Vascular Endothelial Growth Factor-B Blockade with CSL346 in Diabetic Kidney Disease: A Phase 2A Randomized Controlled Trial

Abstract

Key Points:

1. The vascular endothelial growth factor B inhibitor CSL346 (8 or 16 mg/kg q4w) did not reduce urinary albumin-creatinine ratio at week 16 versus placebo in patients with type 2 diabetes mellitus and diabetic kidney disease.

2. CSL346 was generally well tolerated at both doses; however, CSL346 (16 mg/kg) significantly increased diastolic BP versus placebo.

Background: Increased vascular endothelial growth factor B (VEGF-B) expression in patients with diabetic kidney disease (DKD) is associated with increased lipid deposition in glomerular podocytes. Reducing VEGF-B activity in animal models of DKD using an anti–VEGF-B antibody improved histological evidence of glomerular injury and reduced albuminuria, effects attributed to prevention of ectopic lipid deposition in the kidney. CSL346 is a novel humanized monoclonal antibody that binds VEGF-B with high affinity. Targeting VEGF-B in patients with type 2 diabetes mellitus may improve DKD progression markers.

Methods: An international, randomized, double-blind, placebo-controlled, phase 2a study (NCT04419467) assessed CSL346 (8 or 16 mg/kg subcutaneously every 4 weeks for 12 weeks) in participants with type 2 diabetes mellitus and a urinary albumin-creatinine ratio (UACR) ≥150 mg/g (17.0 mg/mmol), and eGFR >20 ml/min per 1.73 m². Efficacy, safety/tolerability, pharmacokinetics, and pharmacodynamics of CSL346 were evaluated. The primary analysis compared the change from baseline in log-transformed UACR between the two CSL346 dose groups combined versus placebo at week 16.

Results: In total, 114 participants were randomized. CSL346 did not significantly reduce UACR compared with placebo at week 16 (combined CSL346 group difference from placebo [95% confidence interval], 4.0% [−14.7 to 26.8]). Furthermore, no effect was seen in participant subgroups (degree of kidney impairment or sodium-glucose cotransporter 2 inhibitor use) or on urinary biomarkers reflecting proximal tubular injury. CSL346 was generally well tolerated; however, diastolic BP was significantly higher with CSL346 16 mg/kg versus placebo from week 2 onward, with differences ranging from +3.8 to +5.3 mm Hg (P = 0.002 at week 16).

Conclusions: CSL346 did not reduce UACR compared with placebo at 16 weeks in participants with type 2 diabetes mellitus and DKD and was associated with an increase in diastolic BP.

Clinical Trial registry name and registration number:: VEGF-B Blockade with the Monoclonal Antibody CSL346 in Subjects with DKD, NCT04419467.