Insilico Medicine (“Insilico”), an end-to-end artificial intelligence (AI)-driven drug discovery company announced that it has dosed multiple healthy volunteers in Phase I clinical trial evaluating ISM001-055, the first anti-fibrotic small molecule inhibitor generated by Insilico’s AI-powered drug discovery platform for idiopathic pulmonary fibrosis (IPF). The double-blind, placebo controlled single and multiple ascending dose ISM001-055 is a small molecule inhibitor against a novel target discovered by target identification engine PandaOmics, and with a molecule structure designed by small molecule generation engine Chemistry42. The mechanism of action for the target is also relatively novel in fibrosis. Both PandaOmics and Chemistry42 are parts of Pharma.AI, Insilico’s end-to-end AI-driven drug discovery and development platform. Phase I clinical trial will evaluate the safety, tolerability, and pharmacokinetics of this drug. Eighty healthy volunteers will be enrolled in ten cohorts comprising of five single ascending doses and five multiple ascending dose cohorts.
The primary endpoints determine the maximum tolerated dose and establish dosage recommendations for potential Phase II clinical trials in the future. In order to better understand compound distribution, establish a dose, and provide insights into ISM001-055’s safety profile in humans, Insilico initiated a Phase 0 exploratory microdose trial of ISM001-055 in November 2021, which was conducted in Australia and included eight healthy volunteers. The results identified a microdose of ISM001-055 with a favorable pharmacokinetics and safety profile. Michael Levitt, 2013 Nobel Prize in Chemistry and member of Insilico Medicine’s Scientific Advisory Board, commented: “There are groups who try to do target discovery and groups who do chemistry, but Insilico goes end-to-end. The best way to validate the performance of an AI system is to conduct comprehensive testing with novel targets and novel molecules. Human safety testing is crucial. I am delighted that Insilico’s AI-powered, end-to-end anti-fibrotic program just passed microdose study in humans and has entered Phase I.”
But there are other oppotunities to be explored with the consolidated strategy of the drug repurposing. In several medical branches, from infectivology to oncology, repurposing known drugs with previously acknowledged cellular mechanisms, has led to the identification of approved drug to be easily redirected to dedicated and much shorter clinical trials. This would mean shorter times of studies with a consequental spare of money and efforts. This could be the case for nifuroxazide: this antiparasitic drug was originally used against tropical diarrhoeas, but more recently, it has been found to have additional anti-tumour and antinflammatory effects against diabetic nephropathy. Intraperitoneal injection of the drug in living mice with a bleomycin-induced IPF relieved and reversed pulmonary fibrosis. In addition, nifuroxazide inhibited the expression of a variety of cellular inflammatory factors and immune cells, suppressed the activation of fibroblasts and the mesenchimal transition of epithelial cells induced by TGF-β1.
Moreover, nifuroxazide inhibited the TGF-β/Smad pathway in vitro and decreased the expression of phosphorylated STAT-3 in vitro and in vivo, confirming the previous knowledge of this molecule interfering with this transcription factor. The discovery has its advantages, because nifuroxazide is a very old, well-known drug and practically everything is known about its handling and clinical toxicity risks. So it is likely that in the years immediately to come, this molecule will be introduced as an additional weapon in a virtually devoided therapeutic arsenal for IPF.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Adviced in this website
Lung fibrosis: a new mutation reveal an earlier thread to follow “on the path of death” (14/10/2019)
Lung fibrosis: “scar” is the problem for a condition with “scarce” options (26/12/2018)
Scientific references
Zhang Q et al. Clin Chim Acta. 2022 Feb; 530:8-12.
Wilson AC et al. Sci Rep. 2022 Feb 23; 12(1):3080.
Gan C, Zhang Q et al. Respir Res. 2022; 23(1):32.
Ring NAR et al. Cell Death Dis. 2021 Dec; 13(1):2.

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