A CETR-based partnership accelerator for rapid drug development targeting SARS-CoV-2 and pan-CoVs

基于 CETR 的合作加速器，用于针对 SARS-CoV-2 和泛冠状病毒的快速药物开发

• 批准号: 10187269
• 负责人: David S Perlin
• 金额: $ 61.99万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-25 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187269
• 关键词: 2019-nCoV; Address; Advanced Development; Animal Model; Anti-Infective Agents; Antiviral Agents; Authorization documentation; Bacterial Infections; Biological Assay; COVID-19; COVID-19 pandemic; Cells; Chemicals; Clinic; Clinical; Clinical Research; Clinical Trials; Collection; Complement; Coronavirus; Data; Development; Disease Outbreaks; Dose; Drug Kinetics; Emergency Situation; Enzymes; Excretory function; FDA approved; Future; Goals; Hospitals; Human; In Vitro; Infection; Lead; Libraries; Metabolic; Metabolism; Middle East Respiratory Syndrome; Modeling; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Plasma; Property; Protease Inhibitor; Regimen; Research; Respiratory Tract Infections; Rodent; Rodent Model; SARS coronavirus; Safety; Structure-Activity Relationship; Therapeutic; Time; Toxic effect; Translational Research; Treatment Efficacy; United States National Institutes of Health; Vaccines; Viral; Viral Proteins; Virus; Zoonoses; absorption; base; clinical development; coronavirus disease; drug candidate; drug development; drug discovery; first-in-human; global health; in silico; in vivo; interest; lead candidate; lead series; novel; novel coronavirus; nucleoside inhibitor; pandemic disease; patient population; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; public-private partnership; remdesivir; response; sample collection; small molecule; translational research program

SUMMARY The unprecedented COVID-19 global health crisis is fueled by the absence of an effective vaccine and no specific antiviral drugs. Consequently, major research efforts have focused on identifying efficacious therapies. The most effective short-term solution is repurposing and repositioning of approved drugs or clinical-stage drug candidates, as this approach shortens the time to the clinic. Furthermore, as there are no drugs against any zoonotic coronaviruses associated with human respiratory infections, pan-coronavirus drug regimens are vital to counter future outbreaks. To best address this urgency, a drug development Accelerator has been established as a formal partnership between our NIH Center of Excellence in Translational Research (CETR) and Merck and Co., Inc., a global leader in the discovery and development of antiviral drugs. The CETR program, which is focused on novel and repositioned drugs against high-threat bacterial infections, provides a comprehensive platform for drug discovery. Merck brings a full complement of approved antiviral drugs and advanced candidates for repurposing and repositioning, with an emphasis on novel nucleoside and protease inhibitors. Firstly, small molecule compounds representing both FDA approved drugs and clinical stage drug candidates discovered against other viruses will be evaluated in viral cytopathic and neutralization assays to assess inhibition of SARS- CoV-2. Lead candidates will be assessed for EC50/90/CC50 values, ADME pharmacokinetics, and safety to determine their potential for immediate use in therapy. If data supports a robust therapeutic window, then repurposed compound(s) will be submitted for an IND under FDA EUA. A rodent model utilizing SARS-CoV-2 infection will be used to assess in vivo PK/PD parameters supporting clinical dose ranging and safety margins. Secondly, a pan-coronavirus drug development candidate will be identified from either drug repositioning or from Merck’s focused compound libraries for existing antiviral classes discovered against other conserved viral targets, as well as new lead series to host and viral targets representing >65 mechanisms of action. These compounds will be screened in a high throughput virus challenge assay. SAR will benefit from the multi-million compound Merck sample collection via in silico substructure and similarity searches. Lead compounds will be assessed for robust in vivo therapeutic efficacy against SARS-CoV-2; metabolic stability, toxicity, ADME, rodent tolerability; pharmacologic properties consistent with QD or BID dosing, and acceptable safety margins supportive of initiation of first in human clinical studies. The ultimate goal is the identification of development candidates that can enter preclinical IND enabling safety derisking studies. This is an unprecedented public-private partnership for drug discovery The goal of this drug Accelerator is to identify a repurposed compound(s) that can treat COVID-19 patients within 4-6 months and by the end of Year 2, identify candidates with pan-coronavirus efficacy that can enter preclinical IND-enabling and derisking studies.

概括 由于缺乏有效的疫苗且没有具体的措施，加剧了史无前例的 COVID-19 全球健康危机 经过测试，主要研究工作集中在确定最有效的治疗方法上。 有效的短期解决方案是重新利用和重新定位已批准的药物或临床阶段的候选药物， 因为这种方法缩短了到诊所的时间此外，因为没有针对任何人畜共患疾病的药物。 与人类呼吸道感染相关的冠状病毒，泛冠状病毒药物疗法对于对抗至关重要 为了最好地解决这一紧迫问题，我们建立了药物开发加速器。 我们的 NIH 卓越转化研究中心 (CETR) 与默克公司建立了正式合作伙伴关系 Co, Inc.，抗病毒药物发现和开发的全球领导者，该项目是 CETR 项目。 专注于针对高威胁细菌感染的新型和重新定位药物，提供全面的 默克带来了全套已批准的抗病毒药物和先进候选药物。 用于重新利用和重新定位，重点是新型核苷和蛋白酶抑制剂。 发现了代表 FDA 批准的药物和临床阶段候选药物的分子化合物 将在病毒细胞病变和中和试验中评估对其他病毒的抑制作用，以评估对 SARS- 将评估主要候选药物的 EC50/90/CC50 值、ADME 药代动力学和安全性。 确定它们立即用于治疗的潜力 如果数据支持强大的治疗窗口，那么 重新利用的化合物将根据 FDA EUA 提交 IND 使用 SARS-CoV-2 的啮齿动物模型。 感染将用于评估支持临床剂量范围和安全裕度的体内 PK/PD 参数。 其次，将通过药物重新定位或从药物中确定泛冠状病毒药物开发候选药物。 默克针对其他保守病毒发现的现有抗病毒药物的重点化合物库 靶点，以及代表超过 65 种作用机制的宿主和病毒靶点的新先导系列。 化合物将通过高通量病毒挑战试验进行筛选，这将受益于数百万美元。 化合物默克样品收集将通过计算机子结构和相似性搜索进行。 评估针对 SARS-CoV-2 的强大体内治疗功效、代谢稳定性、毒性、ADME、 啮齿类动物的耐受性；与 QD 或 BID 给药一致的药理学特性以及可接受的安全性 支持首次人体临床研究的利润率最终目标是鉴定。 可以进入临床前 IND 的开发候选者，从而实现安全性去风险研究。 前所未有的药物发现公私合作伙伴关系 该药物加速器的目标是确定 重新调整用途的化合物可以在 4-6 个月内治疗 COVID-19 患者，并在第 2 年年底之前确定 具有泛冠状病毒功效的候选者，可以进入临床前 IND 支持和降低风险的研究。