25 agosto, 2021

COVID-19 Treatment: Investigational Drugs and Other Therapies

Coronavirus disease 2019 (COVID-19) is defined as illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; formerly called 2019-nCoV), which was first identified amid an outbreak of respiratory illness cases in Wuhan City, Hubei Province, China. [1] It was initially reported to the World Health Organization (WHO) on December 31, 2019. On January 30, 2020, the WHO declared the COVID-19 outbreak a global health emergency. [2, 3] On March 11, 2020, the WHO declared COVID-19 a global pandemic, its first such designation since declaring H1N1 influenza a pandemic in 2009. [4] 

Utilization of programs established by the FDA to allow clinicians to gain access to investigational therapies during the pandemic has been essential. The expanded access (EA) and emergency use authorization (EUA) programs allowed for rapid deployment of potential therapies for investigation and investigational therapies with emerging evidence. A review by Rizk et al describes the role for each of these measures and their importance to providing medical countermeasures in the event of infectious disease and other threats. [5]

As of October 22, 2020, remdesivir, an antiviral agent, is the only drug fully approved for treatment of COVID-19. It is indicated for treatment of COVID-19 disease in hospitalized adults and children aged 12 years and older who weigh at least 40 kg. [6]  An emergency use authorization (EUA) remains in place for treat pediatric patients weighing 3.5 kg to less than 40 kg or children younger than 12 years who weigh at least 3.5 kg. [7] An EUA for convalescent plasma was announced on August 23, 2020. [8]

The FDA issued an emergency use authorization (EUA) for outpatient monoclonal directed therapies (ie, sotrovimab, casirivimab plus imdevimab, bamlanivimab plus etesevimab) for individuals who test positive and are at high risk of severe COVID-19 or hospitalization. [9, 10] 

Baricitinib was issued an EUA on November 19, 2020 for use, in combination with remdesivir, for treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) in hospitalized patients aged 2 years and older who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). [11]  Tocilizumab, an interleukin-6 inhibitor, was granted an EUA June 24, 2021 for treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults and pediatric patients (aged >2 years) who are receiving systemic corticosteroids and require supplemental oxygen, noninvasive or invasive mechanical ventilation, or ECMO.

The FDA has granted EUAs for 3 SARS CoV-2 vaccines since December 2020. Two are mRNA vaccines – BNT-162b2 (Pfizer) and mRNA-1273 (Moderna), whereas the third is a viral vector vaccine – Ad26.COV2.S (Johnson & Johnson).

Information, including allocation, for COVID-19 therapies granted emergency use authorization is located at the United States Public Health Emergency webpage.

Numerous other antiviral agents, immunotherapies, and vaccines continue to be investigated and developed as potential therapies. Searching for effective therapies for COVID-19 infection is a complex process. Guidelines and reviews of pharmacotherapy for COVID-19 have been published. [12, 13, 14, 15, 16, 17, 18]  The Milken Institute maintains a detailed COVID-19 Treatment and Vaccine Tracker of research and development progress.

Information, including allocation, for COVID-19 therapies granted emergency use authorization is located at the United States Public Health Emergency [link] webpage.

The urgent need for treatments during a pandemic can confound the interpretation of resulting outcomes of a therapy if data are not carefully collected and controlled. Andre Kalil, MD, MPH, writes of the detriment of drugs used as a single-group intervention without a concurrent control group that ultimately lead to no definitive conclusion of efficacy or safety. [19]

Rome and Avorn write about unintended consequences of allowing widening access to experimental therapies. First, efficacy is unknown and may be negligible, but, without appropriate studies, physicians will not have evidence on which to base judgement. Existing drugs with well-documented adverse effects (eg, hydroxychloroquine) subject patients to these risks without proof of clinical benefit. Expanded access of unproven drugs may delay implementation of randomized controlled trials. In addition, demand for unproven therapies can cause shortages of medications that are approved and indicated for other diseases, thereby leaving patients who rely on these drugs for chronic conditions without effective therapies. [20] 

Drug shortages during the pandemic go beyond off-label prescribing of potential treatments for COVID-19. Drugs that are necessary for ventilated and critically ill patients and widespread use of inhalers used for COPD or asthma are in demand. [21, 22]

It is difficult to carefully evaluate the onslaught of information that has emerged regarding potential COVID-19 therapies within a few months’ time in early 2020. A brief but detailed approach regarding how to evaluate resulting evidence of a study has been presented by F. Perry Wilson, MD, MSCE. By using the example of a case series of patients given hydroxychloroquine plus azithromycin, he provides clinicians with a quick review of critical analyses. [23]

As an example of the number of compounds being evaluated, Gordon et al identified 332 high-confidence SARS-CoV-2 human protein-protein interactions. Among these, they identified 66 human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials, and/or preclinical compounds. As of March 22, 2020, these researchers are in the process of evaluating the potential efficacy of these drugs in live SARS-CoV-2 infection assays. [24]

How these potential COVID-19 treatments will translate to human use and efficacy is not easily or quickly understood. The question of whether some existing drugs that have shown in vitro antiviral activity might achieve adequate plasma pharmacokinetics with current approved doses was examined by Arshad et al. The researchers identified in vitro anti–SARS-CoV-2 activity data from all available publications up to April 13, 2020, and recalculated an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). The researchers also calculated the unbound drug to tissue partition coefficient to predict lung concentrations that would exceed their reported EC50 levels. [25]

The NIH Accelerating Covid-19 Therapeutics Interventions and Vaccines (ACTIV) trials public-private partnership to develop a coordinated research strategy has several ongoing protocols that are adaptive to the progression of standard care.

Another adaptive platform trial is the I-SPY COVID-19 Trial for treating critically ill patients. The clinical trial is designed to allow numerous investigational agents to be evaluated in the span of 4-6 months, compared with standard of care (supportive care for ARDS, remdesivir backbone therapy). Depending on the time course of COVID-19 infections across the US. As the trial proceeds and a better understanding of the underlying mechanisms of the COVID-19 illness emerges, expanded biomarker and data collection can be added as needed to further elucidate how agents are or are not working. [26]

The WHO developed a blueprint of potential therapeutic candidates in January 2020. WHO has embarked on an ambitious global “megatrial” called SOLIDARITY in which confirmed cases of COVD-19 are randomized to standard care or one of four active treatment arms (remdesivir, chloroquine or hydroxychloroquine, lopinavir/ritonavir, or lopinavir/ritonavir plus interferon beta-1a). In early July 2020, the treatment arms in hospitalized patients that included hydroxychloroquine, chloroquine, or lopinavir/ritonavir were discontinued owing to the drugs showed little or no reduction in mortality compared with standard of care. [27]  Interim results released mid-October 2020 found the 4 aforementioned repurposed antiviral agents appeared to have little or no effect on hospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. The 28-day mortality was 12% (39% if already ventilated at randomization, 10% otherwise). [28] 

The next phase of the trial, Solidarity PLUS, continued in August 2021. WHO announced over 600 hospitals in 52 countries will participate in testing 3 drugs (ie, artesunate, imatinib, infliximab). Patients will be randomized to standard of care (SOC) or SOC plus one of the study drugs. The drugs for the trial were donated by the manufacturers; however, approximate costs are $400/day for imatinib, $3,500 for a dose of infliximab, and $50,000 for a course of artesunate.

Créditos: Comité científico Covid

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