ELSPIRE: Elafibranor Achieves ALP Normalization in 85% With PBC

Elafibranor (Iqirvo) normalized alkaline phosphatase (ALP) in 85.3% of patients with primary biliary cholangitis (PBC) whose ALP remained above the upper limit of normal (ULN) but below 1.67× ULN despite ursodeoxycholic acid (UDCA), compared with 23.3% of patients receiving placebo, according to results from the phase 3 ELSPIRE trial published in Hepatology.¹

The findings will also be presented as a late-breaking abstract at The Liver Meeting 2026, hosted by the American Association for the Study of Liver Diseases (AASLD), November 5–9 in Denver, Colorado.²

“While traditional measures of treatment response have focused on reducing ALP below 1.67 times the upper limit of normal, growing evidence suggests that achieving normal ALP levels may be associated with better long-term outcomes,” Kris V. Kowdley, MD, of Liver Institute Northwest, Velocity Clinical Research, and Washington State University, said in a statement. “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.”²

PBC is a chronic, immune-mediated cholestatic liver disease that destroys intrahepatic bile ducts and can progress to fibrosis, cirrhosis, and liver failure.¹ In a large analysis of US health systems, PBC prevalence was estimated at 29.3 per 100,000 persons, with the highest rates among women (42.8 per 100,000).³ UDCA remains first-line therapy, but up to 40% of patients have an inadequate response, according to the ELSPIRE investigators.¹

Most phase 3 trials of second-line PBC therapies have enrolled patients with ALP of at least 1.67× ULN. That threshold comes from the POISE response criteria, so patients with milder elevations have gone largely unstudied. Elevated ALP above the ULN has nonetheless been associated with shorter transplant-free survival. The investigators noted that updated clinical guidelines increasingly emphasize ALP normalization as a treatment target.¹

The oral peroxisome proliferator-activated receptor (PPAR)-α/δ agonist received US Food and Drug Administration (FDA) accelerated approval in June 2024 for adults with PBC with an inadequate response or intolerance to UDCA.⁴ The approval was based on the phase 3 ELATIVE trial, in which 51% of patients receiving elafibranor achieved a biochemical response compared with 4% receiving placebo. ALP normalized in 15% of patients on elafibranor and none on placebo.⁴,⁵ ELSPIRE results also arrive alongside phase 3 IDEAL data for seladelpar, a PPAR-δ agonist, in a similar ALP range.⁶

How Did Elafibranor Perform in the ELSPIRE Trial?

ELSPIRE (NCT06383403) randomly assigned 92 adults in a 2:1 ratio to elafibranor 80 mg once daily (n = 62) or placebo (n = 30) for 52 weeks. Enrollment ran from July 2024 through May 2025 at sites in 10 countries. Eligible patients had ALP >1 to <1.67× ULN after at least 12 months of UDCA, or were intolerant to UDCA. Randomization was stratified by ALP of >1 to ≤1.33× ULN or >1.33 to <1.67× ULN.¹

Median age was 61 years, 92.4% of patients were female, and 96.7% were receiving concurrent UDCA, for a median of approximately 5 years. The primary endpoint was ALP normalization, defined as ALP ≤120 U/L, at week 52 without rescue therapy, a liver-related event, or death.¹

The trial met its primary endpoint (treatment difference, 62.0%; 95% CI, 44.3%–79.7%; P < .0001). Results were consistent across strata. In the lower stratum, 80.4% of patients on elafibranor vs 26.1% on placebo achieved normalization. In the higher stratum, the rates were 87.5% vs 14.3%.¹

ALP fell rapidly, with a least squares (LS) mean reduction of 31.9% by week 4. At week 52, the LS mean change from baseline was −36.5% with elafibranor vs −4.2% with placebo.¹

Elafibranor also outperformed placebo on composite secondary endpoints¹:

• ALP normalization with a reduction of at least 15% from baseline: 84.5% vs 20.0%
• Complete biochemical response, defined as normal ALP, total bilirubin, transaminases, albumin, and international normalized ratio (INR): 64.3% vs 16.7%

The LS mean difference in total bilirubin change favored elafibranor by 15.0% (95% CI, −28.2% to −1.8%). Formal significance testing applied only to the primary endpoint, so P values for secondary and exploratory outcomes were descriptive.¹

What Safety Findings Were Reported With Elafibranor?

Treatment-emergent adverse events (TEAEs) occurred in 79.0% of patients receiving elafibranor and 70.0% of those receiving placebo, and most were mild or moderate. Serious TEAEs occurred in 4.8% and 13.3% of patients, respectively, and none were considered treatment related. TEAEs led to discontinuation in 4.8% and 3.3% of patients, respectively. The 1 death, from traumatic intracranial hemorrhage, occurred in the placebo arm.¹

Weight gain of more than 5% from baseline was reported in 22.6% of patients receiving elafibranor vs 6.7% receiving placebo. Mean weight change at week 52 was 1.4 kg vs 0.1 kg. Bone fractures occurred in 8.1% vs 3.3% of patients. All fractures were traumatic, and none were considered treatment related. Investigators observed no cases of drug-induced liver injury, transaminase elevations of at least 3× ULN, or creatine phosphokinase elevations above 3× ULN.¹

“These results underscore the potential of [elafibranor] to raise the standard of biochemical response in PBC,” Naga P. Chalasani, MD, incoming co-editor-in-chief of Hepatology, said in the release.²

What Questions Remain for Elafibranor in Lower-ALP PBC?

The investigators acknowledged several limitations¹:

• Symptoms: too few patients had moderate-to-severe pruritus or fatigue at baseline for formal analysis.
• Disease stage: most participants did not have cirrhosis or advanced fibrosis.
• Generalizability: 83.7% of patients were White and 16.3% were Asian, with no patients of other races.
• Risk scores: UK-PBC and GLOBE scores improved with elafibranor, but the authors cautioned that these projection models were developed for use after first-line UDCA.

The trial was funded by Ipsen. Under its accelerated approval, elafibranor has not demonstrated improved survival or prevention of liver decompensation.⁴ The ongoing placebo-controlled phase 3 ELFIDENCE trial (NCT06016842) is evaluating its effect on long-term clinical outcomes.¹

References

1. Kowdley KV, Lawitz E, Bowlus CL, et al. 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. Hepatology. Published online ahead of print. doi:10.1097/HEP.0000000000001906
2. American Association for the Study of Liver Diseases. Phase III ELSPIRE trial results published in HEPATOLOGY demonstrates elafibranor achieves ALP normalization in more than 85% of patients with primary biliary cholangitis. Published November 5, 2026. Accessed November 5, 2026. https://www.aasld.org/phase-iii-elspire-trial-results-published-hepatology-demonstrates-elafibranor-achieves-alp
3. Lu M, Li J, Haller IV, et al. Factors associated with prevalence and treatment of primary biliary cholangitis in United States health systems. Clin Gastroenterol Hepatol. 2018;16(8):1333-1341. doi:10.1016/j.cgh.2017.10.018
4. Ipsen. Ipsen’s Iqirvo receives U.S. FDA accelerated approval as a first-in-class PPAR treatment for primary biliary cholangitis. Published June 10, 2024. Accessed November 5, 2026. https://www.ipsen.com/?p=59199
5. 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
6. Brooks A. IDEAL: seladelpar achieves ALP normalization in second-line PBC. HCPLive. Published November 5, 2026. Accessed November 5, 2026. https://www.hcplive.com/view/ideal-seladelpar-achieves-alp-normalization-in-second-line-pbc