title: Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: A proof-of-concept study.
abstract: 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] >1.67× 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 1.67×-2.8× ULN) or <1.67× ULN (if baseline ALP >2.8× 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 μmol/L); 13 of 20 (65%) patients had baseline ALP >3× 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 μmol/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.
  
  
  
  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. (Hepatology 2016;64:189-199).
authors.affiliation: National Institute of Health Research (NIHR) Biomedical Research Unit (BRU) and Center for Liver Research, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.affiliation: Division of Rheumatology, Allergy & Immunology, The University of California School of Medicine, Davis, CA.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA.
authors.forename: Richard
authors.initials: R
authors.lastname: Strauss
authors.affiliation: University of Texas Southwestern, Dallas, TX.
authors.forename: Marlyn J
authors.initials: MJ
authors.lastname: Mayo
authors.affiliation: University of Miami, Miami, FL.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Levy
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zou
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA.
authors.forename: Jewel
authors.initials: J
authors.lastname: Johanns
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA.
authors.forename: Ivo P
authors.initials: IP
authors.lastname: Nnane
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA.
authors.forename: Bidisha
authors.initials: B
authors.lastname: Dasgupta
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Li
authors.affiliation: Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, Milan, Italy.|BIOMETRA Department, University of Milan, Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Selmi
authors.affiliation: Sahlgrenska Academy, Institute of Medicine, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.affiliation: Institute of Cellular Medicine, University of Newcastle, Newcastle Upon Tyne, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Jones
authors.affiliation: Arizona State University, Phoenix, AZ.
authors.forename: Keith
authors.initials: K
authors.lastname: Lindor
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002761:Cholangitis / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid; D000069549:Ustekinumab / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; D014580:Ursodeoxycholic Acid; D000069549:Ustekinumab