Title

Efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor delta agonist, in primary biliary cholangitis: 52-week analysis of an ongoing international, randomized, dose ranging phase 2 study.

Document Type

Conference Proceeding

Publication Date

2018

Publication Title

Hepatology (Baltimore, Md.)

Abstract

Background: Seladelpar is a potent, selective PPARdelta agonist and a candidate therapy for inflammatory liver diseases. We report the safety and efficacy of daily seladelpar treatment for up to 52 weeks from an ongoing open-label phase 2 study in primary biliary cholangitis (PBC). The 52-week time-point has been previously used for regulatory approval. Methods: This open-label study (NCT02955602) randomized PBC patients with either an inadequate response to ursodeoxycholic acid (UDCA) or an intolerance to UDCA and an alkaline phosphatase (AP) ≥1.67 x upper limit of normal (ULN) to seladelpar 5 or 10 mg. After 12 weeks, patients on 5 mg could escalate to 10 mg if AP treatment goal was not met (5/10 mg group). Follow-up to 52 weeks evaluated dose regimens of 5/10 and 10 mg/day. The primary efficacy outcome was the AP % change from baseline. Other outcomes included a responder analysis defined as a composite of AP<1.67 x ULN, ≥15% decrease in AP, and total bilirubin ≤ULN, as well as changes in liver, metabolic, and inflammatory markers. Pruritus was evaluated with a visual analogue scale (VAS). Safety analyses included adverse events (AE) and laboratory markers. Results: As of 7/2018, 119 patients were exposed to at least one dose of seladelpar. In each group, 17 patients completed 52-week treatment. At baseline, mean (SD) AP were 351 (166) U/L and 279 (74) U/L in the 5/10 and 10 mg groups, respectively. At 52 weeks, the mean decreases in AP were-47% and-46% in the 5/10 and 10 mg groups, respectively. At 52 weeks, 59% and 71% of patients responded to the composite efficacy outcome in the 5/10 and 10 mg groups, respectively. AP normalization occurred in 24% and 29% of patients in the 5/10 and 10 mg groups, respectively. Median ALT decreases were-31% and-33% in the 5/10 and 10 mg groups, respectively. Baseline median VAS were 20 and 41 in the 5/10 and 10 mg groups, respectively. Median changes in VAS were-30% and-66% in the 5/10 and 10 mg groups, respectively. There was no transaminase safety signal. There were 11 serious AEs in the study, none considered related to seladelpar. One discontinuation for a grade 1 gastroesophageal reflux was deemed related to seladelpar. Conclusion: Seladelpar maintained a potent anti-cholestatic effect over 52 weeks. Seladelpar was generally safe, well tolerated and not associated with pruritus. A 52-week phase 3 PBC study has been initiated to confirm these results.

Volume

68

Issue

1

First Page

1446A

Last Page

1447A

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