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（由申请方提供）：持续性呼吸道耐甲氧西林金黄色葡萄球菌（MRSA）感染在囊性纤维化（CF）患者中越来越常见，在美国CF患者中的患病率几乎为30%。这是值得关注的，因为与没有MRSA的CF患者相比，MRSA阳性与肺功能更快下降和中位预期寿命缩短6年相关。不幸的是，对于CF患者，持续性MRSA感染没有有效和安全的治疗方法。萨瓦拉公司正在开发一种新的万古霉素吸入干粉形式（AeroVanc），用于治疗CF患者的呼吸道MRSA感染。该产品旨在方便在家自行给药。它被设想为改善肺功能，以及减少静脉注射（IV）抗生素和住院治疗的需要。万古霉素是治疗MRSA引起的支气管肺炎的首选药物，但其仅以IV形式可用，其通过IV给药难以穿透肺部，并且还可能与全身毒性相关，通常限制其在医院环境中的使用。直接将万古霉素递送至感染部位以提高临床疗效并减少全身暴露具有显著的临床优势。IV产品的标签外给药已被证明是令人鼓舞的。临床试验4 -11的已发表数据表明，万古霉素肺部给药安全且耐受性良好，可减少甚至消除CF患者痰中的MRSA。然而，IV制剂尚未针对肺部给药进行优化。其使用存在相当大的技术挑战和限制，尚未得到充分解决，并影响其临床可行性。Savara通过使用创新的颗粒包衣技术，克服了开发可吸入万古霉素粉末的重大技术挑战，首次开发了实用有效的肺部MRSA感染吸入治疗。Savara的新型万古霉素干粉制剂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装置进行递送。Savara迅速推进了产品开发，并完成了1期SBIR的目标，并通过在健康志愿者中进行成功的I期临床研究取得了进展。AeroVanc的气雾剂性能、大鼠5天吸入毒理学研究以及I期临床研究表明，AeroVanc是一种高效且耐受性良好的万古霉素制剂，非常适合在MRSA感染的CF患者中进行进一步的非临床研究和进一步的临床开发。该SBIR II期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工艺，完成两个种属的IND-启用28天吸入毒理学研究，提交IND，最后在呼吸道MRSA感染的CF患者中进行IIa期临床概念验证研究。