Ridgeback Biotherapeutics, 3480 Main Highway, Unit 402, Miami, FL, 33133, USA.
Emory University School of Medicine, Drug Innovations at Emory (DRIVE) and Emory Institute of Drug Development (EIDD), 954 Gatewood Road, Atlanta, GA, 30329, USA.
Trials. 2021 Aug 23;22(1):561. doi: 10.1186/s13063-021-05538-5.
A recently published article described the safety, tolerability, and pharmacokinetic profile of molnupiravir (Painter et al. 2021), a novel antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Here, we report an unprecedented collaboration between sponsor, contract research organization (CRO), and regulatory authorities that enabled accelerated generation of these phase I data, including administration of the first-in-human (FIH) dose of molnupiravir within 5 days of receiving regulatory approval in the United Kingdom (UK). Single and multiple ascending dose (SAD and MAD, respectively) cohorts were dosed in randomized, double-blind, and placebo-controlled fashion, with a 6:2 active-to-placebo ratio in each cohort. A food-effect (FE) cohort included 10 subjects who were randomized to receive drug in the fasted or fed state followed by the fed or fasted state to complete a fed and fasted sequence for each subject. Dose escalation decisions were accelerated and MAD cohorts were initiated prior to completion of all SAD cohorts with the provision that the total daily dose in a MAD cohort would not exceed a dose proven to be safe and well-tolerated in a SAD cohort. Dosing in healthy volunteers was completed for eight single ascending dose (SAD) cohorts, seven multiple ascending dose (MAD) cohorts, and one food-effect (FE) cohort within approximately 16 weeks of initial protocol submission to the Research Ethics Committee (REC) and Medicines and Healthcare products Regulatory Agency (MHRA). Working to standard industry timelines, the FIH study would have taken approximately 46 weeks to complete and 33 weeks to enable phase 2 dosing. Data from this study supported submission of a phase 2/3 clinical trial protocol to the US Food and Drug Administration (FDA) within 8 weeks of initial protocol submission, with FDA comments permitting phase 2 study initiation within two additional weeks. In the setting of a global pandemic, this model of collaboration allows for accelerated generation of clinical data compared to standard processes, without compromising safety.
最近发表的一篇文章描述了莫努匹韦（Painter 等人，2021 年）的安全性、耐受性和药代动力学特征。莫努匹韦是一种新型抗病毒药物，对导致 2019 年冠状病毒病（COVID-19）的严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）具有强大的活性。在这里，我们报告了赞助商、合同研究组织（CRO）和监管机构之间前所未有的合作，使这些 I 期数据得以加速生成，包括在英国（UK）获得监管批准后 5 天内给予莫努匹韦的首次人体（FIH）剂量。单剂量递增（SAD）和多剂量递增（MAD）队列分别以随机、双盲和安慰剂对照的方式给药，每个队列的活性药物与安慰剂的比例为 6:2。一个食物效应（FE）队列包括 10 名受试者，他们随机接受空腹或进食状态下的药物治疗，然后再接受进食或空腹状态下的药物治疗，以完成每个受试者的空腹和进食序列。加速了剂量递增决策，并在完成所有 SAD 队列之前启动了 MAD 队列，前提是 MAD 队列中的总日剂量不会超过在 SAD 队列中证明安全且耐受良好的剂量。在向研究伦理委员会（REC）和药品和保健品管理局（MHRA）提交初始方案约 16 周内，健康志愿者完成了 8 个单剂量递增（SAD）队列、7 个多剂量递增（MAD）队列和 1 个食物效应（FE）队列的给药。按照标准行业时间表，FIH 研究大约需要 46 周才能完成，33 周才能进行 2 期给药。该研究的数据支持在向初始方案提交后 8 周内向美国食品和药物管理局（FDA）提交 2/3 期临床试验方案，FDA 的意见允许在另外两周内启动 2 期研究。在全球大流行的背景下，与标准流程相比，这种合作模式允许加速生成临床数据，同时不影响安全性。
