Combination Therapies Including Cilofexor and Firsocostat... : Hepatology (original) (raw)

Original Articles: Steatohepatitis and Metabolic Liver Disease

Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH

Loomba, Rohit*,1; Noureddin, Mazen2; Kowdley, Kris V.3; Kohli, Anita4; Sheikh, Aasim5; Neff, Guy6; Bhandari, Bal Raj7; Gunn, Nadege8; Caldwell, Stephen H.9; Goodman, Zachary10; Wapinski, Ilan11; Resnick, Murray11; Beck, Andrew H.11; Ding, Dora12; Jia, Catherine12; Chuang, Jen‐Chieh12; Huss, Ryan S.12; Chung, Chuhan12; Subramanian, G. Mani12; Myers, Robert P.12; Patel, Keyur13; Borg, Brian B.14; Ghalib, Reem15; Kabler, Heidi16; Poulos, John17; Younes, Ziad18; Elkhashab, Magdy19; Hassanein, Tarek20; Iyer, Rajalakshmi21; Ruane, Peter22; Shiffman, Mitchell L.23; Strasser, Simone24; Wong, Vincent Wai‐Sun25; Alkhouri, Naim26; for the ATLAS Investigators

1NAFLD Research CenterUniversity of California at San DiegoLa JollaCA

2Fatty Liver ProgramCedars‐Sinai Medical CenterLos AngelesCA

3Liver Institute NorthwestSeattleWA

4Arizona Liver HealthChandlerAZ

5GI Specialists of GeorgiaMariettaGA

6Covenant Research, LLCSarasotaFL

7Delta Research Partners, LLCBastropLA

8Pinnacle Clinical ResearchAustinTX

9University of VirginiaCharlottesvilleVA

10Inova Fairfax HospitalFalls ChurchVA

11PathAIBostonMA

12Gilead Sciences Inc.Foster CityCA

13University of TorontoTorontoOntarioCanada

14Southern Therapy and Advanced ResearchJacksonMS

15Texas Clinical Research InstituteArlingtonTX

16Jubilee Clinical ResearchLas VegasNV

17Cumberland Research AssociatesFayettevilleNC

18Gastro OneGermantownTN

19Toronto Liver CentreTorontoOntarioCanada

20Southern California Research CenterCoronadoCA

21Iowa Digestive Disease CenterCliveIA

22Ruane Medical and Liver Health InstituteLos AngelesCA

23Bon Secours Mercy HealthRichmondVA

24Royal Prince Alfred Hospital and The University of SydneyCamperdownNew South WalesAustralia

25Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongHong Kong

26Texas Liver InstituteUT Health San AntonioSan AntonioTX

* Address Correspondence and Reprint Requests to:
Rohit Loomba, M.D., M.H.Sc.
NAFLD Research Center, Division of Gastroenterology and Epidemiology, University of California, San Diego
9500 Gilman Drive, MC 0887
La Jolla, CA 92093
E‐mail: [email protected]
Tel.: +1‐858‐246‐2201

A complete list of investigators in ATLAS is provided in the Supporting Appendix.

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.