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

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.