Liver and Bile
N Engl J Med. 2024;390(9):795–805
Efficacy and safety of elafibranor in primary biliary cholangitis
Background: Primary biliary cholangitis (PBC) is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor α and δ agonist, may have benefit as a treatment for PBC is unknown.
Methods: In this multinational, phase 3, double-blind, placebo-controlled trial, the authors randomly assigned (in a 2:1 ratio) patients with PBC who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase [ALP] level of < 1.67 times the upper limit of the normal range, with a reduction of ≥ 15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the ALP level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]).
Results: A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55/108) who received elafibranor and in 4% (2/53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI]: 32–57; p < 0.001). The ALP level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI: 6–23; p = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI: -1.99–0.42; p = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting.
Conclusions: Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo.