Prevention of photoreceptor cell death with intravitreal Fas-receptor antagonist

描述（由申请人提供）：感光细胞的死亡是导致患者严重视力丧失的许多急性和慢性视网膜疾病的结果。如果能够帮助光感受器在疾病期间存活下来，患者的视力结果将显着改善。视网膜变性疾病和损伤是美国和发达国家不可逆视力丧失和失明的主要原因之一，每年影响数十万人，并导致数十亿美元的医疗费用。 增加了医疗成本，降低了生产力。限制当前治疗的功效的问题是，目前没有可以特异性地防止感光细胞损伤的干预措施。 细胞死亡;因此，安全、有效的光感受器保护剂将每年为数十万人提供显著的视觉益处。ONL Therapeutics正在开发一种候选产品，一种新型Fas受体小肽抑制剂（ONL-101），用于急性视网膜脱离患者（孤儿适应症）的围手术期预防性使用，目的是防止感光细胞死亡，直到最终的手术修复发生。这种急性适应症提供了一种快速开发途径，这将为ONL-101在慢性适应症如AMD（年龄相关性黄斑变性）的未来扩展开发奠定基础。用于治疗急性视网膜脱离的产品将是单剂量玻璃体内注射的处方药（眼科中的一种既定给药途径）。在完成该SBIR I期研究后，ONL Therapeutics将测试并验证通过玻璃体内注射将治疗水平的ONL-101递送至视网膜是可行的假设。我们将证明：1）ONL-101的玻璃体内注射导致视网膜中可测量水平的药物，2）ONL-101的玻璃体内注射导致视网膜脱离的良好建立的啮齿动物模型中的剂量依赖性光感受器保存，以及3）如啮齿动物研究中所确定的，在兔中玻璃体内注射后可以实现治疗目标视网膜浓度，在大小和功能上比啮齿动物模型更接近人眼的大型动物模型。从该I期研究获得的结果将为II期SBIR应用奠定基础，其将集中于制剂、毒性研究和IND包的最终确定，所述IND包是开始使用ONL-101作为黄斑脱落视网膜脱离患者的预防性治疗的临床试验所需的。ONL Therapeutics的商业化战略是与一家大型眼科制药公司合作进行I-III期临床试验，以确定人体的安全性和有效性。 公共卫生相关性：视网膜疾病是美国不可逆失明的主要原因，并对患者和社会造成巨大的社会和经济影响。ONL Therapeutics，LLC致力于开发一种新型治疗剂，可防止视网膜疾病期间感光细胞死亡。我们的主要产品ONL-101（一种Fas受体的小肽拮抗剂）的成功开发将成为第一种可供医生使用的感光神经保护剂，以改善患者的视力结果并减少失明。

DESCRIPTION (provided by applicant): Death of photoreceptor cells is a consequence of many acute as well as chronic retinal diseases which lead to severe vision loss in patients. If photoreceptors could be helped to survive the period of disease, the visual outcomes for patients would be significantly better. Retinal degenerative disease and injury are among the leading causes of irreversible vision loss and blindness in the United States and the developed world, affecting hundreds of thousands of people every year and resulting in billions of dollars in added healthcare costs and lost productivity. A problem limiting the efficacy of current treatments is that currently there are no interventions that can specifically prevent photoreceptor cell death; therefore, a safe, potent, photoreceptor protectant would provide a significant visual benefit to hundreds of thousands of people every year. ONL Therapeutics is developing a product candidate, a novel small peptide inhibitor of the Fas receptor (ONL-101), for peri-operative adjunctive use in patients with acute retinal detachment (an orphan indication), with the goal of preventing photoreceptor cell death until definitive surgical repair can occur. This acute indication provides a rapid development pathway that will lay the groundwork for future expansion of ONL-101 development for chronic indications such as AMD (Age Related Macular Degeneration). The product for acute retinal detachment will be a prescription drug for single dose intravitreal injection (an established route of administration in ophthalmology). Upon completion of this SBIR Phase I study, ONL Therapeutics will have tested and validated the hypothesis that it is feasible to deliver therapeutic levels of ONL-101 to the retina by intravitrel injection. We will demonstrate that: 1) Intravitreal injection of ONL-101 results in measurable levels of drug in the retina, 2) Intravitreal injection of ONL-101 results in dose-dependent photoreceptor preservation in a well-established rodent model of retinal detachment, and 3) the therapeutic target retinal concentration, as determined in the rodent studies, can be achieved after intravitreal injection in the rabbit, a large animal model that that more closely resembles te human eye in size and function than the rodent model. The results obtained from this Phase I study will lay the foundation for the Phase II SBIR application, which will focus on formulation, toxicity studies and finalization of the IND package required to begin clinical trials for the use f ONL-101 as an adjunctive treatment in patients with macula-off retinal detachments. The commercialization strategy for ONL Therapeutics is to partner with a large ocular pharmaceutical company for Phase I-III clinical trials to establish safety and efficacy in humans. PUBLIC HEALTH RELEVANCE: Diseases of the retina are a leading cause of irreversible blindness in the United States and result in tremendous social and economic impact on patients and society. ONL Therapeutics, LLC is dedicated to the development of a novel therapeutic agent that will prevent photoreceptor cell death during retinal disease. Successful development of our lead product, ONL-101, a small peptide antagonist of the Fas-receptor, would result in the first photoreceptor neuroprotective agent available to physicians to improve visual outcomes and reduce blindness in patients.