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.

项目概要/摘要 CMTx Biotech 是一家药物开发公司，致力于抢救、开发和商业化专有药物 临床阶段候选药物，incyclinide (CMT-3 / COL-3)，用于治疗有急性发作风险的脓毒症患者 根据美国疾病控制中心 (CDC) 的数据，呼吸窘迫综合征 (ARDS) 至少为 1.7。 每年有 100 亿美国成年人患上败血症，导致近 27 万人死于败血症。 超过 50% 的医院死亡，并且死亡率随着疾病严重程度的增加而急剧增加：10-20% 脓毒症，严重脓毒症占 20-40%，脓毒症休克占 40-80%。 ARDS 是由严重的免疫失调引起的，具有非常复杂的免疫发病机制，是一种毁灭性的并发症。 严重脓毒症，两者具有相似的潜在机制，以炎症和内皮细胞为特征 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，这与显着的 院内死亡风险增加。目前尚无针对脓毒症引起的 ARDS 的具体治疗方法。 此外，研究人员尚未阐明脓毒症诱发 ARDS 的多因素机制， 或者为什么炎症细胞因子风暴最终会引起弥漫性肺泡损伤和严重缺氧。 近几十年来，治疗方式的进步改善了结果，包括肺保护 通气、俯卧位、使用神经肌肉阻滞和体外膜肺氧合， 死亡率仍然居高不下，对开发安全有效的药物的需求仍未得到满足。 预防脓毒症引起的 ARDS 发作、防止肺损伤并提高生存率的治疗方法。 CMTx Biotech 正在致力于开发一种新颖且专有的 incyclinide 纳米制剂并将其商业化 （nCMT-3）可以雾化，并且可以专门针对肺部并治疗脓毒症 诱导 ARDS，同时限制全身毒性。 Incyclinide 是一种临床阶段、非抗生素、化学修饰的药物。 四环素属于一类多效性基质金属蛋白酶 (MMP) 调节剂，可抑制 病理性过度胶原溶解并解决全身炎症，重要的是 incyclinide 的安全性。 已在研究性新药 (IND) 启用研究中得到证实，并且 incyclinide 已被 在许多人体临床试验中评估了其治疗与艾滋病相关的卡波西氏症等不同疾病的效果 肉瘤、复发性高级别神经胶质瘤、难治性转移癌、痤疮、红斑痤疮和牙周炎。 临床前疗效研究表明，全身给予 incyclinide 可以预防疾病的发生 ARDS 和感染性休克，并提高了几种慢性隐袭性 ARDS 动物模型的生存率 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 我们强烈预期 nCMT-3 将抑制疾病进展，减轻病情。 急性肺损伤和呼吸窘迫，减少重症监护和插管的需要，并改善临床 我们的具体目标是 (a) 确定脓毒症患者的预后。 雾化 nCMT-3 在健康机械通气猪体内的药代动力学、生物分布和安全性 肺部，(b) 证明雾化 nCMT-3 在降低脓毒症发病率和死亡率方面的功效 在高保真、临床适用的猪败血症诱导的 ARDS 模型中介导的 ARDS，以及 (c) 成功证明雾化 nCMT-3 在减少局部和全身炎症方面的功效。 这些研究的完成将使 CMTx Biotech 能够将 nCMT-3 推向人体临床试验 ARDS 患者的治疗。