Development of Inhaled Vancomycin for Treatment of MRSA Infections in CF

描述（由申请人提供）：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阳性患者肺功能下降更快，平均预期寿命缩短6年。不幸的是，对于CF患者的持续性MRSA感染，目前还没有有效和安全的治疗方法。Savara公司正在开发一种新型的吸入干粉万古霉素（AeroVanc），用于治疗CF患者的呼吸道MRSA感染。本品适用于方便在家自行给药。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，但它只能静脉注射，静脉注射对肺部的渗透性差，还可能与全身毒性有关，通常限制其在医院的使用。万古霉素直接给药于感染部位，提高临床疗效，减少全身暴露，具有显著的临床优势。IV产品的标签外管理已被证明是令人鼓舞的。临床试验公布的数据表明，肺部给药万古霉素是安全且耐受性良好的，可以减少甚至消除CF患者痰中的MRSA。然而，静脉制剂尚未优化肺给药。其使用存在相当大的技术挑战和限制，这些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涂层技术，克服了开发可吸入万古霉素粉末的重大技术挑战，首次开发出实用有效的肺部MRSA感染吸入治疗方法。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输送。Savara迅速推进了产品开发，并已完成了第一阶段SBIR的目标，并通过在健康志愿者中进行成功的第一阶段临床研究而超越了目标。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，非常适合进一步的非临床研究，以及MRSA感染CF患者的进一步临床开发。SBIR二期项目的重点是开发一种自动化胶囊填充和包装工艺，用于进一步的临床研究，完成为期28天的两种物种的吸入毒理学研究，提交IND，最后在呼吸道MRSA感染CF患者中进行IIa期临床概念验证研究。

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.