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Abstract Details
Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis due to NASH
Hepatology. 2020 Nov 10. doi: 10.1002/hep.31622. Online ahead of print.
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, ATLAS Investigators
Author information
1NAFLD Research Center, University of California at San Diego, La Jolla, California, USA.
2Fatty Liver Program, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3Liver Institute Northwest, Seattle, Washington, USA.
4Arizona Liver Health, Chandler, Arizona, USA.
5GI Specialists of Georgia, Marietta, Georgia, USA.
6Covenant Research, LLC, Sarasota, Florida, USA.
7Delta Research Partners, LLC, Bastrop, Louisiana, USA.
8Pinnacle Clinical Research, Austin, Texas, USA.
9University of Virginia, Charlottesville, Virginia, USA.
10Inova Fairfax Hospital, Falls Church, Virginia, USA.
11PathAI, Boston, Massachusetts, USA.
12Gilead Sciences Inc, Foster City, California, USA.
13University of Toronto, Toronto, ON, Canada.
14Southern Therapy and Advanced Research, Jackson, Mississippi, USA.
15Texas Clinical Research Institute, Arlington, Texas, USA.
16Jubilee Clinical Research, Las Vegas, Nevada, USA.
17Cumberland Research Associates, Fayetteville, North Carolina, USA.
18Gastro One, Germantown, Tennessee, USA.
19Toronto Liver Centre, Toronto, ON, Canada.
20Southern California Research Center, Coronado, California, USA.
21Iowa Digestive Disease Center, Clive, Iowa, USA.
22Ruane Medical and Liver Health Institute, Los Angeles, CA, USA.
23Bon Secours Mercy Health, Richmond, Virginia, USA.
24Royal Prince Alfred Hospital, The University of Sydney, New South Wales, Australia.
25Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
26Texas Liver Institute, UT Health San Antonio, Texas, USA.
Abstract
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.