry engine, yielded 3 promising hit series in the first round of compound generation. After that, Chemistry42 provided additional information about affinity and novelty scores, assisting researchers in the molecular optimization leading to the ISM6331. 

In preclinical studies, ISM6331 shows broad anti-tumor effect in multiple cell lines and potent efficacy at low doses in animal models, as well as a high safety margin and favorable ADMET profiles. The promising data further motivated Insilico to nominate ISM6331 as a preclinical candidate for the program in June 2023. Insilico is committed to advancing the clinical translation of the program and accelerating the delivery of to meet unmet medical needs.

"About 10% of cancer patients are affected by abnormalities in the Hippo signaling pathway. By effectively targeting the TEAD family, ISM6331 provides a strategic approach. The potential applications are vast, including the promising enhancement of chemotherapy efficacy, bolstering tumor immunity, improving small molecule targeting, and overcoming current drug resistance challenges", says Feng Ren, Ph.D., Co-CEO and Chief Scientific Officer of Insilico Medicine. "We remain committed to harnessing the power of AI to push the boundaries of medical science, offering new hope and potential therapies for patients with rare and challenging conditions."

Previously, ISM6331 was granted Orphan Drug Designation by the FDA for the treatment of mesothelioma. The designation would qualify ISM6331 for certain benefits and incentives, including seven years of marketing exclusivity following the regulatory approval of the designated indication, potential tax credits for certain activities, eligibility for orphan drug grants, and the waiver of certain administrative fees. The FDA's

Orphan Drug Designation program supports the development and evaluation of drugs that address rare diseases which affect fewer than 200,000 people in the United States. 

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 and clinical development. Powered by Pharma.AI, Insilico has nominated 18 preclinical candidates in its comprehensive portfolio of over 30 assets since 2021 and has received IND approval for 9 molecules.

During the recent Insilico Medicine Generative AI Action (IMGAIA) webinar, updates on the Pharma.AI platform were presented, highlighting its latest features, including Biology42: PandaOmics Box hardware for confidential computing, Precious-3 GPT for virtual data generation and biomedical research, and Science42: DORA for drafting scientific documents. These enhancements underline Insilico's commitment to pioneering breakthroughs responsibly and sustainably. Those who are interested in trial versions of the abovementioned platforms are encouraged to contact [email protected].