A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis

Abstract

We 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] ≥1.67xupper limit of normal [ULN]) who were receiving or intolerant to ursodeoxycholic acid. In this 52-week, phase II, dose-ranging, open-label study, patients were randomized (1:1) to seladelpar 5mg/day (n=53) or 10mg/day (n=55) or assigned to 2mg/day (n=11; United Kingdom sites after interim analysis) for 12 weeks. Doses could then be uptitrated to 10mg/day. The primary efficacy endpoint was ALP change from baseline to Week8. Mean baseline ALP was 300, 345, and 295U/L in the 2mg, 5mg, and 10mg cohorts, respectively. Twenty-one percent 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 2mg (n=11), 5mg (n=49), and 10mg (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 2mg and 5mg cohorts, respectively. At Week 52, composite response (ALP <1.67xULN, ≥15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2mg, 5mg, and 10mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5mg and 10mg cohorts. There were no treatment-related serious adverse events, and 4 patients discontinued due to adverse events. Seladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in patients with PBC at risk of disease progression. Seladelpar appeared safe and well tolerated and was not associated with any increase in pruritus. NCT02955602 CLINICALTRIALSREGISTER. 2016-002996-91 LAY SUMMARY: Current treatment options for patients living with primary biliary cholangitis (PBC) are not optimal due to inadequate effectiveness or undesirable side effects. Patients with PBC who took seladelpar, a new treatment being developed for PBC, at increasing doses (2, 5, or 10mg/day) for 1 year had clinically significant, dose-dependent improvements in key liver tests. Treatment appeared safe and was not associated with any worsening in patient self-reported itch scores.