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

项目总结/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有的 临床阶段候选药物，incyclinide（CMT-3 / COL-3），用于治疗有急性败血症风险的脓毒症患者 呼吸窘迫综合征（ARDS）。根据美国疾病控制中心（CDC）的数据， 每年有100万美国成年人患上败血症，导致近27万人死亡。脓毒症占比 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： 脓毒症为20-40%，严重脓毒症为40-80%，脓毒性休克为40-80%。脓毒症是一种医疗紧急情况， 由严重的免疫失调引起的，具有非常复杂的免疫发病机制。急性呼吸窘迫综合征是一种毁灭性的并发症 严重脓毒症，两者具有相似的基础机制，其特征在于炎症和内皮细胞 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，这与严重的急性呼吸衰竭相关。 增加住院死亡的风险。目前没有针对脓毒症诱导的ARDS的特异性治疗。 此外，研究人员尚未阐明脓毒症诱导ARDS的多因素机制， 或者为什么炎性细胞因子风暴最终导致弥漫性肺泡损伤和严重缺氧。虽然 近几十年来，治疗方式的进步改善了结果，包括肺保护性治疗。 通气、俯卧位、使用神经肌肉阻滞和体外膜肺氧合， 死亡率仍然很高。在开发安全有效的药物方面， 治疗，以防止败血症诱导的ARDS的发作，保护免受肺损伤和提高生存。 CMTx生物技术公司正致力于开发和商业化一种新颖的和专有的incyclinide纳米制剂 （nCMT-3），其可以被雾化，并且其可以被递送以特异性靶向肺并治疗败血症。 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 四环素，其属于一类多效基质金属蛋白酶（MMP）调节剂， 病理性过度胶原溶解和解决全身炎症。重要的是， 已经在新药临床试验（IND）中得到了证实，而incyclinide已经被 在许多治疗艾滋病相关卡波西病等不同疾病的人体临床试验中进行了评估 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。发表 临床前疗效研究表明，incyclinide的全身给药可防止 ARDS和感染性休克，并提高了几种慢性隐匿性发病的ARDS动物模型的生存率， 几个物种，包括小鼠，大鼠，猪和羊。我们的长期目标是获得监管机构的批准， FDA和类似的国际监管机构将雾化nCMT-3上市用于治疗， 预防脓毒症引起的ARDS。我们强烈预期，nCMT-3将抑制疾病进展，减轻 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 脓毒症患者的结局，包括总生存期。我们的具体目标是：（a）确定 雾化nCMT-3在健康机械通气猪中的药代动力学、生物分布和安全性 肺，（B）证明雾化nCMT-3在降低败血症发生率和死亡率方面的功效- 在高保真、临床适用的猪脓毒症诱导的ARDS模型中， 证明了雾化nCMT-3在减少局部和全身炎症方面的功效。成功 这些研究的完成将使CMTx Biotech能够将nCMT-3推向人类临床试验， 治疗ARDS患者。

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.