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, patients can access the drug mainly through five active clinical trials.
RDV is a prodrug of a nucleoside analogue, which disrupts viral replication by inhibiting the enzyme RNA polymerase in the virus (3). It is an investigational product, currently not authorised by any health authority. It was initially developed as a therapy against the Ebola virus, though in a clinical trial it registered higher mortality than other monoclonal antibody therapies (4). 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 (5).
A CRITICAL APPRAISAL OF THE CLINICAL EVIDENCE
The ClinicalTrials.gov website (https://clinicaltrials.gov) informs about 7 active 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.
There are currently one clinical trial with available results on the use of RDV in COVID- 19 patients.
This randomized 2:1, double-blind, multicenter, placebo-controlled study was terminated prematurely due to recruitment difficulties. The 237 patients included had severe COVID-19 infection, with confirmed pneumonia and oxygen saturation <95% or PaO2/FiO2 ≤300 mmHg (7). They were randomized to receive RDV 200 mg on day 1 followed by 100 mg on days 2-10, for 10 days, or placebo. Other antiviral drugs, interferon and corticoids were allowed in both groups. The main outcome was time to clinical improvement within 28 days. No differences were found between RVD and placebo for the main [Hazard Ratio 1.23 CI95% (0.87-1.75)] or secondary outcomes, including mortality. The rate of adverse effects was similar in both groups, although treatment discontinuation was more frequent in patients with RVD (12%) than in the placebo group (5%).
These data contrast with the statement made by Gilead, maker of RVD, about other study results on patients with severe COVID-19 (8). In the absence of publication, the company’s statement claims that patients who received RVD for 5 days improved their clinical status to the same extent as those who received RVD for 10 days. However, as the study did not have a control group, nothing can be concluded about the potential role of RVD in the claimed improvement.
On the other hand, an unusual press release has been published by the National Institute of Allergy and Infectious Diseases (NIAID), an institution that is sponsoring a RVD study (ACTT Study). The purpose of the statement was to comment on the results of an interim analysis (9). The clinical trial has an adaptive design, in which several treatments can be evaluated at the same time and, by means of interim analyses, drugs can be either ruled out or introduced. Preliminary results would indicate a shorter recovery time in patients assigned to the RVD group (11 days) compared to the placebo group (15 days). However, it is imperative await for the full study completion and publication to confirm these potential findings. In addition, the protocol can only be accessed through ClinicalTrials.gov (NCT04280705), which shows that the main outcome has been modified at least twice before the current definition was set on April 16. This exploratory strategy may provide value for a first screening of drugs but, at the same time, it is difficult to ensure the same level of evidence as in a fully pre-planned trial clinical.
Finally, it is worth mentioning the case report described by Grein et al (10). 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.
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 (5).
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, as rifampicin (5). On the basis of their rapid distribution, metabolism and excretion pharmacokinetics, the probability of clinically relevant interactions seems low (monitoring is recommended when used concomitantly with metamizole). RDV does not cause alterations in the QTc interval (11).
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. 16/04/2020. [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. 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.
4. 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.
5. 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
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. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020. Doi: 10.1016/S0140- 6736(20)31022-9.
8. Gilead announces results from Phase 3 trial of investigational antiviral remdesivir in patients with severe COVID-19. Available at: https://www.gilead.com/news-and-press/press-room/press- releases/2020/4/gilead-announces-results-from-phase-3-trial-of-investigational-antiviral-remdesivir- in-patients-with-severe-covid-19
9. NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19. Available at: https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery- advanced-covid-19
10. 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
11. Liverpool Drug Interactions Group. Interactions with experimental COVID-19 therapies. 09/04/2020. Available at: http://www.covid19-druginteractions.org/