Insilico Medicine("Insilico"), a clinical-stage biotechnology company driven by generative artificial intelligence (AI), today announces that the first patient has been dosed in a global multicenter clinical trial (NCT06414460) to evaluate ISM3412, a potentially best-in-class, AI-empowered MAT2A inhibitor with novel structure, in patients with locally advanced and metastatic solid tumors.
The Phase 1 study consists of two parts: dose escalation and dose selection optimization, where participants will receive ISM3412 orally once daily, not only to evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics properties and preliminary anti-tumor efficacy of ISM3412, but also to determine the recommended dose in further studies. To date, the trial has completed enrollment for the first subject and DLT (Dose-Limiting Toxicities) observation for the first dose cohort at Cancer Hospital Chinese Academy of Medical Sciences, the leading site in China.
The first-in-patient dosing is a critical milestone for any drug candidate, marking its transition from preclinical research into evaluations within human bodies. We are thrilled to see ISM3412 emerging as a potential treatment option, developed with the support of AI—— particularly for patients with advanced or metastatic tumors, who could benefit from novel and more efficient treatment methods."
Feng Ren PhD, Co-CEO and CSO of Insilico Medicine
ISM3412 is an orally bioavailable, highly selective, and potent MAT2A (methionine adenosyltransferase 2A) inhibitor empowered by Insilico's proprietary generative chemistry platform, Chemistry42. The drug targets cancers with MTAP deletion, a common genetic alteration found in multiple solid tumors, including non-small cell lung cancer (NSCLC), pancreatic cancer, and bladder cancer. MTAP deletions create a synthetic lethality vulnerability that ISM3412 exploits by inhibiting MAT2A, reducing levels of S-adenosylmethionine (SAM)—a molecule essential to cell function—and selectively killing MTAP-deficient cancer cells while sparing healthy cells.
Guided by the synthetic lethality strategy, ISM3412 was designed using ligand-based AI-enabled drug design by Insilico's generative chemistry application, Chemistry42, and was nominated as a preclinical candidate compound in May 2022. In preclinical studies, ISM3412 demonstrated excellent drug-likeness with good solubility and permeability, good activity at low doses in animal models, and a favorable safety profile with promising safety margin in preclinical studies. Relevant data has been presented as abstract and poster on the AACR (American Association for Cancer Research) Annual Meeting 2023. In April and May 2024, ISM3412 received IND clearance from the U.S. FDA and NMPA, paving the way for future clinical studies.
"In preclinical studies, ISM3412 has demonstrated a promising safety profile, highlighting its potential to improve treatment options for patients. Beyond its efficacy as a monotherapy, ISM3412 also exhibited synergistic effects when combined with chemotherapy and PRMT5 inhibitors. We look forward to validating these results in our ongoing phase 1 study in patients." said Sujata Rao, MD, Chief Medical Officer of Insilico Medicine.
By integrating advanced AI and automation technologies, Insilico Medicine has demonstrated significant efficiency improvements in practical applications, setting a benchmark for AI-driven drug research and development. Compared to the typical 2.5-4 years required in traditional drug discovery, Insilico's 22 nominated candidate drugs from 2021 to 2024 took only 12-18 months on average to progress from project initiation to nomination of preclinical candidates (PCCs), with each project requiring synthesis and testing of only about 60-200 molecules. The success rate from PCC to IND-enabling stage reached 100%.
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