Insilico announces first-in-human study for oral PHD inhibitor for IBD

Biotech aims to accelerate clinical trials to reach unmet clinical needs for inflammatory bowel disease.

Insilico Medicine, a generative AI-driven clinical-stage biotech, has announced it has initiated the first-in-human study for ISM5411, a potentially first-in-class PHD inhibitor for the treatment of inflammatory bowel disease (IBD). 

Longevity.Technology: Designed and developed by Insilico’s proprietary end-to-end AI drug discovery platform, Pharma.AI, this is Insilico’s fifth AI drug program to enter the clinic. The ongoing Phase I study is designed to evaluate the safety, tolerability, pharmacokinetics and food effects of ISM5411 at increasing oral doses in 76 healthy subjects, with the first dose in healthy volunteers now completed in Australia. To further evaluate  ISM5411 in wider populations, Insilico plans to conduct global multi-center Phase Ib trials in patients with ulcerative colitis following the Phase Ia study.

“IBD impacts a large patient population who currently have limited therapeutic options,” says Sujata Rao, MD, Chief Medical Officer at Insilico Medicine who is leading the clinical trial.

“We believe this new treatment – which is potentially first-in-class – could offer a promising alternative.”  

IBD is a chronic inflammatory disease of the gastrointestinal tract, including ulcerative colitis (UC) and Crohn’s disease (CD), that affects huge populations globally, and 3 million adults in the US alone. Neither disorder is curable, and they both increase the risk of colorectal cancer up to four times. The current standard of treatment for IBD consists of anti-inflammatory drugs which offer limited improvement in mucosal healing, which is closely correlated to positive prognosis according to genetic and clinical evidence.

The intricate relationship between cellular senescence, characterized by the irreversible cessation of cell division, and the phenomenon of inflammaging plays a pivotal role in the pathogenesis of inflammatory bowel disease (IBD). As aging progresses, heightened senescence-associated secretory phenotype (SASP) contributes to chronic low-grade inflammation, fostering an environment conducive to the development and exacerbation of IBD. The age-related decline in immune regulatory mechanisms further accentuates these processes, underscoring the increased susceptibility of the elderly to inflammatory bowel diseases.

Insilico announces first-in-human study for oral PHD inhibitor for IBD

“Aging is both accelerated and accelerates the degradation of barrier function in the gut and in other organs, increasing the risk of the inflammatory bowel disease (IBD),” Alex Zhavoronkov, PhD, founder and co-CEO of Insilico told Longevity.Technology. “It is also commonly associated with inflammation and loss of regenerative capacity.

“To effectively treat IBD, the drug needs to repair the epithelial barrier and reduce inflammation in the gut without getting into the blood. These are the key properties we wanted our “042” compound to have.”

Research shows that PHD plays a critical role in regulating the stability and transcriptional activity of the hypoxia-inducible factor-1α (HIF-1α), which drives the expression of barrier protective genes. PHD is significantly up-regulated in IBD patients, and shows strong correlation with the expression of inflammatory cytokines and the apoptosis marker, suggesting that PHD is a potential target for IBD treatment.

In January 2022, Insilico announced the nomination of ISM5411 as a preclinical drug candidate (PCC) for the treatment of IBD targeting PHD. ISM5411 was developed by Chemistry42, Insilico’s generative AI engine for molecule development, and features a novel scaffold and a unique binding mode. In preclinical studies, ISM5411 demonstrated a favorable safety profile and significant anti-colitis efficacy as an oral, gut-restricted small molecule inhibitor.

“The rising incidence of IBD places a heavy burden on healthcare systems globally,” said Feng Ren, PhD, co-CEO and Chief Scientific Officer of Insilico Medicine.

“Designed by AI from scratch, ISM5411 targets mucosal healing with the unique mechanism of barrier protection enhancement, which could potentially lead to innovative clinical options for IBD patients. We are committed to accelerating ISM5411 clinical trials to reach unmet clinical needs as soon as possible.”

Driven by generative artificial intelligence, Insilico stands at the intersection of artificial intelligence and state-of-the-art technologies. The company has developed a comprehensive portfolio of more than 30 pipelines with 4 programs currently in the clinical stage developed using Pharma.AI, an integrated AI-driven drug discovery platform connecting biology, chemistry, and clinical development. Recently, Insilico launched the Company’s Al R&D Center in Montreal, Canada to further strengthen its AI algorithm research and platform building capabilities.

“At Insilico, we are driven to help patients in need using state-of-the-art AI technology combined with human ingenuity,” said Zhavoronkov. “This IBD program is the latest example of how we are using our AI algorithms to advance new cures for difficult-to-treat diseases.”

Photos courtesy of Insilico Medicine