By: Luis Carlos Saiz, PharmD, Phd.
Innovation and Organization Unit, Navarre Health Service, Spain.
Among the explored options by the scientific community against the SARS-CoV-2 virus (COVID-19), drugs with antiviral activity stand out. This report assesses the scientific evidence shown by remdesivir (RDV) so far, in the context of the current pandemic.
RDV has been the subject of controversy when it was first granted an orphan drug status by the US FDA. Based on this designation, the manufacturing company was entitled to tax benefits and other rights. Eventually the FDA cancelled this decision at the manufacturer’s own request (1).
INTRODUCTION
The Spanish Agency for Medicines and Healthcare Products (AEMPS) has issued a document where it provides a brief analysis on the most representative pharmacological alternatives against COVID-19, describing several aspects of interest for each drug (2).
The RDV section provides information about dosage, adverse effects and how to reconstitute the drug prior to intravenous administration. In Spain, the compassionate use program has been temporarily suspended except for pregnant women and children with serious medical conditions (2). In order to regulate its use when it becomes again available, the European Medicines Agency has unified the criteria for access in the European Union. These criteria include being a COVID-19 confirmed case with age > 12 years, adequate hepatic and renal function, and need for mechanical ventilation (3).
RDV is a prodrug of a nucleoside analogue, which disrupts viral replication by inhibiting the enzyme RNA polymerase in the virus (4). It is an investigational product, currently not authorised by any health authority. It was initially developed as a therapy against the Ebola virus, although in a clinical trial it registered higher mortality than other monoclonal antibody therapies (5). It has been shown to be active against COVID-19 and other coronaviruses (SARS-CoV and MERS-CoV) in in vitro studies and animal models. However, data are still very limited regarding the use of RDV in COVID-19 patients (3).
A CRITICAL APPRAISAL OF THE CLINICAL EVIDENCE
There are currently no available results from clinical trials on the use of RDV in COVID- 19 patients.
The ClinicalTrials.gov website (https://clinicaltrials.gov) informs about 7 controlled clinical trials initiated with RDV. One of the most ambitious projects underway is the SOLIDARITY trial, sponsored by the World Health Organization, in which several Spanish centers are expecting to participate (6). A study protocol synopsis can be consulted in the Spanish Clinical Trials Registry (https://reec.aemps.es). It will compare 5 treatment strategies against COVID-19: Lopinavir/ritonavir, remdesivir, Lopinavir/ritonavir + interferon β, chloroquine / hydroxychloroquine and standard care. The primary variable is all-cause mortality, stratified by severity of disease at the time of randomization.
From a clinical perspective, it is only possible to highlight the case report described in the study by Grein et al. This non-controlled study provides information on 53 COVID- 19 confirmed patients who had an oxygen saturation < 95% or had a need for oxygen support. All received RDV through the compassionate use program for a maximum of 10 days, consisting of a loading dose of 200 mg on day 1, plus 100 mg daily for the following 9 days. Follow-up was to continue through at least 28 days after the beginning of treatment with RDV or until discharge or death.
As for the results, 68% of patients improved in their need for oxygen and 15% got worse. Improvement was seen more often in those patients with less severity. Around 13% of the participants died after completing RDV treatment, with those over 70 years old, higher serum creatinine and requiring invasive ventilation having the greatest risk. The most frequent adverse effects with RDV were increased liver enzymes, diarrhea, rash, renal failure, and hypotension. Four patients (8%) discontinued RDV treatment prematurely.
There are important study limitations, such as the poor methodological quality derived from a non-controlled cohort. Other noteworthy features are the small sample size, short duration of follow-up, absence of information on viral load and the lack of knowledge about 8 initially treated patients without additional information. Beyond the interest aroused, as it is the first study describing COVID-19 patients treated with RDV, we are still awaiting results with real relevance from properly designed comparative studies.
RISK OF ADVERSE EVENTS WITH REMDESIVIR
As RDV is still an experimental drug, the adverse effect profile is not known in detail yet. Up to now, the most characteristic adverse event seems to be increased liver enzymes (ALT, AST). For that reason it is recommended to estimate their levels before the treatment is started. RDV should be suspended or not initiated when ALT > 5 x upper limit of normal were confirmed. Regarding the renal function, RDV should not be used with a glomerular filtration rate <30 mL/min (3).
As far as potential interactions with other drugs are concerned, no major contraindications have been identified so far, except for the precaution of using them together with other drugs with proven hepatotoxicity (3). On the basis of their rapid distribution, metabolism and excretion pharmacokinetics, the probability of clinically relevant interactions seems low. RDV does not cause alterations in the QTc interval (8).
CONFLICT OF INTEREST
The author declares no conflict of interest.
BIBLIOGRAPHY
1. Mahase E. Covid-19: what treatments are being investigated? BMJ 2020;368:m1252 doi: 10.1136/bmj.m1252
2. Tratamientos disponibles para el manejo de la infección respiratoria por SARS-CoV-2. Agencia Española del Medicamento y Productos Sanitarios. 28/03/2020. [In Spanish] Available at: https://www.aemps.gob.es/la-aemps/ultima-informacion-de-la-aemps-acerca-del- covid%e2%80%9119/tratamientos-disponibles-para-el-manejo-de-la-infeccion-respiratoria-por-sars- cov-2/
3. EMA – Human Medicines Division. Summary on compassionate use. 03/04/2020. EMA/178637/2020 Disponible en: https://www.ema.europa.eu/en/documents/other/summary-compassionate-use- remdesivir-gilead_en.pdf
4. Alhazzani W, Møller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med (2020). https://doi.org/10.1007/s00134-020-06022-5.
5. Mulangu S, Dodd LE, Davey RT, Jr., Tshiani Mbaya O, Proschan M, Mukadi D, et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. NEJM 2019;381(24):2293-303. doi: 10.1056/NEJMoa1910993.
6. World Health Organization. “Solidarity” clinical trial for COVID-19 treatments. Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel- coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
7. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A. Compassionate Use of Remdesivir for Patients with Severe Covid-19. NEJM 2020; DOI: 10.1056/NEJMoa2007016
8. Liverpool Drug Interactions Group. Evaluating the drug-drug interaction risk of experimental COVID- 19 therapies. 03/04/2020. Disponible en: http://www.covid19-druginteractions.org/