title: A phase I trial of an interleukin-12/23 monoclonal antibody in relapsing multiple sclerosis.
abstract: OBJECTIVE
  To assess the safety, tolerability and pharmacokinetics of an interleukin (IL)-12/23 monoclonal antibody (mAb) in subjects with a relapsing form of multiple sclerosis (MS).
  
  
  METHODS
  A phase I, double-blind, placebo-controlled, sequential dose escalation study was conducted in 20 subjects with MS. Subjects were randomized (4:1) to receive a single subcutaneous injection of either IL-12/23 mAb (0.3, 0.75, 1.5, and 3.0 mg/kg) or placebo. Clinical and laboratory evaluations were performed through 16 weeks following administration.
  
  
  RESULTS
  IL-12/23 mAb was well tolerated in this study. Adverse events were generally mild or moderate, with no apparent dose-related trends. One subject with a family history of breast cancer was diagnosed during the study with breast cancer 21 days after IL-12/23 mAb administration. There were no significant changes in laboratory indicators of systemic or neurotoxicity. There was a large degree of variability in T2 lesion volume and total number of gadolinium-positive lesions, both unaffected by dose escalation. Three relapses of MS occurred in two placebo-treated subjects. Over the range of single doses studied, the median Tmax ranged from 9.0 to 16.5 days, and the median T1/2 ranged from 20.2 to 30.9 days.
  
  
  CONCLUSIONS
  Single subcutaneous administrations of IL-12/23 mAb in this first study of relapsing MS were generally well tolerated. Safety of the agent will need to be tested in a study of longer duration and involving a larger cohort of subjects.
authors.affiliation: Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA. lloyd.h.kasper@dartmouth.edu
authors.forename: Lloyd H
authors.initials: LH
authors.lastname: Kasper
authors.forename: Daniel
authors.initials: D
authors.lastname: Everitt
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Leist
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Ryan
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Mascelli
authors.forename: Kenneth
authors.initials: K
authors.lastname: Johnson
authors.forename: Aparna
authors.initials: A
authors.lastname: Raychaudhuri
authors.forename: Tim
authors.initials: T
authors.lastname: Vollmer
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects* / Q000276:immunology / Q000493:pharmacokinetics; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000276:immunology / Q000628:therapy*; D010919:Placebos
chemical_list: D000911:Antibodies, Monoclonal; D053762:Interleukin-12 Subunit p40; D010919:Placebos