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.

Study design: Phase 1 clinical trial to assess the pharmacokinetics, tolerability, and safety of adalimumab, a human monoclonal antibody to tumor necrosis factor alpha.

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 m(2) were studied.

Intervention: Adalimumab, 24 mg/m(2), 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 > or = 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.

Trial registration: ClinicalTrials.gov NCT00814255.

Figure 1

CONSORT diagram summarizing patient screening and enrollment in the FONT Phase I trial

Figure 2

Adalimumab concentration versus time curves after Single Dose. Note that the drug concentrations are provided as ng/mL to enhance the clarity of the graphs.

Figures 3a and 3b

3a: Linear regression model of ranked T_½ versus UP:C (urine protein-creatinine ratio) at steady state. Data were ranked so that they would follow a normal distribution. The model resulted in r = −0.8990 (95% Confidence Interval −0.9761 to −0.6207), r² −0.6207, p<0.001. 3b: Linear regression model of ranked T_½ versus ranked serum albumin at steady state. Data were ranked so that they would follow a normal distribution. The model resulted in r = 0.7586 (95% Confidence Interval 0.2467 to 0.9395), r² 0.5755, p=0.01

Figures 3a and 3b

3a: Linear regression model of ranked T_½ versus UP:C (urine protein-creatinine ratio) at steady state. Data were ranked so that they would follow a normal distribution. The model resulted in r = −0.8990 (95% Confidence Interval −0.9761 to −0.6207), r² −0.6207, p<0.001. 3b: Linear regression model of ranked T_½ versus ranked serum albumin at steady state. Data were ranked so that they would follow a normal distribution. The model resulted in r = 0.7586 (95% Confidence Interval 0.2467 to 0.9395), r² 0.5755, p=0.01

Figures 4a and 4b

4a: Linear regression model of Cl/F_ss versus UPCR (urine protein-creatinine ratio). The model resulted in r = 0.8465 (95% Confidence Interval −0.1615 to −0.0693), r² 0.7165, p=0.02. 4b: Linear regression model of lnAUC_ss versus UP:C (urine protein-creatinine ratio). The model resulted in r = 0.9446 (95% Confidence Interval 1.3 to 8.095), r² 0.8923, p=0.001

Figures 4a and 4b

4a: Linear regression model of Cl/F_ss versus UPCR (urine protein-creatinine ratio). The model resulted in r = 0.8465 (95% Confidence Interval −0.1615 to −0.0693), r² 0.7165, p=0.02. 4b: Linear regression model of lnAUC_ss versus UP:C (urine protein-creatinine ratio). The model resulted in r = 0.9446 (95% Confidence Interval 1.3 to 8.095), r² 0.8923, p=0.001