Phase 1 Study of Anti-CTGF Monoclonal Antibody in Patients with Diabetes and Microalbuminuria

• Published in: Clinical journal of the American Society of Nephrology Vol. 5; no. 8; pp. 1420 - 1428
• Main Authors: Adler, Sharon G., Schwartz, Sherwyn, Williams, Mark E., Arauz-Pacheco, Carlos, Bolton, Warren K., Lee, Tyson, Li, Dongxia, Neff, Thomas B., Urquilla, Pedro R., Sewell, K. Lea
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01.08.2010
• Series: Original Articles
• Subjects: Adult; Aged; Albuminuria - drug therapy; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - therapeutic use; Connective Tissue Growth Factor - antagonists & inhibitors; Connective Tissue Growth Factor - blood; Connective Tissue Growth Factor - urine; Diabetes Mellitus, Type 1 - complications; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - etiology; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - physiopathology; Drug Administration Schedule; Female; Glomerular Filtration Rate - drug effects; Humans; Hypoglycemic Agents - therapeutic use; Infusions, Intravenous; Kidney Tubules - drug effects; Kidney Tubules - metabolism; Kidney Tubules - physiopathology; Male; Middle Aged; Original; Treatment Outcome
• ISSN: 1555-9041; 1555-905X
• DOI: 10.2215/CJN.09321209

This report summarizes the first phase 1 trial treating patients with microalbuminuric diabetic kidney disease (DKD) using FG-3019, a human monoclonal antibody to connective tissue growth factor (CTGF). CTGF is critically involved in processes of progressive fibrosis, including DKD. This phase 1, open-label, dose-escalation trial evaluated safety, pharmacokinetics, and possible therapeutic effects of FG-3019 on albuminuria, proteinuria, and tubular proteins. Microalbuminuric subjects (n = 24) with type 2 (79%) or type 1 (21%) diabetes received 3 or 10 mg/kg FG-3019 dosed intravenously every 14 days for four doses. Albuminuria and safety follow-up were to days 62 and 365, respectively. No infusion was interrupted for symptoms, although 5 of 24 subjects had mild infusion-day adverse events thought to be possibly drug-related. No subject developed anti-FG-3019 antibodies. FG-3019 clearance was lower at 10 mg/kg than at 3 mg/kg, suggesting a saturable elimination pathway. Although this study was not designed for efficacy testing, it was notable that urinary albumin/creatinine ratio (ACR) decreased significantly from mean pretreatment ACR of 48 mg/g to mean post-treatment (day 56) ACR of 20 mg/g (P = 0.027) without evidence for a dose-response relationship. Treatment of microalbuminuric DKD subjects using FG-3019 was well tolerated and associated with a decrease in albuminuria. The data demonstrate a saturable pathway for drug elimination, minimal infusion adverse events, and no significant drug-attributable adverse effects over the year of follow-up. Changes in albuminuria were promising but require validation in a prospective, randomized, blinded study.