Amid the current pandemic, there is currently no official approved drug indicated to treat patients with coronavirus disease 2019 (COVID-19). However, the FDA has temporarily approved certain antiviral medications and anti-inflammatory drugs to use for the emergency treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to potentially reduce hospitalization rates for infected patients.

Coronaviruses are a family of viruses consisting of positive, single-stranded RNA that infects animals and humans. It can cause respiratory and intestinal infections and can present a diversity of clinical presentations from asymptomatic to respiratory failure. Common symptoms include fever, cough, myalgia, headache, and, in some cases, diarrhea.¹  

Remdesivir (Veklury) is currently indicated by the FDA for emergency use to treat COVID-19 patients. Gilead Sciences began research on remdesivir originally in 2009 to treat hepatitis C, respiratory syncytial virus (RSV), Ebola, and other human coronaviruses (SARS and Middle East respiratory syndrome). Remdesivir is a nucleoside analog prodrug, so it works to mimic a component of viral RNA that the virus needs to replicate itself.

The virus uses an enzyme called RNA-dependent RNA polymerase to replicate the viral genome. When the RNA polymerase picks up remdesivir instead, the drug inhibits viral replication by preventing the RNA assembly line from copying and replicating the viral genome.

The stopping of the viral replication by remdesivir is likely the cause for shortened hospitalization time for patients infected with SARS-CoV-2, as the body has less viral load to fight off but is not necessarily effective in terms of eliminating the virus from the body.¹

Possible adverse effects of remdesivir include increased liver enzymes (indicating inflammation of the liver), infusion-related reactions (bruising, bleeding, swelling), low blood pressure, dizziness, nausea, vomiting, sweating, chills, and shivering.²

Baricitinib (Olumiant) is a product licensed by Eli Lilly and Company that is approved for treatment for rheumatoid arthritis.³ Baricitinib is an oral, selective Janus kinase (JAK1 and JAK2) inhibitor that works by inhibiting cytokine signaling in the body, which causes an inflammatory response.

It is additionally thought to assist the inhibition of AP2-associated cell proteins that host viral reproduction, thus reducing the ability of infected cells to replicate.⁴

National Institute of Allergy and Infectious Diseases (NIAID) Director Anthony S. Fauci, MD, stated, “ACTT 2 trial is currently being conducted and will examine if adding an anti-inflammatory agent to remdesivir can provide additional benefit for patients with COVID-19 and improve mortality outcomes.”³

Interferon Beta-1a (Rebif) is available as an intramuscular or subcutaneous (SC) injection that works as a cytokine in the interferon family generally indicated to treat multiple sclerosis. It has antiviral properties and works in regulating the immune response.

INF-I are the first cytokines produced during a viral infection and interfere with viral replication by several different mechanisms, either by slowing down cell metabolism or secreting more cytokines to promote adaptive immunity. The theory behind this drug is that it is able to strengthen immunity to the virus by turning on dormant parts of the immune system and directing them towards defending SARS-CoV-2 strains.⁵

Dosing
Remdesivir: Standard dosing for treatment of COVID-19 is a loading dose of 200 mg intravenous (IV) followed by 100 mg IV daily for 10 days.⁶

Baricitinib: Standard dosing for treatment of COVID-19 is a 4 mg daily by mouth for 14 days.⁷

Interferon Beta-1a: Standard dosing for treatment of COVID-19 is 0.5 mL SC injection every other day for 7 days while hospitalized for a total of 4 doses.⁸

Clinical Trials
Adaptive COVID-19 Treatment Trial 1 (ACTT 1)
This trial, sponsored by the NIAID, showed that hospitalized patients with COVID-19 showing lung involvement who received remdesivir recovered faster than patients receiving placebo. Preliminary results of the double-blind placebo trial indicate that patients who received remdesivir had a 31% faster time to recovery than those who received placebo.
The median time to recovery was 11 days for patients who took remdesivir compared with 15 days for those who received placebo. It did not show statistical significance on lowering mortality rates.⁶

Adaptive COVID-19 Treatment Trial 2 (ACTT 2)
This trial aims to evaluate combination therapy of baricitinib and remdesivir compared with remdesivir alone in patients with COVID-19 in recovery time. It is a randomized double-blind trial in which patients will be assessed daily in the hospital to undergo evaluation of efficacy and safety during the time of hospitalization.⁷ The study is still currently in progress.

Adaptive COVID-19 Treatment Trial 3 (ACTT 3)
This trial aims to compare remdesivir with SC interferon beta-1a combination therapy and remdesivir alone in the treatment for COVID-19 and evaluate whether recovery time is shorter in the combination group. This study is an adaptive randomized double-blind placebo multicenter trial and subjects will be assessed daily while hospitalized at approximately 100 sites globally.⁸ The study is still currently in progress.

Study to Evaluate the Safety and Antiviral Activity of Remdesivir in Participants with Coronavirus Disease (SIMPLE)
The open label, randomized, phase 3 SIMPLE trial evaluated 5- and 10-day treatments of remdesivir in hospitalized patients diagnosed with moderate and severe cases of COVID-19.⁹ The study showed a similar improvement in either dosing duration. A shorter dosing regimen would allow the current supply of drugs to be distributed to more patients with COVID-19.¹⁰

Discussion
Remdesivir is thought to work similarly to Tamiflu (an antiviral for influenza), as it is more beneficial to use in the earlier stages of infection. It is hoped that remdesivir reduces a patient’s viral load, so it would only be beneficial in earlier stages while the virus hasn’t replicated throughout the body as much, because once patients already develop extended lung damage, this drug alone will not be effective in treating COVID-19.

Although the results of these drugs currently show modest improvement, it is shown to be better than no therapy as currently related to people infected by the COVID-19 pandemic. The emergency use of these drugs to shorten hospitalization and prolong time for vaccine research and development will serve as a critical temporary buffer for an efficient vaccine to combat SARS-CoV-2.

About the Authors
Amy Jang is a PharmD Candidate at the University of Arizona’s School of Pharmacy, anticipated to graduate in Spring 2021.

Jonathan Ogurchak, PharmD, CSP, is the CEO and Co-Founder of STACK, a pharmacy compliance management software, and serves as preceptor for a virtual Advanced Pharmacy Practice Experiential Rotation for specialty pharmacy, during which this article was composed.

References
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  2. Commissioner, O. (2020, May 1). Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment. Retrieved August 17, 2020, from https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment
  3. National Institute of Allergy and Infectious Diseases. (2020, May 8). NIH Clinical Trial Testing Antiviral Remdesivir Plus Anti-Inflammatory Drug Baricitinib for COVID-19 Begins. Retrieved August 17, 2020, from https://www.niaid.nih.gov/news-events/nih-clinical-trial-testing-antiviral-remdesivir-plus-anti-inflammatory-drug-baricitinib
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