17 - Seladelpar Treatment Resulted in Correlated Decreases in Serum IL-31 and Pruritus in Patients with Primary Biliary Cholangitis (PBC): Post-Hoc Results from the Phase 3 Randomized, Placebo-Controlled ENHANCE Study
Andreas Kremer, MD, PhD, MHBA1, Marlyn Mayo, MD2, Gideon Hirschfield, PhD3, Cynthia Levy, MD4, Christopher Bowlus, MD5, David Jones, PhD6, Charles McWherter, PhD7, Yun-Jung Choi, PhD7 1University of Zürich, Zurich, Zurich, Switzerland; 2UT Southwestern, Dallas, TX; 3Toronto Centre for Liver Disease, Toronto, ON, Canada; 4University of Miami Health System, Miami, FL; 5UC Davis, Davis, CA; 6Newcastle University, Newcastle, England, United Kingdom; 7CymaBay Therapeutics, Newark, CA
Introduction: Pruritus is a debilitating symptom impacting the quality of life for many people living with PBC. Interleukin-31 (IL-31) is a cytokine reported to be mechanistically relevant to pruritus and its treatment, including those with cholestasis. Treatment with seladelpar, a selective PPAR-delta agonist, is associated with significant improvement in pruritus in PBC. Here we report the effect of seladelpar on serum IL-31 levels and its association with pruritus in patients with PBC.
Methods: IL-31 levels were quantified in serum samples from the ENHANCE study of seladelpar (EudraCT 2018-001171-20) in patients with PBC who received daily oral doses of placebo (n = 55), seladelpar 5 mg (n = 53) or 10 mg (n = 53) for 3 months. Serum IL-31, bile acids and their correlation with patient-reported pruritus numerical rating scale (NRS, 0-10) were assessed.
Results: Baseline IL-31 levels positively correlated with pruritus NRS (r = 0.54, p < 0.0001). Patients with NRS ≥ 4 had significantly higher baseline median [IQR] IL-31 compared to patients with pruritus NRS < 4 (7.6 pg/mL [1.2, 14.5] vs 1.2 pg/mL [0.3, 2.8], p < 0.0001). At baseline, IL-31 was also correlated with serum total bile acids (r = 0.54, p < 0.0001) and ALP (r = 0.44, p < 0.0001). Seladelpar treatment strongly decreased mean IL-31 levels from baseline to Month 3: seladelpar 5 mg (3.8 to 1.7 pg/mL, p < 0.001), 10 mg (4.2 to 1.7 pg/mL, p < 0.001) compared to placebo (4.3 to 3.9 pg/mL, not significant). A substantial dose-dependent % decrease in IL-31 was observed with seladelpar treatments: seladelpar 5 mg (-30%, p < 0.001) and 10 mg (-52%, p < 0.0001) compared to placebo (+31%). Patients with a clinically meaningful improvement in pruritus NRS (≥ 2 decrease) demonstrated greater dose-dependent reductions in IL-31 from baseline compared to those without pruritus improvement. We also observed significant correlations between changes in IL-31 vs pruritus NRS (r = 0.54, p < 0.0001) and ALP (r = 0.40, p < 0.01), but neither with ALT nor AST, in the seladelpar 10 mg group. Changes in IL-31 and total bile acids correlated in the seladelpar 10 mg group (r = 0.63, p < 0.0001).
Discussion: Seladelpar dose-dependently decreased IL-31 in patients with PBC. Reduction in serum IL-31 correlated with pruritus improvement. These results suggest that IL-31 may have a role in pruritus in patients with PBC. It may also be a biomarker related to the anti-pruritic effects of seladelpar.
Charles McWherter indicated no relevant financial relationships.
Yun-Jung Choi indicated no relevant financial relationships.
Andreas Kremer, MD, PhD, MHBA1, Marlyn Mayo, MD2, Gideon Hirschfield, PhD3, Cynthia Levy, MD4, Christopher Bowlus, MD5, David Jones, PhD6, Charles McWherter, PhD7, Yun-Jung Choi, PhD7, 17, Seladelpar Treatment Resulted in Correlated Decreases in Serum IL-31 and Pruritus in Patients with Primary Biliary Cholangitis (PBC): Post-Hoc Results from the Phase 3 Randomized, Placebo-Controlled ENHANCE Study, ACG 2023 Annual Scientific Meeting Abstracts. Vancouver, BC, Canada: American College of Gastroenterology.
