Seladelpar Reduces Serum IL-31, Improves Pruritus in Patients with Primary Biliary Cholangitis

Andreas Kremer MD, PhD, MHBA

Credit: ResearchGate

CymaBay Therapeutics has announced the publication of findings from a post hoc analysis of the phase 3 ENHANCE study demonstrating the impact of seladelpar on serum interleukin-31 (IL-31) levels and its correlation with pruritus improvement in patients with primary biliary cholangitis (PBC).

Published in Hepatology on January 3, 2024, the results come as part of the first peer-reviewed, published report of a correlation between decreases in IL-31, bile acids, and pruritus symptoms in PBC following treatment with an investigational agent, confirming the cytokine’s role in the etiology of pruritus in PBC and paving the way for its targeted treatment.¹

"Pruritus is a debilitating symptom for many people living with PBC, yet the underlying mechanism of itch is not well understood," said Andreas Kremer MD, PhD, MHBA, professor and head of hepatology at University Hospital Zurich, in a press release.¹ "These latest data are critical in advancing our understanding of potential mediators of cholestatic itch and suggest that IL-31 may have a role in driving pruritis in people with PBC. While current treatments for cholestatic pruritus remain limited, these data can help inform potential novel therapeutic approaches."

Billed as a first-in-class oral, selective peroxisome proliferator-activated receptor delta (PPARδ) agonist, seladelpar has been shown to regulate critical metabolic and liver disease pathways as well as genes involved in bile acid synthesis, inflammation, fibrosis and lipid metabolism, storage, and transport.²

Seladelpar was granted Breakthrough Therapy Designation by the US Food and Drug Administration (FDA) in 2019, although it was later revised in 2023 to reflect treatment of PBC, including pruritus, in adults without cirrhosis or with compensated cirrhosis. CymaBay Therapeutics submitted a New Drug Application (NDA) to the FDA for seladelpar for the management of PBC on December 15, 2023, additionally requesting a Priority Review of the NDA.²

A multicenter, randomized, double-blind, placebo-controlled phase 3 study of seladelpar in patients with PBC with an inadequate response or intolerance to ursodeoxycholic acid, ENHANCE enrolled patients aged 18-72 years with a diagnosis of PBC, alkaline phosphatase (ALP) level ≥1.67 times the upper limit of normal (ULN), and total bilirubin ≤2 times ULN. Participants were stratified by ALP level and pruritus numerical rating scale (NRS) and randomly assigned to a treatment group to receive once-daily oral placebo, seladelpar 5 mg, or seladelpar 10 mg.³

Serum levels for IL-31, a cytokine known to mediate pruritus, were measured for ENHANCE participants in the placebo (n=55), seladelpar 5 mg (n=53), and seladelpar 10 mg (n=53) groups and for healthy volunteers (n=55) prospectively recruited by matching age, sex and BMI to the patients in the ENHANCE study.³

Investigators pointed out there were no significant differences in serum IL-31 levels between treatment groups at baseline. Seladelpar treatment resulted in substantial reductions in mean IL-31 levels from baseline to month 3, decreasing from 3.8 to 1.7 pg/mL in the seladelpar 5 mg group (P = .0002) and 4.2 to 1.7 pg/mL in the 10 mg group (P = .0003) compared to placebo (4.3 to 3.9 pg/mL; P = .28). Statistically significant dose-dependent decreases in IL-31 were observed with seladelpar 5 mg (-30%; P = .0003) and 10 mg (-52%; P < .0001) compared to placebo (+31%).³

At baseline, IL-31 levels correlated with pruritus intensity (r = 0.54; P < .0001). A significant, dose-ordered association was maintained between changes in IL-31 and pruritus NRS in the seladelpar treatment groups (5 mg, r = 0.44; P = .0011 and 10 mg, r = 0.54; P < .0001) and placebo group (r = 0.36; P = .0080).³

Investigators noted baseline IL-31 levels also closely correlated with total (r = 0.54; P < .0001) and conjugated bile acids (up to 0.64, P < .0001), further observing strong correlations between changes in IL-31 levels and changes in changes in GCA (r = 0.67; P < .0001), total bile acids (r = 0.63; P < .0001), and TCA (r = 0.62; P < .0001) in the seladelpar 10 mg group.³

“It seems clear that there are multiple likely components of pruritus signaling in cholestatic disease. Considering the well-established role of IL-31 and its receptor in itch, our findings suggest that IL-31 is also a component of the etiology of pruritus in patients with PBC and an addressable target in its treatment,” investigators concluded.³

References:

1. CymaBay Therapeutics. New Published Data Demonstrates Correlation Between Itch Cytokine Interleukin-31 Reduction and Pruritis Improvement in Primary Biliary Cholangitis in Phase 3 Post-Hoc Analysis of CymaBay's Seladelpar. Press Releases. January 3, 2024. Accessed January 5, 2024. https://www.cymabay.com/investors-media/news-events/press-releases/detail/588/new-published-data-demonstrates-correlation-between-itch
2. Brooks, A. Seladelpar NDA Submitted to FDA for Primary Biliary Cholangitis. December 15, 2023. Accessed January 5, 2024. https://www.hcplive.com/view/seladelpar-nda-submitted-to-fda-for-primary-biliary-cholangitis
3. Kremer, AE, Mayo MJ, Hirschfield, GM, et al. Seladelpar treatment reduces interleukin-31 and pruritus in patients with primary biliary cholangitis. Hepatology. doi:10.1097/HEP.0000000000000728