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

NH101的开发：一种简单高效的门诊干粉两性霉素B-DryNeb（干粉雾化器），用于治疗敏感和多重耐药曲霉菌/真菌感染

• 批准号: 9909193
• 负责人: Matthew Reed
• 金额: $ 29.91万
• 依托单位: NOB HILL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9909193
• 关键词: Aerosol Drug Therapy; Aerosols; Allergic; Allergic Bronchopulmonary Aspergillosis; Amphotericin B; Antifungal Agents; Antifungal Therapy; Arts; Aspergillosis; Aspergillus; Asthma; Biological Assay; Breathing; Bronchiectasis; Cavia; Characteristics; Chemicals; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Cystic Fibrosis; Development; Devices; Disease; Dose; Drops; Drug Kinetics; Ensure; Excipients; Formulation; Funding; Fungal Lung Diseases; Future; Histopathology; Immunocompromised Host; In Vitro; Infection; Inhalation; Inhalators; Investigational Drugs; Itraconazole; Label; Legal patent; Location; Lung; Lung Transplantation; Lung diseases; Lung infections; Lung retention; Medical; Metered Dose Inhaler Device; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Mycoses; Nebulizer; New Mexico; Orphan; Outpatients; Particle Size; Patients; Performance; Pharmaceutical Preparations; Phase; Positioning Attribute; Powder dose form; Preparation; Public Health; Reproducibility; Research Institute; Respiratory physiology; Safety; Site; Small Business Innovation Research Grant; Source; Technical Expertise; Techniques; Testing; Therapeutic; Toxicology; Triazoles; Universities; aerosolized; asthmatic; base; chemotherapy; clinically relevant; commercialization; cystic fibrosis patients; efficacy study; fine particles; fungus; milligram; mortality; novel; off-label use; particle; performance tests; phase 1 study; portability; pressure; programs; prototype; recruit; resistant Aspergillus; resistant strain; respiratory; safety study; scale up; solid state

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.

该项目的总体目标是开发NH01，一种纯（纯）两性霉素干粉 B (AMB) 与我们新颖、易于使用的 DryNeb™ 干粉雾化器相结合，经过验证 肺部给药原理、功效、药代动力学 (PK) 和装置配方 该计划的结果将成为后续研究的决策门。 通过 II 期 SBIR 资助的新药 (IND) 毒理学和设备改进 NH101 (AMB-DryNeb™) 通过针对常见的情况满足未满足的医疗需求。 和三唑（抗真菌类，例如伊曲康唑）多重耐药（MDR）菌株 NH101 会在肺部感染部位产生肺部感染真菌（包括曲霉菌）。 最初关注囊性纤维化（CF）和哮喘相关的过敏性支气管肺 曲霉病 (ABPA)，一种罕见的、孤儿的、严重的曲霉病子集，可导致严重的 据估计，2.5% 的患者会出现过敏性加重和支气管扩张。 哮喘患者（约 500 万）和 15%（约 20,000）的 CF 患者获得了令人兴奋的原理结果证明。 在许多针对 AMB 雾化静脉注射制剂的“标签外”研究中，产生了 真菌性肺病，包括 ABPA，但目前尚无监管部门批准的气雾剂。 对于该项目，AMB 将用于治疗肺部真菌感染/疾病。 使用标准技术（即喷射 磨机、球磨机等）与我们在 Lonza 的老牌合作伙伴合作，后者避免了需要。 混合、非传统辅料以及与载体相关的先进技术专业知识 基于喷雾干燥的干粉制剂将通过 DryNeb™ 进行临床交付。 （US 9078985）由 Hugh D. Smyth 博士（项目顾问）开发并独家授权给 Nob Hill Therapeutics (NHT) 结合了高剂量容量和轻松潮汐功能。 按需雾化器的呼吸，具有干式雾化器的便携性和稳定性特征 AMB-DryNeb 将与我们的合作者 Pavin Mutilli 博士一起在 新墨西哥大学 (UNM) 的设施位于洛夫莱斯呼吸研究所。 位于新墨西哥州阿尔伯克基的研究所 (LRRI) 校园将利用这一独特的地理位置和 LRRI 的设施。 在豚鼠中进行原理功效和安全性研究证明的科学专业知识 **我们。 Betty Change 和 Don 博士进一步招募了临床和监管专家。 Burstyn，以确保我们在项目进展过程中考虑了“下一步” 临床和 II 期 SBIR 提交。** 在项目结束时，NH101 将准备好继续进行 通过 II 期 SBIR 或替代来源资助的 IND 毒理学研究。