DOI: 10.1097/hep.0000000000001895 ISSN: 0270-9139

A phase 2b/3 trial of saroglitazar in primary biliary cholangitis

Raj Vuppalanchi, Alejandra Villamil, Yusuf Yilmaz, Ramazan Idilman, Beatriz Margarita Ameigeiras, Farheen Shaikh, Meral Akdoğan, Murat Kiyici, Kris V. Kowdley, Cynthia Levy, Taufik Momin, Deven Parmar, Naga Chalasani
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Background:

Saroglitazar, a dual PPAR alpha/gamma agonist, improved serum alkaline phosphatase (ALP) levels in patients with primary biliary cholangitis (PBC) in a phase 2a clinical trial.

Methods:

EPICS-III is a phase 2b/3 adaptive, double-blind, randomized controlled trial in patients with PBC who had an inadequate response to or were intolerant of ursodeoxycholic acid (UDCA). In phase 2b, 37 participants received placebo or saroglitazar magnesium 1 or 2 mg for 16 weeks. Saroglitazar magnesium 1 mg (0.97 mg of saroglitazar) was selected for phase 3, which randomized 148 patients to saroglitazar (n=97) or placebo (n=51) for 52 weeks. The primary endpoint was biochemical response at week 52, defined as ALP <1.67 x ULN with ≥15% reduction from baseline and total bilirubin below ULN; the key secondary endpoint was ALP normalization.

Results:

Baseline characteristics in the phase 3 efficacy population were comparable except for higher baseline ALP and other liver biochemistries in the saroglitazar group. Biochemical response was achieved in 56.7% versus 9.8% with placebo (difference, 48.0%; 95% CI, 35.3 to 60.8; p <0.001). Among participants with baseline ALP ≤3xULN, biochemical response rates were 79.0% versus 14.3%, and 83.1% versus 14.7% in the per-protocol analysis. ALP normalization occurred in 8.2% with saroglitazar versus 0% with placebo (difference, 8.5%; 95% CI, 2.9 to 14; p =0.016). Among participants with baseline 5-D Itch score ≥12, the week-24 treatment difference was −3.2 points (95% CI, −5.66 to −0.82) but was not maintained at week 52. Adverse events occurred in 81.1% with saroglitazar versus 90.5% with placebo, and serious adverse events occurred in 6.3% and 11.1%, respectively.

Conclusion:

Saroglitazar 0.97 mg significantly improved biochemical response and ALP normalization and was well tolerated over 52 weeks.

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