title: Phase 1 trial of adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) study group.
abstract: BACKGROUND
  Patients with primary focal segmental glomerulosclerosis (FSGS) resistant to current treatment regimens are at high risk of progression to end-stage kidney disease. Antifibrotic agents, such as tumor necrosis factor alpha antagonists, are a promising strategy to slow or halt the decline in renal function, based on preclinical and clinical data.
  
  
  METHODS
  Phase 1 clinical trial to assess the pharmacokinetics, tolerability, and safety of adalimumab, a human monoclonal antibody to tumor necrosis factor alpha.
  
  
  METHODS
  10 patients (4 male and 6 female) aged 16.8 +/- 9.0 years with an estimated glomerular filtration rate of 105 +/- 50 mL/min/1.73 m(2) were studied.
  
  
  METHODS
  Adalimumab, 24 mg/m(2), every 14 days for 16 weeks (total, 9 doses).
  
  
  RESULTS
  Pharmacokinetic assessment, tolerability, and safety.
  
  
  METHODS
  Estimated glomerular filtration rate, proteinuria, and pharmacokinetic assessment after initial dosing and steady state.
  
  
  RESULTS
  Pharmacokinetic evaluation indicated that the area under the curve was decreased by 54% (P < 0.001) and clearance was increased by 160% (P < 0.01) in patients with resistant FSGS compared with healthy controls and patients with rheumatoid arthritis. Adalimumab was well tolerated with no serious adverse events or infectious complications attributable to the drug. Proteinuria decreased by > or = 50% in 4 of 10 treated patients.
  
  
  CONCLUSIONS
  Insufficient power to assess the safety or efficacy of adalimumab therapy for patients with resistant FSGS.
  
  
  CONCLUSIONS
  Pharmacokinetic assessment showed increased clearance of adalimumab in patients with resistant primary FSGS and validated the need to evaluate the disposition of novel therapies for this disease to define appropriate dosing regimens. The study provides a rationale to evaluate the efficacy of adalimumab as an antifibrotic agent for resistant FSGS in phase 2/3 clinical trials.
authors.affiliation: UNC Kidney Center and Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Joy
authors.forename: Debbie S
authors.initials: DS
authors.lastname: Gipson
authors.forename: Leslie
authors.initials: L
authors.lastname: Powell
authors.forename: Jacqueline
authors.initials: J
authors.lastname: MacHardy
authors.forename: J Charles
authors.initials: JC
authors.lastname: Jennette
authors.forename: Suzanne
authors.initials: S
authors.lastname: Vento
authors.forename: Cynthia
authors.initials: C
authors.lastname: Pan
authors.forename: Virginia
authors.initials: V
authors.lastname: Savin
authors.forename: Allison
authors.initials: A
authors.lastname: Eddy
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.forename: Daniel
authors.initials: D
authors.lastname: Cattran
authors.forename: Howard
authors.initials: H
authors.lastname: Trachtman
mesh_terms: D000068879:Adalimumab; D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005923:Glomerulosclerosis, Focal Segmental / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008297:Male; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab