Discussion
liver fibrosis, fibrosis, nonalcoholic steatohepatitis, cholestasis, large-duct PSC, liver diseases, PSC, IBD, chronic disease
LIVER FIBROSIS, FIBROSIS, NONALCOHOLIC STEATOHEPATITIS, CHOLESTASIS, EVENTS, LIVER DISEASES, COMPLICATIONS, CHRONIC DISEASE
The PRIMIS trial is the largest multinational, randomized, double-blind, placebo-controlled phase 3 study in PSC to date. Screening for the study initiated in March 2019, and by December 2020, 204 sites in 16 countries in Australasia, Europe, Japan, and North America have been activated. An additional site was later activated. In all, 419 noncirrhotic patients with large-duct PSC have been enrolled and 416 were dosed. The screen failure rate was 29% (171/590 patients screened), with major reasons for screen failure including laboratory abnormalities, current or recent history of PSC-related complications, and noneligible screening liver biopsy, each occurring in > 10% of screen-failed subjects. Among patients who were dosed and have available baseline data as of February 14, 2022, median age is 44 years (range 18–74), 62% are men, 70% have history of IBD, 59% are on UDCA, and 25% have F3 fibrosis on screening liver biopsy. Median serum ALP concentration is 173 U/L (interquartile range 107, 292), with 69% of enrolled patients having elevated serum ALP.The primary endpoint of the PRIMIS trial will provide clinically relevant information on whether cilofexor can reduce progression of liver fibrosis in noncirrhotic patients with large-duct PSC. Currently, no approved pharmacologic treatment for PSC exists, in part, due to lack of clarity regarding which endpoints may reliably serve as surrogates of clinical outcomes in PSC. The rarity of PSC and its generally prolonged natural history pose inherent difficulties in performing adequately powered, clinical outcomes studies [The strengths and limitations of the study reflect the inherent challenge of conducting a study in a chronic disease indication such as PSC with variable clinical course. Regulatory support of the histologic endpoints to be evaluated in the PRIMIS trial is based on the well-accepted observation that severity of liver fibrosis correlates with risk of clinical events in PSC, as well as other liver diseases [The phase 2 study of cilofexor in noncirrhotic patients with PSC demonstrated that cilofexor significantly improved markers of cholestasis, liver biochemistry, and bile acid homeostasis [The long-term safety profile of cilofexor in PSC has been evaluated in the 96-week OLE of the phase 2 study and will be further evaluated in the PRIMIS trial. Available data from the phase 1 and 2 studies in healthy subjects, and patients with PSC and nonalcoholic steatohepatitis indicate that cilofexor was generally well tolerated [