Repurposing Incyclinide for the Treatment of Hospitalized COVID-19 Patients

项目摘要/摘要 CMTx Biotech是一家药物开发公司，致力于拯救和重新使用一种专有的临床阶段药物 治疗严重急性呼吸道感染患者的候选药物因环素(CMT-3/Col-3) 冠状病毒2型综合症(SARS-CoV-2)和患有2019年冠状病毒病(新冠肺炎)。自晚些时候 2019年12月，一起新型人畜共患冠状病毒(SARS-CoV-2/新冠肺炎)暴发，临床表现为 与病毒性肺炎非常相似的表现夺走了全球超过41.8万人的生命，其中包括 仅在美国就有超过11.7万人(截至2020年6月13日)。新冠肺炎传染性很强，感染了740多万人 全球患者到目前为止，平均潜伏期为4天。新冠肺炎常见症状报告 包括发烧、咳嗽、肌肉酸痛或疲劳，以及呼吸急促。大约20%-30%的住院COVID- 19名患者需要重症监护进行呼吸支持。新冠肺炎可导致急性肺损伤、急性呼吸窘迫综合征、 多器官衰竭和死亡。研究表明，新冠肺炎的死亡率高达4.2%。 预测死亡结果的因素包括年龄、潜在疾病或继发感染的存在以及 血液中的炎症指标升高，死亡可能是由于病毒激活的“细胞因子风暴” 综合征“或暴发性心肌炎。目前还没有针对新冠肺炎的疫苗，只有Remdesivir(吉利德) Science)在一项随机、双盲、安慰剂对照的临床试验中显示了有效性，还有 FDA的紧急使用授权。新冠肺炎患者的临床管理包括及时 实施建议的感染预防和控制措施以及支持性管理 并发症的发生，包括机械通气和先进的器官支持。CMTx生物技术公司正在努力 重新调整用途并将因环磷酰胺商业化，作为住院COVID的每日一次口服治疗- 19例患者。因环素是一种临床阶段的、非抗生素的、化学修饰的四环素类药物。 抑制病理性过度胶原酶溶解的多效性基质金属蛋白酶调节剂 并化解全身炎症。最近在Silico上进行的两项独立研究表明 因环素可能对新冠肺炎患者有显著的治疗益处。重要的是， 因环素已经在研究新药(IND)-使能研究中得到证实， 已经在许多人类临床试验中进行了评估，用于治疗像艾滋病这样不同的疾病- 相关的Kaposi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。已发表的临床前疗效研究表明，全身给药依曲环素 预防ARDS和感染性休克的发展，并提高几种慢性潜伏性发作的存活率 几个物种的ARDS动物模型，包括小鼠、大鼠、猪和绵羊。我们的长期目标是 获得FDA的紧急使用授权(EUA)和监管部门的批准，将因环素推向市场 安全有效地治疗新冠肺炎患者，以及与一家医药公司建立合作伙伴关系 公司以许可证或收购的形式。我们强烈预期因环素会抑制新冠肺炎 疾病进展，减轻急性肺损伤和呼吸窘迫，减少对重症监护和 插管，并改善新冠肺炎患者的临床结果，包括总存活率。我们的具体目标 正在设计一项II期临床研究，以评估因环素治疗卵巢癌的安全性和有效性。 住院的新冠肺炎患者，制定IND前简报文件，包括临床研究概要，以及 让FDA参加IND前的会议。此外，我们打算准备关键的临床研究文件，包括 完整的临床研究方案、研究人员手册和知情同意书，以及详细的计划 支持研究新药的统计分析、招募和保留以及数据管理 (IND)提交给FDA。成功完成这项临床试验计划拨款将使我们能够进行 第二阶段人类临床研究，评价每日一次的口服因环素制剂治疗 住院新冠肺炎患者的救治。

PROJECT SUMMARY/ABSTRACT CMTx Biotech is a drug development company working to rescue and repurpose a proprietary clinical-stage drug candidate, incyclinide (CMT-3 / COL-3), for the treatment of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and suffering from Coronavirus disease 2019 (COVID-19). Since late December 2019, an outbreak of a novel zoonotic coronavirus (SARS-CoV-2 / COVID-19) with clinical presentations greatly resembling viral pneumonia has claimed the lives of over 418,000 worldwide, including over 117,000 in the U.S. alone (as of 6/13/2020). COVID-19 is highly contagious, infecting over 7.4 million patients globally so far, with an average incubation period of 4 days. Frequently reported COVID-19 symptoms include fever, cough, myalgia or fatigue, and shortness of breath. Approximately 20-30% of hospitalized COVID- 19 patients have required intensive care for respiratory support. COVID-19 can lead to acute lung injury, ARDS, multiple organ failure and death. Studies have shown that COVID-19 has a mortality rate of up to 4.2%. Predictors of fatal outcomes include age, the presence of underlying diseases or secondary infection, as well as elevated inflammatory indicators in the blood, and mortality may be due to virus-activated “cytokine storm syndrome” or fulminant myocarditis. There is currently no vaccine for COVID-19, and only Remdesivir (Gilead Sciences) has shown efficacy in a randomized, double-blind, placebo-controlled clinical trial, along with Emergency Use Authorization from the FDA. Clinical management of COVID-19 patients includes prompt implementation of recommended infection prevention and control measures, as well as supportive management of complications, including mechanical ventilation and advanced organ support. CMTx Biotech is working to repurpose and commercialize incyclinide as a once-daily, orally-administered treatment for hospitalized COVID- 19 patients. 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. Two recent independent studies performed in silico have suggested that incyclinide may have significant therapeutic benefit in patients with COVID-19. 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 Emergency Use Authorization (EUA) and regulatory approval from the FDA to market incyclinide for the safe and effective treatment of COVID-19 patients, as well as to establish a partnership with a pharmaceutical company in the form of a license or acquisition. We strongly anticipate that incyclinide will inhibit COVID-19 disease progression, mitigate acute lung injury and respiratory distress, reduce the need for intensive care and intubation, and improve clinical outcomes for COVID-19 patients, including overall survival. Our specific aims are to design a Phase II clinical study to evaluate the safety and efficacy of incyclinide for the treatment of hospitalized COVID-19 patients, develop a pre-IND briefing document inclusive of a clinical study synopsis, and engage the FDA in a pre-IND meeting. Moreover, we intend to prepare key clinical study documents, including a full clinical study protocol, investigator brochure and informed consent form, along with detailed plans for statistical analysis, recruitment and retention, and data management, in support of an Investigational New Drug (IND) submission to the FDA. Successful completion of this clinical trial planning grant will allow us to pursue a Phase II human clinical study to evaluate a once-daily, orally-administered formulation of incyclinide for the treatment of hospitalized COVID-19 patients.