Pediatric Research | 2021
Ensuring continued progress for development of COVID-19 therapeutics in children
Abstract
Once it became evident that children can also develop severe illness associated with SARS-CoV-2 infection, 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. 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. 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-1phosphate receptors, and tumor necrosis factor and using dexamethasone to reduce pulmonary inflammation could be used as adjunctive therapies to antivirals. 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. 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. 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. 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. 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 program. This planning will need to consider factors such as the characteristics of the drug, availability of prior efficacy, and safety data that may be available as the result of assessing these drugs in infants and children with non-SARS-CoV-2-related diseases, the timing of intervention in the course of the disease, and practical considerations such as drug formulation which may require substantial efforts to enable administration to infants and young children. In contrast to DAAs where the activity against the virus is expected to be similar regardless of the host once similar concentrations are achieved, advancing host response modifiers as therapies for COVID-19 in children, either alone or in combination with DAAs, may need to proceed at a pace that depends on how rapidly our understanding of the inflammatory processes associated with infection progresses. Because many of the immune responses suspected to mediate SARS-CoV-2associated inflammation involve pathways for which smalland large-molecule inhibitors have already been successfully used to treat chronic inflammatory diseases, the potential for using these drugs to treat patients with SARS-CoV-2 has been widely recognized. Many of these agents have been assessed, and in some instances approved for use in children with chronic inflammatory diseases. This experience provides important information regarding their safety and tolerability and could allow for assessing the potential benefit and risk of studying these therapies in SARS-CoV-2 children such that trials involving children could progress more rapidly than if this information was not available. As this experience is considered in making decisions to advance with trials involving children it will also be important to recognize that the role of these host defense modifiers in modifying the course of an acute respiratory infectious disease process in children or an inflammatory process that is likely the basis for multisystem inflammatory syndrome in children (MIS-C) are not well established. In addition, although there may be