PRIMIS: design of a pivotal, randomized, phase 3 study evaluating the safety and efficacy of the nonsteroidal farnesoid X receptor agonist cilofexor in noncirrhotic patients with primary sclerosing cholangitis

Abstract

Background: Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease leading to biliary fibrosis and cirrhosis. Cilofexor is a nonsteroidal farnesoid X receptor agonist that demonstrated significant improvements in liver biochemistry and markers of cholestasis in patients with PSC in a phase 2 study. We describe here the rationale, design, and implementation of the phase 3 PRIMIS trial, the largest placebo-controlled trial in PSC.

Methods: Adults with large-duct PSC without cirrhosis are randomized 2:1 to receive oral cilofexor 100 mg once daily or placebo for up to 96 weeks during the blinded phase. Patients completing the blinded phase are eligible to receive open-label cilofexor 100 mg daily for up to 96 weeks. The primary objective is to evaluate whether cilofexor reduces the risk of fibrosis progression compared with placebo. Liver biopsy is performed at screening and Week 96 of the blinded phase for histologic assessment of fibrosis. The primary endpoint-chosen in conjunction with guidance from the U.S. Food and Drug Administration-is the proportion of patients with ≥ 1-stage increase in fibrosis according to Ludwig histologic classification at week 96. Secondary objectives include evaluation of changes in liver biochemistry, serum bile acids, liver fibrosis assessed by noninvasive methods, health-related quality of life, and safety of cilofexor.

Conclusion: The phase 3 PRIMIS study is the largest randomized, double-blind, placebo-controlled trial in PSC to date and will allow for robust evaluation of the efficacy and safety of cilofexor in noncirrhotic patients with large-duct PSC.

Trial registration: ClinicalTrials.gov NCT03890120; registered 26/03/2019.

Keywords: Farnesoid X receptor; Liver fibrosis; Primary sclerosing cholangitis.

Conflict of interest statement

MT consults, is on the speakers’ bureau, and has received grants from Gilead, Falk, Intercept, and MSD; consults and has received grants from Albireo; consults for BiomX, Boehringer Ingelheim, Genfit, Janssen, Novartis, Phenex, Pliant, Regulus, and Shire; is on the speakers’ bureau for BMS and Roche; and has received grants from Alnylam, CymaBay, Takeda, and UltraGenyx. CC, KS, X Liu, X Lu, and JX are employed by and own stock in Gilead. CT-A receives funding from Gilead; serves as a medical advisor to Profound Medical and Promaxo; and is an independent contractor for Medscape. ZDG has no personal conflicts of interest with respect to this work; his institution currently receives funding to support his research from Gilead, BMS, CymaBay, Eiger, Inventiva, MSD, NGM, and Novartis. MF has received grant support from Gilead; and is participating in a clinical trial of norUDCA in a study sponsored by Falk. AT consults for Gilead, EA Pharma, and GSK; and has received grants from AbbVie and Chugai. PT is on the speakers’ bureau of Falk and Intercept; consults and has received grants from Gilead, BMS, Falk, Intercept, LifeArc, Medical Research Foundation, National Institute of Health Research, Perspectum, and Wellcome Trust; and is an advisor for CymaBay, Falk, Intercept, and Pliant. KVK has received grant support from Gilead, 89bio, BMS, Celgene, Corcept, CymaBay, Enanta, Genfit, GSK, Hanmi, HighTide, Intercept, Madrigal, Metacrine, Mirum, NGM, Pfizer, Pliant, Protagonist, Terns, and Viking; serves as a consultant and on advisory boards for Gilead, 89bio, CymaBay, Enanta; Genfit, HighTide, Inipharm, Intercept, Madrigal, Mirum, NGM, and Pfizer, and Enanta; and is on speakers’ bureaus for Gilead, AbbVie, and Intercept. CLB advises and has received grants from Gilead, CymaBay, Eli Lilly, and Intercept; advises BiomX, Parvus, Patara, and Pliant; and has received grants from Arena, BMS, Genkyotex, GSK, and Takeda. CL advises and has received grants from Gilead, Cara, CymaBay, Genfit, Genkyotex, GSK, Intercept, Mirum, Pliant, and Target RWE; advises Escient and Teva; and has received grants from Alnylam, Mitsubishi, NGM, Novartis, and Zydus. RPM was formerly employed by Gilead.

© 2023. The Author(s).

Figures

Fig. 1

PRIMIS study design. PSC, primary sclerosing cholangitis; UDCA, ursodeoxycholic acid

Fig. 2

Nonworsening of fibrosis at Weeks 48 and 96 among noncirrhotic patients in the phase 2 simtuzumab primary sclerosing cholangitis (PSC) study was associated with significantly reduced rate of PSC-related events. p values by Fisher’s exact test

Fig. 3

Greater fibrosis burden at baseline, as defined by Ludwig fibrosis stage or hepatic collagen content by morphometry, was associated with a significantly increased risk of disease progression among noncirrhotic patients with PSC in the phase 2 simtuzumab study. Disease progression was defined by progression to cirrhosis (F4), ascending cholangitis, hepatic decompensation, liver transplantation, or death. [15] p values by log-rank test