Elafibranor's safety profile in primary biliary cholangitis looked reassuring, but the evidence is thin

Design

Systematic review, meta-analysis and trial sequential analysis of randomised placebo-controlled trials

Population

274 patients with primary biliary cholangitis and inadequate response to ursodeoxycholic acid (183 elafibranor, 91 placebo)

Primary outcome

Any adverse event, plus nine other safety outcomes

Effect

Any adverse event RR 1.06 (95% CI 0.97 to 1.16); pruritus RR 0.77; fatigue RR 0.71 (nonsignificant)

A systematic review pooled three placebo-controlled randomised trials of elafibranor in 274 patients with primary biliary cholangitis who had an inadequate response to ursodeoxycholic acid (183 on elafibranor, 91 on placebo), all at low risk of bias. Ten safety outcomes were pooled with GRADE and trial sequential analysis.

There was no significant difference between elafibranor and placebo in any outcome. For any adverse event the risk ratio was 1.06 (95% CI 0.97 to 1.16). Trends favoured elafibranor for pruritus (RR 0.77) and fatigue (RR 0.71), with small nonsignificant increases in nausea and treatment-related events. Certainty was moderate, downgraded for imprecision. Trial sequential analysis found only 2.2% to 9.7% of the required information for nine of ten outcomes.

A lack of difference in an underpowered pool is not evidence of safety for rare or long-term events. The drug has regulatory approval as a second-line option, and these data fit with that but do not extend it.

• Elafibranor is a second-line option in patients with an inadequate response to ursodeoxycholic acid
• Monitor liver tests and symptoms as the product information advises
• Pruritus and fatigue trends are encouraging, but not confirmed
• Longer-term and rarer safety questions remain open
• Check availability and cost locally before planning treatment

Why it matters

Second-line options in this disease are limited, and prescribers need to know how much the safety evidence can bear.

Don't overread it

Three small trials cannot rule out rare or long-term adverse events, and the safety analysis says nothing about efficacy.

The statistics, in plain English

Trial sequential analysis estimates how much data are needed to draw firm conclusions. Having 2% to 10% of the information needed for most outcomes means differences could still be missed, so 'no significant difference' mostly reflects limited data.

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