Pegozafermin Shows Early Promise in NASH: Phase 2b ENLIVEN Trial Findings

In the phase 2b ENLIVEN trial of the investigational agent pegozafermin, used to treat adults with biopsy-confirmed nonalcoholic steatohepatitis (NASH), more than 25% of study participants taking the 2 highest doses met criteria for improvement in fibrosis without worsening of disease at 24 weeks, satisfying 1 of 2 primary study endpoints.¹

Results for the second of these endpoints, NASH resolution without worsening of fibrosis, were similar with 23% of participants receiving 30 mg of pegozafermin weekly and 26% of those receiving a 44-mg dose every 2 weeks meeting the criteria for the endpoint.

The ENLIVEN findings were presented at the European Association for the Study of the Liver Congress 2023 and simultaneously published online on June 24 in the New England Journal of Medicine.¹

Pegozafermin, a long-acting glycopegylated fibroblast growth factor 21 (FGF21) analogue, is in development for treatment of both NASH and severe hypertriglyceridemia. Findings for the latter were presented at the 2023 American College of Cardiology Scientific Sessions. (Sidebar, right)

Lead investigator Rohit Loomba, MD, MHSc, chief of the Division of Gastroenterology and Hepatology at University of California San Diego School of Medicine, presented the ENLIVEN findings on the efficacy and safety of pegozafermin in NASH at the EASL Congress 2023.

Methods

The randomized, double-blind study enrolled individuals aged 21 to 75 years with biopsy-confirmed NASH and stage F2 or F3 fibrosis. Participants were randomly assigned to receive subcutaneous pegozafermin 15 mg or 30 mg weekly, pegozafermin 44 mg once every 2 weeks, or placebo on a weekly or biweekly basis. The enrollment period was September 2021 to August 2022.

Loomba and colleagues defined the coprimary outcomes of interest for the study as an improvement in fibrosis with no worsening of NASH at 24 weeks and NASH resolution without worsening of fibrosis at 24 weeks. Investigators defined an improvement in fibrosis as a reduction of 1 stage or greater and NASH resolution as total absence of ballooning and mild or no inflammation without worsening of fibrosis.

The final cohort numbered 222 and mean age was 55.6 years. The majority (94%) were White, 39% were men, and 91% had biopsy-confirmed stage F2 or F3 fibrosis at baseline. Of the 222, 219 received at least 1 dose of pegozafermin or placebo therapy.

Follow-up biopsy was performed at week 24 with assessment performed by a panel of 3 expert liver pathologists.

FINDINGS

Loomba and colleagues report that pegozafermin treatment was associated with significant changes on both primary histology endpoints across doses and dosing schedule. At 24 weeks the percentage of participants receiving pegozafermin with at least 1-stage fibrosis improvement without worsening NASH was higher vs placebo (7%) as follows:

• Weekly 30-mg dose (26% vs. 7%; difference, 19 percentage points; 95% CI, 5 to 32; P=.009)
• Every-2-week 44-mg dose (27% vs. 7%; difference, 7 percentage points; 95% CI, 5 to 35; P=.008)
• Weekly 15-mg dose (22% vs 7%; difference, 14 percentage points; 95% CI, −9 to 38).

At 24 weeks the percentage of participants NASH resolution without worsening fibrosis NASH was higher vs placebo (2%) as follows:

• Weekly 30-mg dose (23% vs. 2%; difference, 21 percentage points; 95% CI, 9 to 33)
• Every-2-week 44-mg dose (26% vs. 2%; difference, 24 percentage points; 95% CI, 10 to 37)
• Weekly 15-mg dose (37% vs 2%; difference, 35 percentage points; 95% CI, 10 to 59)

Safety profile. iIn their analysis of the pegozafermin safety profile, the investigators reported adverse events among 95% of participants receiving pegozafermin 15 mg, 85% who received 30 mg, and 67% of those in the 44-mg group compared to 68% of those receiving placebo therapy.

The researchers found the most common adverse events in the trial were nausea, diarrhea, and injection-site erythema. Serious adverse events were reported by 5% of the pegozafermin 15 mg group, 4% of the 30 mg group, and 11% of the 44 mg group compared to 4% of those receiving placebo.

The investigators discuss the progression of liver fibrosis as a key predictor of clinical outcomes in NASH, both liver-related and all-cause death. Of the ENLIVING findings, they add "Improvement in both steatohepatitis and fibrosis indicates that pegozafermin may affect key aspects of the pathophysiology of NASH."¹

“NASH is highly associated with metabolic syndrome and increased cardiovascular risk, driving its impact far beyond the liver," said said Arun J Sanyal, MD, interim chair of the Division of Gastroenterology, Hepatology and Nutrition at Virginia Commonwealth University," in a statement from pegozafermin developer 89bio.² "Data from ENLIVEN show the promise of FGF21 analogs and potential of pegozafermin as a mainstay treatment for NASH, given it addresses both liver pathology and the underlying metabolic overload that drives it.”

References:

1. Loomba R, Sanyal AJ, Kowdley KV, et al. Randomized, controlled trial of the FGF21 analogue pegozafermin in NASH. N Engl J Med. 2023;10.1056/NEJMoa2304286. doi:10.1056/NEJMoa2304286

2. Data from 89bio’s enliven phase 2b trial of pegozafermin in patients with nonalcoholic steatohepatitis (NASH) published in the New England Journal of Medicine and simultaneously presented in a late-breaker session at the EASL International Liver Congress. 89bio, Inc. June 24, 2023. Accessed June 28, 2023. https://ir.89bio.com/news-releases/news-release-details/data-89bios-enliven-phase-2b-trial-pegozafermin-patients