Cilofexor in Patients With Compensated Cirrhosis Due to Primary Sclerosing Cholangitis: An Open-Label Phase 1B Study

Abstract

Introduction: This proof-of-concept, open-label phase 1b study evaluated the safety and efficacy of cilofexor, a potent selective farnesoid X receptor agonist, in patients with compensated cirrhosis due to primary sclerosing cholangitis.

Methods: Escalating doses of cilofexor (30 mg [weeks 1-4], 60 mg [weeks 5-8], 100 mg [weeks 9-12]) were administered orally once daily over 12 weeks. The primary endpoint was safety. Exploratory measures included cholestasis and fibrosis markers and pharmacodynamic biomarkers of bile acid homeostasis.

Results: Eleven patients were enrolled (median age: 48 years; 55% men). The most common treatment-emergent adverse events (TEAEs) were pruritus (8/11 [72.7%]), fatigue, headache, nausea, and upper respiratory tract infection (2/11 [18.2%] each). Seven patients experienced a pruritus TEAE (one grade 3) considered drug-related. One patient temporarily discontinued cilofexor owing to peripheral edema. There were no deaths, serious TEAEs, or TEAEs leading to permanent discontinuation. Median changes (interquartile ranges) from baseline to week 12 (predose, fasting) were -24.8% (-35.7 to -7.4) for alanine transaminase, -13.0% (-21.9 to -8.6) for alkaline phosphatase, -43.5% (-52.1 to -30.8) for γ-glutamyl transferase, -12.7% (-25.0 to 0.0) for total bilirubin, and -21.2% (-40.0 to 0.0) for direct bilirubin. Least-squares mean percentage change (95% confidence interval) from baseline to week 12 at trough was -55.3% (-70.8 to -31.6) for C4 and -60.5% (-81.8 to -14.2) for cholic acid. Fasting fibroblast growth factor 19 levels transiently increased after cilofexor administration.

Discussion: Escalating doses of cilofexor over 12 weeks were well tolerated and improved cholestasis markers in patients with compensated cirrhosis due to primary sclerosing cholangitis (NCT04060147).

Figure 1.

Participant flow. ^aDetailed reasons for screen failures are provided in Supplementary Digital Content (see Supplementary Table 2, http://links.lww.com/CTG/B163). PI, principal investigator.

Figure 2.

Longitudinal changes from baseline to follow-up (week 16) in efficacy outcomes. (a) Median percentage change (IQR) in liver biochemistry markers, (b) median percentage change (IQR) in liver function markers, (c) median absolute change (IQR) in ELF score, and (d) median percentage change (IQR) in fibrosis markers TIMP1, PIIINP, and HA. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ELF, enhanced liver fibrosis; GGT, γ-glutamyl transferase; HA, hyaluronic acid; IQR, interquartile range; PIIINP, procollagen type 3 N-terminal propeptide; QD, daily; TIMP1, tissue inhibitor of matrix metalloproteinase 1.

Figure 3.

Changes in PD markers of bile acid homeostasis with cilofexor treatment. (a) Longitudinal percentage changes in levels of fasting plasma FGF19, C4, cholic acid, and total bile acids at trough from baseline to follow-up (week 16). The decrease in C4 and cholic acid biomarkers was statistically significant at weeks 8 and 12 as their corresponding 95% CIs did not include zero. (b) Slopes of changes of FGF19 levels at each visit and for pooled doses/visits. The 95% CIs of the FGF19 slopes do not include zero, thus signifying their statistical significance. C4, 7α-hydroxy-4-cholesten-3-one; CI, confidence interval; FGF19, fibroblast growth factor 19; LS, least squares; PD, pharmacodynamic.