Development of Inhaled Vancomycin for Treatment of MRSA Infections in CF

描述（由申请人提供）：Savara Inc.正在开发一种新的万古霉素吸入干粉形式（AEROVANC），用于治疗耐甲氧西林金黄色葡萄球菌（MRSA）感染，最初用于囊性纤维化（CF）患者，随后用于其他高风险患者人群。该产品旨在方便在家自行给药。是 设想改善肺功能，以及降低住院率和静脉内（IV）抗生素的使用。MRSA感染已变得越来越常见，所有CF患者中的患病率高达40-50% 1;与无MRSA的CF患者相比，平均预期寿命缩短6.2年。万古霉素是治疗MRSA引起的支气管肺炎的首选药物，但仅以IV形式提供。万古霉素也与全身毒性相关，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，可减少或消除患有MRSA肺部感染的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，适用于使用现成的吸入器装置递送。该产品处于临床前开发阶段。这项SBIR赠款侧重于两个调查领域。第一个是针对与社区保护委员会有关的活动，即，将实验室规模的制剂转化为能够支持IND和临床研究的制剂和生产工艺。Savara将使用适合cGMP生产的设备，以适合完成临床前项目和I期临床研究的规模扩大制剂。二线研究旨在确定AEROVANC的安全性和最大耐受剂量（MTD），并表征其在肺和血液中的药代动力学特征。将进行单次给药、剂量递增研究，其中将通过吸入给予健康大鼠AEROVANC制剂。将确定急性毒理学特征，并通过临床观察和大体尸检确定终末器官毒性。将采集肺液和血液的系列样本，分析万古霉素水平，并用于建立药代动力学特征。1期SBIR提出的工作完成后，Savara将启动GLP活动并与FDA进行IND前讨论。 公共卫生相关性：囊性纤维化（CF）患者中最常见的死亡原因是继发于慢性肺部感染的呼吸衰竭，包括耐甲氧西林金黄色葡萄球菌（MRSA）感染，其在40-50%的CF患者中普遍存在，并且已被证明与无MRSA的CF患者相比预期寿命较短相关。万古霉素是治疗MRSA引起的支气管肺炎的首选药物，仅以静脉注射形式提供，并且具有严重的毒性，限制了其在以下情况下的使用： 昂贵和不便的医院管理。为了解决记录的额外治疗需求，以解决这种情况，Savara Inc.正在开发一种更安全的万古霉素吸入干粉形式（AEROVANC），用于MRSA感染的局部治疗，其旨在方便、低成本地在家中自我给药。

DESCRIPTION (provided by applicant): Savara Inc. is developing a novel inhaled dry-powder form of vancomycin (AEROVANC) for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection, initially in cystic fibrosis (CF) patients and subsequently in other high risk patient populations. The product is intended for convenient self-administration at home. It is envisioned to improve lung function, as well as, to decrease hospitalization rates and use of intravenous (IV) antibiotics. MRSA infections have become increasingly common, with a prevalence of up to 40-50% of all CF patients1; and are associated with an average of 6.2 years shorter life-expectancy compared to CF patients without MRSA. Vancomycin is the drug of choice for the treatment of bronchopneumonia due to MRSA, but it is only available in IV form. Vancomycin is also associated with systemic toxicity, generally, limiting its use to hospital settings. There is significant clinical advantage in delivering vancomycin directly to the site of infection in order to 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 eliminates MRSA from the sputum of CF patients suffering from MRSA lung infections. 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 suitable for delivery using off-the-shelf inhaler devices. The product is in preclinical development. This SBIR grant focuses on two lines of investigation. The first is directed at CMC- related activities, i.e., translating the laboratory-scale formulatio into a formulation and manufacturing process capable of supporting IND and clinical investigation. Savara will scale-up the formulation using equipment suitable for cGMP manufacture, at a scale suitable for completion of the preclinical program and Phase I clinical studies. The second line of study is directed at establishing the safety and maximum tolerated dose (MTD) of AEROVANC and characterizing its pharmacokinetic profile in the lung and in blood. A single dose, dose-escalation study will be carried out in which the AEROVANC formulation will be administered by inhalation to healthy rats. Acute toxicology profiles will be determined and end-organ toxicities will be identified by clinical observation and gross necropsy. Serial samples of both lung fluid and blood will be drawn, analyzed for vancomycin levels and used to establish pharmacokinetic profiles. The completion of the work proposed by the Phase 1 SBIR will position Savara to initiate GLP activities and pre-IND discussions with FDA. PUBLIC HEALTH RELEVANCE: The most common cause of death among cystic fibrosis (CF) patients is respiratory failure secondary to chronic pulmonary infections, including methicillin-resistant Staphylococcus aureus (MRSA) infections, which are prevalent in 40-50% of CF patients, and have been shown to be associated with a shorter life expectancy compared to CF patients without MRSA. Vancomycin, the drug of choice for the treatment of bronchopneumonia due to MRSA, is available only in intravenous form, and has severe toxicities that limit its use to expensive and inconvenient hospital administration. To address the documented need for additional therapies to address this condition, Savara Inc. is developing a much safer inhaled dry-powder form of vancomycin (AEROVANC) for the local treatment of MRSA infections, which is intended for convenient, low cost self-administration at home.