医学
肾脏疾病
肾功能
内科学
蛋白尿
泌尿科
糖尿病
肌酐
安慰剂
内分泌学
耐受性
血管内皮生长因子
肾
胃肠病学
病理
不利影响
血管内皮生长因子受体
替代医学
作者
Melisa Cooper,David Z.I. Cherney,Tom Greene,Hiddo J.L. Heerspink,Meg Jardine,Julia Lewis,Muh Geot Wong,Elbalejandra Baquero,Mark Heise,Jeanine Jochems,Diana Lanchoney,Charles Liss,David Reiser,Pierre Scotney,Elena Velkoska,Jamie P. Dwyer
出处
期刊:Journal of The American Society of Nephrology
日期:2024-08-16
标识
DOI:10.1681/asn.0000000000000438
摘要
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 mg/kg or 16 mg/kg subcutaneously every 4 weeks for 12 weeks) in participants with type 2 diabetes mellitus and a urinary albumin-to-creatinine ratio (UACR) ≥150 mg/g (17.0 mg/mmol), and eGFR >20 mL/min/1.73m 2 . 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, 26.8]). Furthermore, no effect was seen in participant subgroups (degree of kidney impairment or sodium-glucose cotransporter 2 [SGLT2] inhibitor use) or on urinary biomarkers reflecting proximal tubular injury. CSL346 was generally well tolerated; however, diastolic blood pressure was significantly higher with CSL346 16 mg/kg versus placebo from Week 2 onwards, with differences ranging from +3.8 to +5.3 mmHg (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 blood pressure.
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