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

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.

Keywords: ADA(s), anti-drug antibody(ies); AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANCOVA, analysis of covariance; AST, aspartate aminotransferase; CFB, change from baseline; CTX-1, C-terminal telopeptide of type 1 collagen; C–P, Child-Pugh; DXA, dual-energy X-ray absorptiometry; ELF, enhanced liver fibrosis; FGF21; FGF21, fibroblast growth factor-21; FGFR, fibroblast growth factor receptor; GGT, gamma-glutamyltransferase; HDL-C, HDL-cholesterol; HOMA-IR, homeostatic model assessment of insulin resistance; HPA, hypothalamic-pituitary-adrenal; HbA1c, hemoglobin A1c; INR, international normalized ratio; IRT, interactive response technology; LDL-C, LDL-cholesterol; LS, least squares; MELD, model for end-stage liver disease; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH, non-alcoholic steatohepatitis; NAb, neutralizing antibody; Non-HDL-C, non-HDL-cholesterol; P1NP, procollagen type-I N-terminal propeptide; P3NP, procollagen type III N-terminal propeptide; PAI-1, plasminogen activator inhibitor-1; Pro-C3, N-terminal type III collagen propeptide; TEAE, treatment-emergent adverse event; TIMP-1, tissue inhibitor of metalloproteinase-1; ULN, upper limit of normal; cirrhosis; clinical trial; efruxifermin; histopathology; hs-CRP, high-sensitivity C-reactive protein; liver disease; non-alcoholic steatohepatitis/NASH; nonalcoholic fatty liver disease/NAFLD.

Graphical abstract

Fig. 1

CONSORT clinical study flow diagram. ^aComprises the full analysis set and ^bcomprises the biopsy analysis set.

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. 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. 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. 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.