Development of NH101: A Simple and Efficient Outpatient Dry Powder Amphotericin B-DryNeb(dry powder nebulizer) for Treatment of Susceptible and Multidrug Resistant Aspergillus/ Fungal Infections

该项目的总体目标是开发NH 01，一种纯的（纯的）甘草素干粉 B（AMB）结合我们的新型，简单易用，DryNeB™，干粉雾化器，通过证明 主要肺部给药、疗效、药代动力学（PK）和器械配方 特征化该项目的结果将成为后续研究的决策门槛 新药（IND）-通过第二阶段SBIR资助的毒理学和器械改进， 其他来源NH 101（AMB-DryNeb™）通过针对常见的 和三唑（抗真菌类，例如，伊曲康唑）多药耐药（MDR）菌株 肺部感染部位的肺部感染真菌（包括曲霉菌属）。NH 101将 最初集中于囊性纤维化（CF）和哮喘相关过敏性支气管肺炎 曲霉菌病（ABPA），一种罕见的孤儿和严重的曲霉菌病子集，引起严重的 过敏性加重和支气管扩张。ABPA与估计2.5%的 哮喘患者（约500万）和15%（约20，000）的CF患者。令人兴奋的原理证明结果 在许多AMB雾化IV制剂的“标签外”研究中产生， 真菌性肺病，包括ABPA。然而，目前还没有监管机构批准的气雾剂 适用于肺部真菌感染/疾病的治疗。在这个项目中，AMB将 使用标准技术（即喷射）配制成简单、纯净、微粉化/研磨的干粉 米尔斯、球磨机米尔斯等）我们在龙沙的合作伙伴后者避免了需要 混合、非传统辅料和与载体相关的先进技术专长， 基和喷雾干燥的干粉制剂。AMB将通过DryNeb™进行临床输送 (US 9078985）由Hugh D. Smyth（项目顾问）和独家授权， Nob Hill Therapeutics（NHT）DryNeb结合了高剂量容量和易于潮汐 具有干式雾化器的便携性和稳定性特征的按需雾化器的呼吸 粉末吸入器。AMB-DryNeb将与我们的合作者Pavin Mutilli博士在 新墨西哥州大学。NHT设施位于Lovelace呼吸研究中心 研究所（LRRI）校园在阿尔伯克基，新墨西哥州。NHT将利用这一独特的位置和LRRI的 在豚鼠中进行原理性有效性和安全性研究的科学专业知识。** 我们 我进一步招募了临床和监管专家，贝蒂·钱博士和唐博士， Burstyn，以确保我们已经考虑了“下一步”，因为项目的进展， 临床和第二阶段SBIR提交。**在项目结束时，NH 101将准备继续进行 通过II期SBIR或其他来源资助的IND使能毒理学研究。

The overall objective of this project is to progress NH01, a pure (neat) dry powder of amphotericin B (AMB) combined with our novel, simple to use, DryNeb™, dry powder nebulizer, through proof of principle pulmonary delivery, efficacy, pharmacokinetics (PK), and device-formulation characterization. The results of this program will be a decision gate for follow-on Investigational New Drug (IND)-enabling toxicology and device refinement funded through Phase II SBIR and other sources. NH101 (AMB-DryNeb™) satisfies an unmet medical need by targeting common and triazole (antifungal classes, e.g., itraconazole) multidrug resistant (MDR) strains of pulmonary-infecting fungi (including aspergillus species) at the site of lung infection. NH101 will initially focus on cystic fibrosis (CF) and asthma-associated allergic bronchopulmonary aspergillosis (ABPA), a rare, orphan, and severe subset of aspergillosis that causes severe allergic exacerbations and bronchiectasis. ABPA is associated with an estimated 2.5% of asthmatics (~5 million) and 15% (~20,000) of CF patients. Exciting proof of principle results have been generated in many “off label” studies of aerosolized IV formulations of AMB targeted at fungal lung disease including ABPA. However, there are currently no regulatory-approved aerosol therapies indicated for fungal infections/ diseases in the lung. For this project AMB will be formulated as a simple, neat, micronized/milled dry powder using standard techniques (i.e. jet mills, ball mills, etc.) with our established partners at Lonza. The latter avoids the need for blending, non-traditional excipients, and advanced technical expertise associated with carrier- based and spray-dried dry powder formulations. AMB will be delivered clinically by the DryNeb™ (US 9078985) developed by Dr. Hugh D. Smyth (Project Consultant) and exclusively licensed to Nob Hill Therapeutics (NHT). The DryNeb combines the high-dose capacity and easy tidal breathing of an on-demand nebulizer with the portability and stability characteristics of a dry powder inhaler. The AMB-DryNeb will be tested with our collaborator Dr. Pavin Mutilli at the University of New Mexico (UNM). NHT facilities are located on the Lovelace Respiratory Research Institute (LRRI) campus in Albuquerque, NM. NHT will utilize this unique location and LRRI’s scientific expertise to perform proof of principle efficacy and safety studies in guinea pigs. **We have further recruited clinical and regulatory expertise, Drs. Betty Change and Don Burstyn, to ensure we have considered “next steps” as the project progresses toward the clinical and a Phase II SBIR submission.** At project’s end NH101 will be ready to proceed to IND-enabling toxicology studies funded through a Phase II SBIR or alternate sources.