Introduction
Alkaline phosphatase (ALP) is an important marker in primary biliary cholangitis (PBC) associated with risk for disease progression. In the pivotal, Phase 3, placebo-controlled RESPONSE trial (NCT04620733), seladelpar, a first-in-class delpar (selective PPAR-delta agonist), led to a significantly higher percentage of PBC patients achieving the composite biochemical endpoint (ALP <1.67 x upper limit of normal [ULN], ALP decrease ≥15%, and total bilirubin [TB] ≤ULN) compared with placebo (61.7% vs 20%) and decreased mean ALP levels after one year (-42.4% vs -4.3%, respectively). Here, we report additional data on ALP changes in the RESPONSE trial.
Aims & Methods
PBC patients who received ursodeoxycholic acid (UDCA) for ≥12 months or were UDCA intolerant and had ALP ≥1.67 x ULN and TB ≤2 x ULN were randomised 2:1 to daily seladelpar 10 mg or placebo. We assessed ALP changes across demographic subgroups, baseline ALP quartiles, and in patients who did not meet the composite biochemical endpoint. Worsening of ALP (increase >0 U/L from baseline) and safety by baseline ALP subgroup were also evaluated.
Results
128 patients were randomised to seladelpar and 65 to placebo with mean baseline ALP 314.6 U/L and 313.8 U/L, respectively; 53 (27.5%) patients had baseline ALP ≥350 U/L. Seladelpar reduced ALP at month 12 similarly across all subgroups, including in patients with cirrhosis, aged <50 years at PBC diagnosis, and of Hispanic/Latino ethnicity, vs placebo. For patients with baseline ALP ≥350 U/L, seladelpar led to a greater decrease (-44.8%; -216.1 U/L) in ALP vs placebo (-11.6%; -56.4 U/L); similar percent decreases were seen in patients with baseline ALP <350 U/L. Seladelpar reduced ALP similarly across baseline ALP quartiles. Among patients who did not meet the composite biochemical endpoint at month 12, ALP was decreased by -129.9 U/L for seladelpar vs -6.4 U/L for placebo. Seladelpar prevented worsening of ALP, with 7 (5.5%) seladelpar patients vs 19 (29.2%) placebo with increases in ALP from baseline at month 12. Adverse events were reported in 86.4% of patients with baseline ALP <350 U/L and 84.9% of patients with ALP ≥350 U/L, with similar proportions in seladelpar vs placebo patients.
Conclusion
Seladelpar led to robust and consistent ALP decreases across all subgroups studied. Substantial ALP decreases were also observed in patients who did not meet the composite endpoint criteria at month 12. Seladelpar was overall safe and well tolerated, regardless of baseline ALP level.
Disclosure
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; NGM Bio; Novo Nordisk; 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. KKY reports receiving honoraria from Gilead Sciences, Inc. SK reports receiving grants or contracts from Gilead Sciences, Inc.; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead Sciences, Inc. EM reports receiving payment or honoraria for speakers bureaus from AbbVie; Eli Lilly; Gilead Sciences, Inc.; and Ipsen; and support for attending advisory boards from AbbVie; Eli Lilly; Gilead Sciences, Inc.; and Ipsen. AB reports receiving grants or contracts and consulting fees from Chemomab; CymaBay Therapeutics; Gilead Sciences, Inc.; GSK; Intercept Pharmaceuticals; Ipsen; and Mirum Pharma; royalties or licences from UpToDate; payment for expert testimony from UMass; and participation on a data safety monitoring board or advisory board with Pfizer. KGR reports receiving grants or contracts from COUR Pharmaceuticals; CymaBay Therapeutics; Gilead Sciences, Inc.; and Pliant Therapeutics; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Mallinckrodt Pharmaceuticals and Gilead Sciences, Inc. CC reports consulting for CymaBay Therapeutics and Ipsen. JMS reports consultant honoraria from 89Bio; Alentis; Alexion; Altimmune; AstraZeneca; Bionorica; Boehringer Ingelheim; Gilead Sciences, Inc.; GSK; Inventiva Pharma; Ipsen; Lilly; Madrigal Pharmaceuticals; MSD; NorthSea Therapeutics; Novartis; Novo Nordisk; Pfizer; Roche; Sanofi; and Siemens Healthineers; speaker honoraria from AbbVie; Boehringer Ingelheim; Echosens; Gilead Sciences, Inc.; Madrigal Pharmaceuticals; Medscape; and Novo Nordisk; and stockholder options with AGED Diagnostics and Hepta Bio. 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).
