Ensuring continued progress for development of COVID-19 therapeutics in children.
Ensuring continued progress for development of COVID-19 therapeutics in children.
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DOI：
10.1038/s41390-021-01384-y
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发表时间：
2021-12
影响因子：
3.6
通讯作者：
Connor EM
中科院分区：
文献类型：
--
作者：
Noel GJ;DeBiasi RL;Crandall W;Connor EM
一旦发现儿童也可能发展为与SARS-CoV-2感染相关的严重疾病，1，2就很明显需要开发治疗这些感染儿童的药物。基于从相关冠状病毒工作中积累的知识，COVID-19潜在疗法的鉴定和测试在成人中取得了迅速进展。适应性COVID-19治疗试验（ACTT）的非临床和初步结果提供了足够的证据支持启动试验，以评估Remdesivir在SARS-CoV-2感染儿童中的安全性，药代动力学和活性。3其他直接作用的抗病毒药物（DAA）可以提供类似的好处，如galidesivir，favipirivir，molnupiravir（EIDD-2801）和SARS-CoV-2中和抗体正在通过临床前和早期临床开发取得进展。除了DAA的潜在治疗益处外，与SARS-CoV-2感染相关的免疫病理生理学的贡献提高了针对靶点的免疫调节剂的再利用的可能性，所述靶点例如白细胞介素-6、janus激酶（JAK）、信号转导子和转录激活子、鞘氨醇-1-磷酸受体、应用肿瘤坏死因子及地塞米松减轻肺部炎症可作为抗病毒药物的后续治疗。5与这一策略相一致，ACTT已经被无缝地修改，以研究Remdesivir + baricitinib（JAK抑制剂）在严重COVID-19成人中的组合。6显然，COVID-19治疗正在迅速发展。为了使儿童研究性COVID-19治疗药物的开发与成人研究进展保持同步，重要的是要专注于优化获得数据的方法，以评估有前景的研究药物的安全性和有效性。首先，重要的是要考虑有多少成人疗效数据可以外推到儿童（图1）的基础上的条件和治疗反应的相似性。在最佳开发抗逆转录病毒药物，从而迅速获得治疗感染人类免疫缺陷病毒儿童的创新药物方面的经验，可以指导这一做法。7对于具有抗SARS-CoV-2活性的DAA，在大多数情况下，预期在给定药物暴露下的作用模式和对治疗的反应在年龄范围内是相似的。使用这种模式，Remdesivir的儿科开发计划在中期ACTT结果报告后数周内开始，并得到了成人和儿童的安全性数据的支持，这些数据来自同情使用和使用Remdesivir治疗埃博拉病毒的试验。同样，针对使用Remdesivir治疗住院COVID-19患者发布的紧急使用授权包括基于生理学药代动力学方法估计的体重超过3.5 kg的儿科患者的剂量建议。8虽然瑞德西韦ACTT试验不包括儿童，但吉利德进行的两项III期试验包括青少年（> 12岁）。由于假定成人和儿童的疾病和对治疗的反应相似，因此设计了一项约52例儿科患者（出生至< 18岁）的儿科试验，以评估安全性和PK，病毒学和临床结局作为次要终点。9儿童试验开始时间的考虑因素是风险/效益评估，其中包括考虑疾病的严重性、成人的初步数据和Remdesivir的累积安全性。随着新的DAA的开发，这些相同的元素可以用于规划儿科发展…
Once it became evident that children can also develop severe illness associated with SARS-CoV-2 infection, 1, 2 it was clear that the development of drugs to treat children with these infections would be needed. Building upon knowledge accrued from work in related coronaviruses, the identification and testing of potential therapeutics for COVID-19 has progressed rapidly in adults. The nonclinical and preliminary results from the Adaptive COVID-19 Treatment Trial (ACTT) provided sufficient evidence to support initiation of trials to evaluate the safety, pharmacokinetics, and activity of remdesivir in children with SARS-CoV-2 infections. 3 Other direct acting antivirals (DAAs) that could offer similar benefits such as galidesivir, favipirivir, molnupiravir (EIDD-2801) and SARS-CoV-2-neutralizing antibodies are advancing through preclinical and early clinical development. 4 In addition to the potential therapeutic benefits of DAAs, the contribution of immune pathophysiology associated with SARS-CoV-2 infection has raised the possibility that repurposing immune modulators directed at targets such as interleukin-6, janus kinase (JAK), signal transducer and activator of transcription, sphingosine-1-phosphate receptors, and tumor necrosis factor and using dexamethasone to reduce pulmonary inflammation could be used as adjunctive therapies to antivirals. 5 Aligning with this strategy, ACTT has seamlessly been modified to study the combination of remdesivir plus baricitinib (JAK inhibitor) in adults with serious COVID-19. 6 Clearly COVID-19 treatment is rapidly evolving. For pediatric development of investigational COVID-19 therapeutics to keep pace with progress in adults, it is important to focus on optimizing methods for obtaining data to evaluate the safety and efficacy of promising investigational agents. First, it is important to consider how much adult efficacy data can be extrapolated to children (Fig. 1) based on the similarity of the condition and treatment response. Experience in optimal development of antiretrovirals leading to rapid availability of innovative drugs to treat children with human immunodeficiency virus can serve in guiding this approach. 7 For DAAs with activity against SARS-CoV-2, the mode of action and the response to treatment at a given drug exposure are anticipated to be similar across the age spectrum in most cases. Using this paradigm, the pediatric development program for remdesivir was started within weeks after the interim ACTT results were reported and was supported by safety data from adults and children treated by compassionate use and trials in which remdesivir was used to treat Ebola. Similarly, the Emergency Use Authorization issued for use of remdesivir to treat hospitalized COVID-19 patients included dosing recommendations for pediatric patients weighing greater than 3.5 kg based on estimations using physiologically based pharmacokinetic methods. 8 Although the remdesivir ACTT trial did not include children, adolescents (> 12 years of age) are included in the two phase 3 trials conducted by Gilead. Because the disease and response to therapy were assumed to be similar between adults and children, a pediatric trial of approximately 52 pediatric patients (birth to< 18 year of age) was designed to assess safety and PK with virologic and clinical outcomes as secondary endpoints. 9 A consideration for the timing of the start of pediatric trials was a risk/benefit assessment which included the consideration of the seriousness of the disease, the preliminary data in adults, and the cumulative safety profile of remdesivir. As new DAAs are developed, these same elements can be used for planning a pediatric development …
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