Aldafermin in patients with non-alcoholic steatohepatitis (ALPINE 2/3): a randomised, double-blind, placebo-controlled, phase 2b trial.

Background: Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, and injury, and is associated with an increased risk of liver transplantation and death. NASH affects more than 16 million people in the USA, and there is no approved therapy. The aim of this study was to evaluate the safety and efficacy of aldafermin, an engineered analogue of the gut hormone fibroblast growth factor 19 (FGF19).
Methods: In this randomised, double-blind, placebo-controlled, phase 2b study (ALPINE 2/3) in patients with biopsy-confirmed NASH and stage 2 or 3 fibrosis, we randomly assigned patients stratified by fibrosis stage 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 USA. Patients, investigators, the funder, and all other staff, were masked to treatment assignment throughout the study. The primary endpoint was an improvement in liver fibrosis of at least one stage with no worsening of NASH at week 24. Analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT03912532, and has been completed.
Findings: Between May 16, 2019, and Sept 4, 2020, 786 patients were screened, of whom 171 were randomly assigned to a treatment group and included in the intention-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. In total, 145 (85%) of patients completed treatment. At week 24, among patients with biopsies at both baseline and week 24, was seven (19%) of 36 patients in the placebo group, 11 (31%) of 36 in the 0·3 mg aldafermin group (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) had an improvement in liver fibrosis of at least one stage with no worsening of NASH, without meeting the prespecified significance for dose response (p=0·55). Adverse events were mostly mild or moderate in severity. Diarrhoea 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. Incidences of serious adverse events and discontinuations owing to adverse events were similar between groups.
Interpretation: Aldafermin was generally well tolerated but did not produce a significant dose response on fibrosis improvement of at least one stage with no worsening of NASH, despite positive effects on a number of secondary endpoints. The findings of this trial may have implications for the design of future NASH trials.
Funding: NGM Biopharmaceuticals.
Competing Interests: Declaration of interests SAH reports grant and research support from Akero, Axcella, Bristol-Myers Squibb, Cymabay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, Intercept, Madrigal, Metacrine, NGM, Novartis, Novo Nordisk, Northsea, Pfizer, Sagimet, Viking, and 89 Bio; is a scientific advisor or consultant for Akero, Alentis, Altimmune, Arrowhead, Axcella, Bristol-Myers Squibb, Echosens, Forest Labs, Galectin, Gilead, Hepion, Hepagene, HistoIndex, Intercept, Madrigal, Medpace, Metacrine, NGM, Northsea, Novartis, Novo Nordisk, PathAI, Poxel, Sagimet, Sonic Incytes, Terns, and Viking; and has stock options in Akero, Cirius, Chronwell, Galectin, Genfit, Hepion, HistoIndex, Metacrine, NGM, and Northsea. MFA reports grant and research support from Allergan, Bristol-Myers Squibb, Boeringher Ingelheim, Celgene, Genentech, Hanmi, Intercept, Inventiva, Magrigal, NGM, NovoNordisk, and Viking; is a consultant for Hanmi and Madrigal; and serves on an advisory committee for 89Bio, Bristol-Myers Squibb, Hanmi, NGM, Novo Nordisk, and Thera. CDG reports grant and research support from 89Bio, CymaBay, Madrigal, and NGM; and is a consultant for 89Bio, CymaBay, Madrigal, and NGM. NA reports serving on advisory boards for 89Bio, Gilead, Intercept, LG Chem, NGM, Novo Nordisk, Pfizer, Terns, and Zydus; is a speaker for AbbVie, Alexion, Echosens, Gilead, Intercept, Perspectum, and Simply Speaking; and has received research support from 89Bio, Akero, Albireo, Allergan, Axcella, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Corcept, Gilead, Galmed, Galectin, Genfit, Enanta, Enyo, Fibronostics, Hanmi, Hepagene, Inventiva, Madrigal, Merck, Metacrine, Northsea, Noom, Novartis, Novo Nordisk, Pfizer, Poxel, and Zydus. MRB reports grant and research support from the National Institutes of Health (5U01-DK061713-19, 1R01CA249765-01) as well as Carmot, Corcept, CymaBay, Diabetes & Endocrinology Consultants, Madrigal, Metacrine, NGM, Pinnacle Clinical Research, Polarean Imaging, and Siemens Healthineers. MER reports consulting for Alnylam, Amgen, AMRA, Bristol-Myers Squibb, Boehringer Ingelheim, Centara, Coherus, Enanta, Galecto, Intercept, Madrigal, NGM, Novo Nordisk, Pfizer, Fractyl, Gelesis, Siemens, Thetis, Terns, Rivus, 3vBio (Sagimet), 89Bio, and Novartis. MSS reports consulting for Pfizer and serves on an advisory committee for AMRA. MK reports research grants from Medtronic, SARO, Pfizer, Dexcom, Abbott, Regenacy, Metacrine, Lumos, Ascendis, Sagimet, MannKind, Aeterna-Zentaris, 89Bio, Gilead, Senseonics, KOWA, Allergan, NGM, Tolerion, and Lilly, and is on an advisory board for Quest Diagnostics. ZHY reports grant and research support from Gilead, Bristol-Myers Squibb, Cymabay, HighTide, Madrigal, NGM, Conatus, Novartis, Allergan, Intercept, and Novo Nordisk, and is a consultant for Gilead. MB reports grant support from the National Institutes of Health. SJB reports serving on a scientific advisory board for Altimmune, Amgen, AstraZeneca, Axcella, Boehringer Ingelheim, Eli Lilly, Esperion, Novartis, Regeneron, and Sanofi, and is a consultant for Altimmune, Amgen, Madrigal, Novartis, Regeneron, and Sanofi. BB reports research support from Akero, Axcella, Bristol-Myers Squibb, Conatus, Cymabay, Enyo, Galectin, Genfit, Gilead, Hepion, Hightide, Intercept, Madrigal, NGM, Novartis, Novo Nordisk, Northsea, Viking, AbbVie, Gynkotex, GlaxoSmithKline, Arena, Protagonist, Mirum, Eli Lilly, Ionis, and Poxel. PJR reports serving as speaker and adviser for Gilead Sciences and ViiV. PJT reports grant and research support from AbbVie, Allergan, Bayer, Bristol-Myers Squibb, Cara, Celgene, Cirius, Conatus, Cymabay, Dova, Eisai, Eli Lilly, Elobix, Enanta, Enyo, Exelixis, Gilead, HighTide, Intercept, Mallinckrodt, Novo Nordisk, Pfizer, Sillajen, and Targ, and is a consultant for Mallinckrodt. MG, MK, CC, LM-K, WC, AMD, LL, and HDL report being employees and stockholders of NGM. All other authors declare no competing interests.
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