Aldafermin in Patients with Non-Alcoholic Steatohepatitis (ALPINE 2/3): Randomized, Double-Blind, Placebo-Controlled Phase 2b Trial

context

Nonalcoholic steatohepatitis (NASH) is characterized by fatty liver, inflammation and injury, and is associated with an increased risk of liver transplantation and death. NASH affects more than 16 million people in the United States and there are no approved treatments. The purpose of this study was to evaluate the safety and efficacy of aldafermin, a modified analog of fibroblast growth factor 19 (FGF19), an intestinal hormone.

Methods

In this phase 2b randomized, double-blind, placebo-controlled (ALPINE 2/3) study in patients with biopsy-confirmed NASH and stage 2 or 3 fibrosis, we randomly allocated patients stratified by stage of fibrosis in a 1:1:1:1 ratio to receive placebo, aldafermin 0.3 mg, 1.0 mg, or 3.0 mg once daily for 24 weeks at 30 study sites in the United States. Patients, investigators, funder and all other staff were masked for treatment assignment throughout the study. The primary endpoint was improvement in liver fibrosis by at least one stage without worsening of NASH at week 24. Analyzes were performed on an intention-to-treat basis. This trial is registered with ClinicalTrials.govnumber NCT03912532and has been completed.

Results

Between May 16, 2019 and September 4, 2020, 786 patients were screened, of whom 171 were randomly assigned to a treatment group and included in the intent-to-treat population: 43 in the 0.3 mg aldafermin group , 42 in the 1·0 mg group, 43 in the 3·0 mg group and 43 in the placebo group. A total of 145 (85%) patients completed treatment. At Week 24, among patients who underwent biopsies at both baseline and Week 24, seven (19%) of 36 patients in the placebo group, 11 (31%) of 36 patients in the 0.3 mg d aldafermin (difference 90% CI 12% [−9 to 33]; p=0 11), five (15%) of 34 patients in the 1 0 mg group (difference −5% [−24 to 13]; p=0 80), and 11 (30%) of 37 patients in the 3 0 mg group (difference 10% [−9 to 30]; p = 0.12) showed improvement in liver fibrosis by at least one stage without worsening of NASH, without reaching predefined significance for dose-response (p = 0.55). Adverse events were mostly mild or moderate in intensity. Diarrhea occurred in six (14%) of 43 patients in the placebo group, three (7%) of 43 patients in the 0.3 mg aldafermin group, five (12%) of 41 patients in the 1.0 mg group and ten (23%) of 43 patients in the 3 0 mg group. The incidences of serious adverse events and discontinuations due to adverse events were similar between the groups.

Interpretation

Aldafermin was generally well tolerated but did not produce a significant dose-response in improving fibrosis by at least one stage without worsening NASH, despite positive effects on a number of endpoints. secondary evaluation. The results of this trial could have implications for the design of future NASH trials.

Funding

NGM Biopharmaceuticals.

About Rhonda Lee

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