Phase 3 Data Back ALP Normalization as Treatment Goal in PBC

Most patients with primary biliary cholangitis (PBC) whose alkaline phosphatase (ALP) levels remained above normal but below the traditional threshold for escalating therapy achieved ALP normalization with either elafibranor (Iqirvo; Ipsen) or seladelpar (Livdelzi; Gilead Sciences), according to 2 phase 3 trials presented at The Liver Meeting 2026.^1,2 Two real-world studies at the meeting, hosted by the American Association for the Study of Liver Diseases (AASLD) in Denver, Colorado, compared the drugs and examined who receives second-line therapy.^3,4

Inadequate response to first-line ursodeoxycholic acid (UDCA) has commonly been defined as an ALP of at least 1.67 times the upper limit of normal (ULN), and registrational trials of second-line agents have enrolled patients above that level.^1,2 Because ALP above ULN is associated with active disease and reduced transplant-free survival, ALP normalization is “an increasingly favored treatment target,” the ELSPIRE trial investigators wrote.¹

PBC affects approximately 130,000 people in the US, and the FDA granted accelerated approval to elafibranor—a peroxisome proliferator–activated receptor (PPAR)-α/δ agonist—in June 2024 and to seladelpar—a PPAR-δ agonist—in August 2024 for patients with an inadequate response to UDCA or who cannot tolerate it.^5,6

Both approvals were based on ALP reduction, and improvement in survival or prevention of liver decompensation has not been demonstrated.^5,6 Obeticholic acid (Ocaliva; Intercept) was withdrawn from the US market in 2025 at the FDA’s request,⁷ and the FDA is scheduled to act on saroglitazar, a PPAR-α/γ agonist from Zydus Therapeutics, by November 27, 2026.⁸

ALP Normalization With Elafibranor in ELSPIRE

The phase 3, double-blind ELSPIRE trial (NCT06383403) randomly assigned 92 patients with PBC, ALP between 1 and 1.67 times ULN, and incomplete response or intolerance to UDCA to elafibranor 80 mg daily or placebo in a 2:1 ratio.¹ At week 52, 85.3% of patients receiving elafibranor had normal ALP vs 23.3% receiving placebo (difference, 62.0%; 95% CI, 44.3%-79.7%; P < .001). Using the composite definition of normal ALP plus at least a 15% decrease, rates were 84.5% vs 20.0%, respectively (difference, 64.5%; 95% CI, 47.4%-81.7%).

ALP fell 36.5% from baseline with elafibranor vs 4.2% with placebo, and 64.3% vs 16.7% achieved a complete biochemical response, defined as normal total bilirubin, ALP, aspartate aminotransferase, alanine aminotransferase, albumin, and international normalized ratio. Treatment-emergent adverse events (AEs) occurred in 79.0% vs 70.0% of patients and were mostly mild or moderate. Serious AEs occurred in 3 patients (4.8%) receiving elafibranor, none treatment-related, and 4 (13.3%) receiving placebo, with no drug-induced liver injury.

“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, said in an AASLD news release announcing the results’ publication in Hepatology.^9,10 “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.”

Seladelpar Results From the IDEAL Trial

The phase 3, double-blind IDEAL trial (NCT06060665) randomly assigned 96 patients with PBC and ALP between 1 and 1.67 times ULN who were receiving or intolerant to UDCA to seladelpar 10 mg once daily or placebo in a 2:1 ratio for 12 months.² The primary end point, a composite of ALP at or below ULN plus a decrease of at least 15% from baseline, was met by 75.4% of patients receiving seladelpar vs 16.1% receiving placebo (stratum-adjusted difference, 61.3%; P < .001). ALP decreased 33.8% from baseline with seladelpar vs 5.4% with placebo.

AE incidence was generally similar between groups, and serious AEs occurred in 3.1% and 12.9% of patients, respectively, none deemed related to the study drug.

“These results help inform treatment decisions for an understudied population and demonstrate biochemical normalization as a feasible goal,” the IDEAL investigators concluded.

Real-World Comparison and Disparities in Treatment Escalation

A Cleveland Clinic analysis of data from 111 TriNetX health care organizations matched 238 patients receiving elafibranor with 238 receiving seladelpar.³ The primary outcome, latest ALP within 1 year, did not differ significantly (median, 135 vs 142 U/L; P = .324), although only 57.1% and 65.1% of patients, respectively, had a follow-up value.

Recorded major adverse liver outcomes—a composite of decompensation events, cirrhosis, hepatocellular carcinoma, and death—occurred in 12.6% of patients receiving elafibranor vs 15.5% receiving seladelpar (HR, 0.82; 95% CI, 0.51-1.33). All-cause hospitalization (5.5% vs 5.0%) and cardiovascular events (6.3% vs 8.0%) were also similar. The investigators said the data establish neither superiority nor equivalence and that larger studies with complete follow-up are needed.

ELSPIRE and IDEAL each enrolled fewer than 100 patients, followed them for 1 year, and measured biochemical end points rather than clinical outcomes. The trials also used different primary end points. The real-world comparison relied on diagnosis codes and had incomplete ALP follow-up.

At Mount Sinai in New York, investigators reviewed 262 patients seen from 2010 to 2025 who were eligible for second-line therapy, defined as ALP above 200 IU/L after at least 12 months of UDCA.⁴ Of these, 76 (29%) received second-line therapy, most often obeticholic acid (37 patients) or seladelpar (33); 9 received elafibranor. No Black patients (0 of 19) and 1 of 22 uninsured patients (4.5%) received second-line therapy. Overall, 32% of eligible patients had no documented discussion or offer of escalation, including 57.9% of Black patients and 45.5% of uninsured patients.

In adjusted models, Black race and uninsured status were the only independent predictors of lower odds of escalation, and both associations held after the investigators added bilirubin, albumin, and platelet count. Laboratory markers and fibrosis stage were not associated with escalation, which the investigators said suggests that social determinants of health may influence escalation beyond measured disease burden.

The escalation study was a single-center retrospective review that spanned years before elafibranor and seladelpar were available.

References

1. Kowdley KV, Lawitz E, Bowlus CL, 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. Poster presented at: The Liver Meeting 2026; November 5-9, 2026; Denver, CO. Abstract 5019.

2. Levy C, Carroll S, Kowdley K, et al. Seladelpar for alkaline phosphatase normalization in primary biliary cholangitis: results from the IDEAL phase III randomized-controlled trial. Presented at: The Liver Meeting 2026; November 5-9, 2026; Denver, CO. Abstract 5007.

3. Alabbas M, Eren B, Sims O, Chiang D. Elafibranor versus seladelpar in UDCA-treated primary biliary cholangitis: a 111-health-system propensity-matched comparative effectiveness study. Presented at: The Liver Meeting 2026; November 5-9, 2026; Denver, CO. Abstract 0030.

4. Vittini-Hernandez L, Aliasi-Sinai L, Kim C, et al. Social determinants of health, rather than disease severity, drive second-line therapy escalation in primary biliary cholangitis. Presented at: The Liver Meeting 2026; November 5-9, 2026; Denver, CO. Abstract 0119.

5. Gilead’s Livdelzi (seladelpar) granted accelerated approval for primary biliary cholangitis by US FDA. News release. Gilead Sciences. August 14, 2024. Accessed November 5, 2026. https://www.gilead.com/news-and-press/press-room/press-releases/2024/8/gileads-livdelzi-seladelpar-granted-accelerated-approval-for-primary-biliary-cholangitis-by-us-fda

6. Ipsen’s Iqirvo receives US FDA accelerated approval as a first-in-class PPAR treatment for primary biliary cholangitis. News release. Ipsen. June 10, 2024. Accessed November 5, 2026. https://www.ipsen.com/ipsen-pr_iqirvo-fda-approval_10062024-2

7. Intercept announces voluntary withdrawal of Ocaliva for primary biliary cholangitis (PBC) from the US market; US clinical trials involving obeticholic acid placed on clinical hold. News release. Intercept Pharmaceuticals. September 11, 2025. Accessed November 9, 2026. https://www.interceptpharma.com/about-us/news/?id=3148535

8. Zydus Therapeutics’ new drug application (NDA) for saroglitazar to treat primary biliary cholangitis (PBC) granted priority review by the US FDA. News release. Zydus Lifesciences. May 28, 2026. Accessed November 9, 2026. https://nsearchives.nseindia.com/corporate/Cadilahc_28052026180045_PressRelease28052026.pdf

9. Phase III ELSPIRE trial results published in Hepatology demonstrates elafibranor achieves ALP normalization in more than 85% of patients with primary biliary cholangitis. News release. American Association for the Study of Liver Diseases. November 5, 2026. Accessed November 9, 2026. https://www.aasld.org/phase-iii-elspire-trial-results-published-hepatology-demonstrates-elafibranor-achieves-alp

10. 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 November 5, 2026. doi:10.1097/HEP.0000000000001906