Treatment with elafibranor to normalize alkaline phosphatase in patients with primary biliary cholangitis and incomplete response to ursodeoxycholic acid: Results from the phase III randomized controlled ELSPIRE trial

Background & Aims: Definitions of primary biliary cholangitis (PBC) treatment response commonly include alkaline phosphatase (ALP) <1.67× upper limit of normal (ULN). However, ALP >ULN is associated with active disease and reduced transplant-free survival, whereas ALP normalization is associated with better complication-free survival. Elafibranor, a peroxisome proliferator-activated receptor (PPAR)-α/δ agonist, has been shown to be effective and well-tolerated as a second-line treatment in patients with PBC and ALP ≥1.67x ULN. We report phase III ELSPIRE trial results, evaluating the effect of one year of elafibranor treatment on ALP normalization (ALP ≤ULN; ≤120 U/L) in patients with PBC and ALP >1–<1.67× ULN after incomplete response/intolerance to ursodeoxycholic acid. Approach & Results: In ELSPIRE, 92 patients were randomized, double-blind, 2:1 to elafibranor 80 mg (n=62) or placebo (n=30) for 52 weeks, stratified by ALP at randomization (>1–≤1.33× ULN vs. >1.33–<1.67× ULN). At Week 52, 85.3% of patients receiving elafibranor achieved the primary endpoint of ALP normalization, versus 23.3% receiving placebo (treatment difference: 62.0%; 95% CI: 44.3, 79.7; p <0.0001). Least squares mean percentage change from baseline in ALP at Week 52 was –36.5% with elafibranor versus –4.2% with placebo ( p <0.0001). A greater proportion of patients receiving elafibranor versus placebo achieved ALP normalization with ≥15% reduction from baseline and complete biochemical response (normal ALP, total bilirubin, transaminases, albumin, and INR). Elafibranor was well tolerated; no new safety signals were observed. Conclusions: These results support elafibranor as second-line treatment with UDCA for patients with PBC and ALP >1–<1.67× ULN, with ALP normalization as an achievable treatment goal.