Liver and Bile
J Hepatol. 2022;77(2):353–64
A phase 2, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis
Background and aims: The authors examined the efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, in adults with primary biliary cholangitis (PBC) at risk of disease progression (alkaline phosphatase [ALP] ≥ 1.67 x upper limit of normal [ULN]) who were receiving or intolerant to ursodeoxycholic acid.
Methods: In this 52-week, phase 2, dose-ranging, open-label study, patients were randomized (1:1) to seladelpar 5 mg/day (n = 53) or 10 mg/day (n = 55) or assigned to 2 mg/day (n = 11; United Kingdom sites after interim analysis) for 12 weeks. Doses could then be uptitrated to 10 mg/day. The primary efficacy end point was ALP change from baseline to week 8.
Results: Mean baseline ALP was 300, 345, and 295 IU/l in the 2-mg, 5-mg, and 10-mg cohorts, respectively; 21% of patients had cirrhosis, 71% had pruritus. At week 8, mean ± standard error ALP reductions from baseline were 26 ± 2.8%, 33 ± 2.6%, and 41 ± 1.8% in the 2-mg (n = 11), 5-mg (n = 49), and 10-mg (n = 52) cohorts (all p ≤ 0.005), respectively. Responses were maintained or improved at week 52, after dose escalation in 91% and 80% of the 2-mg and 5-mg cohorts, respectively. At week 52, composite response (ALP < 1.67 x ULN, ≥ 15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2-mg, 5-mg, and 10-mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5-mg and 10-mg cohorts. There were no treatment-related serious adverse events, and 4 patients discontinued due to adverse events.
Conclusions: Seladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in patients with primary biliary cholangitis at risk of disease progression. Seladelpar appeared safe and well tolerated and was not associated with any increase in pruritus.