Remdesivir Leads the Pack of Possible Treatment Drugs for Covid-19

May 14, 2020

There are a variety of medications being studied for the COVID-19, and the possible treatment landscape is rapidly evolving.

There are a variety of medications being studied for the COVID-19, and the possible treatment landscape is rapidly evolving.

There are no FDA-approved medications for the treatment of COVID-19. Currently, medical management consists of infection prevention and supportive care, which includes supplemental oxygen and mechanical ventilator support when indicated. Based on a search of ClinicalTrials.gov, there are at least 181 clinical trials being conducted as of April 14, 2020, both studies at the recruiting stage and those that have already begun. The scientific community is coming together to find safe and effective treatment options to combat COVID-19, which include existing and novel drugs. 

Remdesivir

Remdesivir is an intravenous (IV) drug with broad antiviral activity (for example, SARS virus and Middle East respiratory syndrome) that has been used for the treatment of Ebola virus, and it works by inhibiting viral replication through premature termination of RNA transcription. Additionally, remdesivir appears to have a favorable safety profile based on its having been used to treat approximately 500 individuals, including healthy volunteers and those with acute Ebola virus infection. Remdesivir is being studied by Gilead Sciences for the treatment of COVID-19 and evidence suggests that it is currently one of the most promising investigational drugs.  

On April 29, Anthony Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), announced positive interim results of an NIAID-sponsored study of remdesivir. Fauci said the time to recovery was shorter for COVID-19 patients randomized to the remdesivir arm of the study than the patients in the placebo arm (11 days vs. 15 days) and that difference was statistically significant. However, on the same day, results published in Lancet from a randomized, placebo-controlled trial of remdesivir conducted in the Hubei province in China showed no association between treatment with the antiviral and a difference in time to recovery. Results of a cohort study were published in the New England Journal of Medicine on April 10, 2020, examining compassionate use of remdesivir in 61 patients hospitalized with COVID-19 with an oxygen saturation of 94% or less while breathing ambient air or who required oxygen support.

Patients received a 10-day treatment of remdesivir 200 milligrams (mg) IV on day 1 followed by 100 mg for the remaining 9 days of therapy. Fifty-three patients had data analyzed (seven lacked posttreatment data, one had a dosing error) and clinical improvement was seen in 68% of patients. A total of 32 patients (60%) reported adverse events (AEs) during follow-up. The most common AEs were increased hepatic enzymes, diarrhea, rash, renal impairment and hypotension. Twelve patients (23%) experienced serious AEs, including multiple organ dysfunction syndrome, septic shock, acute kidney injury and hypotension, with most occurring in those receiving invasive ventilation. The results are promising, but  more robust studies are needed to determine the safety and efficacy of remdesivir for patients with COVID-19. Study limitations included the drug not being randomized and lacking a control, missing data, and a short follow-up duration.

Related: The Search is on For Treatment Drugs and a Vaccine

There are currently two phase 3 randomized clinical trials, known as the SIMPLE studies, for patients with severe COVID-19 symptoms (NCT04292899) and for those with moderate symptoms (NCT04292730). Gilead released topline results from the SIMPLE trial studying patients with severe COVID-19, which demonstrated similar improvement with the five- and 10-day treatment regimens of remdesivir.  Time to improvement for 50% of study participants was 10 days in the five-day treatment group, and more than half of patients in both groups were discharged from the hospital by 14 days. Results are expected by May 2020 for the study evaluating patients with moderate COVID-19.  Since January 25, 2020, as part of individual compassionate use protocols, Gilead has been providing emergency access to remdesivir for over 1,800 qualifying patients with severe COVID-19 symptoms who are unable to enroll in ongoing clinical trials. The company is currently working on transitioning to expanded access of remdesivir for patients with severe symptoms and will collect and analyze treatment data.  

Hydroxychloroquine, chloroquine and azithromycin

The FDA recently issued an emergency use authorization (EUA) for the use of the antimalarial drugs chloroquine and hydroxychloroquine (Plaquenil) for the treatment of hospitalized adult and adolescent patients with COVID-19 who are unable to participate in a clinical trial and who weigh 50 kg or more. These medications have immunomodulatory activity that could contribute to an anti-inflammatory response, which is the theoretical mechanism of action for the proposed treatment of COVID-19. The dosage of hydroxychloroquine recommended by the EUA is 800 mg on the first day of treatment followed by 400 mg daily for four  to seven days of total therapy, based on clinical evaluation. Chloroquine’s EUA recommends 1 g on day one followed by 500 mg daily for four to seven days of total treatment, based on clinical evaluation. However, there is controversy surrounding these drugs, as their safety and efficacy for the treatment of COVID-19 have not been established. Limited evidence suggests that these medications may have clinical benefits in patients with COVID-19.  

Hydroxychloroquine with azithromycin was examined in observational and nonrandomized studies in France for the treatment of COVID-19, but data were limited as many individuals were considered to be low risk and only a small number of patients were included. Azithromycin has immunomodulatory and anti-inflammatory properties, but there are currently insufficient data for its adjunctive use in the management of COVID-19. Both hydroxychloroquine and azithromycin are associated with QT prolongation, so patients with chronic medical conditions should be closely monitored to prevent drug-induced cardiac AEs. A jointly published guidance was released on April 8, 2020, by the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society regarding possible serious health risks associated with hydroxychloroquine and azithromycin. Recommendations include QT interval monitoring, withholding hydroxychloroquine and azithromycin in patients with baseline QT prolongation or known congenital long QT syndrome, correcting hypokalemia and hypomagnesemia, and avoiding other QTc-prolonging medications. 

The safety and efficacy of hydroxychloroquine for the treatment of COVID-19 will be further evaluated in the ORCHID Study (NCT04332991)by the National Heart, Lung and Blood Institute. This phase 3 multicenter, placebo-controlled, randomized trial aims to enroll approximately 500 patients, and is estimated to have initial results by April 2021. There are also chloroquine studies underway in China and other countries, as there is currently limited evidence regarding the drug’s effectiveness for COVID-19. One randomized phase 2b clinical trial compared high-dose chloroquine (600 mg twice daily for 10 days) with low-dose chloroquine (450 mg for five days, twice daily only on first day) in 81 patients with severe COVID-19 in Brazil.All patients also received azithromycin and ceftriaxone. The fatality rate was 13.5%, with more deaths and QTc prolongation occurring in the high-dose treatment group.The study halted the high-dose treatment arm and results were posted to medRxiv, the preprint server for health sciences, but the study has not yet been peer reviewed. These results shed light on cardiac AEs potentially being dose dependent.  

One man in Arizona died and his wife was hospitalized after they both ingested chloroquine phosphate, commonly used at aquariums to clean fish tanks, in an attempt to prevent COVID-19.The American Association of Poison Control Centers released a statement about AEs relating to hydroxychloroquine and chloroquine, especially nonpharmaceutical formulations that can be particularly dangerous, as exposure to these drugs has increased.

Tocilizumab   

Tocilizumab (Actemra), manufactured by Genentech, is a recombinant humanized monoclonal antibody that is an interleukin-6 (IL-6) receptor antagonist, with a proposed mechanism of action that combats cytokine release syndrome, or “cytokine storms,”  in some severe cases of COVID-19. The drug is currently approved to treat various conditions such as rheumatoid arthritis; however, there are limited data demonstrating that tocilizumab shows benefit for severe COVID-19 symptoms and results in fever reduction and a decreased need for supplemental oxygen. Because tocilizumab is an immunosuppressive drug, it can increase the risk of serious infections. 

A phase 3 randomized multicenter study is underway to evaluate the safety and efficacy of tocilizumab in hospitalized patients with severe COVID-19 pneumonia.

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