Abstract

Background:

Metabolic dysfunction-associated steatohepatitis (MASH) patients who have developed stage F4 fibrosis (cirrhosis) are at risk of hepatic decompensation, hepatocellular carcinoma, liver transplant, cardiovascular events, liver and all-cause mortality. There are currently no approved therapies for non-cirrhotic or cirrhotic MASH.

Methods:

The ENLIVEN Phase 2b study assessed the effect of treatment for 24 weeks with one of three doses of pegozafermin or placebo on liver histology endpoints in 222 subjects with biopsy confirmed MASH (fibrosis F2 or F3, NAS ≥4 points). Initially, biopsies were assessed by one of two central pathologists; during the study, a novel 3-panel consensus scoring method was introduced to increase objectivity in biopsy reading. Baseline biopsies of subjects enrolled prior to this change were re-read by the panel. Fourteen subjects who met the study histological inclusion criteria based on the original read were re-classified as having stage F4 fibrosis by the consensus panel. All subjects had well compensated cirrhosis. We present post-hoc descriptive data for these subjects.

Results:

Baseline characteristics included: female 57%, mean age 56, average BMI 36.8, mean MRI-PDFF 15%, mean ProC3 65ng/mL, and 86% with a history of diabetes. Treatment assignment of the 14 subjects was: Placebo n=2; Pooled pegozafermin (PGZ) n=12. Follow-up biopsies at week 24 were available for 12 of the 14 subjects (PBO n=1; PGZ pooled n=11). PGZ led to ≥ 1 stage fibrosis improvement in 9 of the 11 treated patients (82%), and to ≥ 1 stage fibrosis improvement without worsening of MASH in 5/11 (45%) subjects. No fibrosis improvement was observed in the placebo group. There was concurrent improvement compared to baseline in the non-invasive fibrosis biomarkers ProC3 and FAST (LS means difference -24% and -53%, respectively). Treatment with PGZ also reduced ALT at week 24 compared to baseline (LS mean -53%). Pegozafermin was well tolerated in these subjects with the most common treatment-emergent adverse events being GI side effects and injection site reactions. No severe adverse events, discontinuations, or deaths were reported.

Conclusion:

These data demonstrate robust fibrosis improvement at 24 weeks in patients with MASH-related cirrhosis who were treated with PGZ. In addition to regression of fibrosis, reductions were observed in liver specific biomarkers of fibrogenesis/fibrosis (ProC3 and FAST) and inflammation (ALT). Pegozafermin appears to maintain a safety and tolerability profile in patients with compensated cirrhosis comparable to those with less advanced disease (MASH with F2/F3 fibrosis). Although this small subset precludes statistical analysis, the numerical improvement observed across both histology and biomarkers is encouraging and supports further evaluation of PGZ as a treatment for subjects with compensated MASH cirrhosis.