Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis due to NASH

Advanced fibrosis due to nonalcoholic steatohepatitis (NASH) is a leading cause of end-stage liver disease. In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg (SEL), cilofexor 30 mg (CILO), or firsocostat 20 mg (FIR), alone or in two-drug combinations, once daily for 48 weeks (W48). The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and W48 based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo-treated patients versus CILO/FIR (21%, p=0.17), CILO/SEL (19%, p=0.26), FIR/SEL (15%, p=0.62), FIR (12%, p=0.94), and CILO (12%, p=0.96). Changes in hepatic collagen by morphometry were not significant, but CILO/FIR led to a significant decrease in ML NASH CRN fibrosis score (p=0.040) and a shift in biopsy area from F3-F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of CILO/FIR patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in ALT, AST, bilirubin, bile acids, CK18, insulin, eGFR, ELF score, and liver stiffness by transient elastography (all p≤0.05). Pruritus occurred in 20-29% of CILO versus 15% of placebo-treated patients. CONCLUSIONS: In patients with bridging fibrosis and cirrhosis, 48 weeks of CILO/FIR was well tolerated, led to improvements in NASH activity, and may have an anti-fibrotic effect. This combination offers potential for fibrosis regression with longer term therapy in patients with advanced fibrosis due to NASH.