Insilico Medicine has announced positive results from two Phase I clinical trials of ISM5411, a novel gut-restricted prolyl hydroxylase domain (PHD) inhibitor designed using the company's AI platform, Chemistry42, for the treatment of inflammatory bowel disease (IBD). The trials, conducted in Australia and China, evaluated the safety, tolerability, and pharmacokinetics of ISM5411 in healthy volunteers.
The data indicate that ISM5411 was generally safe and well-tolerated across all dose groups, with no reports of serious adverse events or treatment-related adverse events leading to discontinuation. The overall occurrence rate of treatment-emergent adverse events (TEAEs) was comparable between all treatment groups and pooled placebo groups in both studies. Most reported TEAEs were Grade 1 and resolved by the end of the studies. No clinically significant increases in red blood cell count or hemoglobin were reported.
Gut-Restricted Properties
The observed human pharmacokinetics (PK) of ISM5411 in healthy volunteers aligned with the company's preclinical modeling, with no significant drug accumulation observed after 14 days of multiple administrations across all dosing groups. ISM5411 also exhibited a favorable PK profile for validating gut-restrictive properties, with very low systemic exposure and a high fecal/plasma ratio in healthy volunteers. This is particularly significant as it suggests a reduced risk of systemic side effects, a common concern with IBD treatments.
AI-Driven Drug Discovery
Insilico Medicine utilized its Chemistry42 AI platform to design and optimize ISM5411. This platform employs generative chemistry, Alchemistry, and ADMET analysis modules to identify drug candidates with desirable properties. The preclinical candidate nomination of ISM5411 was achieved in just 12 months, during which approximately 115 molecules were synthesized and screened.
Alex Zhavoronkov, PhD, Founder and CEO of Insilico Medicine, stated, "Powered by generative AI, the field we pioneered since 2016, Insilico is committed to delivering effective and innovative therapies that improve disease control, reduce disease burden, minimise adverse side effects, improve overall health and productive longevity. The PHD program further demonstrates Insilico's ability to consistently advance valuable programs to the clinical stage."
Next Steps
Based on these results, Insilico Medicine expects to initiate a Phase 2 proof-of-concept study evaluating ISM5411 in active ulcerative colitis patients in the second half of 2025. This study will further assess the efficacy and safety of ISM5411 in a patient population.
Addressing Unmet Needs in IBD
Inflammatory bowel disease (IBD), comprising ulcerative colitis and Crohn's disease, is a chronic inflammatory condition of the gastrointestinal tract. Current standard therapies primarily focus on anti-inflammatory strategies, which often have limited efficacy and unavoidable side effects. Insilico's research is focused on developing therapies that not only reduce intestinal inflammation but also promote epithelial repair, addressing a critical unmet need in IBD treatment.
Published Research
The early drug discovery and development process and preclinical data of ISM5411 were recently published in Nature Biotechnology, highlighting the role of Chemistry42 and its submodules in supporting drug candidate design and optimization. This publication underscores the potential of AI in accelerating drug discovery and development.
