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Remdesivir

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Remdesivir
Remdesivir.svg
Remdesivir-from-xtal-Mercury-3D-ball-and-stick-with-bond-orders.png
Clinical data
Pronunciation/rɛmˈdɛsɪvɪər/ rem-DESS-i-veer
Trade namesVeklury
Other namesGS-5734
AHFS/Drugs.comProfessional Drug Facts
Routes of
administration
Intravenous
ATC code
  • None
Legal status
Legal status
  • Investigational / Rx-only
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC27H35N6O8P
Molar mass602.585 g·mol−1
3D model (JSmol)

Remdesivir, sold under the brand name Veklury,[1] is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences.[2] It is administered via injection into a vein.[3][4] As of 2020, remdesivir is being tested as a specific treatment for COVID-19, and has been authorized for emergency use in the US, India,[5] Singapore,[6] and approved for use in Japan for people with severe symptoms.[1][7][8][1][9] It also received approval in the UK in May 2020, however, it was going to be rationed due to limited supply.[10] It may shorten the time it takes to recover from the infection.[11]

Side effects may include liver inflammation and an infusion-related reaction with nausea, low blood pressure, and sweating.[12] It is a prodrug that is intentended to allow intracellular delivery of GS-441524 monophosphate and subsequent biotransformation into GS-441524 triphosphate, a ribonucleotide analogue inhibitor of viral RNA polymerase [13][14].

Earlier studies found antiviral activity against several RNA viruses including SARS coronavirus and MERS coronavirus, but it is not approved for any indication.[2][7] Remdesivir was originally developed to treat hepatitis C[15] and was then tested against Ebola virus disease and Marburg virus disease, but was ineffective for all of these viral infections.[2]

Side effects

The most common adverse effects in studies of remdesivir for COVID‑19 include respiratory failure and organ impairment, including low albumin, low potassium, low count of red blood cells, low count of platelets that help with clotting, and yellow discoloration of the skin.[16][unreliable medical source?] Other reported side effects include gastrointestinal distress, elevated transaminase levels in the blood (liver enzymes), and infusion site reactions.[4]

Other possible side effects of remdesivir include:

  • Infusion‐related reactions. Infusion‐related reactions have been seen during a remdesivir infusion or around the time remdesivir was given.[17] Signs and symptoms of infusion‐related reactions may include: low blood pressure, nausea, vomiting, sweating, and shivering.[17]
  • Increases in levels of liver enzymes, seen in abnormal liver blood tests.[17] Increases in levels of liver enzymes have been seen in people who have received remdesivir, which may be a sign of inflammation or damage to cells in the liver.[17]

Research

Remdesivir was originally created and developed by Gilead Sciences in 2009, as part of the company's research and development program for hepatitis C.[15] It did not work against hepatitis C as hoped,[15] but was then repurposed and studied as a potential treatment for Ebola virus disease and Marburg virus infections.[18] According to the Czech News Agency, this new line of research was carried out under the direction of scientist Tomáš Cihlář.[19] Gilead Sciences subsequently discovered that remdesivir had antiviral activity in vitro against multiple filoviruses, pneumoviruses, paramyxoviruses, and coronaviruses.[20]

Preclinical and clinical research and development was done in collaboration between Gilead Sciences and various U.S. government agencies and academic institutions.[21][22][23][24]

During the mid-2010s, the Mintz Levin law firm prosecuted various patent applications for remdesivir on behalf of Gilead Sciences before the United States Patent and Trademark Office (USPTO). The USPTO granted two patents on remdesivir to Gilead Sciences on 9 April 2019: one for filoviruses,[25] and one which covered both arenaviruses and coronaviruses.[26]

Ebola

In October 2015, the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) announced preclinical results that remdesivir had blocked the Ebola virus in Rhesus monkeys. Travis Warren, who has been a USAMRIID principal investigator since 2007, said that the "work is a result of the continuing collaboration between USAMRIID and Gilead Sciences".[27] The "initial screening" of the "Gilead Sciences compound library to find molecules with promising antiviral activity" was performed by scientists at the Centers for Disease Control and Prevention (CDC).[27] As a result of this work, it was recommended that remdesivir "should be further developed as a potential treatment."[18][unreliable medical source?][27]

Remdesivir was rapidly pushed through clinical trials due to the West African Ebola virus epidemic of 2013–2016, eventually being used in people with the disease. Preliminary results were promising; it was used in the emergency setting during the Kivu Ebola epidemic that started in 2018, along with further clinical trials, until August 2019, when Congolese health officials announced that it was significantly less effective than monoclonal antibody treatments such as mAb114 and REGN-EB3. The trials, however, established its safety profile.[28]

COVID-19

As of April 2020, remdesivir was viewed as the most promising treatment for COVID-19,[11] and was included among four treatments under evaluation in the international Solidarity trial[29][30] and European Discovery trial.[31] The FDA stated, on 1 May 2020, that it is "reasonable to believe" that known and potential benefits of remdesivir outweigh its known and potential risks in some specific populations hospitalized with severe COVID‑19.[7] As of May 2020, there was no good evidence that remdesivir reduced mortality in people with COVID-19.[32]

In January 2020, Gilead Sciences began laboratory testing of remdesivir against SARS-CoV-2, stating that remdesivir had been shown to be active against severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) in animal models.[33][34][35] On 21 January 2020, the Wuhan Institute of Virology applied for a Chinese "use patent" for treating COVID‑19.[36]

In a trial in China over February–March 2020, remdesivir was not effective in reducing the time for improvement from COVID‑19 or deaths, and caused various adverse effects, requiring the investigators to terminate the trial.[16]

On 18 March 2020, the World Health Organization (WHO) announced the launch of a trial that would include one group treated with remdesivir.[29][37] Other clinical trials are underway or planned.[38][39][40][41][42][43][44][45][46][47][48]

Preliminary data from an international multi-center, placebo controlled double-blind randomized controlled trial carried out by the U.S. National Institutes of Health suggests that remdesivir is effective in reducing the recovery time from 15 to 11 days in people hospitalized with COVID‑19.[49][50] On 29 April 2020, based on results of the ACTT trial,[48] the National Institute of Allergy and Infectious Diseases (NIAID) announced that remdesivir was better than a placebo in reducing time to recovery for people hospitalized with advanced COVID‑19 and lung involvement.[50] The study appeared on The New England Journal of Medicine website almost a month later on 22 May 2020 and, despite generally positive results, the study concluded that "given high mortality despite the use of remdesivir, it is clear that treatment with an antiviral drug alone is not likely to be sufficient."[49][51] A previous Chinese study published in The Lancet did not show significant benefits or drawbacks of using remdesivir, concluding that further research is required to understand the effectiveness of the drug.[16] John David Norrie of the Clinical Trials Unit of the University of Edinburgh Medical School criticised that article as underpowered due to a lack of significant results as well as the fact that the study was ended prematurely.[52] Based on the results of its study, the NIH stopped the ACTT trial and provided remdesivir to participants assigned to received placebo.[53]

In April 2020, the European Medicines Agency (EMA) started a 'rolling review' of data on the use of remdesivir in COVID‑19.[54] It completed the review in May 2020.[55]

In June 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started evaluating remdesivir for a conditional marketing authorization after receiving an application from Gilead Sciences.[56][57] On 25 June 2020, the committee recommended granting a conditional marketing authorization for remdesivir for the treatment of COVID-19 in adults and adolescents from 12 years of age with pneumonia who require supplemental oxygen.[58][59][60] The brand name will be Veklury.[58][59]

A small trial of remdesivir in rhesus macaque monkeys with COVID‑19 infections reported that early treatment with remdesivir reduced damage and disease progression, but not viral shedding.[61]

Veterinary uses

GS-441524 was shown in 2019 to have promise for treating feline infectious peritonitis caused by a coronavirus.[62] It has not been evaluated or approved by the 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 as confirmed by the UC Davis School of Veterinary Medicine.[63]. Because GS-441524 is the main circulating metabolite of Remdesivir and because GS-441524 has similar potency against SARS-Cov-2 inculture, some researchers have argued for the direct administration of GS-441524 as a COVID19 treatement [64].

Access

Compassionate use

On 20 March 2020, United States President Donald Trump announced that remdesivir was available for "compassionate use" for people with COVID‑19; FDA Commissioner Stephen Hahn confirmed the statement at the same press conference.[65] It was later revealed that Gilead had been providing remdesivir in response to compassionate use requests since 25 January.[15] On 23 March 2020, Gilead voluntarily suspended access for compassionate use (excepting cases of critically ill children and pregnant women), for reasons related to supply, citing the need to continue to provide the agent for testing in clinical trials.[11][66]

Pricing

On 29 June 2020, Gilead announced that it had set the price of remdesivir at US$390 per vial for the governments of developed countries, including the United States, and US$520 for U.S. private health insurance companies.[67] The expected course of treatment is six vials over five days for a total cost of US$2,340.[67] Being a repurposed drug, the minimum production cost for remdesivir is estimated at US$0.93 per day of treatment.[68]

Secondary manufacture and distribution

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.[69][70] 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.[69] On 23 June 2020, India granted emergency marketing approval of generic remdesivir manufactured by two Gilead licensees, Cipla and Hetero Drugs.[71]

Canada

As of 11 April 2020, access in Canada was available only through clinical trials.[72]

Czech Republic

On 17 March 2020, the drug was provisionally approved for use for COVID‑19 patients in a serious condition as a result of the outbreak in the Czech Republic.[73]

European Union

In April 2020, the European Medicines Agency (EMA) provided recommendations on compassionate use of remdesivir for COVID‑19 in the EU.[74]

On 11 May 2020, the Committee for Medicinal Products for Human Use (CHMP) of the EMA recommended expanding the compassionate use of remdesivir to those not on mechanical ventilation.[75] In addition to those undergoing invasive mechanical ventilation, the compassionate use recommendations cover the treatment of hospitalized individuals requiring supplemental oxygen, non-invasive ventilation, high-flow oxygen devices or ECMO (extracorporeal membrane oxygenation).[75] The updated recommendations were based on preliminary results from the NIAID-ACTT study,[48] which suggested a beneficial effect of remdesivir in the treatment of hospitalized individuals with severe COVID-19.[75][50] In addition, a treatment duration of five days was introduced alongside the longer ten-day course, based on preliminary results from another study (GS-US-540-5773) suggesting that for those not requiring mechanical ventilation or ECMO, the treatment course may be shortened from ten to five days without any loss of efficacy.[75] Individuals who receive a five-day treatment course but do not show clinical improvement will be eligible to continue receiving remdesivir for an additional five days.[75]

Japan

On 7 May 2020, Japan's Ministry of Health, Labour and Welfare approved the drug for use in Japan, in a fast-tracked process based on the U.S. emergency authorization.[1][9]

United States (and rest-of-world impact)

On 1 May 2020, the U.S. Food and Drug Administration granted Gilead emergency use authorization (EUA) for remdesivir to be distributed and used by licensed health care providers to treat adults and children hospitalized with severe COVID‐19.[8][17] Severe COVID‐19 is defined as patients with an oxygen saturation (SpO2) ≤ 94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO), a heart–lung bypass machine.[76][17][77][78] Distribution of remdesivir under the EUA will be controlled by the U.S. government for use consistent with the terms and conditions of the EUA.[17] Gilead will supply remdesivir to authorized distributors, or directly to a U.S. government agency, who will distribute to hospitals and other healthcare facilities as directed by the U.S. Government, in collaboration with state and local government authorities, as needed.[17] Gilead stated they were donating 1.5 million vials for emergency use[77] and estimated, as of April 2020, they had enough remdesivir for 140,000 treatment courses and expect to have 500,000 courses by October 2020, and one million courses by the end of 2020.[79][80]

The initial distribution of the drug in the U.S. was tripped up by seemingly capricious decision-making and finger-pointing, resulting in over a week of confusion and frustration among health care providers and patients alike.[81][82][83] On 9 May 2020, the United States Department of Health and Human Services (HHS) explained in a statement that it would be distributing remdesivir vials to state health departments, then would allow each department to redistribute vials to hospitals in their respective states based upon each department's insight into "community-level needs."[84] HHS also clarified that only 607,000 vials of Gilead's promised donation of 1.5 million vials would be going to American patients.[84] However, HHS did not explain why several states with some of the highest caseloads had been omitted from the first two distribution rounds, including California, Florida, and Pennsylvania.[84] In May 2020, Gilead indicated they would increase the number of doses donated to the U.S. from 607,000 to around 940,000.[85][83] Some of the initial distribution was sent to the wrong hospitals, to hospitals with no intensive care units, and to facilities without the needed refrigeration to store it.[83]

On June 29, HHS announced an unusual agreement with Gilead in which HHS agreed to Gilead's wholesale acquisition price, HHS would continue to work together with state governments and drug wholesaler AmerisourceBergen to allocate shipments of remdesivir vials to American hospitals through the end of September 2020, and in exchange, during that three-month timeframe (July, August, and September), American patients would be allocated over 90% of Gilead's projected remdesivir output of more than 500,000 treatment courses.[86][87] Absent from these announcements was any discussion of allocation of remdesivir production to the approximately 70 countries omitted from Gilead's generic drug licensing agreements—including much of Europe[88] and countries as populous as Brazil, China, and Mexico—or the 127 countries listed on those agreements (during the time it will take for Gilead's generic licensees to ramp up their own production).[89] As the implications of this began to sink in, several countries publicly confirmed the next day that they already had adequate supplies of remdesivir to cover current needs, including Australia,[90] Germany,[91] and the United Kingdom.[92]

Pharmacology

Activation

Activation of remdesivir into its active triphosphate metabolite[93]

Remdesivir is a ProTide (Prodrug of nucleoTide) that is able to diffuse into cells where it is converted to GS-441524 mono-phosphate via the actions of esterases and a phosphoamidase; this in turn is further phosphorylated to its active metabolite triphosphate by nucleoside-phosphate kinases.[94][95]

Mechanism of action

As an adenosine nucleoside triphosphate analog, the active metabolite of remdesivir interferes with the action of viral RNA-dependent RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production.[2][96] In some viruses such as the respiratory syncytial virus it causes the RNA-dependent RNA polymerases to pause, but its predominant effect (as in Ebola) is to induce an irreversible chain termination. Unlike with many other chain terminators, this is not mediated by preventing addition of the immediately subsequent nucleotide, but is instead delayed, occurring after five additional bases have been added to the growing RNA chain.[97] For the RNA-Dependent RNA Polymerase of MERS-CoV, SARS-CoV-1, and SARS-CoV-2 arrest of RNA synthesis occurs after incorporation of three additional nucleotides.[98][95] Hence, remdesivir is classified as a direct-acting antiviral agent that works as a delayed chain terminator.[93][95]

Pharmacokinetics

In non-human primates, the plasma half-life of the prodrug is 20 minutes, with the main metabolite being the nucleoside, GS-441524. Two hours post injection, the main metabolite GS-441524 is present at micromolar concentrations, whilst intact Remdesivir is no longer detectable. Because of this rapid extracellular conversion to the nucleoside GS-441524, some researchers have questioned whether the active nucleotide triphosphate is truly derived from Remdesivir pro-drug removal or whether it occurs by GS-441524 phosphorylation, and whether direct administration of GS-441524 would constitute a cheaper and easier to administer COVID19 drug compared to Remdesivir.[99][100] The activated nucleotide triphosphate form has sustained intracellular levels in PBMC and presumably in other cells as well.[93]

Resistance

Mutations in the mouse hepatitis virus RNA replicase that cause partial resistance to remdesivir were identified in 2018. These mutations make the viruses less effective in nature, and the researchers believe they will likely not persist where the drug is not being used.[101]

Interactions

Remdesivir is at least partially metabolized by the cytochrome P450 enzymes CYP2C8, CYP2D6, and CYP3A4.[102][103] 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.[104]

On 15 June 2020, the FDA updated the fact sheets for the emergency use authorization of remdesivir to warn that using chloroquine or hydroxychloroquine with remdesivir may reduce the antiviral activity of remdesivir.[105] 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.[103]

Synthesis

Synthesis of remdesivir in structural formulae

Remdesivir can be synthesized in multiple steps from ribose derivatives. The figure to the right is one of the synthesis routes of remdesivir invented by Chun and coauthors from Gilead Sciences.[106][107] In this method, intermediate a is firstly prepared from L-alanine and phenyl phosphorodichloridate in presence of triethylamine and dichloromethane; triple benzyl-protected ribose is oxidized by dimethyl sulfoxide with acetic anhydride and give the lactone intermediate b; pyrrolo[2,1-f] [1,2,4]triazin-4-amine is brominated, and the amine group is protected by excess trimethylsilyl chloride. n-Butyllithium undergoes a halogen-lithium exchange reaction with the bromide at −78 °C (−108 °F) to yield the intermediate c. The intermediate b is then added to a solution containing intermediate c dropwise. After quenching the reaction in a weakly acidic aqueous solution, a mixture of 1: 1 anomers was obtained. It was then reacted with an excess of trimethylsilyl cyanide in dichloromethane at −78 °C (−108 °F) for 10 minutes. Trimethylsilyl triflate was added and reacts for one additional hour, and the mixture was quenched in an aqueous sodium hydrogen carbonate. A nitrile intermediate was obtained. The protective group, benzyl, was then removed with boron trichloride in dichloromethane at −20 °C (−4 °F). The excess of boron trichloride was quenched in a mixture of potassium carbonate and methanol. A benzyl-free intermediate was obtained. The isomers were then separated via reversed-phase HPLC. The optically pure compound and intermediate a are reacted with trimethyl phosphate and methylimidazole to obtain a diastereomer mixture of remdesivir. In the end, optically pure remdesivir can be obtained through chiral resolution methods.[citation needed]

Manufacturing and distribution

Remdesivir requires "70 raw materials, reagents, and catalysts" to make, and approximately "25 chemical steps."[108] Some of the ingredients are extremely dangerous to humans, especially trimethylsilyl cyanide.[108] 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, Gilead Sciences was able to find ways to reduce the production time to six months.[108]

In January 2020, Gilead began working on restarting remdesivir production in glass-lined steel chemical reactors at its manufacturing plant in Edmonton, Alberta.[108] 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.[108] The Edmonton plant finished its first new batch of remdesivir in April 2020.[108] Around the same time, fresh raw materials began to arrive from contract manufacturers reactivated by Gilead in January.[108]

Terminology

Remdesivir is the international nonproprietary name (INN)[109] while the development code name was GS-5734.[110]

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