Ustekinumab for Patients With Primary Biliary Cholangitis Who Have an Inadequate Response to Ursodeoxycholic Acid: A Proof-of-Concept Study

The interleukin(IL)-12 signaling cascade has been associated with primary biliary cholangitis(PBC). This multicenter, open-label, proof-of-concept study evaluated the anti-IL12/23 monoclonal antibody, ustekinumab(90 mg subcutaneous at weeks 0 and 4, then every 8 weeks through week 20), in adults with PBC and an inadequate response to ursodeoxycholic acid therapy (i.e., alkaline phosphatase [ALP] >1.67x upper limit of normal [ULN] after >= 6 months). ALP response was defined as a >40% decrease from baseline and ALP remission as ALP normalization(if baseline ALP 1.673-2.8x ULN) or <1.67x ULN(if baseline ALP >2.8x ULN). Changes in Enhanced Liver Fibrosis(ELF) scores and serum bile acids were also assessed. At baseline, patients had median disease duration of 3.2 years, median ELF score of 9.8, and highly elevated total bile acid concentration(median, 43.3 mu mol/L); 13 of 20(65%) patients had baseline ALP >3x ULN. Although steady-state serum ustekinumab concentrations were reached by week 12, no patient achieved ALP response or remission. Median percent ALP reduction from baseline to week 28 was 12.1%. ELF score decreased slightly from baseline to week 28 (median reduction: 0.173), and total serum bile acid concentrations decreased from baseline to week 28(median reduction: 8.8 mu mol/L). No serious infections or discontinuations resulting from adverse events were reported through week 28. One patient had a serious upper gastrointestinal hemorrhage considered unrelated to test agent by the investigator. Conclusion: Open-label ustekinumab therapy, though associated with a modest decrease in ALP after 28 weeks of therapy, did not otherwise appreciably change ALP and overt proof-of-concept was not established as per prespecified primary endpoint of proposed efficacy. No new ustekinumab safety signals were observed.