Long-term anti-angiogenic activity of intravitreal ellipsoid particles for NVAMD

描述（由申请人提供）：NVAMD玻璃体内椭圆颗粒的长期抗血管生成活性Niranjan B. Pandey博士- PI Aleksander S. Popel博士- Co-I Jordan J. Green博士- Co-I Peter A. Campochiaro医学博士- subaward的Co-I项目总结：目前治疗湿性年龄相关性黄斑变性（AMD）的靶向血管内皮生长因子（VEGFA，和胎盘生长因子PlGF）。这些药物包括雷尼单抗和阿非利西普。雷尼单抗针对所有形式的VEGFA，而阿非利西普也针对两种形式的PlGF。然而，这些药物并不能改善60-65%的AMD患者的视力，这表明其他非vegf /PlGF通路在这些患者中是活跃的。雷尼单抗每月给药，而阿非利西普在每月注射3个月后每月给药。每月注射增加了感染的风险，给患者带来了负担。最近，与雷尼单抗相比，由于aflibercept进入AMD市场的速度很快，患者已经表现出减少注射的愿望。最后，雷尼单抗和阿非利西普虽然有效，但不会导致现有血管的退化，只会抑制新生血管的生长，从而限制了它们的疗效。因此，针对对当前疗法无反应的患者，延长玻璃体内给药间隔时间以实现成本节约和减少副作用，以及能够逆转患者疾病症状的药物，存在未得到满足的医疗需求。我们建议开发一种肽疗法来满足这一医疗需求。我们已经开发出一种创新的长形椭球微粒（微鱼雷），它可以封装各种有效载荷，并且由于其特殊的聚合物设计和抗吞噬的形状，预计将在眼睛中长期使用。抗血管生成肽可以在VEGF和非VEGF生长因子存在的情况下阻断血管生成。在这里，我们建议将这两种技术结合起来，设计和制造一种微型鱼雷，该鱼雷包装了我们的抗血管生成仿生肽，该肽来自于IV型胶原纤维。我们的数据显示，该肽在2种广泛使用的AMD小鼠模型中具有强大的功效，数据显示，该肽的类似物会导致新生血管的退化，并显示出对视网膜脱离的抑制作用。我们的治疗性微型鱼雷被设计成具有较长的体内半衰期，将解决我们着手解决的所有3个问题：它们将在6个月的时间内释放肽，从而将玻璃体内注射的频率从每年12次减少到每年2次，释放的肽因其作用机制而同时抑制多种血管生成信号通路，并且肽还会导致现有新生血管的退化，从而有可能逆转疾病的症状。任何进入这一领域的新药都应该在头对头体内模型中表现得比阿伯西普更好，这样才具有商业可行性；因此，我们建议在我们所有的体内研究中，将我们的治疗方法与阿布西贝进行比较。

DESCRIPTION (provided by applicant): Long-term anti-angiogenic activity of intravitreal ellipsoid particles for NVAMD Niranjan B. Pandey, Ph.D. - PI Aleksander S. Popel, Ph.D. - Co-I Jordan J. Green Ph.D. - Co-I Peter A. Campochiaro M.D. - Co-I of subaward Project Summary: Current therapies for wet age-related macular degeneration (AMD) target vascular endothelial growth factors (VEGFA, and placental growth factor PlGF). These include Ranibizumab and Aflibercept. Ranibizumab targets all forms of VEGFA while aflibercept also targets both forms of PlGF. However these drugs do not improve visual acuity in 60-65% of AMD patients, suggesting that other non-VEGF/PlGF pathways are active in these patients. Ranibizumab is administered intravitreally monthly while aflibercept is administered bimonthly after 3 months of monthly injections. Monthly injections increase the risk of infections and are burdensome to patients. Recently, patients have shown their desire to switch to fewer injections by the rapid pace with which aflibercept is making inroads into the AMD market compared to ranibizumab. Finally ranibizumab and aflibercept, although effective, do not cause regression of existing neovasculature, only inhibition of the growth of new vasculature, thus limiting their efficacy. Thus, there is an unmet medical need to target patients that do not respond to current therapies, to extend the time between intravitreal administrations even more to achieve cost savings and reduce side effects, and for agents that can reverse the symptoms of the disease in patients. We propose to develop a peptide therapeutic that could fulfill this medical need. We have developed an innovative prolate ellipsoid microrparticle (microtorpedo) that can encapsulate a wide variety of payloads and is expected to be long-lived in the eye because of its particular polymeric design and its phagocytosis-resistant shape. The anti-angiogenic peptide can block angiogenesis in the presence of VEGF and non-VEGF growth factors. Here we propose to combine these two technologies to design and fabricate a microtorpedo packaged with our lead anti-angiogenic biomimetic peptide derived from the �5 fibril of collagen IV. We present data showing potent efficacy of the peptide in 2 widely used mouse models of AMD and data showing that a close analog of the peptide causes regression of the neovasculature and shows promising inhibition of retinal detachment. Our therapeutic microtorpedo which has been designed for a long half-life in vivo will solve all 3 problems we set out to solve: they will relese peptide over a period of 6 months thus reducing the frequency of intravitreal injections from 12 times a year to 2 times a year, the released peptide will inhibit multiple angiogenic signaling pathways simultaneously because of its mechanism of action, and the peptide will also cause regression of the existing neovasculature thus potentially reversing symptoms of the disease. Any new drug introduced into this space should perform better than aflibercept in head-to-head in vivo models to be commercially viable; thus we propose to test our therapeutic compared to aflibercept in all of our in vivo studies.