FDA Grants Fast Track Designation to ISM6331 for Advanced Mesothelioma

The FDA has granted fast track designation to ISM6331, an investigational pan-TEAD inhibitor, for adults with unresectable malignant pleural mesothelioma whose disease has progressed after treatment with an anti–PD-1 antibody, with or without an anti–CTLA-4 antibody, and platinum-based chemotherapy.¹

Fast track status is intended to facilitate development and expedite review of therapies for serious conditions that address an unmet medical need. For ISM6331, the designation brings more frequent meetings and written feedback from the FDA on trial design, biomarker strategy, and overall development planning. Depending on whether relevant criteria are ultimately met, the program may also become eligible for rolling review, in which sections of a marketing application can be submitted as they are completed rather than as a single package, along with priority review and accelerated approval.

Background on ISM6331

ISM6331 is a small-molecule, noncovalent inhibitor of the TEAD transcription factor family (TEAD1–4), designed to modulate the Hippo signaling pathway. Dysregulation of this pathway through alterations such as loss of NF2 or mutations in LATS1/2 can drive unchecked activity of the transcriptional co-activators YAP and TAZ, promoting tumor cell proliferation and survival; this mechanism is common in malignant mesothelioma and has been described in a subset of other solid tumors.² In preclinical models, ISM6331 showed antitumor activity in Hippo pathway–dysregulated mesothelioma models and demonstrated synergy with EGFR and KRAS G12C inhibitors, suggesting a potential role in overcoming resistance to targeted therapy as part of a combination regimen.¹ The compound was generated using Chemistry42, Insilico Medicine's generative chemistry platform, which applies structure-based design and computational scoring to prioritize candidate molecules.

Clinical development of ISM6331 is being carried out in a global, multicenter, open-label, first-in-human phase 1 trial (NCT06566079) evaluating safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the compound as monotherapy.³ The study is enrolling adults with advanced or metastatic malignant mesothelioma or other solid tumors and consists of a dose-escalation portion followed by a dose-optimization portion; patients with mesothelioma must have received prior immune checkpoint therapy and platinum-based chemotherapy, while patients with other solid tumor types must have documented Hippo pathway dysregulation. The trial is enrolling at sites in China and the United States, with the first patient dosed in January 2025. Initial first-in-human data from the study have been accepted for a brief oral presentation at the European Society for Medical Oncology (ESMO) 2026 Congress.¹

ISM6331 received orphan drug designation for mesothelioma in June 2024 and investigational new drug clearance in August 2024.

REFERENCES

1. Insilico Medicine. Insilico Medicine receives FDA Fast Track Designation for ISM6331, the AI-driven pan-TEAD inhibitor, in advanced mesothelioma. Published July 29, 2026. Accessed July 29, 2026. https://tinyurl.com/533m8pxy

2. Li Q, Wan J, Liu J, et al. Abstract 1656: ISM6331, a novel and potent pan-TEAD inhibitor, exhibits strong anti-tumor activity in preclinical models of Hippo pathway-dysregulated cancers. Cancer Res. 2024;84(6_Suppl):1656. doi:10.1158/1538-7445.AM2024-1656

3. Study of ISM6331 in participants with advanced/metastatic malignant mesothelioma or other solid tumors. ClinicalTrials.gov. Updated February 17, 2026. Accessed July 29, 2026. https://clinicaltrials.gov/study/NCT06566079