Pegozafermin Significantly Improves Fibrosis in Patients with MASH

Pegozafermin was associated with significantly improved fibrosis in patients with metabolic-associated steatohepatitis (MASH) at just 24 weeks, according to new post-hoc data presented at The Liver Meeting 2023 from the American Association for the Study of Liver Diseases (AASLD) in Boston this weekend.

Findings from the phase 2b randomized, double-blind, placebo-controlled ENLIVEN trial suggest pegozafermin—a long-acting glycopylated fibroblast growth factor 21 (FGF21) analogue under development for MASH and severe hypertriglyceridemia—was linked to fibrosis regression and liver-specific biomarker improvements such as inflammation per ALT. The outcomes from the mid-stage trial provide cause for larger, pivotal research that could implicate pegozafermin as potentially the first marketed treatment for non-cirrhotic or cirrhotic MASH.

Presented by Rohit Loomba, MD, MHSc, chief of the USCD Health division of gastroenterology and hepatology and director of the UCSD NAFLD Research Center, the post-hoc analysis assessed the descriptive data of 14 patients from ENLIVEN who met histological inclusion criteria for stage F4 fibrosis per a new, objective biopsy panel re-read, as well as well-compensated cirrhosis.

ENLIVEN initially assessed 3 doses of pegozafermin versus placebo in 222 participants with biopsy-confirmed MASH per fibrosis F2 or F3, plus NAS scores of ≥4 points at baseline. In the post-hoc analysis, the 14 patients identified with fibrosis F4 were predominately female (57%). Mean patient age was 56 years old; average body mass index (BMI) was 36.8 kg/m²; mean liver fat per magnetic resonance imaging was 15%; mean ProC3 was 65ng/mL; and 86% of patients had a history of diabetes.

Among the population, 12 received pegozafermin doses, versus 2 who received placebo. Among the 12 patients (11 receiving pegozafermin) with follow-up biopsy data at week 24, investigators observed a ≥1 stage fibrosis improvement in 9 (82%) treated patients. They additionally observed a ≥1 stage improvement without worsening of MASH in 5 (45%) patients receiving pegozafermin.

Investigators additionally observed concurrent improvements from baseline in fibrosis biomarkers including ProC3 and FAST, as well as reduced ALT, at 24 weeks. Among the 11 treated patients with biopsy data, treatment tolerability was consistent; the most common treatment-emergent adverse events related to gastric and injection site reactions.

In an interview with HCPLive during The Liver Meeting, Loomba emphasized the sheer scale and implication of MASH in the US population as investigators search for viable treatment options.

“We think currently about 80 – 100 million Americans have MASLD…out of those, about 20 million have the progressive form of disease called MASH,” Loomba said. “Patients with MASH who have stage F2 fibrosis or higher have significantly increased risk of dying from liver-related morbidity and mortality. Those patients may account for somewhere between 10 – 15 million individuals. Those are the ones who need pharmacological therapy.”

Loomba praised the clinical history of pegozafermin showing “strong potency” in reducing liver fat and improving inflammation biomarkers and insulin resistance—as well as tertiary cardiometabolic benefits. These properties informed the original ENLIVEN trial and led to the post-hoc analysis of stage F4 fibrosis patients with MASH.

“This gives us an idea that potentially pegozafermin could improve fibrosis even in the setting of cirrhosis, and this is really important because it has been a big struggle to reverse fibrosis once it reaches cirrhosis, and it can take several years for the cirrhosis to go away. This is an important finding, and of course we’d like to validate that and replicate these data in a larger trial in patients with biopsy-proven cirrhosis randomized to treatment versus placebo over long-term.”

References

1. ^{Sanyal AJ, Kowdley KV, Bhatt DL, Alkhouri N, et al. 4: FIBROSIS IMPROVEMENT WITH PEGOZAFERMIN TREATMENT IN MASH PATIENTS WITH F4 FIBROSIS: ANALYSIS FROM A 24-WEEK RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 2 TRIAL (ENLIVEN). Paper presented at: The Liver Meeting. Boston, MA. November 10 - 14, 2023.}
2. ^{Loomba R, Sanyal AJ, Kowdley KV, et al. Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH. N Engl J Med. 2023;389(11):998-1008. doi:10.1056/NEJMoa2304286}