Seladelpar for the treatment of primary biliary cholangitis: Experience with 26 cirrhotic patients
Mayo MJ, Bowlus C, Michael G, Neff G, Trivedi P, Goel A, Odin J, Bacon B, Borg B, Gordon SC, Gulamhusein A, Harrison S, Levy C, Stanca C, Vierling J, Steinberg A, Varga M, Nguyen J, Bergheanu S, Choi YJ, Standen M, and Boudes P. Seladelpar for the treatment of primary biliary cholangitis: Experience with 26 cirrhotic patients. J Hepatol 2019; 70(1):e76.
Background and aims: Primary biliary cholangitis (PBC) is a progressive liver disease that leads to cirrhosis. Seladelpar, a selective PPAR delta agonist, demonstrates potent anti-cholestatic and anti-inflammatory activity in PBC. We evaluated the efficacy and safety of seladelpar in PBC patients with clinically diagnosed compensated cirrhosis. Method: PBC patients were enrolled into an ongoing, randomized, open-label Phase 2 study (EudraCT 2016-002996-91) and evaluated for the effect of oral seladelpar 5 and 10 mg. Eligible patients had inadequate response (alkaline phosphatase [AP] ≥ 1.67 × upper limit of normal (ULN)) or an intolerance to ursodiol and a total bilirubin ≤ 2 mg/dL. Cirrhosis was diagnosed using liver biopsy, imaging tests, or liver elastography. After 12 weeks, patients on 5 mg were dose-escalated to 10 mg when the AP threshold was not met (5/10 mg group). The primary outcome was AP % change from baseline. Secondary outcome measures included AP responder analyses (< 1.67xULN), changes in hepatic function, inflammatory markers, and pruritus using the visual analogue scale (VAS). Safety analysis included adverse events and laboratory parameters. Results: 119 patients were exposed to at least one dose of seladelpar, 26 of whom had compensated cirrhosis (5/10 mg n = 15 and 10 mg n = 11). Analysis was performed with a July 2018 data cut. At this time 15 of 26 cirrhotic patients received seladelpar for 3 months, 13 of 26 for 6 months, and 8 of 26 for 1 year. In cirrhotic patients, the baseline values for the 5/10 and 10 mg groups were: mean AP-277 U/L and 309 U/L, median total bilirubin-0.73 mg/dL and 0.80 mg/dL, median ALT-32 U/L and 50 U/L, and median VAS 20 and 37, respectively. Mean decreases in AP (%) were –25% and –39% at 3 months, –24% and –41% at 6 months, and –36% and –43% at 1 year in the 5/10 mg and 10 mg groups, respectively. After 1 year, all patients in 5/10 mg and 3 of 5 patients in 10 mg had Ap< 1.67 × ULN; the median decreases in ALT (%) were –31% and –50%, and the median absolute changes in pruritus VAS were 0 and –25 in 5/10 mg and 10 mg groups, respectively. Three patients with cirrhosis experienced an SAE, all unrelated to seladelpar. Total bilirubin, platelets, albumin, and INR remained stable. No liver decompensation events were observed. Conclusion: In PBC patients with compensated cirrhosis, seladelpar was shown to be safe and well tolerated and demonstrated anti-cholestatic and anti-inflammatory effects.