ASSURE: Seladelpar Achieves Clinical Improvement in Primary Biliary Cholangitis

Seladelpar was associated with clinically meaningful improvements in markers of cholestasis and liver injury in patients with primary biliary cholangitis (PBC), according to new data presented at Digestive Disease Week (DDW) 2024.¹

Interim results from the ongoing, phase 3 ASSURE study indicated seladelpar, a selective PPAR-delta agonist, demonstrated an overall strong signal of safety and tolerability through month 12 of the study for treatment of PBC.

“In this open-label, phase 3 study, seladelpar led to clinically meaningful improvements in markers of cholestasis and liver injury, including high rates of alkaline phosphatase (ALP) normalization,” wrote the investigative team, led by Cynthia Levy, MD, a professor of medicine in the division of digestive health and liver diseases, and the associate director of the Schiff Center for Liver Diseases at the University of Miami.

PBC, a rare liver disease, is characterized by the elimination of the small intrahepatic bile ducts and the accumulation of toxic bile acids.² The disease can lead to cholestasis, inflammation, and biliary fibrosis, which can then progress to cirrhosis and liver failure.

Ursodeoxycholic acid (UDCA) is the only agent currently approved by the US Food and Drug Administration (FDA) for first-line treatment of PBC.² However, up to 40% can experience persistent, elevated alkaline phosphatase and bilirubin levels, which can signal disease progression.

Recent Phase 3 data showed the percentage of patients who experienced a biochemical response and ALP normalization was significantly greater among those treated with seladelpar than placebo.³ In addition, seladelpar demonstrated a reduction in pruritis among those with moderate-to-severe pruritis at baseline.

These safety and efficacy results from the ASSURE trial included those who had previously participated in a study of seladelpar for PBC.¹ Patients with PBC remained eligible for ASSURE based on previous participation and an inadequate response or intolerance to ursodeoxycholic acid (UDCA).

In the phase 3 ASSURE trial, all patients were treated with open-label, daily doses of oral seladelpar 10 mg. At the data cutoff in June 2023, 174 patients with previous participation in a seladelpar study were enrolled, with a treatment gap of >1 year.

For the analysis, the biochemical endpoints consisted of a composite response of ALP 1.67 times the upper limit of the normal range (ULN), an ALP decrease of ≥15% from baseline, and total bilirubin levels at 12 months. In addition, investigators measured ALP normalization and the changes from baseline in ALP, Gamma-Glutamyl Transferase (GGLT), Alanine Transaminase (ALT), and total bilirubin through month 12.

Among the 174 patients in ASSURE, the majority were female (94%) and had a mean age of 58.6 years. When stratifying by key baseline characteristics, the mean ALP was 270.5 U/L and total bilirubin was 0.75 mg/dL (13.8% >ULN). Most (n = 168, 96.6%) patients were concurrently treated with UDCA, and nearly one-fifth (19%) had cirrhosis.

At the data cutoff, 148 (85%) patients reached the 12-month treatment mark. Upon analysis, investigators found that 70.3% of patients achieved the composite response endpoint with seladelpair 10 mg. ALP normalization was also confirmed in 37.2% of patients who received seladelpar.

Overall, the mean ALP change from baseline was –44.4% (–144.4 u/L). From baseline. seladelpar treatment reduced GGT, ALT, and total bilirubin levels by 36.4%, 25.2%, and 9.2%, respectively. Meanwhile, safety and tolerability remained normal through month 12.

In particular, Levy and colleagues identified no treatment-related serious adverse events. However, treatment discontinuation due to adverse events did occur in 4.0% of the study population.

“The long-term safety and efficacy of seladelpar continue to be evaluated in the ongoing ASSURE study,” Levy and colleagues indicated.

References

1. _{Levy C, Gordon SC, Lawitz E, Yimam K, Reddy G, Peyton A, Zhuo S, et al. EFFICACY AND SAFETY OF SELADELPAR IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS IN THE ASSURE STUDY: INTERIM RESULTS. Lecture presented at Digestive Disease Week 2024, May 18 - 21, 2024.}
2. _{Galoosian A, Hanlon C, Zhang J, Holt EW, Yimam KK. Clinical Updates in Primary Biliary Cholangitis: Trends, Epidemiology, Diagnostics, and New Therapeutic Approaches. J Clin Transl Hepatol. 2020;8(1):49-60. doi:10.14218/JCTH.2019.00049}
3. _{Hirschfield GM, Bowlus CL, Mayo MJ, et al. A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis. N Engl J Med. 2024;390(9):783-794. doi:10.1056/NEJMoa2312100}