Pegozafermin Enters Phase 3 Clinical Trial Program for MASH, Fibrosis

Rohit Loomba, MD, MHSc

Credit: UC San Diego Health

89bio has announced the initiation of its phase 3 ENLIGHTEN program evaluating the efficacy and safety of pegozafermin in patients with metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH).¹

According to the release, ENLIGHTEN-Fibrosis, the first of a pair of phase 3 trials in the clinical development program, has initiated and is evaluating the use of pegozafermin in non-cirrhotic patients with MASH and fibrosis stage F2-F3. Co-primary endpoints for improvement in fibrosis with no worsening of MASH and MASH resolution with no worsening of fibrosis will be measured at week 52 and are intended to support a filing for accelerated approval in the US.¹

"The ENLIGHTEN-Fibrosis trial is designed to build on the robust anti-fibrotic and metabolic effects observed across non-cirrhotic MASH patients treated with pegozafermin in the Phase 2b ENLIVEN trial,” Rohit Loomba, MD, MHSc, lead investigator and chief of the division of gastroenterology and hepatology at University of California San Diego School of Medicine, said in a press release.¹ “There is a critical need for a therapeutic option that improves liver health and provides anti-fibrotic benefits for MASH patients with fibrosis.”

The specifically engineered glycoPEGylated analog of fibroblast growth factor 21 (FGF21) is in development for the treatment of MASH and severe hypertriglyceridemia (SHTG) and has demonstrated direct anti-fibrotic and anti-inflammatory effects on the liver, reduced triglyceride levels, improved insulin resistance, and glycemic control in clinical trials.¹

Pegozafermin was granted Breakthrough Therapy Designation for MASH with fibrosis by the US Food and Drug Administration (FDA) on September 21, 2023, supported by data from the ENLIVEN phase 2b trial. Results showed both the 44mg every 2 weeks and 30mg weekly doses met the primary histology endpoints and also demonstrated statistically significant and clinically meaningful improvements in liver fat, non-invasive markers of liver fibrosis and inflammation, and meaningful improvements in other metabolic and lipid markers. Additionally, 45% of pegozafermin-treated biopsy-confirmed F4 patients experienced ≥ 1-stage improvement in liver fibrosis with no worsening of NASH by week 24.²

Positive long-term data from ENLIVEN’s blinded extension phase were announced on November 27, 2023, showing both the 30mg weekly and 44mg every-2-week dosing schedules of pegozafermin demonstrated statistically significant improvements across key markers of liver health that were sustained from week 24 through week 48.³

Now, pegozafermin is advancing into the phase 3 ENLIGHTEN trial program for MASH, starting with ENLIGHTEN-Fibrosis, the first of 2 phase 3 trials. A global, randomized, double-blind, placebo-controlled trial, ENLIGHTEN-Fibrosis is expected to enroll 1,000 patients with non-cirrhotic MASH and randomly assign them in a 1:1:1 ratio to receive either 30mg of pegozafermin administered weekly, 44mg administered every 2 weeks, or placebo.¹

The co-primary endpoints measured at week 52 are a 1-point improvement in fibrosis with no worsening of MASH and MASH resolution with no worsening of fibrosis. Key secondary endpoints include additional histological endpoints, noninvasive tests, and metabolic and lipid assessments. According to the release, patients are expected to continue to be treated beyond the 52-week assessment to support full approval.¹

ENLIGHTEN-Cirrhosis, the second of the pair of phase 3 trials in the program, is expected to evaluate the efficacy and safety of pegozafermin in MASH patients with compensated cirrhosis (F4) in the second quarter of 2024.¹

"We are excited to initiate our first Phase 3 trial in MASH for pegozafermin, a leading and potentially best-in-class FGF21 analog, which strikes the right balance of sustained efficacy, favorable tolerability, and dosing convenience,” Hank Mansbach, MD, Chief Medical Officer of 89bio, said in a press release.¹

References:

1. ^{89bio. 89bio Initiates Phase 3 ENLIGHTEN-Fibrosis Trial of Pegozafermin in Non-Cirrhotic Metabolic Dysfunction-Associated Steatohepatitis (MASH) Patients with Fibrosis. Press Releases. March 12, 2024. Accessed March 12, 2024. https://ir.89bio.com/news-releases/news-release-details/89bio-initiates-phase-3-enlighten-fibrosis-trial-pegozafermin}
2. ^{89bio. 89bio Announces U.S. FDA has Granted Breakthrough Therapy Designation for Pegozafermin in Nonalcoholic Steatohepatitis (NASH). Press Releases. September 21, 2023. Accessed March 12, 2024. https://ir.89bio.com/news-releases/news-release-details/89bio-announces-us-fda-has-granted-breakthrough-therapy}
3. ^{Brooks, A. Pegozafermin Shows Sustained Benefit for NASH in Phase 2b Extension Study. November 27, 2023. Accessed March 12, 2024. https://www.hcplive.com/view/pegozafermin-shows-sustained-benefit-for-nash-in-phase-2b-extension-study}