SL346 (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....

中文翻译：

---

CSL346 阻断血管内皮生长因子-B 治疗糖尿病肾病：一项 2A 期随机对照试验


与安慰剂相比，SL346 （16 mg/kg） 显着增加了舒张压。背景 糖尿病肾病 （DKD） 患者血管内皮生长因子 B （VEGF-B） 表达增加与肾小球足细胞中脂质沉积增加有关。使用抗 VEGF-B 抗体降低 DKD 动物模型中的 VEGF-B 活性改善了肾小球损伤的组织学证据，减少了白蛋白尿，这些效果归因于预防肾脏中的异位脂质沉积。CSL346 是一种新型人源化单克隆抗体，以高亲和力结合 VEGF-B。在 2 型糖尿病患者中靶向 VEGF-B 可能会改善 DKD 进展标志物。方法 一项国际、随机、双盲、安慰剂对照的 2a 期研究 （NCT04419467） 评估了 CSL346 （8 或 16 mg/kg，皮下注射，每 4 周一次，持续 12 周） 在 2 型糖尿病参与者中，尿白蛋白-肌酐比值 （UACR） ≥150 mg/g （17.0 mg/mmol） 和 eGFR >20 ml/min 每 1.73 m2。评价 CSL346 的疗效、安全性/耐受性、药代动力学和药效学。主要分析比较了第 16 周时两个 CSL346 剂量组联合与安慰剂之间对数转换的 UACR 相对于基线的变化。结果 共有 114 名参与者被随机分组。与安慰剂相比，CSL346 在第 16 周时未显著降低 UACR （CSL346 组与安慰剂的综合差异 [95% 置信区间]，4.0% [-14.7 至 26.8]）。此外，在参与者亚组 （肾功能损害程度或钠-葡萄糖协同转运蛋白 2 抑制剂的使用） 或反映近端肾小管损伤的尿液生物标志物中未见影响。 CSL346 总体耐受性良好;然而，从第 2 周开始，CSL346 16 mg/kg 与安慰剂组的舒张压显著升高，差异范围为 +3.8 至 +5.3 mm Hg（第 16 周时 P = 0.002）。结论 与安慰剂相比，CSL346 在 2 型糖尿病和 DKD 参与者的 16 周时没有降低 UACR，并且与舒张压的增加有关。临床试验注册名称和注册号： VEGF-B 单克隆抗体 CSL346 阻断 DKD 受试者，NCT04419467....