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Cited by 110Liver Disease Diagnosis and TreatmentHepatitis C virus researchLiver physiology and pathology

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A randomized, double-blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis

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Harrison, Stephen A., Ruane, Peter J., Freilich, Bradley, Neff, Guy, Patil, Rashmee, Behling, Cynthia, Hu, Chen, Shringarpure, Reshma, de Temple, Brittany, Fong, Erica, Tillman, Erik J., Rolph, Timothy, Cheng, Andrew, Yale, Kitty·2023·JHEP Reports
DOI 10.1016/j.jhepr.2022.100563PMC PMC9832280
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Abstract

Background & Aims Efruxifermin has shown clinical efficacy in patients with non-alcoholic steatohepatitis (NASH) and F1–F3 fibrosis. The primary objective of the BALANCED Cohort C was to assess the safety and tolerability of efruxifermin in patients with compensated NASH cirrhosis. Methods Patients with NASH and stage 4 fibrosis (n = 30) were randomized 2:1 to receive efruxifermin 50 mg (n = 20) or placebo (n = 10) once-weekly for 16 weeks. The primary endpoint was safety and tolerability of efruxifermin. Secondary and exploratory endpoints included evaluation of non-invasive markers of liver injury and fibrosis, glucose and lipid metabolism, and changes in histology in a subset of patients who consented to end-of-study liver biopsy. Results Efruxifermin was safe and well-tolerated; most adverse events (AEs) were grade 1 (n = 7, 23.3%) or grade 2 (n = 19, 63.3%). The most frequent AEs were gastrointestinal, including transient, mild to moderate diarrhea, and/or nausea. Significant improvements were noted in key markers of liver injury (alanine aminotransferase) and glucose and lipid metabolism. Sixteen-week treatment with efruxifermin was associated with significant reductions in non-invasive markers of fibrosis including Pro-C3 (least squares mean change from baseline [LSMCFB] −9 μg/L efruxifermin vs. −3.4 μg/L placebo; p = 0.0130) and ELF score (−0.4 efruxifermin vs. +0.4 placebo; p = 0.0036), with a trend towards reduced liver stiffness (LSMCFB −5.7 kPa efruxifermin vs. −1.1 kPa placebo; n.s.). Of 12 efruxifermin-treated patients with liver biopsy after 16 weeks, 4 (33%) achieved fibrosis improvement of at least one stage without worsening of NASH, while an additional 3 (25%) achieved resolution of NASH, compared to 0 of 5 placebo-treated patients. Conclusions Efruxifermin appeared safe and well-tolerated with encouraging improvements in markers of liver injury, fibrosis, and glucose and lipid metabolism following 16 weeks of treatment, warranting confirmation in larger and longer term studies. Lay summary Cirrhosis resulting from non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease, represents a major unmet medical need. Currently there are no approved drugs for the treatment of NASH. This proof-of-concept randomized, double-blind clinical trial demonstrated the potential therapeutic benefit of efruxifermin treatment compared to placebo in patients with cirrhosis due to NASH. Clinical Trial Number NCT03976401

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Crossref · 10.1016/j.jhepr.2022.100563

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Graphical abstract
Graphical abstract CC BY · PubMed Central
Fig. 1 CONSORT clinical study flow diagram. aComprises the full analysis set and bcomprises the biopsy analysis set.
Fig. 1 CONSORT clinical study flow diagram. aComprises the full analysis set and bcomprises the biopsy analysis set.CC BY · PubMed Central
Fig. 2 Time courses for absolute change from baseline in levels of plasminogen activator inhibitor-1, platelets, and high-sensitivity C-reactive protein. Significance is indicated by asterisks: ∗p <0.05, ∗∗p <0.01 vs. placebo (MMRM). The vertical line at week 16 indicates the end of the treatment period, with safety follow-up continuing to week 20.
Fig. 2 Time courses for absolute change from baseline in levels of plasminogen activator inhibitor-1, platelets, and high-sensitivity C-reactive protein. Significance is indicated by asterisks: ∗p <0.05, ∗∗p <0.01 vs. placebo (MMRM). The vertical line at week 16 indicates the end of the treatment period, with safety follow-up continuing to week 20.CC BY · PubMed Central
Fig. 3 Absolute change from baseline to week 16 for liver stiffness and ELF score, pre- and post-treatment FAST score, time course for Pro-C3 and liver enzymes, and absolute change in urate from baseline. Values are shown as LS mean CFB values ± SEs, with p values from an ANCOVA model for FibroScan liver stiffness, Pro-C3, ALT, AST, GGT, ALP; Wilcoxon rank-sum test for median change in ELF score; and an MMRM for urate. p values for FAST score are from repeated-measures two-way ANOVA followed by Sidak’s multiple comparisons test. Refer to statistical analysis in methods for details. For ALT, AST, GGT, and ALP, the last observation carried forward method was used for patients with missing values. For urate, only individuals from the full analysis set with non-missing baseline values and the specified visit are included. Significance is indicated by asterisks: ∗p <0.05, ∗∗p <0.01, ∗∗∗p <0.001, ∗∗∗∗p <0.0001 vs. placebo; ††p <0.01 vs. baseline. The vertical line at 16 weeks indicates end-of-treatment period. ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANCOVA, analysis of covariance; AST, aspartate aminotransferase; CFB, change from baseline; ELF, enhanced liver fibrosis; FAST, FibroScan-AST; GGT, gamma-glutamyltransferase; LS, least-square; MMRM, mixed-model repeated measures; Pro-C3, N-terminal type III collagen propeptide.
Fig. 3 Absolute change from baseline to week 16 for liver stiffness and ELF score, pre- and post-treatment FAST score, time course for Pro-C3 and liver enzymes, and absolute change in urate from baseline. Values are shown as LS mean CFB values ± SEs, with p values from an ANCOVA model for FibroScan liver stiffness, Pro-C3, ALT, AST, GGT, ALP; Wilcoxon rank-sum test for median change in ELF score; and an MMRM for urate. p values for FAST score are from repeated-measures two-way ANOVA followed by Sidak’s multiple comparisons test. Refer to statistical analysis in methods for details. For ALT, AST, GGT, and ALP, the last observation carried forward method was used for patients with missing values. For urate, only individuals from the full analysis set with non-missing baseline values and the specified visit are included. Significance is indicated by asterisks: ∗p <0.05, ∗∗p <0.01, ∗∗∗p <0.001, ∗∗∗∗p <0.0001 vs. placebo; ††p <0.01 vs. baseline. The vertical line at 16 weeks indicates end-of-treatment period. ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANCOVA, analysis of covariance; AST, aspartate aminotransferase; CFB, change from baseline; ELF, enhanced liver fibrosis; FAST, FibroScan-AST; GGT, gamma-glutamyltransferase; LS, least-square; MMRM, mixed-model repeated measures; Pro-C3, N-terminal type III collagen propeptide.CC BY · PubMed Central
Fig. 4 Proportion of patients with NASH cirrhosis achieving an improvement in fibrosis stage or NASH resolution after 16 weeks. The study was not powered to assess statistical significance of histological endpoints. NAS, non-alcoholic fatty liver disease activity score; NASH, non-alcoholic steatohepatitis.
Fig. 4 Proportion of patients with NASH cirrhosis achieving an improvement in fibrosis stage or NASH resolution after 16 weeks. The study was not powered to assess statistical significance of histological endpoints. NAS, non-alcoholic fatty liver disease activity score; NASH, non-alcoholic steatohepatitis.CC BY · PubMed Central
Fig. 5 Mean change (%) from baseline to week 16 of markers of lipid metabolism, glycemic control, and body weight. Relative (A, B, C, D, G, H) or absolute (E, F) change from baseline. ∗∗∗p <0.0001, ∗∗p <0.01, ∗p <0.05 vs. placebo (ANCOVA); ††p <0.01 vs. baseline (ANCOVA). ANCOVA, analysis of covariance; HbA1c, hemoglobin A1c.
Fig. 5 Mean change (%) from baseline to week 16 of markers of lipid metabolism, glycemic control, and body weight. Relative (A, B, C, D, G, H) or absolute (E, F) change from baseline. ∗∗∗p <0.0001, ∗∗p <0.01, ∗p <0.05 vs. placebo (ANCOVA); ††p <0.01 vs. baseline (ANCOVA). ANCOVA, analysis of covariance; HbA1c, hemoglobin A1c.CC BY · PubMed Central

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Authors
Harrison, S. A., Ruane, P. J., Freilich, B., Neff, G., Patil, R., Behling, C., Hu, C., Shringarpure, R., de Temple, B., Fong, E., Tillman, E. J., Rolph, T., Cheng, A., & Yale, K.
Affiliations
  • Pinnacle Clinical Research (US)
  • Ruane Medical (US)
  • Kansas City Research Institute (US)
  • University of California San Diego (US)
  • Medpace (United States) (US)
Corresponding author
Yale, Kitty
ORCID
Venue
JHEP Reports
Publisher
Elsevier BV
Published
2023-01
Volume
5
Issue
1
Pages
100563
ISSN
2589-5559 (ISSN-L)
DOI
10.1016/j.jhepr.2022.100563
PMC
PMC9832280
OpenAlex
W4292830211
Cited by
110
References
51
Citations by year
2026: 20 · 2025: 42 · 2024: 35 · 2023: 13
FWCI
16.24
Type
journal article
Language
en
Open access
Licence
Locations
  • JHEP Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Hepatitis C virus research
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
nonalcoholic steatohepatitis, liver fibrosis, fibrosis regression, liver injury biomarkers, PRO-C3, liver stiffness, glycolipid metabolism, alanine aminotransferase, drug safety and tolerability, SGLT2 inhibitors

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