AASLD 2026: Elafibranor normalizes ALP in 85% of patients treated for PBC

Clinical takeaway: When reassessing response to ursodiol in adults with PBC, consider ALP normalization as a potential treatment goal. Trial results support elafibranor’s biochemical efficacy in patients with residual ALP elevation below traditional response thresholds, while treatment escalation should account for individual disease risk and safety.

Primary biliary cholangitis (PBC) can progress to fibrosis, cirrhosis, and liver failure. Although alkaline phosphatase (ALP) below 1.67 times the upper limit of normal has traditionally indicated an adequate response, normalization is associated with better long-term outcomes.

The randomized, double-blind, placebo-controlled phase 3 ELSPIRE trial enrolled 92 adults with ALP above normal but below 1.67 times the upper limit of normal. Participants received elafibranor 80 mg daily or placebo for 52 weeks; approximately 97% continued ursodeoxycholic acid (ursodiol; UDCA).

At week 52, 85.3% of elafibranor-treated patients achieved normal ALP versus 23.3% receiving placebo, a 62-percentage-point difference. The adjusted mean ALP reduction was 36.5% with elafibranor versus 4.2% with placebo.

Complete biochemical response, defined as normal ALP, total bilirubin, transaminases, albumin, and international normalized ratio, occurred in 64.3% with elafibranor versus 16.7% with placebo.

Most adverse events were mild or moderate, and no serious events were considered treatment related. Weight gain exceeding 5% occurred in 22.6% with elafibranor versus 6.7% with placebo and led to one elafibranor discontinuation; fractures occurred in 8.1% versus 3.3%, respectively, all considered traumatic and unrelated to treatment.

An accompanying editorial emphasized that biochemical improvement has not yet established better clinical outcomes. Fibrosis markers did not significantly improve, symptom benefits remain unestablished, and survival estimates were model projections.

The ELSPIRE investigators noted that the ongoing placebo-controlled phase 3 ELFIDENCE trial is evaluating long-term clinical outcomes.

“The results of this study demonstrate that ALP normalization is an achievable goal for a substantial proportion of patients receiving Elafibranor, even among those with moderately elevated ALP levels,” said study lead author Kris V. Kowdley, MD, of Liver Institute Northwest.

The findings are scheduled for presentation at The Liver Meeting on November 8.

Sources: Kowdley KV, et al. (2026 Nov 5) Hepatology. Treatment with elafibranor to normalize alkaline phosphatase in patients with primary biliary cholangitis and incomplete response to ursodeoxycholic acid: Results from the phase III randomized controlled ELSPIRE trial