A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis
In RCT (n=193), percentage of patients who had a biochemical response (61.7% vs. 20.0%; p<0.001) and alkaline phosphatase normalization (25.0% vs. 0%; p<0.001) was significantly greater with this peroxisome proliferator–activated receptor delta agonist vs placebo.
Source:
New England Journal of Medicine
SPS commentary:
Seladelpar also resulted in a greater reduction in score on pruritus numerical rating scale than placebo (least-squares mean change from baseline, −3.2 vs. −1.7; p=0.005).
Previously reported in the journal were the findings of another RCT of a selective PPAR agonist in patients who had an inadequate response to or unacceptable side effects with ursodeoxycholic acid. The ELATIVE trial (n=161) found elafibranor linked to higher achievement of biochemical response (ALP <1.67 times upper limit of normal & ≥15% decrease from baseline, & normal bilirubin) than placebo at week 52 (51% v 4%, respectively; p<0.001).
An editorial discusses the implications of these trials, noting that they cement the role of PPAR agonists as the preferred second-line treatment in primary biliary cholangitis. It adds that the reduction in serum cholestatic markers and the safety profiles of elafibranor and seladelpar offer clear advantages beyond what was previously shown with obeticholic acid. It also suggests that the trials also cement a new treatment goal for primary biliary cholangitis in which a reduction in pruritus should be expected as part of anticholestatic treatment. It concludes that the results of these trials suggest that use of PPAR agonists in primary biliary cholangitis could improve treatment outcomes while also improving quality of life, however , challenges remain, and more work needs to be done for the sizeable minority of patients who have an incomplete response to PPAR agonists. It points out that ongoing studies are testing combination therapy with ursodeoxycholic acid, obeticholic acid, and PPAR agonists to address these difficult-to-treat cases.
Another editorial on the science behind the study notes that although ursodeoxycholic acid will remain the first-line therapy, choices of medication for patients who do not have a response are increasing, patients with primary biliary cholangitis and a high risk of disease progression might benefit from early combination therapy.