Alkaline phosphatase changes with seladelpar across subgroups of primary biliary cholangitis patients in the response trial

Introduction: Alkaline phosphatase (ALP) is an important marker in primary biliary cholangitis (PBC) associated with risk for disease progression. In the pivotal, Phase 3, placebo-controlled RESPONSE trial (NCT04620733), seladelpar, a first-in-class delpar (selective PPAR-delta agonist), led to a significantly higher percentage of PBC patients (pts) achieving the composite biochemical endpoint (ALP<1.67x upper limit of normal [ULN], ALP decrease≥15%, and total bilirubin [TB]≤ULN) compared to placebo (61.7% vs 20%) and decreased mean ALP levels after one year (-42.4% vs -4.3%, respectively).

Objectives: Here, we report additional data on ALP changes in the RESPONSE trial.

Methodology: PBC pts who received ursodeoxycholic acid (UDCA) for≥12 months or were UDCA intolerant and had ALP≥1.67x ULN and TB≤2x ULN were randomized 2:1 to daily seladelpar 10 mg or placebo. We assessed ALP changes across demographic subgroups, baseline ALP quartiles, and in pts who did not meet the composite biochemical endpoint. Worsening of ALP (increase>0 U/L from baseline) and safety by baseline ALP subgroup were also evaluated.

Results: 128 pts were randomized to seladelpar and 65 to placebo with mean baseline ALP 314.6 U/L and 313.8 U/L, respectively; 53 (27.5%) pts had baseline ALP≥350 U/L. Seladelpar reduced ALP at month 12 similarly across all subgroups, including in pts with cirrhosis, aged<50 years at PBC diagnosis, and of Hispanic/Latino ethnicity, vs placebo. For pts with baseline ALP≥350 U/L, seladelpar led to a greater decrease (-44.8%; -216.1 U/L) in ALP vs placebo (-11.6%; -56.4 U/L); similar percent decreases were seen in pts with baseline ALP<350 U/L. Seladelpar reduced ALP similarly across baseline ALP quartiles. Among pts who did not meet the composite biochemical endpoint at month 12, ALP was decreased by -129.9 U/L for seladelpar vs -6.4 U/L for placebo. Seladelpar prevented worsening of ALP, with 7 (5.5%) seladelpar pts vs 19 (29.2%) placebo with increases in ALP from baseline at month 12. Adverse events were reported in 86.4% of pts with baseline ALP<350 U/L and 84.9% of pts with ALP≥350 U/L, with similar proportions in seladelpar vs placebo pts ([Fig. 1]).

Fig. 1  

Conclusion: Seladelpar led to robust and consistent ALP decreases across all subgroups studied. Substantial ALP decreases were also observed in pts who did not meet the composite endpoint criteria at month 12. Seladelpar was overall safe and well tolerated, regardless of baseline ALP level.

 

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Publication History

Article published online:
04 September 2025