Phase III ENLIGHTEN-Cirrhosis trial of pegozafermin is initiated in metabolic dysfunction-associated steatohepatitis (MASH) patients with compensated cirrhosis

“MASH patients with compensated cirrhosis are in critical need of effective therapies that can halt and ideally reverse the progression of fibrosis to prevent the onset of liver decompensation,” said Arun J. Sanyal, MBBS, M.D., Director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University. “Due to its demonstrated anti-fibrotic benefits, pegozafermin has the potential to be uniquely positioned to meet the needs of compensated cirrhotic MASH patients and could reduce the risk of decompensation. I look forward to evaluating the potential benefits of pegozafermin in this Phase III trial given the severity of symptoms this patient population experiences.”

ENLIGHTEN-Cirrhosis study is a global Phase III, randomized, double-blind, placebo-controlled trial evaluating pegozafermin for the treatment of MASH patients with compensated cirrhosis (F4). The trial will enroll approximately 760 patients, who will be randomized in a 1:1 ratio to either receive 30mg of pegozafermin administered weekly or a placebo. The interim analysis primary endpoint of fibrosis regression is defined as improvement in fibrosis from F4 to an earlier stage. A subset of the 760 patients will be evaluated at 24 months to assess fibrosis regression, potentially supporting an accelerated approval filing in the United States and conditional approval in Europe. The trial will continue to monitor all participants until a pre-defined number of clinical outcome events are observed. The primary endpoint for the final analysis will be a clinical outcome composite and is expected to form the basis for confirmatory or full approval for MASH patients at both stage F4 and as well as stages F2-F3. Based on prior discussions and alignment with regulatory agencies on the modified definitions of cirrhosis clinical outcome events, the timeline for reaching the expected number of events could be expedited compared to previous Phase III trials that have been conducted in MASH patients with compensated cirrhosis.

Key secondary endpoints include noninvasive tests (NITs) evaluating liver health and metabolic markers. The trial is designed to employ a three-panel consensus biopsy reading methodology, which was successfully utilized in the Phase IIb ENLIVEN trial. Patients will self-administer pegozafermin using the planned commercial liquid formulation delivered as a single subcutaneous injection.

The ENLIGHTEN program is comprised of two Phase III global, multi-center, randomized, double-blind, placebo-controlled trials, evaluating the efficacy and safety of pegozafermin in patients with MASH. The ENLIGHTEN-Fibrosis trial, the first of two Phase III trials in the program, will enroll approximately 1,000 patients with non-cirrhotic MASH (fibrosis stage F2-F3) to evaluate the efficacy and safety of pegozafermin. The co-primary endpoints, for which demonstration of an effect on each is needed to support regulatory approval, measured at week 52 are a one-point improvement in fibrosis with no worsening of MASH and MASH resolution with no worsening of fibrosis, assessed at week 52.

ENLIGHTEN-Cirrhosis, the second of two Phase III trials in the program, will evaluate the efficacy and safety of pegozafermin in MASH patients with compensated cirrhosis (F4).