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.

Figure 1.

FG-3019 plasma concentration before and after the first infusion, showing no accumulation for 3 mg/kg (n = 13, first dose; n = 9, fourth dose), but slower clearance for 10 mg/kg (n = 10, first dose; n = 7 to 10, fourth dose) (mean ± SD; safety population). The slower clearance rate and longer T_1/2 with the higher dose suggests a saturable clearance pathway and higher drug exposure (steady-state area under the curve).

Figure 2.

Urine ACR at baseline, at each infusion day, 14 days after the last infusion (day 56, designated primary outcome for efficacy), and during washout. There was a statistically significant decrement in urine ACR at day 56 compared with baseline (P = 0.027).