ELSPIRE: Elafibranor Normalizes ALP in PBC Below the 1.67 Threshold

Elafibranor normalized alkaline phosphatase (ALP) in 85.3% of participants with primary biliary cholangitis (PBC) and mildly elevated ALP despite ursodeoxycholic acid (UDCA), compared with 23.3% receiving placebo, according to late-breaking data from the phase 3 ELSPIRE clinical trial presented at The Liver Meeting 2026 in Denver, Colorado.

“This entire population had a very good rate of response,” presenting author Kris Kowdley, Director at Liver Institute Northwest, told HCPLive. Findings come the phase 3 ESPIRE clinical trial.

Why Target ALP Normalization?

Global PBC Study Group data show 10-year survival of 93.2% among participants with normal ALP, compared with 86.1% among those with ALP between 1 and 1.67 times the upper limit of normal (ULN).1 Yet participants in that range have generally been excluded from registrational trials. Elafibranor (Iqirvo), a peroxisome proliferator-activated receptor (PPAR)-α/δ agonist, was approved as second-line therapy based on the phase 3 ELATIVE trial, which enrolled participants with ALP of 1.67 times ULN or higher. In ELATIVE, 51% of participants receiving elafibranor achieved the composite biochemical response vs 4% receiving placebo, but only 15% normalized ALP.2,3

What Did ELSPIRE Show?

Kowdley and colleagues randomized 92 participants with ALP between 1 and 1.67 times ULN to either elafibranor 80 mg or placebo.2 Response was consistent whether baseline ALP was 1.33 times ULN or lower (80.4% vs 26.1%) or higher (87.5% vs 14.3%), and 64.3% of participants receiving elafibranor achieved complete biochemical response vs 16.7% receiving placebo.2

Adverse events were mostly mild or moderate, with no new safety signals.2 Kowdley notes slightly more fractures and weight gain with elafibranor, consistent with ELATIVE, and says the findings reinforce the need to monitor bone health in this population.

Watch the full interview to hear Kowdley explain why the treatment goal in PBC is shifting, how ELSPIRE compares with ELATIVE, and what the safety findings mean for counseling participants.

References

1. Murillo Perez CF, Harms MH, Lindor KD, et al; Global PBC Study Group. Goals of treatment for improved survival in primary biliary cholangitis: treatment target should be bilirubin within the normal range and normalization of alkaline phosphatase. Am J Gastroenterol. 2020;115(7):1066-1074. doi:10.14309/ajg.0000000000000557
2. Kowdley K, Lawitz E, Bowlus C, et al. 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. Presented at: The Liver Meeting 2026; November 5-9, 2026; Denver, CO.
3. Kowdley KV, Bowlus CL, Levy C, et al. Efficacy and safety of elafibranor in primary biliary cholangitis. N Engl J Med. 2024;390(9):795-805. doi:10.1056/NEJMoa2306185