Development of Inhaled Vancomycin for Treatment of MRSA Infections in CF

吸入万古霉素治疗 CF 中 MRSA 感染的开发

• 批准号: 8453663
• 负责人: Taneli Jouhikainen
• 金额: $ 129.04万
• 依托单位: SAVARA, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8453663
• 关键词: Address; Aerosols; Air; Antibiotics; Biological Assay; Breathing; Bronchopneumonia; Bulla; Canada; Canis familiaris; Cause of Death; Chemicals; Chronic; Cities; Clinical; Clinical Data; Clinical Research; Colony-forming units; Conduct Clinical Trials; Cystic Fibrosis; Development; Devices; Dose; Drug Formulations; Elements; Ensure; Evaluation; Excipients; Exclusion Criteria; Foundations; Grant; Guidelines; Home environment; Hospital Administration; Hospitalization; Hospitals; Humidity; Infection; Inhalation Toxicology; Inhalators; Intravenous; Kansas; Label; Laboratories; Life Expectancy; Light; Lung; Methods; Pamphlets; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Placebos; Powder dose form; Prevalence; Process; Progress Reports; Property; Protocols documentation; Publishing; Pulmonary Function Test/Forced Expiratory Volume 1; Rattus; Recovery; Reference Standards; Relative (related person); Research; Research Design; Research Personnel; Respiratory Failure; Respiratory physiology; Secondary to; Self Administration; Site; Small Business Innovation Research Grant; Solutions; Sprague-Dawley Rats; Sputum; Symptoms; Technology; Time; Toxic effect; Toxicokinetics; United States; Update; Validation; Vancomycin; Weight; Work; Writing; analytical method; assay development; capsule; chemical stability; clinical efficacy; cystic fibrosis patients; design; dosage; healthy volunteer; improved; innovation; intravenous administration; meetings; methicillin resistant Staphylococcus aureus; method development; novel; particle; phase 1 study; product development; programs; public health relevance; randomized placebo controlled trial; respiratory; therapeutic development

DESCRIPTION (provided by applicant): Persistent respiratory methicillin-resistant Staphylococcus aureus (MRSA) infections have become increasingly common in cystic fibrosis (CF) patients, with a prevalence of almost 30% in CF patients in the US. This is concerning, as MRSA positivity is associated with a faster decline of lung function and a 6 years shorter median life-expectancy compared to CF patients without MRSA. Unfortunately, there is no effective and safe treatment of persistent MRSA infections available for CF patients. Savara Inc. is developing a novel inhaled dry-powder form of vancomycin (AeroVanc) for the treatment of respiratory MRSA infection in CF patients. The product is intended for convenient self-administration at home. It is envisioned to improve lung function, as well as to decrease the need for intravenous (IV) antibiotics, and hospitalization. Vancomycin is the drug of choice for the treatment of bronchopneumonia due to MRSA, but it is only available in IV form, it penetrates the lungs poorly by IV administration, and may also be associated with systemic toxicity, generally limiting its use to hospital settings. There is significant clinical advantage n delivering vancomycin directly to the site of infection in order to improve clinical efficacy, and reduce systemic exposure. The off-label administration of the IV product has proven to be encouraging. The published data from clinical trials4-11 indicate that pulmonary administration of vancomycin is safe and well tolerated, and reduces or may even eliminate MRSA from the sputum of CF patients. However, the IV formulation has not been optimized for pulmonary administration. There are considerable technical challenges and limitations to its use that have not been adequately addressed, and that impact its clinical viability. Savara has overcome the significant technical challenges to the development of an inhalable vancomycin powder by using innovative particle coating technology, enabling for the first time the development of a practical and effective inhalation treatment of pulmonary MRSA infection. Savara's novel dry-powder formulation of vancomycin, AeroVanc, has physical, chemical and aerodynamic properties ideally suited for delivery using an off-the-shelf inhaler device. Savara has advanced the product development rapidly, and has completed the aims of a Phase 1 SBIR, as well as progressed beyond the aims by conducting a successful Phase I clinical study in healthy volunteers. The aerosol performance of AeroVanc, the rat 5-day inhalation toxicology study, as well as the Phase I clinical study indicate that AeroVanc is a highly efficient and well-tolerated formulation of vancomycin, and is well suited for further non-clinical studies, and further clinical development in MRSA infected CF patients. This SBIR Phase 2 project focuses on development of an automated capsule filling and packaging process required for further clinical studies, completion of IND- enabling 28-day inhalation toxicology studies in two species, submission of an IND, and finally, the conduct of a Phase IIa clinical proof of concept study in respiratory MRSA infected CF patients.

描述（由申请人提供）：持续性呼吸道甲氧西林金黄色葡萄球菌（MRSA）感染在囊性纤维化（CF）患者中越来越普遍，在美国，CF患者的患病率接近30％。这是关于MRSA的阳性与没有MRSA的CF患者相比，MRSA阳性与肺功能的更快下降和寿命中位数较短6年有关。不幸的是，没有可用于CF患者的持久性MRSA感染有效且安全的治疗。 Savara Inc.正在开发一种新型的吸入的干蒸食物形式的万古霉素（Aerovanc），用于治疗CF患者的呼吸道MRSA感染。该产品旨在在家中方便地进行自我管理。它设想提高肺功能，并减少对静脉内（IV）抗生素和住院的需求。万古霉素是由于MRSA引起的支气管瘤治疗的首选药物，但仅以IV形式使用，它可以通过IV施用渗透肺部较差，并且也可能与全身毒性有关，通常将其用于医院环境限制。 n将万古霉素直接传递到感染部位，以提高临床功效并减少全身暴露。事实证明，IV产品的标签外管理令人鼓舞。临床试验的已发表数据4-11表明，万古霉素的肺部施用是安全且耐受性的，并且可以减少甚至可以从CF患者的痰中消除MRSA。但是，尚未针对肺部施用静脉配方。其使用的技术挑战和局限性尚未得到充分解决，这会影响其临床生存能力。 Savara通过使用创新的颗粒涂层技术克服了吸入万古霉素粉末的重大技术挑战，这是首次开发对肺MRSA感染的实用有效吸入治疗。萨瓦拉（Savara）的新型干股配方万古霉素（Aerovanc）具有物理，化学和空气动力学特性，非常适合使用现成的吸入器设备交付。 Savara迅速推进了产品开发，并完成了1阶段SBIR的目标，并通过在健康志愿者中进行了成功的I期临床研究来超越目标。 Aerovanc的气溶胶性能，5天吸入毒理学研究，以及I期临床研究表明，Aerovanc是Vanomycin的高效且耐受性良好的配方，非常适合进一步的非临床研究，以及MRSA感染CF患者的进一步临床发育。该SBIR 2阶段项目的重点是开发进一步临床研究所需的自动胶囊填充和包装过程，完成了两个物种的28天吸入毒理学研究，提交IND，最后，进行IIA期IIA阶段IIA临床证明MRSA受感染的CF患者的概念证明。