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


METHODS
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.
Division of Nephrology and Hypertension, Los Angeles BioMedical Research Institute, Torrance, California 90502, USA. sadler@labiomed.org
Sharon G
SG
Adler
Sherwyn
S
Schwartz
Mark E
ME
Williams
Carlos
C
Arauz-Pacheco
Warren K
WK
Bolton
Tyson
T
Lee
Dongxia
D
Li
Thomas B
TB
Neff
Pedro R
PR
Urquilla
K Lea
KL
Sewell
D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000188:drug therapy*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors* / Q000097:blood / Q000652:urine; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D004334:Drug Administration Schedule; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007262:Infusions, Intravenous; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C526317:CCN2 protein, human; D007004:Hypoglycemic Agents; D055513:Connective Tissue Growth Factor; C560078:pamrevlumab