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 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. 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. Phase 1 clinical trial to assess the pharmacokinetics, tolerability, and safety of adalimumab, a human monoclonal antibody to tumor necrosis factor α. 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. Adalimumab, 24 mg/m2, every 14 days for 16 weeks (total, 9 doses). Pharmacokinetic assessment, tolerability, and safety. Estimated glomerular filtration rate, proteinuria, and pharmacokinetic assessment after initial dosing and steady state. 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. Insufficient power to assess the safety or efficacy of adalimumab therapy for patients with resistant FSGS. 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.