Pegazofermin Enters Phase 3 ENLIGHTEN Clinical Trial Program for MASH

Pegazofermin will be evaluated for safety and efficacy in 2 phase 3 trials of the investigational agent in individuals with metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), according to an announcement by developer 89bio on Tuesday. ¹

ENLIGHTEN-Fibrosis, the first of the pair of studies in the new phase 3 clinical trial program, is underway and is evaluating the use of pegozafermin in participants without cirrhosis who have MASH and fibrosis stage F2-F3. The study’s co-primary endpoints, 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, 89Bio said.¹

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"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 the 89bio announcement.¹ “There is a critical need for a therapeutic option that improves liver health and provides anti-fibrotic benefits for MASH patients with fibrosis.”¹

Pegozafermin was granted Breakthrough Therapy Designation² 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.³

In ENLIVEN, more than 25% of adults with biopsy-confirmed MASH taking the 2 highest doses of pegozafermin met criteria for improvement in fibrosis without worsening of disease at 24 weeks.³ MASH resolution without worsening of fibrosis was observed in 23% of participants receiving 30 mg of pegozafermin weekly and 26% of those receiving a 44-mg dose every 2 weeks.³ ENLIVEN researchers also reported 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.³

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 antifibrotic and anti-inflammatory effects on the liver as well as reduced triglyceride levels, improved insulin resistance, and glycemic control in clinical trials.¹

Positive long-term data from the blinded extension phase of the ENLIVEN study were announced in November, 2023 and showed both the 30 mg weekly and 44 mg 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 48.⁴

ENLIGHTEN-Fibrosis

The new global phase 3, randomized, double-blind, placebo-controlled ENLIGHTEN-Fibrosis trial looks to enroll 1000 participant with biopsy-confirmed MASH without cirrhosis and investigators will randomly assign them in a 1:1:1 ratio to receive either 30 mg of pegozafermin administered weekly, 44 mg administered every 2 weeks, or placebo.¹

The coprimary endpoints to be assessed 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 histologic endpoints, noninvasive tests, and metabolic and lipid assessments. According to the company news release, patients are expected to continue to be treated beyond the 52-week assessment to support full approval.¹

Participants will self-administer pegozafermin using the planned commercial liquid formulation delivered as a single subcutaneous injection, according to 89Bio.¹

ENLIGHTEN-Cirrhosis, the second of the phase 3 program trials, is expected to evaluate the efficacy and safety of pegozafermin in MASH patients with compensated cirrhosis (F4) and to begin 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 the company statement.¹

References:

1. 89bio initiates phase 3 ENLIGHTEN-Fibrosis trial of pegozafermin in non-cirrhotic metabolic-dysfunction associated steatohepatitis (MASH) patients with fibrosis. News release. 89bio. 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 PCO

3 PCO

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

4. Use 89 press release on extension