Phase 1 Trial of Adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) Study Group
Received 21 April 2009; accepted 17 August 2009. published online 23 November 2009.
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 α antagonists, are a promising strategy to slow or halt the decline in renal function, based on preclinical and clinical data.
Study Design
Phase 1 clinical trial to assess the pharmacokinetics, tolerability, and safety of adalimumab, a human monoclonal antibody to tumor necrosis factor α.
Setting & Participants
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 m2 were studied.
Intervention
Adalimumab, 24 mg/m2, every 14 days for 16 weeks (total, 9 doses).
Outcomes
Pharmacokinetic assessment, tolerability, and safety.
Measurements
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 ≥ 50% in 4 of 10 treated patients.
Limitations
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.
1UNC Kidney Center and Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC
2School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC
3Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC
4Division of Nephrology, Schneider Children's Hospital of North Shore-LIJ Health System, New Hyde Park, NY
5Departments of Pediatrics and Medicine, Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI
6Division of Nephrology, Seattle Children's Hospital, Seattle, WA
7Department of Pathology, Vanderbilt University Medical Center, Nashville, TN
8Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Kidney Diseases Branch, National Institutes of Health, Bethesda, MD
9Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
Address correspondence to Howard Trachtman, MD, Schneider Children's Hospital, Division of Nephrology, 269-01 76th Ave, New Hyde Park, NY 11040
ABSTRACT