Review of Current and Upcoming Second-Line Treatments for Primary Biliary Cholangitis.

Background: Treatment for primary biliary cholangitis (PBC) was defined by its singular relationship with ursodeoxycholic acid (UDCA) for decades. However, nearly 40% of patients fail to achieve adequate biochemical response with UDCA, necessitating second-line therapies.

Aims: The aim of our review was to assess the efficacy and safety of second-line therapies for PBC from phase three trials.

Methods: We conducted a systematic review of PubMed, Medline, and ClinicalTrials.gov for published phase three trial data of second-line PBC therapies.

Results: Four phase three clinical trial evaluating obeticholic acid, bezafibrate, seladelpar, and elafibranor, were identified. All trials but one defined the treatment endpoints of an alkaline phosphatase (ALP) less than 1.67 times the upper limit of normal (ULN), a 15% decrease of ALP from baseline, and normal total bilirubin (TB) after 12 months. All therapies demonstrated statistically significant achievement of primary endpoints relative to placebo. Reduction in ALP from baseline ranged from 113 to 133.9 U/L (- 34.6% to - 50%) across all trials. Primary endpoint treatment differences relative to placebo ranged between 31 and 47%. ALP normalization rates were described for three treatments and varied between 15 and 67% in treatment cohorts,compared to 0% to 2% of placebo cohorts. Only elafibranor and seladelpar demonstrated significant reduction in total 5D itch scale scores. Discontinuation rates across studies ranged from 1 to 14% due to adverse effects.

Conclusion: All reviewed therapies met their respective study endpoints. Effective second-line therapies area available and continue to receive long-term evaluation in patients with PBC.