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.
© 2022 The Author(s).