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Clinical Trial
. 2024 Feb 29;390(9):783-794.
doi: 10.1056/NEJMoa2312100. Epub 2024 Feb 21.

A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis

Gideon M Hirschfield  1 , Christopher L Bowlus  1 , Marlyn J Mayo  1 , Andreas E Kremer  1 , John M Vierling  1 , Kris V Kowdley  1 , Cynthia Levy  1 , Alejandra Villamil  1 , Alma L Ladrón de Guevara Cetina  1 , Ewa Janczewska  1 , Ehud Zigmond  1 , Sook-Hyang Jeong  1 , Yusuf Yilmaz  1 , Yiannis Kallis  1 , Christophe Corpechot  1 , Peter Buggisch  1 , Pietro Invernizzi  1 , Maria Carlota Londoño Hurtado  1 , Sandrin Bergheanu  1 , Ke Yang  1 , Yun-Jung Choi  1 , Daria B Crittenden  1 , Charles A McWherter  1 ; RESPONSE Study Group
Collaborators, Affiliations
Clinical Trial

A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis

Gideon M Hirschfield et al. N Engl J Med. .

Abstract

Background: Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits.

Methods: In this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus).

Results: Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P = 0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively.

Conclusions: In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.).

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