Massachusetts-based Insilico Medicine (HKEX: 3696) announced receipt of US FDA Fast Track Designation (FTD) for ISM6331, a small-molecule pan-TEAD inhibitor. The designation is related to the molecule's potential as a treatment for unresectable malignant pleural mesothelioma in patients whose disease has progressed on or after prior treatment with anti-programmed death-1 (anti-PD-1) antibody therapy, with or without anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody therapy, and platinum-based chemotherapy. The designation is the first FTD granted to any program in Insilico's pipeline.
ISM6331 targets all four members of the TEA Domain (TEAD) transcription factor family (TEAD1–4), the principal downstream effectors of the Hippo signaling pathway. By binding reversibly to the TEAD palmitoylation site via a non-covalent scaffold, the molecule suppresses YAP/TAZ-TEAD transcriptional activity, blocking tumor cell proliferation and survival in cancers with Hippo pathway dysregulation, including NF2-deficient mesothelioma. The molecule was nominated in June 2023 using Insilico's Chemistry42 generative chemistry platform, which applies structure-based drug design and AI-driven scoring pipelines to generate novel molecular scaffolds.
No quantitative clinical efficacy or safety data from the ongoing Phase I trial (NCT06566079) have been publicly disclosed. The global multicenter dose-escalation study, conducted concurrently in the US and China, dosed its first patient in January 2025 and is evaluating safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity as a single agent. Preclinical data presented at the American Association for Cancer Research (AACR) 2024 Annual Meeting demonstrated broad antitumor activity in NF2-deficient mesothelioma xenograft models, pan-TEAD biochemical inhibition, and synergistic effects in combination with EGFR and KRAS G12C inhibitors. The FTD was supported by this preclinical evidence base alongside early Phase I clinical data reviewed by the FDA. ISM6331 also holds FDA Orphan Drug Designation (ODD) for mesothelioma, granted in June 2024.
The FTD enables more frequent FDA interactions on clinical trial design, biomarker strategy, and development planning, and makes ISM6331 eligible — subject to meeting relevant criteria — for Rolling Review, Accelerated Approval, and Priority Review. No pan-TEAD inhibitor has received marketing approval from the FDA, the European Medicines Agency (EMA), or any other major regulator. The designation positions Insilico to refine its Phase I dose-expansion strategy with direct FDA input ahead of any registrational program.