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Randomized Controlled Trial
. 2024 Mar 1;79(3):674-689.
doi: 10.1097/HEP.0000000000000607. Epub 2023 Sep 21.

A randomized, double-blind, placebo-controlled trial of aldafermin in patients with NASH and compensated cirrhosis

Mary E Rinella  1 , Hsiao D Lieu  2 , Kris V Kowdley  3   4 , Zachary D Goodman  5 , Naim Alkhouri  6 , Eric Lawitz  7 , Vlad Ratziu  8 , Manal F Abdelmalek  9 , Vincent Wai-Sun Wong  10 , Ziad H Younes  11 , Aasim M Sheikh  12 , Donald Brannan  13 , Bradley Freilich  14 , Fernando Membreno  15 , Marie Sinclair  16 , Liza Melchor-Khan  2 , Arun J Sanyal  17 , Lei Ling  2 , Stephen A Harrison  18   19
Affiliations
Randomized Controlled Trial

A randomized, double-blind, placebo-controlled trial of aldafermin in patients with NASH and compensated cirrhosis

Mary E Rinella et al. Hepatology. .

Abstract

Background and aims: Aldafermin, an engineered analog of the human hormone FGF19, improves liver histology in patients with noncirrhotic NASH; however, its efficacy and safety in compensated cirrhosis is unknown. No drug has yet to demonstrate benefit in the compensated NASH population.

Approach and results: In this multicenter, double-blind, placebo-controlled, phase 2b trial, 160 patients with compensated NASH cirrhosis were randomized to aldafermin 0.3 mg (n = 7), 1 mg (n = 42), 3 mg (n = 55), or placebo (n = 56) for 48 weeks. The 0.3 mg group was discontinued to limit exposure to suboptimal doses. The primary end point was a change in Enhanced Liver Fibrosis from baseline to week 48. The analyses were performed in the intention-to-treat population. At week 48, the least-squares mean difference in the change in Enhanced Liver Fibrosis was -0.5 (95% CI, -0.7 to -0.2; p = 0.0003) between the 3 mg group and the placebo group. 15%, 21%, and 23% of patients in the placebo, 1 mg, and 3 mg group, respectively, achieved fibrosis improvement ≥ 1 stage; and 13%, 16%, and 20% achieved fibrosis improvement ≥ 1 stage without NASH worsening. Improvement in alanine aminotransferase, aspartate aminotransferase, neoepitope-specific N-terminal pro-peptide of type III collagen, and liver stiffness favored aldefermin groups over placebo. Diarrhea was the most frequent adverse event, occurring at 26% and 40% in the 1 mg and 3 mg groups, respectively, compared to 18% in the placebo group. Overall, 0%, 2%, and 9% of patients in the placebo, 1 mg, and 3 mg group, respectively, discontinued due to treatment-related adverse events.

Conclusions: Aldafermin 3 mg resulted in a significant reduction in Enhanced Liver Fibrosis in patients with compensated NASH cirrhosis.

Trial registration: ClinicalTrials.gov NCT04210245.

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Conflict of interest statement

Mary E. Rinella consults for Boehringer Ingelheim, CytoDyn, GlaxoSmithKline, HistoIndex, Intercept, Madrigal, NGM Bio, Novo Nordisk, and Sonic Incytes. Hsiao D. Lieu is employed by and owns stock in NGM Bio. Kris V. Kowdley consults, is on the speakers’ bureau, and received grants from Gilead and Intercept. He consults and received grants from 89Bio, CymaBay, GENFIT, HighTide, Madrigal, Mirum, NGM Bio, Novo Nordisk, Pfizer, Terns, and Zydus. He consults and owns stock in Inipharm. He consults for Boehringer Ingelheim, Ipsen, and Kowa. He is on the speakers’ bureau for AbbVie, Gilead, and Intercept. He received grants from Boston Pharma, Corcept, GlaxoSmithKline, Hanmi, and Viking. Zachary D. Goodman advises, is on the speakers’ bureau, and received grants from Gilead, Intercept, and Perspectum. He advises and is on the speaker’s bureau for Echosens. He advises and received grants from 89Bio, Madrigal, Novo Nordisk, Pfizer, and Zydus. He is on the speakers’ bureau and received grants from AbbVie. He advises Fibronostics. He is on the speaker’s bureau for Alexion, Eisai, Excelixis, and Theratechnologies. He received grants from Akero, Arbutus, Better Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Corcept, CymaBay, DSM, Galectin, Genentech, Hepagene, Healio, Inventiva, Ionis, Merck, NGM Bio, Noom, NorthSea, Novartis, Poxel, and Viking. Naim Alkhouri consults, advises, is on the speakers’ bureau, and received grants from Gilead, Intercept, Madrigal, Novo Nordisk, Perspectum, Pfizer, and Zydus. He consults, advises, and is on the speakers’ bureau for Echosens. He consults, is on the speakers’ bureau, and received grants from AbbVie. He consults and is on the speakers’ bureau for Allergan. He advises and received grants from 89Bio. He consults for Fibronostics. He advises Fibronostics. He is on the speakers’ bureau for Alexion, Eisai, Excelixis, Salix, and Thera. He received grants from Akero, Arbutus, Better Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Corcept, DSM, Galectin, Genentech, GENFIT, Hepagene, Healio, Inventiva, Ionis, Merck, NGM Bio, Noom, NorthSea, Poxel, and Viking. Eric Lawitz consults, is on the speakers’ bureau, and received grants from Intercept. He consults for and received grants from Akero, Boehringer Ingelheim, Bristol Myers Squibb, Metacrine, Novo Nordisk, Sagimet, and Terns. He is on the speakers’ bureau and received grants from Abbvie and Gilead. He received grants from 89Bio, Allergan, Alnylam, Amgen, Ascelia, Assembly, AstraZeneca, Axcella, BioCryst, Bird Rock Bio, Conatus, CymaBay, CytoDyn, DSM, Durect, Eli Lilly, Enanta, Enyo, Exhalenz, Galectin, Galmed, GENFIT, Genentech, GlaxoSmithKline, Hanmi, HighTide, Inventiva, Janssen, Laboratory for Advanced Medicine, Loxo Oncology, Madrigal, Merck, NGM Bio, NorthSea, Novartis, Pfizer, Poxel, Roche, Synlogic, Takeda, Viking, and Zydus. Vlad Ratziu consults for Boehringer Ingelheim, Enyo, Madrigal, NGM Bio, NorthSea, Novo Nordisk, Pfizer, Poxel, Sagimet, and Terns. He consults and received grants from Gilead and Intercept. Manal F. Abdelmalek consults, advises, and received grants from Hanmi. He advises and received grants from 89Bio, Intercept, Inventiva, Madrigal, NGM Bio, and Novo Nordisk. He advises Medscape, Merck, Sonic Incytes, and Theratechnologies. He serves on the speakers’ bureaus for Chronic Liver Disease Foundation, Clinical Care Options, Fishwack, and Terra Firma. He received grants from Allergan, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Durect, Enanta, Enyo, Galmed, Gilead, Poxel, TARGET-NASH, and Viking. Vincent Wai-Sun Wong consults, serves on the speakers’ bureaus, received grants from Gilead. He consults and serves on the speakers’ bureaus AbbVie, Novo Nordisk. He consults for Boehringer Ingelheim, Echosens, Intercept, Inventiva, Pfizer, Sagimet, TARGET, and Visirna. He is on the speakers’ bureau for Abbott and Unilab. He owns stock in Illuminatio Medical Technology. Ziad H. Younes consults, advises, is on the speakers’ bureau, and received grants from Intercept. He consults and received grants from Madrigal. He consults for Gilead. He received grants from AbbVie, Allergan, Bristol Myers Squibb, CymaBay, Gilead, HighTide, Inventiva, NGM Bio, Novartis, Novo Nordisk, NST, and Poxel. Aasim M. Sheikh received grants from Akero, Altimmune, AstraZeneca, Boehringer Ingelheim, Galectin, Gilead, Hepion, Intercept, Ionis, KOWA, Madrigal, NGM, Novo Nordisk, and Viking. Fernando Membreno received grants from Akero, Ionis, and Madrigal. He is on the speakers’ bureau for Gilead. Liza Melchor-Khan is employed by and owns stock in NGM Bio. Arun J. Sanyal consults and received grants from AstraZeneca, Boehringer Ingelheim, Covance, Eli Lilly, Intercept, Novartis, Novo Nordisk, Pfizer, Salix, and Sequana. He consults and owns stock in GENFIT and Hemoshear. He consults for 89Bio, Akero, Albireo, Alnylam, Amgen, BioCellvia, Fibronest, Fractyl, Genentech, Gilead, GlaxoSmithKline, HistoIndex, Intercept, Inventiva, Jansen, Madrigal, Mallinckrodt, Merck, NGM Bio, NorthSea, PathAI, Poxel, Prosciento, Regeneron, Roche, Siemens, Takeda, TARGET, and Terns. He is employed by and owns stock in Sanyal Bio. He consults and owns stock in NorthSea. He advises Immuron. He received grants from Bristol Myers Squibb, Conatus, Galectin, and Merck. He owns stock in Durect, Exhalenz, GENFIT, Hemoshear, Indalo, Inversago, Rivus, and Tiziana. He has other interests with Echosens. Lei Ling is employed by and owns stock in NGM Bio. Stephen A. Harrison consults, advises, received grants, and owns stock in Akero, Galectin, Hepion, and NorthSea. He consults, advises, and received grants from Altimmune, Enyo, Gilead, GlaxoSmithKline, Intercept, Madrigal, Pfizer, Poxel, Sagimet, and Viking. He consults, advises, and owns stock in ChronWell, Hepta Bio, HistoIndex, and Sonic Incytes. He consults and advises Aligos, Arrowhead, Bluejay, Boxer Capital, Echosens, Foresite, Galecto, Hepagene, Humana, Ionis, Medpace, MGGM, Neurobo, Perspectum, and Terns. He consults and received grants from Novo Nordisk. He received grants and owns stock in GENFIT and NGM Bio. He received grants from Axcella, Bristol Myers Squibb, Corcept, CymaBay, Genentech, Hightide, Immuron, Inventiva, Ionis, Novartis, Novo Nordisk, Poxel, and Terns. He owns stock in Cirius, and Metacrine. The remaining authors have no conflicts to report.

Figures

None
Graphical abstract
FIGURE 1
FIGURE 1
Trial profile. Abbreviations: AE, adverse event; ITT, intention-to-treat.
FIGURE 2
FIGURE 2
Primary end point. (A) Change from baseline in ELF score at week 48. (B–D) Change from baseline to week 48 in the individual components of ELF: HA (B), PIIINP (C), and TIMP-1 (D). Shown are LS mean differences between the aldafermin group (1 or 3 mg) and the placebo group. Enrollment in the aldafermin 0.3 mg group was discontinued during the trial. Abbreviations: ELF, Enhanced Liver Fibrosis; HA, hyaluronic acid; LS, least-squares; PIIINP, N-terminal pro-peptide of type III collagen.
FIGURE 3
FIGURE 3
Secondary end points. (A) Proportion of patients achieving fibrosis improvement of ≥ 1 stage at week 48. (B) Proportion of patients achieving fibrosis improvement of ≥ 1 stage with no worsening of NASH at week 48. (C) Change in serum C4 from baseline to week 48. (D) Change in serum TBA from baseline to week 48. (E) Change from baseline in ALT over time. (F) Change from baseline in AST over time. (G) Change in Pro-C3 from baseline to week 48. (H) Change in LSM from baseline to week 48. Shown are LS mean (SE). Fibrosis improvement of ≥ 1 stage was defined by NASH CRN criteria. No worsening of NASH was defined as no increase in NAS score for steatosis, no increase in ballooning, and no increase in inflammation. *p<0.05, **p<0.01, ***p<0.001 vs. placebo. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; C4, 7alpha-hydroxy-4-cholesten-3-one; LS, least-squares; LSM, liver stiffness measure; NAS, NAFLD activity score; NASH CRN, NASH clinical research network; PBO, placebo; Pro-C3, neoepitope-specific N-terminal pro-peptide of type III collagen; TBA, total bile acids.
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