A phase 2, adaptive randomized, double-blind, placebo-controlled, multicenter, 52-week study of HM15211 in patients with biopsy-confirmed non-alcoholic steatohepatitis - Study design and rationale of HM-TRIA-201 study.

Non-alcoholic steatohepatitis (NASH) is a multifactorial disease with an increasing prevalence worldwide due to the obesity pandemic. HM15211 (efocipegtrutide), a novel, long-acting glucagon-like peptide-1/glucagon/glucose-dependent insulinotropic polypeptide triple incretin agonist has shown promising efficacy in in vitro, preclinical rodent models of NASH and phase 1 studies with manageable toxicity. Though liver biopsy is recommended for grading and staging of NASH, its invasive nature necessitates innovative approaches in clinical trials that decrease the burden of patients otherwise subjected to this invasive procedure. We report an innovative study design of phase 2 study of HM15211. METHODS: HM-TRIA-201 is a multicenter, randomized, double-blind, 52-week, placebo-controlled, parallel-group adaptive design study of 217 patients with biopsy-proven NASH. The primary endpoint is the proportion of patients with complete resolution of steatohepatitis (defined as Non-alcoholic fatty liver disease Activity Score of 0-1 for inflammation, 0 for ballooning, and any other value for steatosis) on overall histopathological reading and no worsening of liver fibrosis on NASH Clinical Research Network fibrosis score. An interim analysis is planned after 15 patients/group complete 26 weeks of treatment, after which one HM15211 dose group will be discontinued based on safety and efficacy risk-to-benefit analysis; patients of the dropped dosing arm will be re-randomized into 2 remaining HM15211 groups. CONCLUSION: The adaptive design study of HM15211 minimizes the number of patients to be exposed to a liver biopsy while optimizing the sample size of patients exposed to safe and effective doses of HM15211 to inform ideal dose for further clinical development in NASH.