By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for remdesivir to treat patients who are severely ill with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), often referred to as COVID-19.1 Remdesivir is a prodrug that is metabolized intracellularly to an analog of adenosine triphosphate, acting as an inhibitor of RNA-dependent RNA polymerase.1 It has shown activity in animal models against two other coronaviruses (SARS-CoV-1 and MERS-CoV), in vitro activity against SARS-CoV-2, and possible evidence of benefit during compassionate use.2,3 Remdesivir is manufactured by Gilead Sciences.
Remdesivir can be used to treat suspected or laboratory-confirmed COVID-19 in children or adults who are hospitalized with severe disease. Severe disease is defined as oxygen saturation ≤ 94% on room air or requiring supplemental oxygen, extracorporeal membrane oxygenation (ECMO), or mechanical ventilation.4
The recommended dose for patients weighing ≥ 40 kg requiring invasive mechanical ventilation and/or ECMO is 200 mg infused intravenously over 30 to 120 minutes on day 1 and 100 mg once daily for nine days.4 For patients between 3.5 kg and < 40 kg, the dose is 5 mg/kg on day 1 and 2.5 mg/kg once daily up to 10 days. Remdesivir is available as a 100-mg vial.
The FDA deemed that the known and potential benefits of remdesivir outweigh the known and potential risks for the treatment of hospitalized patients with COVID-19.1 Currently, there are no adequate, approved, alternative therapies to remdesivir.
The benefit of remdesivir appears to be modest, and survival benefit has not been established. Common adverse events included nausea, acute respiratory failure, and elevated liver enzymes.5
The EUA for remdesivir was based on an interim analysis of the ongoing National Institute of Allergy and Infectious Diseases (NIAID)-sponsored Adaptive COVID-19 Treatment Trial (ACTT, NCT04280705).5 The study included hospitalized subjects with advanced COVID-19 and lung involvement. Subjects were randomized to remdesivir (n = 286) or placebo (n = 286). The primary outcome measure was time to recovery. This was defined as: hospitalized, not requiring supplement oxygen-no longer requiring ongoing medical care; not hospitalized, limitation on activities, and/or requiring home oxygen; not hospitalized, no limitation on activities. The remdesivir group recovered 31% faster, a median of 11 days vs. 15 days for the placebo group (P < 0.001). Numerically, survival benefit favored remdesivir (8% vs. 11.6%) but did not reach statistical significance (P = 0.059).
Recently, Gilead Sciences announced results from an open-label, Phase III trial that demonstrated similar efficacy with five- and 10-day dosing duration (median of 10 days vs. 11 days).6 The authors of a small study out of Wuhan, China (n = 236) that did not reach target enrollment found no difference between remdesivir (n = 158) and placebo (n = 78) in clinical benefit in terms of time to clinical benefit and time to virus clearance.7 However, those who received remdesivir within 10 days of symptom onset recorded a numerically faster (but not statistically significant) time to clinical improvement (median 18 days vs. 23 days). Limitations of this study included lack of statistical power and initiation of treatment later in the disease course because of logistics (hospital bed availability).
As of this writing, there are no curative or FDA-approved therapies for COVID-19 (i.e., deemed to be safe and effective). Remdesivir appears to offer modest benefit and is the first antiviral authorized for emergency use. NIAID decided to terminate ACTT as originally designed, forgoing the opportunity to assess whether there is a definitive survival advantage for remdesivir.8 ACTT2 is evolving to a two-arm study comprised of remdesivir plus an anti-inflammatory agent, baricitinib, compared to remdesivir plus a placebo.9 Baricitinib is a Janus kinase inhibitor that has been approved for treating rheumatoid arthritis. A study of remdesivir in moderate COVID-19 is in process, with results expected soon. Although remdesivir requires a difficult, multistep manufacturing process, Gilead is committed to donating 1.5 million doses of remdesivir. The company is expected to start charging for the drug in July.10
- U.S. Food and Drug Administration. Remdesivir Emergency Use Authorization. May 1, 2020.
- Gordon GJ, et al. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol Chem 2020;295:4773-4779.
- Grein J, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med 2020; April 10. doi: 10.1056/NEJMoa2007016. [Epub ahead of print].
- U.S. Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization of remdesivir.
- National Institute of Allergy and Infectious Diseases. NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19. April 29, 2020.
- Gilead Sciences. Gilead announces results from phase 3 trial of investigational antiviral remdesivir in patients with severe COVID-19. April 29, 2020.
- Wang Y, et al. Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;395:1569-1578.
- Herper M. Inside the NIH’s controversial decision to stop its big remdesivir study. STAT, May 11, 2020.
- National Institutes of Health. NIH clinical trial testing antiviral remdesivir plus anti-inflammatory drug baricitinib for COVID-19 begins. May 8, 2020.
- Liu A. Gilead to start selling remdesivir in coming weeks, expects ‘multi-year commercial opportunity.’ FiercePharma, May 20, 2020.