Introduction
Cholestatic pruritus in patients with primary biliary cholangitis (PBC) is frequently debilitating and lacks effective treatments. In the Phase 3 RESPONSE trial (NCT04620733), seladelpar, a first-in-class delpar (selective PPAR-delta agonist), significantly decreased pruritus in PBC patients with moderate to severe pruritus (numerical rating scale [NRS] ≥4 at baseline) vs placebo. Here, we further evaluated pruritus patterns in RESPONSE.
Aims & Methods
Patients with PBC who received ursodeoxycholic acid (UDCA) for ≥12 months or were UDCA intolerant and had alkaline phosphatase ≥1.67 x upper-limit-of-normal (ULN) and total bilirubin ≤2 x ULN were randomised 2:1 to receive daily oral seladelpar 10 mg or placebo for 12 months. We assessed trends in mean NRS over time and change in pruritus using various thresholds of improvement (eg, ≥3- and ≥4-point reductions in NRS, near resolution of itch [NRS ≤1]) in patients with NRS ≥4 or NRS ≥7 (severe itch) at baseline. Development of pruritus in patients without itch (NRS=0) at baseline and safety by subgroup of baseline NRS (≥4 or <4) were also evaluated.
Results
72 of 193 enrolled patients had a baseline NRS ≥4, with 49 randomised to seladelpar and 23 to placebo; 16 seladelpar and 12 placebo patients had NRS ≥7. Among patients with NRS ≥4 at baseline, seladelpar reduced the mean itch intensity from moderate to mild from Month 3 through 12, whereas the mean itch intensity for placebo remained moderate. For patients with baseline NRS ≥4, 46.9% of patients on seladelpar had a ≥3-point NRS decrease vs 21.7% on placebo at Month 12; a ≥4-point NRS decrease was achieved by 30.6% of seladelpar patients vs 8.7% placebo. A higher proportion of patients with baseline NRS ≥4 (26.5%) and NRS ≥7 (18.8%) on seladelpar experienced near resolution of itch at Month 12 vs 0% of patients on placebo. In patients without itch at baseline, 26.7% (4/15) of placebo patients reported pruritus at Month 12 vs 0% (0/30) of seladelpar patients. Adverse events were reported in 88.9% and 84.3% of patients with baseline NRS ≥4 and NRS <4, respectively, with similar proportions across treatment arms.
Conclusion
Seladelpar reduced pruritus severity in PBC patients with a durable effect over time and even led to near resolution of itch in some patients, an effect not observed with placebo. Seladelpar mitigated new onset of itch in patients without pruritus and was overall safe and well tolerated regardless of baseline itch.
Disclosure
AEK reports receiving grants or contracts from Gilead Sciences, Inc., Intercept Pharmaceuticals and Roche; consulting fees from AbbVie; Advanz Pharma; Alentis Therapeutics; Alfasigma; Astellas; AstraZeneca; Attovia Therapeutics; Avior Bio; Bayer; Bristol Myers Squibb; Böhringer-Ingelheim; CymaBay Therapeutics; Escient Pharmaceuticals; Falk; Gilead Sciences, Inc.; GSK; Guidepoint; Intercept Pharmaceuticals; Ipsen; Merck Sharp & Dohme; Mirum Pharma; Novo Nordisk; Rectify Pharma; Roche; and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie; Advanz Pharma; AOP Orphan Pharmaceuticals; Bayer; Bristol Myers Squibb; CymaBay Therapeutics; Falk; Gilead Sciences, Inc.; GSK; Intercept Pharmaceuticals; Ipsen; Johnson & Johnson; Medscape; Merck Sharp & Dohme; Mirum Pharma; NewBridge Pharmaceuticals; Novartis; Roche; Vertex Pharmaceuticals; and Viofor; support for attending meetings and/or travel from Gilead Sciences, Inc.; participation on a data safety monitoring board with AbbVie; Advanz Pharma; Alentis Therapeutics; Alfasigma; AstraZeneca; Avior Bio; Bayer; Bristol Myers Squibb; CymaBay Therapeutics; Escient Pharmaceuticals; Falk; Gilead Sciences, Inc.; GSK; Guidepoint; Intercept Pharmaceuticals; Ipsen; Merck Sharp & Dohme; Mirum Pharma; Novo Nordisk; Roche; and Takeda; and a leadership or fiduciary role in other board, society, committee, or advocacy groups (paid or unpaid) with PBC Foundation, Swiss Association for the Study of the Liver (SASL), Swiss Gastroenterology Society (SGG), Swiss Hepa, and Swiss Transplant Society (STS). CL reports receiving research grants paid to her institution from Calliditas Therapeutics; CymaBay Therapeutics; Escient Pharmaceuticals; EWR; Gilead Sciences, Inc.; GSK; Intercept Pharmaceuticals; Ipsen; Kowa; Mirum Pharma; Target; and Zydus Pharmaceuticals; consulting fees from Calliditas Therapeutics; CymaBay Therapeutics; Gilead Sciences, Inc.; GSK; Intercept Pharmaceuticals; Ipsen; Kowa; and Mirum Pharma; and participation on a data safety monitoring board with COUR Pharmaceuticals. MJM reports receiving grants or contracts from CymaBay Therapeutics; Genfit; Gilead Sciences, Inc.; GSK; Ipsen; and Mirum Pharma; consulting fees from CymaBay Therapeutics, GSK, Intra-Sana Laboratories, Ipsen, Ironwood Pharmaceuticals, Mallinckrodt Pharmaceuticals, and Mirum Pharma; and support for attending meetings and/or travel from CymaBay Therapeutics, GSK, Ipsen, and Mallinckrodt Pharmaceuticals. CLB reports receiving grants or contracts to his institution from Boston Scientific; Bristol Myers Squibb; Calliditas Therapeutics; Cara Therapeutics; Chemomab; COUR Pharmaceuticals; CymaBay Pharmaceuticals; Gilead Sciences, Inc.; GSK; and Hanmi Pharmaceuticals; and consulting fees from Alnylam Pharmaceuticals; Chemomab; CymaBay Therapeutics; Gilead Sciences, Inc.; GSK; Ipsen; and NGM Bio. KVK reports receiving grants or contracts from 89Bio; Boston Scientific; Corcept Therapeutics; CymaBay Therapeutics; Genfit; Gilead Sciences, Inc.; GSK; Hanmi Pharmaceuticals; Intercept Pharmaceuticals; Ipsen; Janssen; Madrigal Pharmaceuticals; Mirum Pharma; Novo Nordisk; NGM Bio; Pfizer; Pliant Therapeutics; Terns Pharmaceuticals; Viking Therapeutics; and Zydus Pharmaceuticals; royalties or licences from UpToDate; consulting fees from 89Bio; CymaBay Therapeutics; Genfit; Gilead Sciences, Inc.; GSK; HighTide Biopharma; Inipharm; Intercept Pharmaceuticals; Ipsen; Madrigal Pharmaceuticals; Mirum Pharma; NGM Bio; and Zydus Pharmaceuticals; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie; Gilead Sciences, Inc.; and Intercept Pharmaceuticals; participation on a data safety monitoring board or advisory board with CTI and Medpace; and stock or stock options with Inipharm. GMH reports having consulted for Advanz Pharma; CymaBay Therapeutics; Falk; Gilead Sciences, Inc.; GSK; Intercept Pharmaceuticals; Ipsen; Kowa; Mirum Pharma; and Pliant Therapeutics. CH, SC, KY, and DBC are employees of Gilead Sciences, Inc., and may own stock in Gilead Sciences, Inc. CAM reports former employment with CymaBay Therapeutics, a Gilead Sciences, Inc., company, from 2007 to 2024; receiving consulting fees from Gilead Sciences, Inc.; being listed as an inventor on seladelpar patents; and a leadership or fiduciary role (paid or unpaid) with 89Bio (independent director). DEJJ reports receiving consulting fees for CymaBay Therapeutics, Ipsen, Kowa, and Umecrine, grants from Intercept, and participation on a speakers’ bureau for Falk, GlaxoSmithKline, Intercept, and Ipsen.