Rohit Loomba1, Mazen Noureddin2, Kris V Kowdley3, Anita Kohli4, Aasim Sheikh5, Guy Neff6, Bal Raj Bhandari7, Nadege Gunn8, Stephen H Caldwell9, Zachary Goodman10, Ilan Wapinski11, Murray Resnick11, Andrew H Beck11, Dora Ding12, Catherine Jia12, Jen-Chieh Chuang12, Ryan S Huss12, Chuhan Chung12, G Mani Subramanian12, Robert P Myers12, Keyur Patel13, Brian B Borg14, Reem Ghalib15, Heidi Kabler16, John Poulos17, Ziad Younes18, Magdy Elkhashab19, Tarek Hassanein20, Rajalakshmi Iyer21, Peter Ruane22, Mitchell L Shiffman23, Simone Strasser24, Vincent Wai-Sun Wong25, Naim Alkhouri26. 1. NAFLD Research Center, University of California at San Diego, La Jolla, CA. 2. Fatty Liver Program, Cedars-Sinai Medical Center, Los Angeles, CA. 3. Liver Institute Northwest, Seattle, WA. 4. Arizona Liver Health, Chandler, AZ. 5. GI Specialists of Georgia, Marietta, GA. 6. Covenant Research, LLC, Sarasota, FL. 7. Delta Research Partners, LLC, Bastrop, LA. 8. Pinnacle Clinical Research, Austin, TX. 9. University of Virginia, Charlottesville, VA. 10. Inova Fairfax Hospital, Falls Church, VA. 11. PathAI, Boston, MA. 12. Gilead Sciences Inc., Foster City, CA. 13. University of Toronto, Toronto, Ontario, Canada. 14. Southern Therapy and Advanced Research, Jackson, MS. 15. Texas Clinical Research Institute, Arlington, TX. 16. Jubilee Clinical Research, Las Vegas, NV. 17. Cumberland Research Associates, Fayetteville, NC. 18. Gastro One, Germantown, TN. 19. Toronto Liver Centre, Toronto, Ontario, Canada. 20. Southern California Research Center, Coronado, CA. 21. Iowa Digestive Disease Center, Clive, IA. 22. Ruane Medical and Liver Health Institute, Los Angeles, CA. 23. Bon Secours Mercy Health, Richmond, VA. 24. Royal Prince Alfred Hospital and The University of Sydney, Camperdown, New South Wales, Australia. 25. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong. 26. Texas Liver Institute, UT Health San Antonio, San Antonio, TX.
Abstract
BACKGROUND AND AIMS: Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease. APPROACH AND RESULTS: In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks 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 cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat 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 cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients. CONCLUSIONS: In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH.
RCT Entities:
BACKGROUND AND AIMS: Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease. APPROACH AND RESULTS: In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks 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 cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat 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 cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients. CONCLUSIONS: In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH.