Treatment of Diabetic Macular Edema with an Inhibitor of Vascular Endothelial-Protein Tyrosine Phosphatase That Activates Tie2
Treatment of Diabetic Macular Edema with an Inhibitor of Vascular Endothelial-Protein Tyrosine Phosphatase That Activates Tie2
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DOI：
10.1016/j.ophtha.2014.09.023
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发表时间：
2015-03-01
期刊：
影响因子：
13.7
通讯作者：
Peters, Kevin
中科院分区：
文献类型：
--
作者：
Campochiaro, Peter A.;Sophie, Raafay;Peters, Kevin
目的：AKB-9778是血管内皮细胞蛋白酪氨酸磷酸酶(VE-PTP)的小分子竞争性抑制剂，能促进Tie2的激活，减少小鼠模型中的血管渗漏和新生血管形成。本研究旨在测试AKB-9778治疗糖尿病黄斑水肿(DME)的安全性、耐受性、药代动力学和生物活性。设计：开放标签、剂量递增的临床试验。参与者：6例DME患者，每天两次皮下注射AKB-9778 5 mg、15 mg、22.5 mg或30 mg，共4周。方法：在为期4周的治疗期间每周观察一次，根据早期治疗糖尿病视网膜病变研究方案进行最佳矫正视力(BCVA)评估。用光谱域光学相干层析成像测量中心子场厚度(CST)。在6周、8周和12周进行额外的安全性评估。主要结果评估：安全性评估、基线BCVA的变化和基线CST的变化。结果：所有剂量均耐受性良好。每天两次服用22.5毫克或更多剂量的AKB-9778，血压和与血管扩张活性一致的不良事件都会出现轻微的、短暂的降低。在第4周的主要终点，在每天两次接受15 mg或以上治疗的18名患者中，13名患者的BCVA比基线提高了5个字母或更多；1名患者的BCVA提高了10到15个字母，2名患者的BCVA提高了15个字母以上。每日2次服用15 mg或以上的18例患者中，CST下降超过100微米者5例，下降50~100微米者2例。结论：DME患者全身应用AKB-9778 4周后，未发现安全性问题，每日2次15 mg或以上剂量可减轻黄斑水肿，改善视力。这是对VE-PTP抑制剂和Tie2激活剂的临床安全性和有效性的初步证明。(C)2015年由美国眼科学会颁发。
Purpose: AKB-9778 is a small-molecule competitive inhibitor of vascular endothelial-protein tyrosine phosphatase (VE-PTP) that promotes Tie2 activation and reduces vascular leakage and neovascularization in mouse models. The purpose of this study was to test the safety, tolerability, pharmacokinetics, and biological activity of AKB-9778 in patients with diabetic macular edema (DME).Design: Open-label, dose-escalation clinical trial.Participants: Four dose cohorts of 6 patients with DME self-administered subcutaneous injections of 5 mg, 15 mg, 22.5 mg, or 30 mg AKB-9778 twice daily for 4 weeks.Methods: Patients were seen weekly during a 4-week treatment period for safety assessments, best-corrected visual acuity (BCVA) assessment by Early Treatment Diabetic Retinopathy Study protocol, and measurement of central subfield thickness (CST) by spectral-domain optical coherence tomography. Additional safety assessments were performed at 6, 8, and 12 weeks.Main Outcome Measures: Safety assessments, change from baseline BCVA, and change from baseline CST.Results: All doses were well tolerated. A modest, transient reduction in blood pressure and adverse events consistent with vasodilatory activity of AKB-9778 emerged at doses of 22.5 mg or more twice daily. At the week 4 primary end point, BCVA improved 5 letters or more from baseline in 13 of the 18 patients receiving 15 mg or more twice daily; 1 patient improved by 10 to 15 letters, and 2 patients improved by more than 15 letters. Among 18 patients receiving 15 mg or more twice daily, CST decreased by more than 100 mu m in 5 patients and by 50 to 100 mu m in 2 patients. There was a significant correlation between reduction in CST and improvement in BCVA.Conclusions: No safety concerns were identified after systemic administration of AKB-9778 for 4 weeks in patients with DME, and doses of 15 mg or more twice daily reduced macular edema and improved vision in some patients. This is a preliminary demonstration of clinical safety and efficacy of a VE-PTP inhibitor and Tie2 activator. (C) 2015 by the American Academy of Ophthalmology.