title: Phase I, randomized, double-blind, placebo-controlled, multiple intravenous, dose-ascending study of sirukumab in cutaneous or systemic lupus erythematosus.
abstract: OBJECTIVE
  We undertook a 2-part, phase I, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetics of multiple intravenous infusions of sirukumab, a human anti-interleukin-6 monoclonal antibody, in patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE).
  
  
  METHODS
  In part A, patients with histologically confirmed CLE were randomized to 4 infusions of placebo or 1, 4, or 10 mg/kg sirukumab every 2 weeks. In part B, SLE patients diagnosed according to American College of Rheumatology criteria with a score of 5-12 on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index were randomized to 4 infusions of placebo or 10 mg/kg sirukumab every 2 weeks.
  
  
  RESULTS
  We treated 31 CLE patients (23 with sirukumab, 8 with placebo) and 15 SLE patients (10 with sirukumab, 5 with placebo). Adverse events (AEs) occurred more often with sirukumab than placebo in CLE patients (91% versus 63%) and in SLE patients (90% versus 80%). Sirukumab led to sustained, dose-independent decreases in white blood cell counts, absolute neutrophil counts (neutropenia), and platelet counts (thrombocytopenia) and to minor elevations in total cholesterol levels. The majority of infections were mild respiratory infections. which were reported similarly across CLE cohorts but more often in sirukumab-treated than in placebo-treated SLE patients. Two serious AEs of infection occurred (pneumonia in the 10 mg/kg-treated group and iatrogenic wound infection in the 4 mg/kg-treated group). Sirukumab showed linear pharmacokinetics in CLE patients. Systemic exposure and half-life were comparable between CLE and SLE patients. No patient developed antibodies to sirukumab through 22 weeks. C-reactive protein and serum amyloid A mean concentrations were suppressed with sirukumab from week 1 to week 14.
  
  
  CONCLUSIONS
  Treatment with intravenous sirukumab infusions was generally well tolerated in both CLE and SLE patients with mild, stable, active disease. Sirukumab demonstrated linear pharmacokinetics over the dose range studied and comparable systemic exposure and half-life in CLE and SLE patients.
authors.affiliation: Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Jacek C
authors.initials: JC
authors.lastname: Szepietowski
authors.forename: Surasak
authors.initials: S
authors.lastname: Nilganuwong
authors.forename: Anna
authors.initials: A
authors.lastname: Wozniacka
authors.forename: Annegret
authors.initials: A
authors.lastname: Kuhn
authors.forename: Filippa
authors.initials: F
authors.lastname: Nyberg
authors.forename: Ronald F
authors.initials: RF
authors.lastname: van Vollenhoven
authors.forename: Anders A
authors.initials: AA
authors.lastname: Bengtsson
authors.forename: Adam
authors.initials: A
authors.lastname: Reich
authors.forename: Dick E
authors.initials: DE
authors.lastname: de Vries
authors.forename: Bart
authors.initials: B
authors.lastname: van Hartingsveldt
authors.forename: Donald W
authors.initials: DW
authors.lastname: Robinson
authors.forename: Robert
authors.initials: R
authors.lastname: Gordon
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hsu
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D002097:C-Reactive Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015850:Interleukin-6 / Q000276:immunology; D007391:International Cooperation; D008178:Lupus Erythematosus, Cutaneous / Q000097:blood / Q000188:drug therapy*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D000685:Serum Amyloid A Protein / Q000378:metabolism; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015850:Interleukin-6; D000685:Serum Amyloid A Protein; C568922:sirukumab; D002097:C-Reactive Protein