Remdesivir
Remdesivir, sold under the brand name Veklury,[13][14] is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences.[15] It is administered via injection into a vein.[16][17] During the COVID‑19 pandemic, remdesivir was approved or authorized for emergency use to treat COVID‑19 in numerous countries.[18]
Clinical data
Remdesivir was originally developed to treat hepatitis C,[19] and was subsequently investigated for Ebola virus disease and Marburg virus infections[20] before being studied as a post-infection treatment for COVID‑19.[21]
Remdesivir is a prodrug that is intended to allow intracellular delivery of GS-441524 monophosphate and subsequent biotransformation into GS-441524 triphosphate, a ribonucleotide analogue inhibitor of viral RNA polymerase.[22]
The most common side effect in healthy volunteers is raised blood levels of liver enzymes.[13] The most common side effect in people with COVID‑19 is nausea.[13] Side effects may include liver inflammation and an infusion-related reaction with nausea, low blood pressure, and sweating.[23]
The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[24]
Medical uses
In the European Union, remdesivir is indicated for the treatment of COVID‑19 in adults and adolescents (aged twelve years and older with body weight at least 40 kilograms (88 lb)) with pneumonia requiring supplemental oxygen and for adults who do not require supplemental oxygen and who are at increased risk of progressing to severe COVID‑19.[10][13]
In the United States, remdesivir is indicated for the treatment of COVID‑19 in people 28 days of age and older and weighing at least 3 kilograms (6.6 lb) who are hospitalized; or not hospitalized and have mild-to-moderate COVID‑19, and are at high risk for progression to severe COVID‑19, including hospitalization or death.[12][25]
In November 2020, the FDA issued an emergency use authorization (EUA) for the combination of baricitinib with remdesivir, for the treatment of suspected or laboratory confirmed COVID‑19 in hospitalized people two years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).[26]
In Australia, it is approved for those aged four weeks of age and older with a body weight at least 3 kilograms (6.6 lb) with pneumonia requiring supplemental oxygen or those aged four weeks of age and older with body weight at least 40 kilograms (88 lb) who do not require supplemental oxygen and who are at high risk of progressing to severe COVID‑19.[27][2]
The most common adverse effects in people treated with remdesivir were respiratory failure and blood biomarkers of organ impairment, including low albumin, low potassium, low count of red blood cells, low count of thrombocytes, and elevated bilirubin (jaundice).[28] Other reported adverse effects include gastrointestinal distress, elevated transaminase levels in the blood (liver enzymes), infusion site reactions, and electrocardiogram abnormalities.[17] Remdesivir may cause infusion-related reactions, including low blood pressure, nausea, vomiting, sweating or shivering.[29]
Other possible side effects of remdesivir include:
Interactions
Remdesivir is at least partially metabolized by the cytochrome P450 enzymes CYP2C8, CYP2D6, and CYP3A4.[39][23] Blood plasma concentrations of remdesivir are expected to decrease if it is administered together with cytochrome P450 inducers such as rifampicin, carbamazepine, phenobarbital, phenytoin, primidone, and St John's wort.[40]
Using chloroquine or hydroxychloroquine with remdesivir may reduce the antiviral activity of remdesivir.[12][10][41] Coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not recommended based on in vitro data demonstrating an antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of remdesivir.[12]
In vitro experiments
An in vitro study of remdesivir assessing antiviral activity against SARS-CoV-2 was performed.[44] Cells were pre-treated with the different doses of remdesivir for 1 hour, and the virus (MOI of 0.05) was subsequently added to allow infection for 2 hours.[44] The results found that remdesivir functioned well as an inhibitor of the infection.[44] The study was published as a letter to the editor, and as such did not undergo peer review.
Manufacturing
Remdesivir requires "70 raw materials, reagents, and catalysts" to make, and approximately "25 chemical steps."[45] Some of the ingredients are extremely dangerous to humans, especially trimethylsilyl cyanide.[45] The original end-to-end manufacturing process required 9 to 12 months to go from raw materials at contract manufacturers to finished product, but after restarting production in January 2020, Gilead Sciences was able to find ways to reduce the production time to six months.[45]
In January 2020, Gilead began working on restarting remdesivir production in glass-lined steel chemical reactors at its manufacturing plant in Edmonton, Alberta.[45] On 2 February 2020, the company flew its entire stock of remdesivir, 100 kilograms in powder form (left over from Ebola research), to its filling plant in La Verne, California to start filling vials.[45] The Edmonton plant finished its first new batch of remdesivir in April 2020.[45] Around the same time, fresh raw materials began to arrive from contract manufacturers reactivated by Gilead in January.[45]
Another challenge is getting remdesivir into patients despite the drug's "poor predicted solubility and poor stability."[46] In June 2020, Ligand Pharmaceuticals revealed that Gilead has been managing those issues by mixing Ligand's proprietary excipient Captisol (based on University of Kansas research into cyclodextrin) with remdesivir at a 30:1 ratio.[46] Since that implies an enormous amount of Captisol is needed to stabilize and deliver remdesivir (on top of amounts needed for several other drugs for which the excipient is already in regular use), Ligand announced that it is trying to boost Captisol annual manufacturing capacity to as much as 500 metric tons.[46]
On 12 May 2020, Gilead announced that it had granted non-exclusive voluntary licenses to five generic drug companies in India and Pakistan to manufacture remdesivir for distribution to 127 countries.[47][48][49] The agreements were structured so that the licensees can set their own prices and will not have to pay royalties to Gilead until the WHO declares an end to the COVID‑19 emergency or another medicine or vaccine is approved for COVID‑19, whichever comes first.[47] On 23 June 2020, India granted emergency marketing approval of generic remdesivir manufactured by two Gilead licensees, Cipla and Hetero Drugs.[50]
Society and culture
Legal status
Remdesivir is approved, or authorized for emergency use, to treat COVID‑19 in many countries.[18] Remdesivir has been authorized for emergency use in India,[51] Singapore,[52] and approved for use in Japan,[53] the European Union, the United States, and Australia for people with severe symptoms.[13][14][54][55][56][57][58][59][60]
Remdesivir is the first treatment for COVID‑19 to be approved by the U.S. Food and Drug Administration (FDA).[60] The approval by the FDA does not include the entire population that had been authorized to use remdesivir under an Emergency Use Authorization (EUA) originally issued in May 2020.[60] In order to ensure continued access to the pediatric population previously covered under the EUA, the FDA revised the EUA for remdesivir to authorize the drug's use for treatment of suspected or laboratory-confirmed COVID‑19 in hospitalized pediatric patients weighing 3.5 kilograms (7.7 lb) to less than 40 kilograms (88 lb) or hospitalized pediatric patients less than twelve years of age weighing at least 3.5 kilograms (7.7 lb).[60]
Veterinary uses
In 2019, GS-441524 was shown to have promise for treating feline infectious peritonitis caused by a coronavirus.[138] It has not been evaluated or approved by the US Food and Drug Administration (FDA) for the treatment of feline coronavirus or feline infectious peritonitis but has been available since 2019, through websites and social media as an unregulated black market substance.[139] Because GS-441524 is the main circulating metabolite of remdesivir and because GS-441524 has similar potency against SARS-Cov-2 in vitro, some researchers have argued for the direct administration of GS-441524 as a COVID‑19 treatment.[140]