Phase 1 trial of adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) study group.
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.
Joy
Melanie S
MS
UNC Kidney Center and Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Gipson
Debbie S
DS
Powell
Leslie
L
MacHardy
Jacqueline
J
Jennette
J Charles
JC
Vento
Suzanne
S
Pan
Cynthia
C
Savin
Virginia
V
Eddy
Allison
A
Fogo
Agnes B
AB
Kopp
Jeffrey B
JB
Cattran
Daniel
D
Trachtman
Howard
H
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
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab