Cilofexor plus firocostat well tolerated by patients with fibrosis due to NASH

Cilofexor plus firsocostat for 48 weeks was safe and well tolerated in patients with fibrosis due to nonalcoholic steatohepatitis, according to research presented at The Digital International Liver Congress.

“Cilofexor plus firsocostat led to a nonsignificant but higher rate of fibrosis improvement without worsening of NASH and reduced progression to cirrhosis vs. placebo,” Rohit LoombaMD, MHSc, from the division of gastroenterology at the University of California at San Diego, said during his presentation.

In the ATLAS phase 2b trial, Loomba and colleagues randomly assigned 392 patients with advanced fibrosis (stage f3 to f4) due to NASH to either receive placebo, selonsertib18 mg (SEL), cilofexor 30 mg (CILO), or firsocostat (FIR) at 20 mg, alone or in two-drug combinations once daily for 48 weeks. A machine learning approach (PathAI, Boston, Massachusetts) was used to assess the biopsies from baseline and 48 weeks. The proportion of patients with a 1-stage or greater improvement in fibrosis without worsening of NASH served as the primary endpoint. Other endpoints were changes in NAFLD Activity Score (NAS), liver biochemistry and noninvasive biomarkers.

Results showed most patients had cirrhosis, diabetes and a NAS score of 5 or greater. Investigators noted more patients treated with combination therapy compared with placebo achieved a 1-stage or greater improvement in fibrosis without worsening of NASH, with CILO plus FIR (21%, P = .17), CILO plus SEL (19%, P= .26), FIR plus SEL (15%, P = 0.62), FIR (12%, P = .94), CILO (12%, P = .96) and placebo (11%). CILO plus FIR significantly decreased the NASH clinical research network fibrosis score and a shift in biopsy proportionate area from F3 to F4 to F2 or less fibrosis. CILO plus FIR compared with placebo significantly increased proportions of patients with 2-point or less reduction in NAS and 1-grade or more improvements in steatosis, lobular inflammation, and ballooning (all P < .05).

“Fibrosis improvement without worsening of NASH with CILO/FIR was more frequent in patients with a 2 or more point NAS response (35% vs 14%, P = .060),” Loomba said.

In addition, CILO plus FIR significantly improved serum [alanine aminotransferase], [aspartate aminotransferase], bilirubin, total bile acids, CK18, insulin, estimated glomerular filtration rate, and enhanced liver fibrosis score (all P .05). It also significantly increased the proportion of patients with 25% or more reduction in liver stiffness by transient elastography (45% vs. 20% with placebo, P = .016). All therapy regimens were well tolerated.

According to Loomba, pruritus occurred in 28% of patients who received CIRO plus FIR compared with 15% of patients who received placebo.

“CIROFIR was associated [with] manageable pruritus and hypertriglyceridemia,” Loomba said. “Future studies of combination therapies for advanced fibrosis due to NASH are warranted.”