IND-enabling Preclinical Development of Sustained Release Inner Ear Delivery of Corticosteroid

项目总结 自身免疫性内耳疾病(Aed)是用来描述一种疾病的名称，在这种疾病中耳朵是 免疫系统过度活跃，导致进行性听力损失和/或头晕的症状。大多数情况下 AIED伴有听力损失和耳鸣，在几个月的病程中1，2进展 迅速到达第二耳，表明AIED。3目前还没有FDA批准的治疗AIED的药物 治疗AIED或任何类型的内耳听力损失。大剂量口服或鼓室注射的应用 糖皮质激素抑制免疫功能是AIED最常用的治疗方法。但是，使用High 剂量的皮质类固醇会导致严重的副作用。为了回应这一未得到满足的医疗需求，O-Ray Pharma已经开发出一种用于治疗的氟替卡松缓释微丸(OR-102)的主要配方 这将在三个月的时间内为耳蜗组织提供持续的低剂量皮质类固醇。 小球被直接植入耳蜗处，并在受影响的部位释放类固醇以防止 听力损失。OR-102制剂已证明其安全性、药代动力学(PK)和疗效。 多项豚鼠研究。 为了在首次人类临床试验中测试OR-102在受AED影响的患者中的安全性和初步疗效， O-Ray Pharma已经向FDA提交了IND申请。FDA提供了多数人的默许。 除了请求执行额外的动物研究和建议进行额外的 化学/制造/控制(CMC)工作。作为回应，没有临床上与 临床方案和化学/制造/控制程序。因此，IND处于临床搁置状态 完成符合良好实验室规范(GLP)的毒性和药代动力学研究。这个行业 通信为我们提供了一个关于IND津贴的明确框架。这样做的具体目的是 因此，直接到第二阶段的提案是完成以下支持IND的活动：1)药物产品 根据动物和人体试验的现行良好制造规范(CGMP)进行制造； 2)在FDA反馈指导下进行的符合GLP的豚鼠研究，3)制备和 提交IND答复。成功完成这笔赠款的里程碑将是赠款 获得IND批准。 O-Ray的调查团队是唯一有资格执行本文建议的工作的团队，并已 耳科、监管事务和业务发展方面的专业知识。O-Ray的科学家已经成功地 开发了从概念到FDA批准的其他治疗配方，包括眼内持续- 释放类固醇植入物，能够维持抗炎玻璃体内药物水平长达三年 从一次植入。O-Ray的管理层此前已将三种药物递送产品的许可授予 较大的制药公司在目标患者群体中进行概念验证。

PROJECT SUMMARY Autoimmune inner ear disease (AIED) is the name given to describe a disorder where the ear is the target of an overactive immune system, causing symptoms of progressive hearing loss and/or dizziness. Most cases of AIED are accompanied by hearing loss and tinnitus that occur over a course of a few months1,2 that progresses rapidly to the second ear, indicative of AIED.3 There are currently no FDA-approved medications for the treatment of AIED, or any type of inner ear hearing loss. The use of high dose oral or intratympanic injection corticosteroids to suppress immune function is the most common treatment for AIED. However, the use of high doses of corticosteroids leads to significant side effects. In response to this unmet medical need, O-Ray Pharma has developed a lead formulation of sustained-release fluticasone pellets (OR-102) for the treatment of AIED that will provide a consistent low dose of corticosteroid to the cochlea over a period of three months. The pellet is implanted directly into the cochlea and releases steroid at the affected site to protect against hearing loss. The OR-102 formulation has demonstrated its safety, pharmacokinetics (PK), and efficacy in multiple guinea pig studies. To test the safety and preliminary efficacy of OR-102 in a first-in-human clinical trial in AIED-affected patients, O-Ray Pharma has submitted an IND application to the FDA. The FDA provided tacit approval of the majority of the application save for a request to perform an additional animal study and suggestions for additional Chemistry/Manufacturing/Control (CMC) work. In response, there were no clinical holds pertaining to the clinical protocol and the chemistry/manufacturing/controls procedures. Thus, the IND is on clinical hold pending the completion of a Good Laboratory Practices (GLP) compliant toxicity and pharmacokinetics study. This IND correspondence has provided us with a clear framework towards an IND allowance. The Specific Aims of this Direct to Phase II proposal are, therefore, to complete the following IND-enabling activities: 1) Drug product manufacturing in accordance with current Good Manufacturing Practices (cGMP) for animal and human trials; 2) Performance of a GLP-compliant guinea pig study as guided by FDA feedback, 3) Preparation and submission of an IND response. The milestone for the successful completion of this grant will be the granting of an IND approval. The team of investigators at O-Ray is uniquely qualified to perform the work proposed herein, and has expertise in otology, regulatory affairs, and business development. O-Ray’s scientists have successfully developed other therapeutic formulations from concept to FDA approval, including an intraocular sustained- release steroid implant capable of maintaining anti-inflammatory intravitreal drug levels for up to three years from a single implantation. O-Ray’s management has previously out-licensed three drug delivery products to larger pharmaceutical companies upon demonstration of proof-of-concept in the target patient populations.