Insilico Medicine has advanced into the clinic its fifth pipeline candidate discovered and designed using generative artificial intelligence (AI), a treatment for inflammatory bowel disease (IBD) that could be the first to treat the disorder by inhibiting the prolyl hydroxylase domain (PHD).

PHD has been shown to play a critical role in regulating the stability and transcriptional activity of the hypoxia-inducible factor-1α (HIF-1α), leading to the expression of those gut barrier protective genes.

ISM5411 is an oral, PHD-specific inhibitor designed to treat IBD by inducing the expression of those genes. ISM5411 is designed to directly regulate the intestinal immune microenvironment, simultaneously exhibiting anti-inflammatory activity as well as promoting mucosal repair.

“PHD is significantly upregulated in IBD patients and is strongly correlated with inflammatory cytokines, all of which makes it a promising target for treating IBD,” Alex Zhavoronkov, PhD, founder and co-CEO of Insilico Medicine, told GEN Edge. “Insilico’s ISM5411 has shown gut restriction in preclinical studies, allowing it to act directly in the gut, the target organ of IBD disease, without overexposure to other parts of the system, such as the blood.”

While some small molecule drug candidates with IBD indications are designed to target PHD, they are in preclinical development. Last year, Gossamer Bio ended clinical development of GB004, a PHD inhibitor designed to treat ulcerative colitis by stabilizing HIF-1α, after it missed its primary endpoint, the proportion of participants with clinical remission at week 12, in the Phase II SHIFT-UC trial (NCT04556383). Gossamer had developed GB004 by licensing rights from Aerpio Pharmaceuticals (since merged with Aadi Bioscience), which had initially developed the drug as AKB-4924.

Zhavoronkov said PHD inhibitors are now primarily used for treating systemic diseases, but these drugs can produce side effects stemming from systemic exposure. ISM5411 avoids that problem, he said, because its lower systemic exposure means that the drug has a higher safety profile than other products in development.

ISM5411 is under study in a Phase I trial (NCT06012578) being conducted in Australia. The trial is designed to evaluate the safety, tolerability, pharmacokinetics and food effects of ISM5411 at increasing oral doses in 76 healthy volunteers.

First dose groups completed

“The first two dose groups of single ascending dose (SAD) have been completed, with a third dose group of 200 mg subjects having completed dosing. Based on the design, Insilico expects to do the single ascending dose of seven groups and to do the multiple ascending dose of three groups,” Zhavoronkov said.

Insilico expects to receive results for the trial before the end of 2024. The company’s clinical team is led by its chief medical officer Sujata Rao, MD.

Insilico plans to further assess ISM5411 in wider populations by conducting global multi-center Phase Ib trials in patients with ulcerative colitis following the initial first-in-human study.

While ISM5411 is wholly owned, Zhavoronkov has not ruled out eventually co-developing the IBD treatment candidate with a partner: “We also look forward to companies with relevant experience and resources co-developing this asset with our team.”

Insilico announced its nomination of ISM5411 as a preclinical drug candidate targeting PHD to treat IBD in January 2022.

ISM5411 was developed by Insilico using its Chemistry42 platform. Chemistry42 is an automated, machine-learning de novo drug design and scalable engineering platform, which according to the company, enables users to find novel lead-like molecules in as little as a week. Drawing on large numbers of compounds and molecular fragments, Chemistry42 uses generative AI to create new drug-like molecules optimized to have specific properties.

Insilico won the FDA’s first Orphan Drug Designation for an AI drug in February. Based in Hong Kong, privately-held Insilico supports every one of its development programs through an autonomous robotics laboratory in Suzhou, China, that Zhavoronkov showcased earlier this year for an exclusive report by GEN Edge.

Alex Philippidis is Senior Business Editor of GEN.

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