Metacrine Reports Positive Results from Phase 1 Trial of MET642 for NASH

Metacrine has reported preliminary results from its Phase 1 trial of MET642, a farnesoid X receptor (FXR) agonist being developed for the treatment of non-alcoholic steatohepatitis (NASH) and inflammatory bowel disease. Findings show that treatment with MET642 was safe and generally well-tolerated and demonstrated a sustained pharmacokinetic (PK) profile and robust FXR target engagement after 14 days of daily oral dosing in healthy volunteers.

“There are no treatments currently available for NASH patients, and given FXR agonism works through multiple mechanisms to improve NASH and fibrosis, I believe that an optimized FXR agonist could become both a first-line monotherapy and foundation for combination therapies in the future,” said Stephen A. Harrison, M.D., Visiting Professor of Hepatology at University of Oxford’s Radcliffe Department of Medicine, Medical Director of Pinnacle Clinical Research and President of Summit Clinical Research. “I am encouraged by the sustained activity and safety demonstrated with MET642, in particular the lack of pruritis and LDL-cholesterol increases, which support its continued evaluation in patients with NASH.”

Metacrine has developed a proprietary FXR platform utilizing a unique chemical scaffold, which has demonstrated a clinically differentiated and improved therapeutic profile. The company’s lead FXR clinical candidate, MET409, has successfully completed a 12-week trial in patients with NASH. MET642, Metacrine’s second clinical candidate, is derived from the same chemical scaffold as MET409 and has shown comparable FXR target engagement and pharmacology in preclinical studies, as well as increased potency and differentiated pharmaceutical properties.

The MET642 Phase 1 trial was a first-in-human, randomized, placebo-controlled, double-blind single-ascending dose (SAD) and multiple-ascending dose (MAD) trial, in which healthy volunteers received once-daily MET642 doses ranging from 10 mg to 300 mg in the SAD cohorts and 2.5 mg to 10 mg in the MAD cohorts for 14 days. The primary objective of the trial was to evaluate safety and tolerability, and the secondary objectives were to assess PK parameters and FXR target engagement, the latter through the measurement of 7α-hydroxy-4-cholesten-3-one (C4), a blood biomarker of bile acid synthesis that decreases with FXR activation.

MET642 was safe and generally well-tolerated, with no serious adverse events reported, and all adverse events were mild to moderate in severity. Importantly, pruritus and LDL-cholesterol increases were not seen at any dose level.

MET642 exhibited a sustained PK profile as well as robust FXR target engagement throughout 24 hours after once-daily oral dosing, with notable C4 repression – up to an approximately 95% decrease in area-under-the-curve (AUC) relative to placebo – observed after the last dose in all MAD cohorts of the trial. The magnitude of C4 decrease can be used to project potential levels of liver fat reduction in NASH patients, with ≥30% relative liver fat reduction being associated with increased likelihood of histological benefits upon liver biopsy.

“We are encouraged by the overall safety profile of MET642, and with meaningful target engagement seen at as low as the 2.5 mg dose level, we intend to evaluate the 3 mg and 6 mg dose levels in our upcoming Phase 2a trial in NASH patients,” said Hubert C. Chen, M.D., chief medical officer of Metacrine. “With the benefit of greater potency and improved pharmaceutical properties, we believe MET642 has the potential to be another best-in-class FXR agonist in our proprietary portfolio.”