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

基本信息

批准号：
10543163
负责人：
Matthew Ku
金额：
$ 87.91万
依托单位：
O-RAY PHARMA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-22 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543163
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 Collaborations 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 Good Manufacturing Process Grant Hearing Protection Human Hydrogels Immune system Implant Injections Investigational Drugs Investigational New Drug Application Kinetics Label Labyrinth Lead Legal patent Letters Licensing 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 Qualifying Regulatory Affairs Research Personnel Residual state Safety Scientist Shapes Site Steroids Suggestion 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 manufacture 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

项目摘要

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.

项目概要自身免疫性内耳疾病（AIED）是描述一种以耳朵为目标的疾病的名称。免疫系统过度活跃，导致进行性听力损失和/或头晕症状。 AIED 会伴随听力损失和耳鸣，这些症状会在几个月的过程中发生1,2并且不断进展迅速到达第二只耳朵，这是 AIED 的指标。3 目前尚无 FDA 批准的药物用于治疗使用高剂量口服或鼓室内注射治疗 AIED 或任何类型的内耳听力损失。皮质类固醇抑制免疫功能是 AIED 最常见的治疗方法，但使用率较高。一定剂量的皮质类固醇会导致显着的副作用，为了满足这一未满足的医疗需求，O-Ray 开发了这种药物。 Pharma 开发了一种用于治疗的缓释氟替卡松微丸 (OR-102) 的先导制剂 AIED 将为耳蜗提供持续三个月的低剂量皮质类固醇。该颗粒被直接植入耳蜗并在受影响的部位释放类固醇以防止 OR-102 制剂已在治疗听力损失方面证明了其安全性、药代动力学 (PK) 和功效。多项豚鼠研究。为了在受 AIED 影响的患者中进行首次人体临床试验来测试 OR-102 的安全性和初步疗效，欧瑞制药已向 FDA 提交了 IND 申请，获得了 FDA 多数的默认批准。除了要求进行额外的动物研究和额外的建议外，申请的其他部分化学/制造/控制（CMC）工作作为回应，没有与此相关的临床保留。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。信件为我们提供了 IND 津贴的明确框架。因此，直接进入第二阶段提案是完成以下 IND 支持活动：1) 药品按照现行的动物和人体试验良好生产规范 (cGMP) 进行生产； 2) 在 FDA 反馈的指导下进行符合 GLP 要求的豚鼠研究，3) 准备和提交 IND 回复将是成功完成此项资助的里程碑。 IND 批准。 O-Ray 的研究人员团队具有执行此处提议的工作的独特资质，并且拥有欧瑞科学家在耳科、监管事务和业务开发方面的专业知识已取得成功。开发了从概念到 FDA 批准的其他治疗制剂，包括眼内持续- 释放类固醇植入物，能够维持玻璃体内抗炎药物水平长达三年 O-Ray 管理层此前已将三种药物输送产品授权给大型制药公司在目标患者群体中进行概念验证后。