RESPONSE Trial and PBC

The RESPONSE trial was a pivotal phase 3 study designed to evaluate the efficacy and safety of seladelpar, a selective peroxisome proliferator–activated receptor delta (PPARδ) agonist, in patients with primary biliary cholangitis (PBC) who had an inadequate response to or could not tolerate ursodeoxycholic acid (UDCA). Conducted across 24 countries, the trial enrolled 193 patients who were randomized 2:1 to receive seladelpar (10 mg daily) or placebo, with or without UDCA background therapy, over 12 months.

The primary endpoint was achieving a biochemical response, defined as alkaline phosphatase (ALP) <1.67× upper limit of normal (ULN), ≥15% reduction from baseline, and normal total bilirubin at month 12. Seladelpar demonstrated superior efficacy, achieving a biochemical response in 61.7% of patients versus 20.0% in the placebo group (P<0.001). Additionally, 25% of seladelpar-treated patients achieved full ALP normalization compared to 0% with placebo (P<0.001), indicating significant disease control. Seladelpar also reduced mean ALP levels by 42.4%, compared to only 4.3% with placebo, reflecting strong anticholestatic activity.

Secondary endpoints included improvements in pruritus and quality of life. Among patients with moderate-to-severe itching, seladelpar reduced pruritus scores by −3.2 points versus −1.7 with placebo (P=0.005), providing clinically meaningful relief. Patients also reported improvements in fatigue, itch, and social functioning on quality-of-life measures.

Seladelpar exhibited a favorable safety profile, with adverse events mostly mild and similar between groups. Unlike obeticholic acid, seladelpar improved itch and had a cleaner safety profile, establishing it as a potentially superior second-line therapy for PBC.