89bio, Inc. announced the initiation of ENLIGHTEN-Cirrhosis, a Phase 3 trial of pegozafermin in patients with MASH with compensated cirrhosis (F4). ENLIGHTEN-Cirrhosis is a global Phase 3, 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 3 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 2b ENLIVEN trial. Patients will self-administer pegozafermin using the planned commercial liquid formulation delivered as a single subcutaneous injection. MASH, also known as nonalcoholic steatohepatitis (NASH), is a chronic and progressive condition that represents a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD).

It is characterized by fat accumulation in the liver, which causes inflammation and can ultimately lead to scarring or fibrosis. By 2030, it is projected to affect over 27 million people in the U.S. The disease is categorized based on the extent of liver fibrosis. In cases of advanced fibrosis, the treatment goal is to improve liver health, reverse fibrosis, and prevent the progression of the disease and related complications such as cirrhosis and cardiovascular risks.

Estimates suggest that approximately 20% of patients with MASH may develop cirrhosis, a serious condition that significantly impairs liver function. Cirrhosis can lead to life-threatening complications from esophageal varices, ascites, or hepatocellular carcinoma. Patients may ultimately require a liver transplant to avoid death from liver failure.

The ENLIGHTEN program is comprised of two Phase 3 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 3 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 3 trials in the program, will evaluate the efficacy and safety of pegozafermin in MASH patients with compensated cirrhosis (F4). Pegozafermin is a specifically engineered glycoPEGylated analog of fibroblast growth factor 21 (FGF21) being developed for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) and severe hypertriglyceridemia (SHTG). FGF21 is an endogenous hormone that has broad effects such as regulating energy expenditure, glucose and lipid metabolism.

In clinical trials, pegozafermin has demonstrated direct anti-fibrotic and anti-inflammatory effects on the liver, as well as reduced triglyceride levels, improved insulin resistance and glycemic control, and continued to demonstrate a favorable safety and tolerability profile. Pegozafermin received Breakthrough Therapy designation (BTD) status from the U.S. Food and Drug Administration (FDA) and Priority Medicines (PRIME) status from the European Medicines Agenda (EMA) for the treatment of MASH with fibrosis. Pegozafermin is being studied in the Phase 3 ENLIGHTEN trial program for MASH and is being studied in the Phase 3 ENTRUST trial for SHTG.