Elafibranor normalizes ALP in PBC, but clinical benefit remains uncertain

ELSPIRE was a phase IIIb, randomized, double-blind, placebo-controlled trial in 92 patients with primary biliary cholangitis (PBC) who had an inadequate response to, or intolerance of, ursodeoxycholic acid (UDCA) and baseline alkaline phosphatase (ALP) above the upper limit of normal (ULN) but below 1.67×ULN. Participants received elafibranor 80 mg once daily or placebo for 52 weeks; the primary endpoint was ALP normalization.

At week 52, ALP had normalized in 85.3% of patients receiving elafibranor and 23.3% receiving placebo. The treatment effect was similar or greater in the subgroup with higher baseline ALP. Liver stiffness, enhanced liver fibrosis score, and patient-reported pruritus and fatigue did not significantly improve versus placebo. Projected 15-year transplant-free survival favored elafibranor in risk-model calculations, but these were modeled estimates, not observed clinical outcomes.

Adverse events were broadly consistent with elafibranor’s known safety profile; fractures were imbalanced relative to placebo, and weight gain led to at least one discontinuation. The commentary argues that biochemical efficacy alone does not establish improved prognosis, particularly in patients with mild residual ALP elevation and generally favorable baseline risk. The findings do not establish that treatment escalation improves clinical outcomes; longer-term outcomes evidence is awaited from the phase IV ELFINITY study (NCT06447168).