NGM Biopharmaceuticals announced positive preliminary topline results from the 24-week double-blind, randomized, placebo-controlled cohort (Cohort 4) of an adaptive Phase 2 study evaluating the efficacy, safety and tolerability of 1 mg aldafermin in patients with biopsy-confirmed non-alcoholic steatohepatitis (NASH) with stage 2 or 3 liver fibrosis (F2-F3). Aldafermin (formerly NGM282), NGM’s lead wholly-owned drug candidate, is an engineered variant of the human hormone FGF19 being developed as a once-daily treatment for patients with NASH. Cohort 4 was powered to demonstrate the effect of aldafermin treatment versus placebo on the primary endpoint of change in absolute liver fat content (LFC), which achieved statistical significance. In addition, the study assessed secondary and exploratory endpoints of liver histology and biomarkers of disease activity, many of which also achieved statistical significance.
The histology results revealed that treatment with aldafermin led to clinically meaningful improvements at 24 weeks versus placebo in fibrosis and in resolution of NASH. Treatment with aldafermin 1 mg resulted in a fibrosis improvement of ≥1 stage with no worsening of NASH in 38% of patients compared to 18% in the placebo arm. 24% of patients in the aldafermin treatment arm achieved the endpoint of resolution of NASH with no worsening of liver fibrosis as compared to 9% of placebo patients. Of note, 22% of patients in the aldafermin treatment arm versus 0% in the placebo arm achieved the composite endpoint of both fibrosis improvement and resolution of NASH, which was statistically significant. Draft guidance by the U.S. Food and Drug Administration (FDA) indicates that each of these is an acceptable endpoint for potential accelerated approval in a future pivotal trial.
Patients treated with aldafermin also demonstrated statistically significant improvements in each of the non-alcoholic fatty liver disease (NAFLD) activity score (NAS) components: steatosis, lobular inflammation and hepatocellular ballooning. In addition, a statistically significant proportion of patients in the aldafermin treatment arm (62%) experienced a two-point improvement in total NAS without worsening of fibrosis, compared to the placebo arm (9%).
"To my knowledge, aldafermin is the first drug to demonstrate a robust, statistically significant effect of greater than 20% of patients achieving the FDA composite regulatory endpoint of fibrosis improvement and resolution of NASH versus placebo, as well as show an impressive impact on both of these endpoints independently," said Stephen A. Harrison, M.D., Medical Director at Pinnacle Clinical Research, Visiting Professor of Hepatology at University of Oxford, UK and principal investigator on the study. "These preliminary results are remarkable and show that aldafermin’s rapid and profound effect across all histological measures of NASH previously seen at 12 weeks is sustained, and also suggest that extended treatment may lead to further improvement in liver health. Moreover, these data further strengthen aldafermin’s potential as a transformative monotherapy for NASH patients with established fibrosis."
Aldafermin was generally well tolerated with no study withdrawals due to adverse events as compared to one withdrawal due to an adverse event in the placebo arm. The most common adverse events (>10% in either treatment arm) in the study (diarrhea, headache, abdominal distension, nausea, fatigue, diabetes mellitus and peripheral edema) were primarily mild to moderate and occurred with comparable frequency in both the aldafermin and placebo arms. None of the reported serious adverse events (two in the aldafermin arm and three in the placebo arm) was deemed related to treatment by the site investigator.
"We’re very pleased with these data, as they are consistent with the comprehensive body of efficacy and tolerability data generated in over 200 aldafermin-treated NASH patients across our multi-cohort Phase 2 aldafermin program," Hsiao D. Lieu, M.D., Senior Vice President and Chief Medical Officer of NGM, said. "Given that aldafermin has a promising effect on fibrosis and NASH resolution and is well tolerated, we believe this drug could be a central tool in the future treatment landscape of NASH. We look forward to furthering our Phase 2b clinical development program and advancing aldafermin into pivotal studies."
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