Remdesivir: Review of Pharmacology, Pre‐clinical Data, and Emerging Clinical Experience for COVID‐19

The global pandemic of novel coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has created an urgent need for effective antivirals. Remdesivir (formerly GS‐5734) is a nucleoside analogue pro‐drug currently being evaluated in COVID‐19 clinical trials. Its unique structural features allow high concentrations of the active triphosphate metabolite to be delivered intracellularly and it evades proofreading to successfully inhibit viral RNA synthesis. In pre‐clinical models, remdesivir has demonstrated potent antiviral activity against diverse human and zoonotic β‐coronaviruses, including SARS‐CoV‐2. In this article, we critically review available data on remdesivir with an emphasis on biochemistry, pharmacology, pharmacokinetics, and in vitro activity against coronaviruses as well as clinical experience and current progress in COVID‐19 clinical trials.

[1]  Lee-Jen Wei,et al.  Remdesivir for the Treatment of Covid-19 - Preliminary Report. , 2020, The New England journal of medicine.

[2]  S. Anzick,et al.  Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2 , 2020, Nature.

[3]  L. Dodd,et al.  Remdesivir for the Treatment of Covid-19 — Final Report , 2020, The New England journal of medicine.

[4]  Yi Wang,et al.  Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial , 2020, The Lancet.

[5]  Reem A Mustafa,et al.  Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[6]  N. Uriel,et al.  COVID-19 in solid organ transplant recipients: Initial report from the US epicenter , 2020, American Journal of Transplantation.

[7]  Catherine M. Brown,et al.  Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States , 2020, Nature Medicine.

[8]  Joy Y. Feng,et al.  Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency , 2020, The Journal of Biological Chemistry.

[9]  Julie J. Belfer,et al.  Delayed Initiation of Remdesivir in a COVID‐19‐Positive Patient , 2020, Pharmacotherapy.

[10]  T. Jodlowski,et al.  Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. , 2020, JAMA.

[11]  Erwan L'Her,et al.  Compassionate Use of Remdesivir for Patients with Severe Covid-19 , 2020, The New England journal of medicine.

[12]  E. Decroly,et al.  Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites , 2020, Antiviral Research.

[13]  Xuhui Huang,et al.  Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro , 2020, Antiviral Research.

[14]  M. Schivo,et al.  A Community Transmitted Case of Severe Acute Respiratory Distress Syndrome due to SARS CoV2 in the United States , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  Xavier Duval,et al.  Clinical and virological data of the first cases of COVID-19 in Europe: a case series , 2020, The Lancet Infectious Diseases.

[16]  Jason M Pogue,et al.  Coronavirus Disease 2019 Treatment: A Review of Early and Emerging Options , 2020, Open forum infectious diseases.

[17]  E. Fischer,et al.  Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2 , 2020, bioRxiv.

[18]  Zunyou Wu,et al.  Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. , 2020, JAMA.

[19]  Joy Y. Feng,et al.  The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus , 2020, The Journal of Biological Chemistry.

[20]  H. Feldmann,et al.  Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection , 2020, Proceedings of the National Academy of Sciences.

[21]  Gengfu Xiao,et al.  Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro , 2020, Cell Research.

[22]  R. Baric,et al.  Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV , 2020, Nature Communications.

[23]  Michael Proschan,et al.  A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. , 2019, The New England journal of medicine.

[24]  S. Mulangu 843. The PALM Consortium: A Multicenter, Multioutbreak Randomized Controlled Trial of Ebola Virus Disease Therapeutics , 2019, Open Forum Infectious Diseases.

[25]  R. Baric,et al.  Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase , 2019, Antiviral Research.

[26]  Xiaotao Lu,et al.  Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease , 2018, mBio.

[27]  John D Harding,et al.  Nonhuman Primates and Translational Research: Progress, Opportunities, and Challenges. , 2017, ILAR journal.

[28]  Lisa E. Gralinski,et al.  Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses , 2017, Science Translational Medicine.

[29]  William A. Lee,et al.  Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses , 2017, Journal of medicinal chemistry.

[30]  William A. Lee,et al.  Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys , 2016, Nature.

[31]  Hongbin Song,et al.  The Antiviral Activity of Approved and Novel Drugs against HIV-1 Mutations Evaluated under the Consideration of Dose-Response Curve Slope , 2016, PloS one.

[32]  C. Aquilante,et al.  Evaluation of sulfobutylether-β-cyclodextrin (SBECD) accumulation and voriconazole pharmacokinetics in critically ill patients undergoing continuous renal replacement therapy , 2015, Critical Care.

[33]  H. Feldmann,et al.  Pneumonia from human coronavirus in a macaque model. , 2013, The New England journal of medicine.

[34]  S. Straus,et al.  Clinical Trials and Novel Pathogens: Lessons Learned from SARS , 2004, Emerging infectious diseases.

[35]  L. Mayer,et al.  Hydroxychloroquine treatment of patients with human immunodeficiency virus type 1. , 1995, Clinical therapeutics.