Abstract INTRODUCTION Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease characterized by intestinal inflammation, encompassing Crohn’s disease (CD) and ulcerative colitis (UC), both of which cause swelling and ulceration in the inner wall of gastrointestinal tract 1. ISM5411 is an oral, gut-restricted small-molecule inhibitor targeting PHD1/2 to stabilize hypoxia-inducible factor (HIF)-1α, thus promoting the expression of genes protective of the intestinal mucosa, leading to maintenance and repair of mucosa integrity and function, and reduction of inflammation. Preclinical studies demonstrated that ISM5411 can significantly alleviate the symptoms of multiple animal models of colitis without significant increase in systemic erythropoietin (EPO) or vascular endothelial growth factor (VEGF) 2. This first-in-human Phase I study in Australia was completed to evaluate safety, tolerability, pharmacokinetics and food effect in healthy subjects. Aims & Methods This first-in-human study was a randomized, double-blind, placebo-controlled, single- and multiple-dosed Phase I trial conducted in healthy subjects at a single site in Australia (NCT06012578). Seven dose levels (50 mg to 1000 mg) of single ascending doses and three dose levels (200 mg, 400 mg, and 800 mg daily) for 14 days of multiple doses of ISM5411 were administrated orally. Safety and tolerability, pharmacokinetics (PK) parameters (plasma, urine and feces) and circulating biomarkers (EPO and VEGF) were evaluated. RESULTS Seventy-six subjects were dosed with ISM5411 with no serious adverse events (SAEs) or deaths recorded. One treatment emergent adverse event (TEAE) leading to discontinuation of treatment was reported (grade 1, rectal hemorrhage) in 200 mg once-daily ISM5411 but was judged as not related to ISM5411. The incidence of TEAEs was 25.0% and 55.0% in the ISM5411 pooled cohort (n = 56) and placebo cohort (n = 20), respectively. All TEAEs reported in the ISM5411 pooled cohorts were Grade 1 (n = 14/48, 25%). After single and multiple dose administration, ISM5411 was rapidly absorbed and metabolized to metabolite ISM5411-M15. The plasma exposure of both analytes was very low without apparent dose-proportionality, whereas ISM5411 was excreted in the feces in its prototypic form by more than 30%. Systemic EPO increased post-dose in most cohorts then decreased, and most changes were within or near the normal range. No clear trend was observed in systemic VEGF levels across cohorts. CONCLUSION ISM5411 tablets were safe and well-tolerated at all doses administered and demonstrated good gut restriction, consistent with preclinical findings and potential disease-localized activity. Phase 2a proof-of-concept testing of ISM5411 is ongoing in patients with UC to explore the safety, PK, and clinical efficacy. References 1. Chang JT. NEJM, 2020. 2. Fu Y et al. Nat Biotech, 2024.
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