For patients with nonalcoholic steatohepatitis (NASH), aldafermin was well-tolerated but did not show significant efficacy for the primary endpoint in a phase 2b trial. The study findings were published in The Lancet Gastroenterology and Hepatology.
Researchers conducted a randomized, double-blind, placebo-controlled trial, called ALPINE 2/3, (ClinicalTrials.gov Identifier: NCT03912532) at 30 sites in the United States between 2019 and 2020. Patients (N=171) with NASH were randomly assigned 1:1:1:1 to receive 24 weeks of placebo (n=43) or 0.3 mg (n=43), 1.0 mg (n=42), or 3.0 mg (n=43) aldafermin, a human gut hormone fibroblast growth factor 19 (FGF19) analogue. Safety and efficacy were evaluated up to week 30, and liver biopsies were collected at screening and week 24. The primary efficacy outcome was an improvement of liver fibrosis of 1 or more stages with no worsening of steatohepatitis.
The 4 cohorts included individuals with a mean age of 49.8-54.3 years, 60% to 69% were women, 90% to 95% were White, 42% to 56% had type 2 diabetes, 30% to 42% were on statins, and 63% to 65% had fibrosis stage II.
Fibrosis improvement without NASH worsening was achieved by 19% in the placebo group compared with 31% in the 0.3 mg aldafermin group (P =.11), 15% in the 1.0 mg group (P =.80), and 30% in the 3.0 mg group (P =.12).
Compared with placebo, the high-dose aldafermin group had significantly greater proportion of patients achieving greater than or equal to 1-point improvement in steatosis (P <.0001), greater than or equal to 1-point improvement in ballooning (P =.013), NASH resolution with no worsening of fibrosis (P =.019), both improvement in fibrosis and NASH resolution (P =.026), and greater than or equal to 2-point NASH improvement with no worsening fibrosis (P =.0034).
At week 24, liver fat content was reduced in a dose-dependent matter, with 57% (0.3 mg) to 81% (3.0 mg) having reduction in liver fat compared with 5% for placebo recipients. Similarly, alanine aminotransferase and aspartate aminotransferase were reduced in a dose-dependent manner in the intervention arms.
Total cholesterol (P =.0027) and low-density lipoprotein cholesterol (P <.0001) were more greatly reduced among the low-dose aldafermin group compared with placebo. No significant group differences were observed for the intermediate and high doses compared with control.
Adverse events were reported by 70% to 88% of aldafermin recipients compared with 84% of placebo recipients. One participant in each of the 3 aldafermin groups and 2 in the placebo group discontinued due to adverse events. The most common adverse events included diarrhea, nausea, headache, abdominal pain, fatigue, injection site erythema, constipation, and sinusitis.
The study was limited by the small sample size and the short study duration. Additional larger, longer-term studies are needed.
“In conclusion, in this randomized, phase 2b trial in patients with NASH and stage II or III fibrosis, treatment with the first-in-class FGF19 analogue aldafermin did not achieve the primary objective of a dose response on fibrosis improvement with no worsening of NASH, despite positive effects on a number of secondary endpoints,” the study authors wrote. “The results of the ALPINE 2/3 trial provide important information on the benefits of aldafermin for the treatment of NASH.”
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Harrison SA, Abdelmalek MF, Neff G, et al. Aldafermin in patients with non-alcoholic steatohepatitis (ALPINE 2/3): a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol. Published online March 21, 2022. doi:10.1016/S2468-1253(22)00017-6