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Remdesivir

Authors: Chip Norwood & Oleg Kolupaev

Today, our first-ever The Pipeline Blog post will cover the antiviral drug Remdesivir. This therapeutic has received a lot of attention from the media and researchers across the globe to treat COVID-19. Herein, we detail several topics related to Remdesivir, including its discovery, mechanism of action, clinical data, and commercialization.

According to the World Health Organization (WHO), COVID-19 which is caused by the SARS-CoV-2 viral strain has affected over 2 million people globally. This virus has been extremely detrimental worldwide resulting in 435,000 deaths. Due to these facts, a spur of research was initiated to discover effective tests and therapeutics to diagnose and treat the current pandemic. Remdesivir (GS-5734) was developed by Gilead Sciences and discovery stemmed from a collaboration between Gilead, U.S. Centers for Disease Control and Prevention (CDC), and the U.S. Army Medical Research Institute of Infectious Disease (USAMRIID). The primary purpose of this collaboration was to identify therapeutic agents for RNA-based viruses that had global pandemic potential (e.g., SARS).

Like other viruses in the coronavirus family, SARS-CoV-2 is an enveloped virus covered in a plethora of spike proteins which are utilized to avoid the host’s immune system and assist in cell-binding/entry. In detail, SARS-CoV-2 utilizes the receptor angiotensin-converting enzyme 2 (ACE2) for cell entry and infection. Viral entry into the host cell initiates a cellular cascade which eventually leads to translation and RNA replication, packaging, and virion release. Remdesivir targets the translation and RNA replication stage of the virus by inhibiting the RNA-dependent RNA polymerase (RdRp). This results in chain termination and decreased viral RNA production.

The mechanism of action of Remdesivir is dictated by its chemical structure which is composed of two key components including the prodrug (highlighted blue, see below) and nucleoside (highlighted black, see below). The prodrug segment of this drug allows for better cell-permeability. Subsequently, Remdesivir undergoes several key intracellular transformations, including: 1) cleavage of the ester via an esterase, 2) cleavage of the phosphorylamine group via phosphoramidase, and 3) phosphorylation via nucleoside-phosphate kinase. The resultant active metabolite is shuttled to be incorporated into the growing RNA chain and initiate chain termination.

Remdesivir was forwarded to clinical studies due to its promising activity against SARS-CoV-2. Two separate studies found that recovery speeds increased (i.e., 11 vs. 15 days) with Remdesivir treatment in comparison to the control group. Based on these results, Remdesivir has been granted emergency use authorization by the FDA. A variety of phase 2–3 clinical trials are underway with adult or pediatric patients investigating either Remdesivir alone or in combination with other drugs such as the anti-inflammatory agent Baricitinib. In June, Gilead, the maker of Remdesivir, announced a phase I clinical trial of an inhalable formulation of the drug that could be administered outside of a hospital setting.

Several additional antiviral drugs that operate through similar mechanisms of action are being investigated as well, namely, Favipiravir and EIDD-2801.

Favipiravir (Avigan) was developed by Fujifilm Pharmaceuticals for influenza aimed at patients with new influenza strains with pandemic potential. The mechanism of action for Favipiravir is believed to be like Remdesivir by targeting RdRp in SARS-CoV-2. Two clinical trials are underway in the US which are sponsored by Fujifilm Pharmaceuticals and Stanford University examining the time intervals of viral clearance in the upper airways of patients. Moreover, in Russia, Favipiravir has been granted emergency use status by the Ministry of Health of the Russian Federation due to positive results obtained from initial clinical studies. DCGI, an Indian drug regulator, also approved Favipiravir for treating patients with mild-to-severe symptoms of COVID-19.

EIDD-2801 is a broad-spectrum antiviral agent that was developed by Emory University which is orally bioavailable. This compound was found to be active against SARS-CoV-2 and other RNA viruses after being evaluated by researchers at Vanderbilt and UNC-Chapel Hill. Additionally, a study in MERS- and SARS-infected mice found that EIDD-2801 reduced the pathogenesis of these viruses when administered. In March 2020, this compound was licensed to Ridgeback Biotherapeutics for phase 1 clinical trials, soon after, Merck and Ridgeback Biotherapeutics signed a strategic collaboration for Merck to commercialize EIDD-2801 and its derivatives.

In conclusion, more time must pass to reveal the effectiveness of antiviral drugs at combating this terrible pandemic. Development of orally bioavailable drugs with a safe profile will be a huge step forward and will be extremely beneficial to patients. In addition, vaccines are currently being pursued as well, which opens another window of opportunity.

References & Further Reading:

  1. Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS Cent. Sci. 2020, 6, 672–683.
  2. Antiviral Therapy in Management of COVID-19: a Systematic Review on Current Evidence. Archive of Academic Emergency Medicine 2020, 8, e45.
  3. Approved antiviral drugs over the past 50 years. Microbiol. Rev. 2016, 29, 695–747.
  4. Remdesivir for 5 or 10 days in patients with severe COVID-19. Engl. J. Med. 2020, DOI: 10.1056/NEJMoa2015301.
  5. Remdesivir for the treatment of COVID-19 — Preliminary report. Engl. J. Med. 2020, DOI: 10.1056/NEJMoa2007764.
  6. Coronavirus (COVID-19) Update: FDA issues emergency use authorization for potential COVID-19 treatment. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment (accessed June 22, 2020)
  7. Oral Favipiravir compared to placebo in subjects with mild COVID-19; Study of the use of Favipiravid in hospitalized subjects with COVID-19. https://clinicaltrials.gov/ct2/results?term=favipiravir&cond=COVID-19&cntry=US&draw=2&rank=1#rowId0 (accessed June 22, 2020).
  8. Russians claim to have an effective treatment for the coronavirus, which hospitals will start using this month. https://www.cnbc.com/2020/06/01/russia-approves-drug-to-treat-covid-19-hospitals-to-use-in-june.html. (accessed June 22, 2020).
  9. COVID-19 First in human study to evaluate safety, tolerability, and pharmacokinetics of EIDD-2801 in healthy volunteers. https://clinicaltrials.gov/ct2/show/NCT04392219 (accessed June 22, 2020).
  10. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Science Transl. Med. 2020, 12, eabb5883.
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