Aerosolized Chemically Modified Tetracycline Nanoformulation for the Treatment of Acute Respiratory Distress Syndrome

雾化化学修饰四环素纳米制剂治疗急性呼吸窘迫综合征

• 批准号: 10602896
• 负责人: Michaela Christina Kollisch-Singule
• 金额: $ 42.67万
• 依托单位: CMTX BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602896
• 关键词: AIDS with Kaposi' s sarcoma; Accounting; Acne; Acute Lung Injury; Acute Respiratory Distress Syndrome; Adult; Agreement; Alveolar; American; Animal Model; Animals; Area; Authorization documentation; Biodistribution; Biotechnology; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemicals; Chronic; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Complex; Complication; Data; Dermatology; Development; Diffuse; Disease; Disease Progression; Disparate; Disseminated Malignant Neoplasm; Dose; Drug Kinetics; Etiology; Extracorporeal Membrane Oxygenation; FDA approved; Family suidae; Formulation; Glioma; Goals; Hospital Mortality; Hospitals; Human; Hydrophobicity; Hypoxia; Immune; Incidence; Induction of neuromuscular blockade; Inflammation; Inflammatory; Intensive Care; International; Intervention; Intubation; Investigational Drugs; Knowledge; Licensing; Lung; Marketing; Matrix Metalloproteinases; Mechanical ventilation; Mediating; Medical; Medical emergency; Methods; Modality; Modeling; Morbidity - disease rate; Mus; Oncology; Oral; Outcome; Pathologic; Pathway interactions; Patients; Periodontitis; Periostat; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Prevention; Prone Position; Public Health; Publishing; Rattus; Recurrence; Refractory; Research; Research Personnel; Respiratory distress; Risk; Rosacea; Safety; Schedule; Sepsis; Septic Shock; Severity of illness; Sheep; Small Business Technology Transfer Research; Supportive care; Tetracyclines; Therapeutic; Therapeutic Intervention; Therapy trial; Tissues; Toxic effect; Work; aerosolized; authority; clinical application; clinical development; commercial application; commercialization; cytokine release syndrome; design; drug candidate; drug development; efficacy evaluation; efficacy study; endothelial dysfunction; experimental study; forging; improved; improved outcome; lung injury; mortality; nanoformulation; novel; pharmacokinetics and pharmacodynamics; pre-Investigational New Drug meeting; preclinical development; preclinical efficacy; prevent; repository; safety study; sepsis induced ARDS; septic patients; side effect; systemic inflammatory response; systemic toxicity; therapeutically effective; ventilation

PROJECT SUMMARY/ABSTRACT CMTx Biotech is a drug development company working to rescue, develop and commercialize a proprietary clinical-stage drug candidate, incyclinide (CMT-3 / COL-3), for the treatment of sepsis patients at risk of acute respiratory distress syndrome (ARDS). According to the U.S. Centers for Disease Control (CDC), at least 1.7 million American adults develop sepsis annually, resulting in nearly 270,000 deaths. Sepsis accounts for more than 50% of hospital deaths, and mortality increases dramatically with greater disease severity: 10–20% for sepsis, 20–40% for severe sepsis, and 40–80% for septic shock. Sepsis is a medical emergency characterized by severe immune dysregulation with a very complex immunopathogenesis. ARDS is a devastating complication of severe sepsis, both with similar underlying mechanisms characterized by inflammation and endothelial dysfunction. Sepsis is the leading cause of ARDS and accounts for 32% of the etiology of the condition. Approximately 6-7% of sepsis patients rapidly progress to ARDS, which is associated with a significantly increased risk of in-hospital mortality. There is currently no specific treatment for sepsis-induced ARDS. Moreover, researchers have not yet elucidated the multifactorial mechanisms by which sepsis induces ARDS, or why the inflammatory cytokine storm eventually induces diffuse alveolar damage and severe hypoxia. Though advances in treatment modalities have improved the outcome over recent decades, including lung protective ventilation, prone positioning, use of neuromuscular blockade, and extracorporeal membrane oxygenation, the mortality rate still remains high. There remains a critical unmet need for the development of safe and efficacious therapeutics to prevent the onset of sepsis-induced ARDS, protect against lung injury and improve survival. CMTx Biotech is working to develop and commercialize a novel and proprietary nanoformulation of incyclinide (nCMT-3) that can be aerosolized, and which can be delivered to specifically target the lung and treat sepsis- induced ARDS while limiting systemic toxicity. Incyclinide is a clinical-stage, non-antibiotic, chemically-modified tetracycline that belongs to a class of pleiotropic matrix metalloproteinase (MMP) modulators which inhibit pathologically-excessive collagenolysis and resolve systemic inflammation. Importantly, the safety of incyclinide has already been demonstrated in Investigational New Drug (IND)-enabling studies, and incyclinide has been evaluated in a number of human clinical trials for the treatment of diseases as disparate as AIDS-related Kaposi’s sarcoma, recurrent high-grade gliomas, refractory metastatic cancer, acne, rosacea and periodontitis. Published pre-clinical efficacy studies have shown that systemic administration of incyclinide prevents the development of ARDS and septic shock, and improves survival in several chronic insidious onset animal models of ARDS across several species, including mice, rats, pigs, and sheep. Our long-term goal is to obtain regulatory approval from the FDA and comparable international regulatory authorities to market aerosolized nCMT-3 for the treatment and prevention of sepsis-induced ARDS. We strongly anticipate that nCMT-3 will inhibit disease progression, mitigate acute lung injury and respiratory distress, reduce the need for intensive care and intubation, and improve clinical outcomes for sepsis patients, including overall survival. Our specific aims are (a) to determine the pharmacokinetics, biodistribution, and safety of aerosolized nCMT-3 in mechanically ventilated pigs with healthy lungs, (b) to demonstrate the efficacy of aerosolized nCMT-3 in reducing the incidence and mortality of sepsis- mediated ARDS in a high-fidelity, clinically applicable porcine sepsis-induced ARDS model, and (c) to demonstrate the efficacy of aerosolized nCMT-3 at reducing local and systemic inflammation. Successful completion of these studies will allow CMTx Biotech to advance nCMT-3 towards human clinical trials for the treatment of ARDS patients.

项目摘要/摘要 CMTx Biotech是一家药物开发公司，致力于拯救、开发和商业化一种专利 临床阶段候选药物因环素(CMT-3/Col-3)，用于治疗有急性发作风险的脓毒症患者 呼吸窘迫综合征(ARDS)。根据美国疾病控制中心(CDC)的数据，至少有1.7 每年有数百万美国成年人患上败血症，导致近27万人死亡。脓毒症所占比例更大 超过50%的医院死亡，死亡率随着疾病严重程度的增加而急剧增加：10%-20% 脓毒症，20-40%为严重脓毒症，40-80%为感染性休克。脓毒症是一种以医疗急症为特征的 通过严重的免疫失调和非常复杂的免疫发病机制。急性呼吸窘迫综合征是一个毁灭性的并发症 严重脓毒症，两者具有相似的潜在机制，以炎症和内皮为特征 功能障碍。脓毒症是ARDS的主要原因，占该病病因的32%。 大约6-7%的脓毒症患者迅速进展为ARDS，这与显著的 院内死亡风险增加。目前还没有针对脓毒症引起的ARDS的特效治疗方法。 此外，研究人员尚未阐明脓毒症导致ARDS的多因素机制。 或者为什么炎性细胞因子风暴最终会导致弥漫性肺泡损伤和严重缺氧。尽管 近几十年来，治疗方法的进步改善了结果，包括肺保护 呼吸机、俯卧位、使用神经肌肉阻滞剂和体外膜氧合。 死亡率仍然居高不下。开发安全和有效的药物仍然存在尚未得到满足的迫切需要 预防脓毒症引起的ARDS的治疗方法，保护肺损伤并提高存活率。 CMTx生物技术公司正在努力开发和商业化一种新型的、专有的环磷酰胺纳米制剂 (nCMT-3)，可以雾化，并可以输送到特定的肺部靶点和治疗败血症- 在限制全身毒性的同时诱发ARDS。因环素是一种临床阶段、非抗生素、化学修饰的药物 四环素是一类多效性基质金属蛋白酶调节剂，它能抑制 病理上-过度的胶原蛋白溶解和消除全身炎症。重要的是，因环素的安全性 已经在研究性新药(IND)使能研究中得到证明，而因环素 在许多人类临床试验中进行评估，以治疗与艾滋病相关的卡波西氏症等不同的疾病 肉瘤、复发的高级别胶质瘤、难治性转移癌、痤疮、酒渣鼻和牙周炎。已出版 临床前疗效研究表明，全身应用因环素可防止 ARDS和感染性休克，并提高了几种慢性隐匿性ARDS动物模型的存活率 几个物种，包括老鼠、老鼠、猪和绵羊。我们的长期目标是获得监管部门的批准 FDA和类似的国际监管机构将雾化nCMT-3用于治疗和 预防脓毒症引起的ARDS。我们强烈预期nCMT-3将抑制疾病的进展，缓解 急性肺损伤和呼吸窘迫，减少重症监护和插管的需要，改善临床 脓毒症患者的预后，包括总存活率。我们的具体目标是：(A)确定 雾化吸入nCMT-3在健康猪体内的药代动力学、生物分布和安全性 (B)证明雾化nCMT-3在降低脓毒症的发病率和死亡率方面的有效性。 在高保真、临床适用的猪败血症诱导的ARDS模型中介导性ARDS，以及(C) 证明雾化nCMT-3在减少局部和全身炎症方面的效果。成功 这些研究的完成将使CMTx Biotech能够将nCMT-3推进到人类临床试验中 ARDS患者的治疗。