In this article an infectious diseases pharmacist provides insights on remdesivir.
Authored By: Matt Davis, Pharm.D.
[Last updated: 6 May 2020]
Remdesivir (GS-5734) is a mopophosphoramidate 1’Cyano-C-adenosine nucleoside analogue antiviral manufactured by Gilead Sciences Inc . Mechanistically, it prevents viral replication through competitive inhibition of RNA-dependent RNA polymerase resulting in RNA chain termination. In vitro studies have demonstrated potent antiviral activity across a large array of RNA viral families including the filovirus Ebola virus along with zoonotic coronaviruses MERS, and SARS-CoV-1 [2-4].
Prior to its candidacy as an agent for SARS-CoV-2 (the coronavirus that causes COVID-19 disease), it was previously studied in a multi-arm randomized clinical trial assessing therapeutic options in the treatment of Ebola virus disease . Despite its potent in vitro activity against Ebola virus, patients randomized to the remdesivir arm had an intolerably high 28-day mortality rate (53%) prompting early cessation of the remdesivir arm. Following these discouraging data, remdesivir was no longer considered a viable candidate for the treatment of Ebola virus disease.
Looking towards the current COVID-19 pandemic due to SARS-CoV-2, remdesivir has demonstrated potent in vitro activity with EC50 values in the nanomolar range , clinical benefit in animal models , but mixed clinical results in humans [8-11]. First, a randomized, placebo-controlled, clinical trial comparing remdesivir to placebo failed to detect a significant difference in time to clinical improvement, time to deterioration or mortality, and viral load reduction . It is worth noting this trial was underpowered due to termination after the outbreak was contained in Wuhan. On the same day of the trial’s publication, top-line results were announced from the NIAID-sponsored ACTT study showing a significant reduction in time to recovery prompting remdesivir’s consideration as the new “standard of care” with a subsequent FDA-issued Emergency Use Authorization (EUA). Additionally, top-line data from the Gilead-sponsored SIMPLE Severe trial suggested no significant benefit of 10-days vs. 5-days of therapy in severe COVID-19.
Pharmacists are now left to navigate an evolving complex drug procurement process whilst simultaneously awaiting full datasets for analysis. Here are five things to know about remdesivir…
1. Remdesivir is formulated for intravenous use only
Given its formulation as a phosphoramidate prodrug which is cleaved to a nucleoside monophosphate intracellularly by esterases, remdesivir is not a candidate for oral administration because it would be subjected to significant degradation via first-pass effect from hepatic esterases. This would result in a high proportion of charged monophosphate intermediates unable to traverse cellular membranes efficiently.
2. Remdesivir has been granted Emergency Use Authorization (EUA) for severe COVID-19
Adult and pediatric patients with confirmed or suspected COVID-19 who meet criteria for severe disease (SpO2 ≤ 94% on room air or requiring O2 support) can receive remdesivir under this authorization. Current releases indicate facilities designated by the U.S. government to receive supply will be proactively contacted by AmerisourceBergen regarding distribution. This authorization does not mean remdesivir has been granted full FDA-approval and the authorization is only valid during the state of declared emergency.
3. It appears remdesivir is well-tolerated compared to placebo
In the aforementioned placebo-controlled clinical trial, patients receiving remdesivir had low rates of discontinuation due to adverse events (12% remdesivir vs. 5% placebo). Notable adverse effects include transaminitis, which appears to be self-resolving, and phlebitis.
Pharmacists should consider risks/benefits in patients with significant renal dysfunction given its formulation with sulfobutylether-β-cyclodextrin. Remdesivir is not recommended for adults or pediatric patients with an eGFR below 30 mL/min or in full term neonates with a serum creatinine greater than or equal to 1 mg/dL unless the potential benefit outweighs the potential risk.
4. The benefit of remdesivir is theoretically optimized with early administration
It is biologically plausible that an antiviral targeting viral replication would be best given early in the course of illness prior to reaching peak viral loads. This is not specific to remdesivir and is consistent with experience with other antivirals (e.g., oseltamivir). This is particularly challenging given the intravenous formulation of remdesivir and inability to feasibly scale outpatient prescribing.
5. Significant gaps remain in our understanding of remdesivir for COVID-19
Despite the issuance of the EUA, there are still several unanswered questions. Particularly important questions include which patient groups benefit most from remdesivir and if there is a role for remdesivir in patients presenting late in their course of illness.
ABOUT THE AUTHOR
Matthew Davis received his doctorate of pharmacy degree from The University of Texas at Austin. He completed two years of post-graduate pharmacy residency training including a post-graduate year 2 specialty residency in infectious diseases at the University of California, Davis Medical Center.
Dr. Davis currently works as an infectious diseases pharmacist at UCLA Ronald Reagan Medical Center in Los Angeles, California. His clinical interests include antifungal PK/PD, gram-negative resistance, and now remdesivir.
1. Siegel D, Hui HC, Doerffler E, 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. J Med Chem. 2017;60(5):1648-1661.
2. Brown AJ, Won JJ, Graham RL, et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Res. 2019;169:104541.
9. Sanville B, Corbett R, Pidcock W, et al. A Community Transmitted Case of Severe Acute Respiratory Distress Syndrome due to SARS CoV2 in the United States. Clin Infec Dis. 2020. Accepted Pre-print: https://doi.org/10.1093/cid/ciaa347.
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