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 Draft guidance by the U.S. Food and Drug Administration (FDA) indicates that each of these is an acceptable endpoint for potential accelerated approval in a future pivotal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."

NGM’s ongoing Phase 2b ALPINE 2/3 clinical study is designed to assess the efficacy, safety and tolerability of 0.3 mg, 1 mg and 3 mg of aldafermin compared to placebo in patients with biopsy-confirmed NASH and F2-F3 liver fibrosis. NGM expects to enroll approximately 150 patients in the ALPINE 2/3 study, with data expected in the first half of 2021. In addition, NGM plans to initiate the Phase 2b ALPINE 4 study, which is designed to evaluate aldafermin in NASH patients with F4 liver fibrosis and well-compensated cirrhosis, in the first half of 2020.

"I want to thank our team, all of the investigators, clinical site staff and, most importantly, the patients, whose participation and dedication enabled this important and highly informative Phase 2 clinical exploration of aldafermin," said David J. Woodhouse, Ph.D., Chief Executive Officer at NGM. "We are committed to delivering powerful new therapies to address some of today’s most widespread and difficult medical challenges. The successful completion of this Phase 2 study brings us a critical step closer to achieving that goal for NASH patients."

Cohort 4 is a multi-center, double-blind, randomized, placebo-controlled Phase 2 study evaluating the efficacy, safety and tolerability of 1 mg once daily subcutaneous injections of aldafermin over 24 weeks of treatment. The study enrolled 78 patients with biopsy-confirmed NASH with F2-F3 liver fibrosis who were randomized 2:1 to receive once-daily aldafermin 1 mg (n=53) or placebo (n=25). The primary endpoint was the treatment effect on absolute LFC as measured by magnetic resonance imaging-estimated proton density fat fraction, or MRI-PDFF, compared to placebo at 24 weeks, with a ≥5% absolute LFC reduction identified as clinically meaningful. Secondary and exploratory endpoints included relative changes in LFC, biomarkers of liver function and effect on liver histology. Patients were also evaluated at week 30 following six weeks off treatment for safety and non-invasive measures.

Patient liver biopsies were performed at baseline screening and at the end of 24 weeks of treatment and were read using the NASH CRN criteria by one central, independent hepatopathologist who was blinded to patient and treatment assignment. As per protocol, liver biopsy data were analyzed using the "liver histologic population," which was defined as the subset of enrolled patients who had valid, non-missing biopsy data at both baseline and week 24 (n=72). Six patients (three in the aldafermin arm and three in the placebo arm) withdrew prior to the week 24 biopsy for reasons not due to adverse events related to treatment.

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