Seladelpar for alkaline phosphatase normalization in primary biliary cholangitis: The IDEAL phase III randomized controlled trial
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Cynthia Levy1, Susheela Carroll2, Kris V Kowdley3
1Division of Digestive Health and Liver Diseases, Miller School of Medicine, University of Miami, Miami, FL, USA; Schiff Center for Liver Diseases, Miller School of Medicine, University of Miami, Miami, FL, USA.
Background & Aims:
Alkaline phosphatase (ALP) <1.67× the upper limit of normal (ULN) has historically been a treatment goal in primary biliary cholangitis (PBC). However, elevation in ALP below this threshold has been shown to increase the risk of disease progression, especially in patients with additional risk factors. We evaluated the effect of seladelpar, a selective peroxisome proliferator-activated receptor delta agonist approved for PBC, on ALP normalization when levels are above normal but <1.67× ULN.
Methods:
In this phase III, double-blind trial, patients receiving ursodeoxycholic acid (UDCA) or intolerant to UDCA with ALP between 1-1.67× ULN were randomized 2:1 to receive once-daily seladelpar 10 mg or placebo for 12 months. The primary endpoint was ALP normalization defined as a composite of ALP ≤ULN with at least a 15% decrease from baseline at Month 12. Secondary endpoints included ALP change over time.
Results:
Overall, 96 patients underwent randomization. At Month 12, ALP normalization based on the composite endpoint occurred in a significantly higher proportion of patients receiving seladelpar (75.4%, 49/65) compared with placebo (16.1%, 5/31; stratum-adjusted treatment difference [95% CI]: 61.3% [44.9%, 77.7%], p <0.0001). ALP reduction with seladelpar was observed starting from Month 1 and throughout the treatment period (least squares [LS] mean percent change from baseline at Month 12 was -33.8% for the seladelpar group and -5.4% for the placebo group). Adverse event incidence was similar between seladelpar and placebo groups; serious adverse events occurred in 3.1% and 12.9% of patients, respectively.
Conclusions:
Seladelpar normalized ALP in a substantial proportion of patients with PBC and ALP levels between 1-1.67× ULN despite UDCA use and was generally safe and well tolerated in this population.
Impact And Implications:
Most clinical trials in primary biliary cholangitis (PBC) have enrolled patients with alkaline phosphatase (ALP) ≥1.67× the upper limit of normal (ULN). However, evidence indicates that any ALP elevation reflects disease activity and may increase the risk of serious clinical events, including liver transplantation and death. Interest is growing in normalizing biochemical markers in PBC, particularly for patients with high liver stiffness, advanced disease, younger age at diagnosis, or other high-risk features. This is the first phase III study of second-line treatment in patients with PBC and ALP above normal but <1.67× ULN using seladelpar. Compared with placebo, seladelpar led to ALP normalization (ALP ≤ULN with at least a 15% decrease from baseline) in a significantly higher proportion of patients at Month 12, and was consistently observed across subgroups, including those with features associated with disease progression. No new safety concerns were identified. These findings show that ALP normalization with seladelpar is achievable in patients with PBC and baseline ALP levels between 1-1.67× ULN, which may help guide its clinical use.
Clinical Trial Number:
ClinicalTrials.gov, NCT06060665.
