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

皮质类固醇持续释放内耳递送的 IND 临床前开发

• 批准号: 10383347
• 负责人: Matthew Ku
• 金额: $ 88.66万
• 依托单位: O-RAY PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-22 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383347
• 关键词: Address; Adrenal Cortex Hormones; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Autoimmune Inner Ear disease; Businesses; Cavia; Chemistry; Ciprofloxacin; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Cochlea; Cochlear Implants; Cochlear implant procedure; Complication; Development; Development Plans; Dexamethasone; Disease; Dizziness; Documentation; Dose; Drug Delivery Systems; Drug Kinetics; Ear; Ear Diseases; Environment; FDA approved; Feedback; Fluticasone propionate; Formulation; Frequencies; Goals; Grant; Hearing Protection; Human; Hydrogels; Immune system; Implant; Injections; Investigational Drugs; Investigational New Drug Application; Kinetics; Label; Labyrinth; Lead; Legal patent; Letters; Lifting; Medical; Methods; Names; New Drug Approvals; Operative Surgical Procedures; Oral; Otitis Media; Otology; Patients; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Polymer Chemistry; Preparation; Procedures; Protocols documentation; Published Comment; Regulatory Affairs; Research Personnel; Residual state; Safety; Scientist; Site; Steroids; Suggestion; Sustainable Development; Symptoms; Techniques; Technology; Testing; Therapeutic; Therapeutic Index; Tinnitus; Toxic effect; Toxicology; Universities; Virginia; Work; biocompatible polymer; clinical material; common treatment; deaf; design; experience; first-in-human; fluticasone; good laboratory practice; hearing impairment; hearing loss treatment; immune function; implantation; innovation; meetings; novel; novel therapeutics; patient population; phase 1 study; phase 2 study; phase 3 study; pre-clinical; preclinical development; progressive hearing loss; response; safety testing; side effect; stability testing

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.

项目摘要 自身免疫性内耳疾病（AIED）是一种疾病，其中耳朵是目标的名称。 过度活跃的免疫系统，导致渐进性听力损失和/或头晕的症状。的大多数情况 AIED伴有听力损失和耳鸣，发生在几个月的过程中， 目前还没有FDA批准的药物用于治疗AIED。 治疗AIED或任何类型的内耳听力损失。使用大剂量口服或鼓室内注射 皮质类固醇抑制免疫功能是AIED最常用的治疗方法。然而，使用高 皮质类固醇的剂量导致显著的副作用。为了满足这一未满足的医疗需求，O-Ray 制药公司已经开发出一种用于治疗的缓释氟替卡松微丸（OR-102）的领先配方 的AIED，这将在三个月的时间内向耳蜗提供一致的低剂量皮质类固醇。 小球直接植入耳蜗，并在受影响的部位释放类固醇，以防止 听力损失OR-102制剂已经证明了其安全性、药代动力学（PK）和在治疗中的功效。 多项豚鼠研究。 为了测试OR-102在受AIED影响的患者中的首次人体临床试验中的安全性和初步疗效， O-Ray Pharma已向FDA提交IND申请。FDA默许了大多数人 申请中除了要求进行额外的动物研究和建议进行额外的 化学/生产/控制（CMC）工作。作为回应，没有与 临床方案和化学/生产/控制程序。因此，IND处于临床搁置状态 完成符合药物非临床研究质量管理规范（GLP）的毒性和药代动力学研究。该IND 通信为我们提供了一个明确的框架，对IND津贴。具体目标是 因此，直接进入II期提案的是完成以下IND使能活动：1）制剂 按照现行药品生产质量管理规范（cGMP）进行动物和人体试验; 2)按照FDA反馈指导开展符合GLP的豚鼠研究，3）准备和 提交IND回复。成功完成这项赠款的里程碑将是授予 IND批准。 O-Ray的研究人员团队是唯一有资格执行本文提出的工作的团队， 耳科、监管事务和业务发展方面的专业知识。O-Ray的科学家们成功地 从概念到FDA批准，开发了其他治疗制剂，包括眼内持续- 能够维持抗炎性玻璃体内药物水平长达三年的释放类固醇植入物 从一次植入开始。O-Ray的管理层此前已授权三种药物输送产品， 在目标患者人群中验证概念后，更大的制药公司。