Prevention of photoreceptor cell death with intravitreal Fas-receptor antagonist

描述(申请人提供)：感光细胞的死亡是许多急性和慢性视网膜疾病的结果，这些疾病导致患者严重的视力丧失。如果光感受器能够帮助患者挺过疾病时期，患者的视觉结果将显著改善。视网膜退行性疾病和损伤是美国和发达国家不可逆转的视力丧失和失明的主要原因之一，每年影响数十万人，导致数十亿美元的 增加了医疗成本和生产力损失。限制目前治疗效果的一个问题是，目前还没有专门预防感光的干预措施。 细胞死亡；因此，一种安全、有效的感光细胞保护剂每年将为数十万人提供显著的视觉益处。ONL治疗公司正在开发一种候选产品，一种新型的Fas受体小肽抑制剂(ONL-101)，用于急性视网膜脱离(孤儿适应症)患者的围手术期辅助使用，目的是防止光感受器细胞死亡，直到可以进行明确的手术修复。这一急性指征提供了一条快速发展的途径，将为未来扩展ONL-101对AMD(年龄相关性黄斑变性)等慢性指征的开发奠定基础。治疗急性视网膜脱离的产品将是单次玻璃体内注射(眼科公认的给药途径)的处方药。在这项SBIR第一阶段研究完成后，ONL治疗公司将测试和验证通过玻璃体内注射将治疗水平的ONL-101输送到视网膜是可行的假设。我们将证明：1)玻璃体内注射ONL-101可导致可测量到的药物在视网膜中的水平，2)玻璃体内注射ONL-101可使已建立的视网膜脱离啮齿动物模型中的光感受器得到剂量依赖的保护，以及3)啮齿动物研究中确定的治疗目标视网膜浓度可在兔玻璃体内注射后实现，这是一个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。从这项第一阶段研究获得的结果将为第二阶段SBIR的应用奠定基础，这将集中在配方、毒性研究和IND包的最终确定上，这是开始使用ONL-101作为治疗黄斑脱离视网膜脱离患者的辅助治疗所需的临床试验。ONL治疗公司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，以确定在人类身上的安全性和有效性。 公共卫生相关性：视网膜疾病是美国不可逆转失明的主要原因，对患者和社会造成巨大的社会和经济影响。ONL Treateutics，LLC致力于开发一种新型治疗剂，可防止视网膜疾病期间光感受器细胞死亡。我们领先产品ONL-101的成功开发将导致医生获得第一种光感受器神经保护剂，以改善患者的视觉结果和减少患者的失明。

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.