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.

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Copyright © 2023. Published by Elsevier Inc.

Déclaration de conflit d'intérêts

Declaration of Competing Interest Dr. Manal F. Abdelmalek has received grants or research funding from Allergan, Boeringher-Ingelheim, Bristol-Myers Squibb, Celgene, Durect, Enanta, Enyo, Galmed, Genentech, Genfit, Gilead, Hanmi, Intercept, Inventiva, Madrigal, NGM Bio, Novo Nordisk, Poxel, Target NASH, Viking. Dr. Manal is on the advisory board for 89 Bio, Bristol-Myers Squibb, Hanmi, Intercept, Inventiva, Madrigal, Merck, NGM Bio, Novo Nordisk, SonicIncytes, Theratechnologies and received honorarium from Clinical Care Options, Fishwack, Inc., Medscape, Terra Firma, Inc. Dr. Manal serves on editorial board of Hepatology Journal. Dr. Ayako Suzuki and Dr. William Sanchez do not have any known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Dr. Eric Lawitz has received grants or research funds from for 89Bio Inc., AbbVie, Akero Therapeutics, Allergan, Alnylam Pharmaceuticals Inc., Amgen, Ascelia Pharma, Assemblybio, Astrazeneca, Axcella Health, Biocryst Pharmaceuticals, Bird Rock Bio Inc., Boehringer Ingelheim, Bristol-Myers Squibb, Conatus Pharmaceuticals, Cymabay Therapeutics, CytoDyn, DSM, Durect Corporation, Eli Lilly and Company, Enanta Pharmaceuticals, Enyo Pharma, Exalenz Bioscience, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Genentech, Gilead Sciences, GlaxoSmithKline, Hanmi Pharmaceuticals, Hightide Biopharma, Intercept Pharmaceuticals, Inventiva, Janssen Pharmaceuticals, Laboratory for Advanced Medicine, Loxo Oncology, Madrigal Pharmaceuticals, Merck & Co., Metacrine, NGM Biopharmaceuticals Inc., Northsea Therapeutics, Novartis, Novo Nordisk Inc., Pfizer, Poxel Co., Roche, Sagimet Biosciences, Synlogic Therapeutics, Terns Pharmaceuticals, Viking Therapeutics, Zydus Pharmaceuticals. Dr. Eric is on the advisory board of Akero, Boehringer Ingelheim, BMS, Intercept, Novo Nordisk, Metacrine, Sagimet, and Terns and a speaker at Abbvie, Gilead Sciences, Intercept. Dr. Claudia Filozof is an employee and shareholder at Labcorp Drug Development. Hyungjin Cho, Eunhye Baek(,) JaeDuk Choi(,) and Seungjae Baek are employees at Hanmi Pharmaceuticals.