Insilico Medicine Reports Positive Results from Phase I Trials of ISM5411, an AI-Designed Drug for Inflammatory Bowel Disease
Insilico Medicine announced favorable outcomes from two Phase I clinical trials of ISM5411, a gut-restricted PHD1/2 inhibitor designed for inflammatory bowel disease (IBD). Conducted in Australia and China, the trials demonstrated that ISM5411 was safe and well-tolerated across all dose groups, with a pharmacokinetic (PK) profile confirming its gut-restricted action.
The trials, involving 76 healthy participants in Australia and 48 in China, investigated the safety, tolerability, and PK of ISM5411 in single ascending dose (SAD) and multiple ascending dose (MAD) studies. Results showed no significant adverse events, with most treatment-emergent adverse events being mild and resolving during the study period. Importantly, ISM5411 exhibited a high fecal-to-plasma concentration ratio, indicating minimal systemic exposure and validating its gut-restrictive properties.
ISM5411 was developed using Insilico’s Chemistry42 platform, an AI-powered tool for generative chemistry and drug optimization. The preclinical candidate nomination took 12 months (nomintaed in January 2022), during which 115 molecules were synthesized and screened. More on discovery and development process, and preclinical data of ISM5411—in a recently published article in Nature Biotechnology.
The PHD1/2 inhibitors target the hypoxia-inducible factor (HIF) pathway, which plays a critical role in maintaining intestinal barrier integrity and reducing inflammation. Unlike systemic PHD inhibitors, which have faced challenges due to off-target effects, ISM5411 is designed to act locally in the gut, minimizing risks associated with systemic exposure.
Preclinical studies of ISM5411 demonstrated its ability to reduce inflammation and improve epithelial repair in colitis models. These findings, combined with its favorable PK profile in human trials, support further development. A Phase II proof-of-concept study in patients with ulcerative colitis is planned for the second half of 2025.
PHD1/2 enzymes regulate HIF stability, a key factor in epithelial repair and immune homeostasis. Gut-restricted inhibitors like ISM5411 aim to promote these benefits without the systemic side effects observed with prior PHD inhibitors. In preclinical studies, ISM5411 demonstrated selective PHD1/2 inhibition, reduced inflammation markers (IL-6, IL-17, TNF-α), and increased expression of epithelial barrier-protective genes.
Carol Satler, MD, PhD, Vice President for Clinical Development, Non-Oncology, who will support
the further development of ISM5411 for the treatment of IBD:
These positive Phase I results from the IBD program are highly encouraging, particularly in validating the gut-restricted pharmacokinetic profile. Given the limited therapeutic options and the challenges with current IBD treatments, we believe that new therapies will benefit patients in the near future. We look forward to advancing the next phase of validation in patients.
IBD, which includes Crohn’s disease and ulcerative colitis, is characterized by chronic inflammation, impaired intestinal barrier function, and increased cancer risk. Current therapies focus on suppressing inflammation but often fail to address the underlying epithelial damage.
Insilico Medicine, has nominated over 20 preclinical candidates using its AI platforms since 2019. For more information on Insilico’s clinical trials, visit ClinicalTrials.gov (NCT06012578).
Topics: Clinical Trials
