DISCUSSION
itch, Pruritus, points)Seladelpar, liver injury, pruritus, PBC, deaths
DISEASE PROGRESSION, PBC, PRURITUS, DISEASE, ADVERSE EVENT
New approved therapies remain important for people living with PBC. Current agents do not optimally address disease activity or symptoms. Seladelpar is a selective PPARδ agonist that has documented anticholestatic, anti-inflammatory, and antipruritic effects.Among patients with clinically significant itch (baseline pruritus NRS ≥4), the pruritus NRS significantly decreased at month 3 with seladelpar 10 mg compared with placebo. The proportion of patients with a clinically meaningful reduction (≥2 points)Seladelpar appeared safe and well tolerated, with no deaths or grade 3 or greater ALT or AST elevations. Pruritus (qualitative) was the most common adverse event; however, incidence was highest in the placebo group.A variety of approaches are being pursued for new therapies in PBC. Direct comparisons are difficult because of study design differences. The 78.2% composite end point response rate at month 3 observed for seladelpar 10 mg in this study seems to be similar or better than those reported with other PBC therapies, including obeticholic acid,The anticholestatic, anti-inflammatory, and potentially antifibrotic properties of seladelpar are predicted to affect disease progression and improve outcomes. PPARδ is expressed in hepatocytes,A limitation of this study is its short duration due to early termination. However, although the study was stopped early and the primary composite biochemical end point was amended to 3 months, more than three-fourths of patients achieved the end point. In addition, in a phase 2 study, seladelpar efficacy observed after 3 months of treatment was sustained through 1 year, including ALP reduction and achievement of ALP normalization and composite efficacy end point.In conclusion, in this placebo-controlled, randomized trial, the potent and selective PPARδ agonist seladelpar, at an optimal dose of 10 mg daily, provided clinically significant anticholestatic effects and reduced signs of liver injury and pruritus in patients with PBC. Treatment was not associated with emergent safety concerns. The efficacy and safety profile of seladelpar in this and previous studies suggests its potential use as second-line therapy to address disease activity and symptoms. A 52-week, phase 3, randomized, placebo-controlled, registration study to confirm seladelpar 10 mg QD efficacy and safety is ongoing (NCT04620733).