Abstract
Background:
While elafibranor’s safety has been addressed within a 3 outcome network meta-analysis of second-line primary biliary cholangitis (PBC) agents and within a mixed design review using serious adverse events (AEs) as its sole safety endpoint, no review has yet applied trial sequential analysis (TSA) or Grading of Recommendations Assessment, Development and Evaluation (GRADE) certainty assessment to a dedicated, 10-outcome, placebo-controlled elafibranor evidence base. PBC is a chronic autoimmune liver disease affecting the small bile ducts, with approximately 30% to 40% of patients failing to respond adequately to first-line ursodeoxycholic acid (UDCA) therapy. Elafibranor, a dual peroxisome proliferator-activated receptor α/δ agonist, received Food and Drug Administration and European Medicines Agency approval in 2024 as a second-line option, yet no pooled randomized evidence for its safety profile had been synthesized.
Methods:
We conducted a systematic review and meta-analysis of RCTs comparing elafibranor with placebo in UDCA-inadequate-responder PBC patients, searching PubMed, Scopus, and Embase through June 2026. Three RCTs (Schattenberg 2021, Kowdley 2024/ELATIVE, Levy 2026/ELMWOOD) enrolling 274 patients (elafibranor n = 183; placebo n = 91) were included, all with low risk of bias. Ten safety outcomes were pooled via a random-effects model, with GRADE and TSA.
Results:
Elafibranor showed no significant difference from placebo across any prespecified safety outcome. The primary outcome, any AE, showed RR 1.06 (95% CI: 0.97–1.16;
I
2
= 0%). Trends favored elafibranor for pruritus (RR 0.77) and fatigue (RR 0.71), with modest nonsignificant increases for nausea and treatment-related AEs. GRADE certainty was moderate across outcomes, downgraded solely for imprecision. TSA confirmed futility for any AE but found the remaining 9 outcomes substantially underpowered, with only 2.2% to 9.7% of required information accrued.
Conclusion:
Elafibranor shows a broadly reassuring safety profile, with encouraging trends toward improved pruritus and fatigue. However, evidence remains insufficient for definitive conclusions on rare or long-term safety signals, underscoring the need for larger, adequately powered trials. Jointly applying GRADE and TSA to this dedicated, placebo-controlled elafibranor evidence base clarifies which safety signals are genuinely null versus underpowered, a distinction broader second-line PBC comparisons have not resolved.