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

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A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis. Journal of hepatology Bowlus, C. L., Galambos, M. R., Aspinall, R. J., Hirschfield, G. M., Jones, D. E., Dorffel, Y., Gordon, S. C., Harrison, S. A., Kremer, A. E., Mayo, M. J., Thuluvath, P. J., Levy, C., Swain, M. G., Neff, G. W., Sheridan, D. A., Stanca, C. M., Berg, C. P., Goel, A., Shiffman, M. L., Vierling, J. M., Boudes, P., Steinberg, A., Choi, Y., McWherter, C. A. 2022

Abstract

BACKGROUND & AIMS: 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 for disease progression (alkaline phosphatase [ALP] =1.67*upper limit of normal [ULN]) 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 (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. Primary efficacy endpoint was ALP change from baseline to Week 8.RESULTS: Mean baseline ALP was 300, 345, and 295 U/L in the 2-mg, 5-mg, and 10-mg 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 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*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 (AEs), and 4 patients discontinued due to AEs.CONCLUSIONS: Seladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in PBC patients at risk for disease progression. Seladelpar appeared safe and well tolerated with no increase in pruritus.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 10 mg/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.CLINICALTRIALS: GOV NUMBER: NCT02955602 CLINICALTRIALSREGISTER.EU NUMBER: 2016-002996-91.

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