American Journal of Kidney Diseases
Volume 55, Issue 1 , Pages 50-60, January 2010

Phase 1 Trial of Adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) Study Group

  • Melanie S. Joy, PharmD

      Affiliations

    • UNC Kidney Center and Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC
    • School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC
    • ,
  • Debbie S. Gipson, MD, MSPH

      Affiliations

    • UNC Kidney Center and Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC
    • ,
  • Leslie Powell, RN, CPNP

      Affiliations

    • UNC Kidney Center and Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC
    • ,
  • Jacqueline MacHardy, BS

      Affiliations

    • UNC Kidney Center and Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC
    • ,
  • J. Charles Jennette, MD

      Affiliations

    • Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC
    • ,
  • Suzanne Vento, RN

      Affiliations

    • Division of Nephrology, Schneider Children's Hospital of North Shore-LIJ Health System, New Hyde Park, NY
    • ,
  • Cynthia Pan, MD

      Affiliations

    • Departments of Pediatrics and Medicine, Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI
    • ,
  • Virginia Savin, MD

      Affiliations

    • Departments of Pediatrics and Medicine, Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI
    • ,
  • Allison Eddy, MD

      Affiliations

    • Division of Nephrology, Seattle Children's Hospital, Seattle, WA
    • ,
  • Agnes B. Fogo, MD

      Affiliations

    • Department of Pathology, Vanderbilt University Medical Center, Nashville, TN
    • ,
  • Jeffrey B. Kopp, MD

      Affiliations

    • Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Kidney Diseases Branch, National Institutes of Health, Bethesda, MD
    • ,
  • Daniel Cattran, MD, FRCPC

      Affiliations

    • Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
    • ,
  • Howard Trachtman, MD

      Affiliations

    • Division of Nephrology, Schneider Children's Hospital of North Shore-LIJ Health System, New Hyde Park, NY
    • Corresponding Author InformationAddress correspondence to Howard Trachtman, MD, Schneider Children's Hospital, Division of Nephrology, 269-01 76th Ave, New Hyde Park, NY 11040

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.

Index Words: Focal segmental glomerulosclerosis (FSGS), pharmacokinetics, nephrotic syndrome, adalimumab, tumor necrosis factor α, antifibrotic

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 Originally published online as doi:10.1053/j.ajkd.2009.08.019 on November 23, 2009.

 Trial registration: www.ClinicalTrials.gov; study number: NCT00814255.

PII: S0272-6386(09)01188-3

doi:10.1053/j.ajkd.2009.08.019

American Journal of Kidney Diseases
Volume 55, Issue 1 , Pages 50-60, January 2010

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