Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria.

Abstract

BACKGROUND AND OBJECTIVES:

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.

DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Sharon G Adler, Sherwyn Schwartz, Mark E Williams, Carlos Arauz-Pacheco, Warren K Bolton, Tyson Lee, Dongxia Li, Thomas B Neff, Pedro R Urquilla, K Lea Sewell
• Journal: Clinical journal of the American Society of Nephrology : CJASN (Clin J Am Soc Nephrol) Vol. 5 Issue 8 Pg. 1420-8 (Aug 2010) ISSN: 1555-905X [Electronic] United States
• PMID: 20522536 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• CCN2 protein, human
• Hypoglycemic Agents
• Connective Tissue Growth Factor
• pamrevlumab

Topics

• Adult
• Aged
• Albuminuria (drug therapy)
• Antibodies, Monoclonal (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Connective Tissue Growth Factor (antagonists & inhibitors, blood, urine)
• Diabetes Mellitus, Type 1 (complications, drug therapy, metabolism)
• Diabetes Mellitus, Type 2 (complications, drug therapy, metabolism)
• Diabetic Nephropathies (drug therapy, etiology, metabolism, physiopathology)
• Drug Administration Schedule
• Female
• Glomerular Filtration Rate (drug effects)
• Humans
• Hypoglycemic Agents (therapeutic use)
• Infusions, Intravenous
• Kidney Tubules (drug effects, metabolism, physiopathology)
• Male
• Middle Aged
• Treatment Outcome