(M-031) Exposure-Response Analysis of Seladelpar in Patients With Primary Biliary Cholangitis

Xiaoning Wang – Gilead Sciences, Inc., Foster City, CA, USA; Jin Zhou – Gilead Sciences, Inc., Foster City, CA, USA; Shuang Xu – Certara, Radnor, PA, USA; Bill Poland – Certara, Radnor, PA, USA; Daria Crittenden – Gilead Sciences, Inc., Foster City, CA, USA; Ana Ruiz-Garcia – Gilead Sciences, Inc., Foster City, CA, USA

Objectives: Seladelpar (SEL) is a first-in-class delpar (selective peroxisome proliferator–activated receptor delta [PPARδ] agonist) shown to significantly improve the disease marker of alkaline phosphatase (ALP) and reduce pruritus in patients with primary biliary cholangitis (PBC).1-4 Here, we evaluated the exposure-response (E-R) relationships between SEL exposure and efficacy and safety responses in patients with PBC and the effects of intrinsic and extrinsic factors on these E-R relationships.

Methods: Efficacy and safety data were pooled from 1 Phase 2, 2 placebo-controlled, Phase 3, and 2 long-term, open-label, safety studies in PBC patients. A population pharmacokinetic model of SEL was previously developed and used to provide exposure metrics, which included AUCtau, Cmax, Ctrough at steady state, and average daily AUC to event (AUCavg).5 AUCavg accounted for dose interruptions/modifications and reflected SEL exposure over time from treatment start to event time. Efficacy responses included a composite efficacy response (CER; ALP < 1.67× upper limit of normal [ULN], ALP decrease ≥15%, and total bilirubin ≤ULN), ALP change from baseline, ALP normalization, and pruritus numerical rating scale (NRS) reduction. Safety responses included treatment-emergent adverse events (TEAEs) with ≥10% incidence, and changes in renal and muscle toxicity biomarkers (creatinine, estimated glomerular filtration rate, and creatine kinase). Candidate E-R models included linear and saturable (Emax) logistic regression for binary endpoints, linear regression or Emax models for continuous endpoints, and longitudinal E-R models for time-course ALP levels. Covariates were evaluated via stepwise forward addition–backward elimination. Final models were evaluated by standard model diagnostic plots and were used to simulate efficacy and safety responses in patients receiving placebo, SEL 5 mg, or SEL 10 mg.

Results: The pooled analysis included 752 PBC patients. Within the examined exposure range, a higher SEL AUCavg led to higher probabilities of achieving CER and ALP normalization, along with greater reductions in pruritus NRS and ALP change from baseline; all relationships were statistically significant (P <.05). An Emax logistic regression model fit the E-R relationships of CER and ALP normalization better than linear models. A longitudinal regression model described the relationship well between the time-course of ALP decrease and SEL AUC. Model-based simulations indicated improved efficacy responses with SEL 10 mg compared with SEL 5 mg. Pruritus was the only TEAE with ≥10% incidence (15.3%). There was no significant relationship between TEAE pruritus and SEL exposure. E-R relationships were identified for muscle toxicity and renal biomarkers but were considered not clinically relevant because the magnitude of these changes was negligible and simulated changes for placebo vs SEL 10 mg overlapped.

Conclusions: Statistically significant relationships between SEL exposure and efficacy endpoints indicated a better response for SEL 10 mg as compared with SEL 5 mg. No exposure-related safety concerns were seen at the analyzed doses. These findings support a favorable benefit–risk profile of SEL 10 mg once daily in PBC patients.

Citations: [1] Livdelzi. US prescribing information. Gilead Sciences, Inc.; 2024.
[2] Livdelzi. UK Summary of Product Characteristics. Gilead Sciences, Inc.; 2024.
[3] Seladelpar Gilead. EMA prescribing information. Gilead Sciences, Inc.; 2025.
[4] Hirschfield GM, et al. A phase 3 trial of seladelpar in primary biliary cholangitis. N Engl J Med. 2024;390:783-94.
[5] Wang X, et al. Population pharmacokinetic analysis of seladelpar in patients with primary biliary cholangitis. Population Approach Group Europe. Gilead Sciences Inc.; 2025.

Keywords: Exposure-response, Seladelpar, Primary Biliary Cholangitis