Network meta-analysis: relative clinical efficacy and safety of elafibranor versus seladelpar as second-line treatment for patients with primary biliary cholangitis.

Aim: To indirectly compare the efficacy and safety of elafibranor and seladelpar, as second-line treatments for primary biliary cholangitis. Materials & methods: Bayesian network meta-analyses compared data from randomized-controlled studies of elafibranor and seladelpar identified by a systematic literature review up to June 2024: (a) elafibranor (n = 108) versus placebo (n = 53; ELATIVE [NCT04526665]) and (b) seladelpar (n = 128) versus placebo (n = 65; RESPONSE [NCT03301506]). Patients from ELATIVE not meeting the RESPONSE upper limit of normal (ULN) criteria for alkaline phosphatase (ALP) and total bilirubin were excluded (n = 16); summary statistics for ELATIVE were recalculated using the new dataset. Random-effects models assessed the outcomes of cholestasis response (ALP <1.67 × ULN, ALP reduction ≥15% from baseline and total bilirubin ≤ULN), ALP normalization, change from baseline in ALP and pruritus, pruritus as a treatment-emergent adverse event and all-cause discontinuation. Results: Elafibranor-treated patients had greater odds of achieving cholestasis response than placebo- (median odds ratio [95% credible interval]: 84.79 [12.49, 2513.00]) or seladelpar-treated patients (13.02 [1.45, 420.20]), with posterior probabilities ≥99% that odds were higher with elafibranor than seladelpar or placebo. Among patients with ALP ≥350 U/l, the median odds ratio [95% credible interval] of cholestasis response for elafibranor-treated patients versus seladelpar-treated patients was 18.71 [0.65, 10,610.00], with a 95.2% posterior probability that odds were higher with elafibranor than seladelpar. For all other outcomes, there was no strong evidence of a difference between treatments. Conclusion: Bayesian network meta-analyses found strong probabilistic evidence supporting the treatment benefit of elafibranor compared with seladelpar for the achievement of cholestasis response at 52 weeks, while the treatment effect on other outcomes was uncertain. Head-to-head studies are needed to validate results of these indirect comparisons.