89bio, Inc. announced positive topline data from the Phase 2b ENLIVEN trial evaluating treatment with pegozafermin in patients with nonalcoholic steatohepatitis (NASH). In the study, both the 44mg every-two-week (Q2 W) and 30mg weekly (QW) doses met, with high statistical significance, both the primary histology endpoints per the U.S. Food and Drug Administration (FDA) guidance on endpoints and statistical analysis. The 44mg Second Quarter W and the 30mg QW dose groups both demonstrated at least one-stage fibrosis improvement without worsening of NASH (27% and 26%, respectively) at 3.5 times the placebo rate (7%) and NASH resolution without worsening of fibrosis (26% and 23%, respectively), between 12 to 14 times the placebo rate (2%).

The ENLIVEN study followed a stringent analytical plan consistent with FDA guidance, and the low placebo response rate provides high confidence that this trial showed the true potential treatment effect of pegozafermin. improvement in liver fibrosis by =1 stage and no worsening of steatohepatitis defined as no increase in NAFLD Activity Score (NAS) for ballooning, inflammation, or steatosis (FDA draft guidance). Resolution of steatohepatitis is defined as absent fatty liver disease or isolated or simple steatosis without steatosis and a NAS score of 0-1 for inflammation, 0 for ballooning and any value for steatosis (FDA Draft guidance).) Resolution of steatohepatitis is defined as absent fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS score of 0-1 for inflammation, 0 for ballooning and any value for steatosis (FDA draft guidance).

Results were consistent and achieved statistical significance for the 44mg Second Quarter W and 30mg QW dose groups using multiple imputation analysis (as shown in table 1), completers analysis (patients who had baseline and end of treatment biopsies at week 24), and intention-to-treat (ITT) analysis (Phase 3 analysis plan). Using the completers analysis methodology on the fibrosis endpoint, the placebo-adjusted effect size for the 44mg Second Quarter W and 30mg QW dose groups was 20% and 19%, respectively (p=0.008 and p=0.009, respectively), and on the NASH resolution endpoint, the placebo-adjusted effect size for the 44mg Second Quarter W and 30mg QW dose groups was 24% and 21%, respectively (p=0.0004 and p=0.0009, respectively). Results were also statistically significant for both doses on both primary histology endpoints using an ITT analysis that imputes patients with missing biopsies as non-responders.

Meaningful changes were observed compared to baseline in liver fat and other key non-invasive tests (‘NITs') of liver inflammation and fibrosis. Improvements were also observed in HbA1c and across important lipid markers that are important factors for an effective treatment for NASH. The ENLIVEN study also included 14 biopsy-confirmed NASH patients with compensated cirrhosis (F4 patients) who were not part of the primary analysis but continued in the study, 12 of which underwent a follow-up biopsy at week 24.

In descriptive analysis of these data, five out of 11 pegozafermin-treated patients experienced at least one-stage improvement in liver fibrosis with no worsening of NASH by week 24 compared with zero out of one patient on placebo. An additional four pegozafermin-treated patients experienced at least one-stage improvement in liver fibrosis. Pegozafermin continued to demonstrate a favorable safety and tolerability profile consistent with prior studies.

Across dose groups, the most frequently reported treatment-related adverse events (AEs) were Grade 1 or 2 gastrointestinal events (diarrhea, nausea and increased appetite) most of which were mild to moderate in nature. Rates of treatment-related AEs observed were less frequent with the Second Quarter W dosing regimen. A total of five patients treated with pegozafermin were discontinued due to treatment-related AEs all of which were Grade 2 compared with none for placebo.

A single drug-related serious adverse event of uncomplicated pancreatitis was experienced by a patient in the 44mg Second Quarter W dose group after a single dose of pegozafermin which resolved in a short time period.