Remdesivir
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Remdesivir, sold under the brand name Veklury, Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. is a broad-spectrum antiviral medication developed by the
biopharmaceutical A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, t ...
company
Gilead Sciences Gilead Sciences, Inc. () is an American biopharmaceutical company headquartered in Foster City, California, that focuses on researching and developing antiviral drugs used in the treatment of HIV/AIDS, hepatitis B, hepatitis C, influenza, and CO ...
. It is administered via injection into a vein. During the COVID19 pandemic, remdesivir was approved or authorized for emergency use to treat COVID19 in numerous countries. Remdesivir was originally developed to treat
hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include ...
, and was subsequently investigated for
Ebola virus disease Ebola, also known as Ebola virus disease (EVD) and Ebola hemorrhagic fever (EHF), is a viral hemorrhagic fever in humans and other primates, caused by ebolaviruses. Symptoms typically start anywhere between two days and three weeks after infe ...
and
Marburg virus Marburg virus (MARV) is a hemorrhagic fever virus of the '' Filoviridae'' family of viruses and a member of the species '' Marburg marburgvirus'', genus '' Marburgvirus''. It causes Marburg virus disease in primates, a form of viral hemorrhag ...
infections before being studied as a post-infection treatment for COVID19. Remdesivir is a
prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...
that is intended to allow intracellular delivery of GS-441524 monophosphate and subsequent biotransformation into GS-441524 triphosphate, a ribo nucleotide analogue inhibitor of viral
RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that catalyzes the chemical reactions that synthesize RNA from a DNA template. Using the e ...
. The most common side effect in healthy volunteers is raised blood levels of liver enzymes. The most common side effect in people with COVID19 is
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
. Side effects may include liver inflammation and an
infusion Infusion is the process of extracting chemical compounds or flavors from plant material in a solvent such as water, oil or alcohol, by allowing the material to remain suspended in the solvent over time (a process often called steeping). An inf ...
-related reaction with nausea, low blood pressure, and sweating. The US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) considers it to be a
first-in-class medication A first-in-class medication is a prototype drug that uses a "new and unique mechanism of action" to treat a particular medical condition. While the Food and Drug Administration's Center for Drug Evaluation and Research tracks first-in-class medic ...
.


Medical uses

In the European Union, remdesivir is
indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...
for the treatment of COVID19 in adults and adolescents (aged twelve years and older with body weight at least ) with
pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...
requiring supplemental oxygen and for adults who do not require supplemental oxygen and who are at increased risk of progressing to severe COVID19. In the United States, remdesivir is indicated for the treatment of COVID19 in people 28 days of age and older and weighing at least who are hospitalized; or not hospitalized and have mild-to-moderate COVID19, and are at high risk for progression to severe COVID19, including hospitalization or death. In November 2020, the FDA issued an emergency use authorization (EUA) for the combination of
baricitinib Baricitinib, sold under the brand name Olumiant among others, is an immunomodulatory medication used for the treatment of rheumatoid arthritis, alopecia areata, and COVID-19. It acts as an inhibitor of janus kinase (JAK), blocking the subty ...
with remdesivir, for the treatment of suspected or laboratory confirmed COVID19 in hospitalized people two years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or
extracorporeal membrane oxygenation Extracorporeal membrane oxygenation (ECMO) is a form of extracorporeal life support, providing prolonged cardiac and respiratory system, respiratory support to people whose human heart, heart and human lung, lungs are unable to provide an adequa ...
(ECMO). In Australia, it is approved for those aged four weeks of age and older with a body weight at least with
pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...
requiring supplemental oxygen or those aged four weeks of age and older with body weight at least who do not require supplemental oxygen and who are at high risk of progressing to severe COVID19. In 2024, a retrospective study found treatment with the antiviral remdesivir plus dexamethasone was associated with fewer deaths in hospitalized COVID-19 patients compared to dexamethasone alone. The combination led to a 26% reduction in mortality at 14 days and a 24% reduction at 28 days.


Side effects

The most common adverse effects in people treated with remdesivir were
respiratory failure Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a r ...
and blood
biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
s of
organ Organ and organs may refer to: Biology * Organ (biology), a group of tissues organized to serve a common function * Organ system, a collection of organs that function together to carry out specific functions within the body. Musical instruments ...
impairment, including low albumin, low potassium, low count of red blood cells, low count of thrombocytes, and elevated bilirubin (jaundice). Other reported adverse effects include gastrointestinal distress, elevated
transaminase Transaminases or aminotransferases are enzymes that catalyze a transamination reaction between an amino acid and an α-keto acid. They are important in the synthesis of amino acids, which form proteins. Function and mechanism An amino acid con ...
levels in the blood ( liver enzymes),
infusion Infusion is the process of extracting chemical compounds or flavors from plant material in a solvent such as water, oil or alcohol, by allowing the material to remain suspended in the solvent over time (a process often called steeping). An inf ...
site reactions, and electrocardiogram abnormalities. Remdesivir may cause infusion-related reactions, including low blood pressure, nausea, vomiting, sweating or shivering. 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. Signs and symptoms of infusion-related reactions may include: low blood pressure, nausea, vomiting, sweating, and shivering. * Increases in levels of liver enzymes, seen in abnormal liver blood tests. 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.


Pharmacology


Activation

Remdesivir is a protide (
prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...
of nucleotide) able to diffuse into cells, where it is converted to GS-441524 monophosphate via the actions of
esterase In biochemistry, an esterase is a class of enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis (and as such, it is a type of hydrolase). A wide range of different esterases exist that differ ...
s ( CES1 and CTSA) and a phosphoamidase ( HINT1); this in turn is further phosphorylated to its active metabolite triphosphate by
nucleoside-phosphate kinase In enzymology, a nucleoside-phosphate kinase () is an enzyme that catalysis, catalyzes the chemical reaction :ATP + nucleoside phosphate \rightleftharpoons ADP + nucleoside diphosphate Thus, the two substrate (biochemistry), substrates of this en ...
s. This pathway of bioactivation is meant to occur
intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
ly, but a substantial amount of remdesivir is prematurely
hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysi ...
in plasma, with GS-441524 being the major metabolite in plasma, and the only metabolite remaining two hours after dosing.


Mechanism of action

As an
adenosine Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside build ...
nucleoside triphosphate analog (GS-443902), the active metabolite of remdesivir interferes with the action of viral
RNA-dependent RNA polymerase RNA-dependent RNA polymerase (RdRp) or RNA replicase is an enzyme that catalyzes the self-replication, replication of RNA from an RNA template. Specifically, it catalyzes synthesis of the RNA strand Complementarity (molecular biology), compleme ...
and evades
proofreading Proofreading is a phase in the process of publishing where galley proofs are compared against the original manuscripts or graphic artworks, to identify transcription errors in the typesetting process. In the past, proofreaders would place corr ...
by viral
exoribonuclease An exoribonuclease is an exonuclease ribonuclease, which are enzymes that degrade RNA by removing terminal nucleotides from either the 5' end or the 3' end of the RNA molecule. Enzymes that remove nucleotides from the 5' end are called ''5'-3 ...
(ExoN), causing a decrease in viral RNA production. In some viruses, such as the
respiratory syncytial virus Respiratory syncytial virus (RSV), also called human respiratory syncytial virus (hRSV) and human orthopneumovirus, is a virus that causes infections of the respiratory tract. It is a negative-sense, single-stranded RNA virus. Its name is derive ...
, it causes the RNA-dependent RNA polymerases to pause, but its predominant effect (as in Ebola) is to induce an irreversible
chain termination In polymer chemistry, chain termination is any chemical reaction that ceases the formation of reactive intermediates in a chain propagation step in the course of a polymerization, effectively bringing it to a halt. Mechanisms of 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. For the RNA-dependent RNA polymerases of MERS-CoV,
SARS-CoV-1 Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), previously known as severe acute respiratory syndrome coronavirus (SARS-CoV), is a strain (biology), strain of coronavirus that causes severe acute respiratory syndrome (SARS), the ...
, and
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19, the respiratory illness responsible for the COVID-19 pandemic. The virus previously had the Novel coronavirus, provisional nam ...
, arrest of RNA synthesis occurs after incorporation of three additional nucleotides. Hence, remdesivir is classified as a direct-acting antiviral agent that works as a delayed chain terminator.


Pharmacokinetics

In non-human primates, the plasma
half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...
of the prodrug is 20 minutes, with the main metabolite being the
nucleoside Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotid ...
, 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. The activated nucleotide triphosphate form has sustained intracellular levels in PBMC and presumably in other cells as well.


Resistance

Mutations in the mouse hepatitis virus
RNA replicase RNA-dependent RNA polymerase (RdRp) or RNA replicase is an enzyme that catalyzes the replication of RNA from an RNA template. Specifically, it catalyzes synthesis of the RNA strand complementary to a given RNA template. This is in contrast to ...
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.


Interactions

Remdesivir is at least partially metabolized by the
cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
enzymes
CYP2C8 Cytochrome P4502C8 (CYP2C8) is a member of the cytochrome P450 mixed-function oxidase system involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-chain polyunsat ...
,
CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...
, and
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
.
Blood plasma Blood plasma is a light Amber (color), amber-colored liquid component of blood in which blood cells are absent, but which contains Blood protein, proteins and other constituents of whole blood in Suspension (chemistry), suspension. It makes up ...
concentrations of remdesivir are expected to decrease if it is administered together with cytochrome P450 inducers such as rifampicin,
carbamazepine Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medications and as ...
,
phenobarbital Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of ...
,
phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anticonvulsant, anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence se ...
, primidone, and St John's wort. Using chloroquine or hydroxychloroquine with remdesivir may reduce the antiviral activity of remdesivir. 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.


Synthesis

Remdesivir can be synthesized in multiple steps from
ribose Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally occurring form, , is a component of the ribonucleotides from which RNA is built, and so this comp ...
derivatives. The figure to the right is one of the synthesis routes of remdesivir invented by Chun and coauthors from Gilead Sciences.


''In vitro'' experiments

An ''
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
'' study of remdesivir assessing antiviral activity against SARS-CoV-2 was performed. 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. The results found that remdesivir functioned well as an inhibitor of the infection. 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." Some of the ingredients are extremely dangerous to humans, especially
trimethylsilyl cyanide Trimethylsilyl cyanide is the chemical compound with the chemical formula, formula . This volatile liquid consists of a cyanide group, that is CN, attached to a trimethylsilyl group. The molecule is used in organic synthesis as the equivalent of h ...
. 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. In January 2020, Gilead began working on restarting remdesivir production in glass-lined steel
chemical reactor A chemical reactor is an enclosed volume in which a chemical reaction takes place. In chemical engineering, it is generally understood to be a process vessel used to carry out a chemical reaction, which is one of the classic unit operations in che ...
s at its manufacturing plant in
Edmonton, Alberta Edmonton is the capital city of the Provinces and territories of Canada, Canadian province of Alberta. It is situated on the North Saskatchewan River and is the centre of the Edmonton Metropolitan Region, which is surrounded by Central Alberta ...
. 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 La Verne is a city in Los Angeles County, California, United States. The population was 31,334 at the 2020 United States census, 2020 census. History The area was home to Native Americans. The European history of the area dates back to the ...
to start filling vials. The Edmonton plant finished its first new batch of remdesivir in April 2020. Around the same time, fresh raw materials began to arrive from contract manufacturers reactivated by Gilead in January. Another challenge is getting remdesivir into patients despite the drug's "poor predicted solubility and poor stability." In June 2020, Ligand Pharmaceuticals revealed that Gilead has been managing those issues by mixing Ligand's proprietary
excipient An excipient is a substance formulated alongside the active ingredient of a medication. They may be used to enhance the active ingredient’s therapeutic properties; to facilitate drug absorption; to reduce viscosity; to enhance solubility; to i ...
Captisol (based on
University of Kansas The University of Kansas (KU) is a public research university with its main campus in Lawrence, Kansas, United States. Two branch campuses are in the Kansas City metropolitan area on the Kansas side: the university's medical school and hospital ...
research into
cyclodextrin Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocycle, macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds. Cyclodextrins are produced from starch by enzyme, enzymatic conversion. They are used in ...
) with remdesivir at a 30:1 ratio. 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. On 12 May 2020, Gilead announced that it had granted non-exclusive voluntary licenses to five
generic drug A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
companies in India and Pakistan to manufacture remdesivir for distribution to 127 countries. 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 COVID19 emergency or another medicine or vaccine is approved for COVID19, whichever comes first. On 23 June 2020, India granted emergency marketing approval of generic remdesivir manufactured by two Gilead licensees, Cipla and Hetero Drugs.


Society and culture


Legal status

Remdesivir is approved, or authorized for emergency use, to treat COVID19 in many countries. Remdesivir has been authorized for emergency use in India, Singapore, and approved for use in Japan, the European Union, the United States, and Australia for people with severe symptoms. Remdesivir is the first treatment for COVID19 to be approved by the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA). 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. 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 COVID19 in hospitalized pediatric patients weighing to less than or hospitalized pediatric patients less than twelve years of age weighing at least .


Australia

In July 2020, remdesivir was provisionally approved for use in Australia for use in adults and adolescents with severe COVID19 symptoms who have been hospitalized. Australia claims to have a sufficient supply of remdesivir in its national stockpile.


Canada

As of 11 April 2020, access in Canada was available only through clinical trials.
Health Canada Health Canada (HC; )Health Canada is the applied title under the Federal Identity Program; the legal title is Department of Health (). is the Structure of the Canadian federal government#Departments, with subsidiary units, department of the Gove ...
approved requests to treat twelve people with remdesivir under the department's special-access program (SAP). Additional doses of remdesivir are not available through the SAP except for pregnant women or children with confirmed COVID19 and severe illness. In June 2020, Health Canada received an application from Gilead for the use of remdesivir for treating COVID19. On 27 July 2020, Health Canada conditionally approved the application. In September 2020,
Minister of Public Services and Procurement The minister of government transformation, public services and procurement () is the minister of the Crown in the Cabinet of Canada, Canadian Cabinet who is responsible for overseeing the Government of Canada's "common service organization" (Pub ...
Anita Anand announced that Canada had entered into a deal to obtain up to 150,000 vials of remdesivir from Gilead starting in October. As of 8 October, remdesivir was still not widely available in
Alberta Alberta is a Provinces and territories of Canada, province in Canada. It is a part of Western Canada and is one of the three Canadian Prairies, prairie provinces. Alberta is bordered by British Columbia to its west, Saskatchewan to its east, t ...
, because
Alberta Health Services Alberta Health Services (AHS) is the single Health regions of Canada, health authority for the Provinces and territories of Canada, Canadian province of Alberta and the "largest integrated provincial health care system" in Canada. Headquartered ...
was undertaking a " formulary review" to be completed by mid-November.


Czech Republic

In March 2020, the drug was provisionally approved for use for COVID19 patients in a serious condition as a result of the outbreak in the Czech Republic.


European Union

In February 2016, orphan designation (EU/3/16/1615) was granted by the European Commission to Gilead Sciences International Ltd, United Kingdom, for remdesivir for the treatment of Ebola virus disease. In April 2020, the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
(EMA) provided recommendations on compassionate use of remdesivir for COVID19 in the EU. In May 2020, the
Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as the Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regar ...
(CHMP) of the EMA recommended expanding the compassionate use of remdesivir to those not on mechanical ventilation. 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). The updated recommendations were based on preliminary results from the NIAID-ACTT study, which suggested a beneficial effect of remdesivir in the treatment of hospitalized individuals with severe COVID19. 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. 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. In July 2020, the European Union granted a conditional marketing authorization for remdesivir with an indication for the treatment of COVID19 in adults and adolescents (aged twelve years and older with body weight at least ) with pneumonia requiring supplemental oxygen. In August 2022, the European Union granted a full marketing authorization for remdesivir.


Iran

Remdesivir has been also produced in Iran by Barakat; Iran is planning to increase the productions of Remdesivir ampoules from 20,000 to 150,000 ampoules per month. It has also the permission of the "Food and Drug Administration" of MOHME


Japan

In 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 US emergency authorization.


Mexico

In October 2020, Deputy Secretary of Prevention and Health Promotion Hugo López-Gatell Ramírez stated at a news conference that Mexico would not necessarily follow the United States in approving the drug for use in Mexico. López-Gatell explained that the Federal Commission for the Protection against Sanitary Risk (Cofepris) had already twice denied the approval of remdesivir because, in that agency's view, the evidence does not suggest "sufficient efficacy". In March 2020, Cofepris authorized the drug for emergency cases, advising to give continuous surveillance of the integral health of the patient.


Singapore

In June 2020, Singapore's Health Sciences Authority conditionally approved the usage of remdesivir in Singapore.


United States

In March 2020, United States President
Donald Trump Donald John Trump (born June 14, 1946) is an American politician, media personality, and businessman who is the 47th president of the United States. A member of the Republican Party (United States), Republican Party, he served as the 45 ...
announced that remdesivir was available for " compassionate use" for people with COVID19; FDA Commissioner Stephen Hahn confirmed the statement at the same press conference. It was later revealed that Gilead had been providing remdesivir in response to compassionate use requests since 25 January. 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. In May 2020, the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
granted Gilead emergency use authorization (EUA) for remdesivir to be distributed and used by licensed healthcare providers to treat adults and children hospitalized with severe COVID19. Severe COVID19 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 Extracorporeal membrane oxygenation (ECMO) is a form of extracorporeal life support, providing prolonged cardiac and respiratory system, respiratory support to people whose human heart, heart and human lung, lungs are unable to provide an adequa ...
(ECMO), a heart–lung bypass machine. Distribution of remdesivir under the EUA was controlled by the US government for use consistent with the terms and conditions of the EUA. Gilead supplied remdesivir to authorized distributors, or directly to a US government agency, who distributed it to hospitals and other healthcare facilities as directed by the US government, in collaboration with state and local government authorities, as needed. Gilead stated they were donating 1.5million vials for emergency use 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. The initial distribution of the drug in the US was tripped up by seemingly capricious decision-making and finger-pointing, resulting in over a week of confusion and frustration among healthcare providers and patients alike. On 9 May 2020, the
United States Department of Health and Human Services The United States Department of Health and Human Services (HHS) is a cabinet-level executive branch department of the US federal government created to protect the health of the US people and providing essential human services. Its motto is ...
(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." HHS also clarified that only 607,000 vials of Gilead's promised donation of 1.5million vials would be going to American patients. 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. In May 2020, Gilead indicated they would increase the number of doses donated to the US from 607,000 to around 940,000. 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. In June 2020, 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 Cencora, Inc., formerly known as AmerisourceBergen, is an American drug wholesale company and a contract research organization, that was formed by the merger of Bergen Brunswig and AmeriSource in 2001. It is one of the largest pharmaceutica ...
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. 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 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). 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, Germany, and the United Kingdom. In August 2020, the FDA broadened the Emergency Use Authorization (EUA) for remdesivir to include all hospitalized patients with suspected or laboratory-confirmed COVID19, irrespective of the severity of their disease. The Fact Sheet was updated to reflect the new guidance. In October 2020, Gilead and HHS announced that HHS was relinquishing control over remdesivir allocation because production of the drug had finally caught up with US domestic demand. AmerisourceBergen will remain the sole distributor of Veklury in the US through the end of 2020. On 22 October 2020, the FDA approved remdesivir and also revised the EUA to permit the use of remdesivir for treatment of suspected or laboratory confirmed COVID19 in hospitalized children weighing to less than or hospitalized children less than twelve years of age weighing at least . This decision was criticized for an alleged lack of previous consultation on part of the FDA given the complications of antiviral drug issues. In November 2020, the FDA issued an EUA for the combination of
baricitinib Baricitinib, sold under the brand name Olumiant among others, is an immunomodulatory medication used for the treatment of rheumatoid arthritis, alopecia areata, and COVID-19. It acts as an inhibitor of janus kinase (JAK), blocking the subty ...
with remdesivir, for the treatment of suspected or laboratory-confirmed COVID19 in hospitalized people two years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). The data supporting the EUA for baricitinib combined with remdesivir are based on a randomized, double-blind, placebo-controlled clinical trial (ACTT-2), which was conducted by the National Institute of Allergy and Infectious Diseases (NIAID). The EUA was issued to Eli Lilly and Company. Remdesivir received approval from the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) in October 2020, for use in adults and children twelve years and older requiring hospitalization for treatment of severe COVID19 infections. In January 2022, the FDA gave regulatory approval to remdesivir for use in adults and children (twelve years of age and older who weigh at least and are positive for COVID19, not hospitalized, and are ill with COVID19 having high risk for developing severe COVID19, including hospitalization or death. In April 2022, the FDA expanded the approval of remdesivir to include people 28 days of age and older weighing at least . The FDA also provided emergency use authorization in 2022, for remdesivir treatment of children under age twelve who are COVIDpositive and not hospitalized, but have mild-to-moderate COVID19 with high risk of developing severe infection, including hospitalization or death.


Economics

In June 2020, Gilead announced that it had set the price of remdesivir at per vial for the governments of developed countries, including the United States, and for US private health insurance companies. The expected course of treatment is six vials over five days for a total cost of . Being a repurposed drug, the minimum production cost for remdesivir is estimated at per day of treatment. In July 2020, the European Union secured a () contract with Gilead, to make the drug available there in early August 2020. In October 2020, Gilead Sciences and the European Commission announced they had signed a joint procurement framework contract in which Gilead agreed to provide up to 500,000 remdesivir treatment courses over the next six months to 37 European countries. Among the contracting countries were all 27 EU member states plus the United Kingdom, "Albania, Bosnia & Herzegovina, Iceland, Kosovo, Montenegro, North Macedonia, Norway, and Serbia". At the time, the price per treatment course was not disclosed; Reuters reported the price was 2,070 euros, thereby implying the total value of the contract (if all 500,000 courses are ordered) is approximately €1.035 billion. Under the contract, each participating country will directly place orders with Gilead and pay Gilead directly for its own orders.


Names

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


Research

Remdesivir was originally created and developed by
Gilead Sciences Gilead Sciences, Inc. () is an American biopharmaceutical company headquartered in Foster City, California, that focuses on researching and developing antiviral drugs used in the treatment of HIV/AIDS, hepatitis B, hepatitis C, influenza, and CO ...
in 2009, to treat
hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include ...
and
respiratory syncytial virus Respiratory syncytial virus (RSV), also called human respiratory syncytial virus (hRSV) and human orthopneumovirus, is a virus that causes infections of the respiratory tract. It is a negative-sense, single-stranded RNA virus. Its name is derive ...
(RSV). It did not work against hepatitis C or RSV, but was then repurposed and studied as a potential treatment for
Ebola virus disease Ebola, also known as Ebola virus disease (EVD) and Ebola hemorrhagic fever (EHF), is a viral hemorrhagic fever in humans and other primates, caused by ebolaviruses. Symptoms typically start anywhere between two days and three weeks after infe ...
and
Marburg virus Marburg virus (MARV) is a hemorrhagic fever virus of the '' Filoviridae'' family of viruses and a member of the species '' Marburg marburgvirus'', genus '' Marburgvirus''. It causes Marburg virus disease in primates, a form of viral hemorrhag ...
infections. According to the Czech News Agency, this new line of research was carried out under the direction of scientist Tomáš Cihlář. A collaboration of researchers from the
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the National public health institutes, national public health agency of the United States. It is a Federal agencies of the United States, United States federal agency under the United S ...
(CDC) and
Gilead Sciences Gilead Sciences, Inc. () is an American biopharmaceutical company headquartered in Foster City, California, that focuses on researching and developing antiviral drugs used in the treatment of HIV/AIDS, hepatitis B, hepatitis C, influenza, and CO ...
subsequently discovered that remdesivir had antiviral activity ''in vitro'' against multiple filoviruses, pneumoviruses, paramyxoviruses, and
coronavirus Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the comm ...
es. Preclinical and clinical research and development was done in collaboration between Gilead Sciences and various US government agencies and academic institutions. 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 The United States Patent and Trademark Office (USPTO) is an List of federal agencies in the United States, agency in the United States Department of Commerce, U.S. Department of Commerce that serves as the national patent office and trademark ...
(USPTO). The USPTO granted two patents on remdesivir to Gilead Sciences on 9 April 2019: one for filoviruses, and one which covered both
arenavirus An arenavirus is a bi- or trisegmented ambisense RNA virus that is a member of the family ''Arenaviridae''. These viruses infect rodents and occasionally humans. A class of novel, highly divergent arenaviruses, properly known as reptarenavirus ...
es and coronaviruses.


Ebola

In October 2015, the
United States Army Medical Research Institute of Infectious Diseases The United States Army Medical Research Institute of Infectious Diseases (USAMRIID; ) is the United States Army's main institution and facility for defensive research into countermeasures against biological warfare. It is located on Fort D ...
(USAMRIID) announced preclinical results that remdesivir had blocked the
Ebola virus ''Orthoebolavirus zairense'' or Zaire ebolavirus, more commonly known as Ebola virus (; EBOV), is one of six known species within the genus ''Ebolavirus''. Four of the six known ebolaviruses, including EBOV, cause a severe and often fatal vira ...
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". 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 The Centers for Disease Control and Prevention (CDC) is the National public health institutes, national public health agency of the United States. It is a Federal agencies of the United States, United States federal agency under the United S ...
(CDC). As a result of this work, it was recommended that remdesivir "should be further developed as a potential treatment." Remdesivir was rapidly pushed through clinical trials due to the
West African Ebola virus epidemic The 2013–2016 epidemic of Ebola virus disease, centered in West Africa, was the most widespread outbreak of the disease in history. It caused major loss of life and socioeconomic disruption in the region, mainly in Guinea, Liberia and Sie ...
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 The Kivu Ebola epidemic was an outbreak of Ebola virus disease (EVD) mainly in eastern Democratic Republic of the Congo (DRC), and in other parts of Central Africa, from 2018 to 2020. Between 1 August 2018 and 25 June 2020 it resulted in 3,470 ...
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 A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodie ...
treatments such as ansuvimab and atoltivimab/maftivimab/odesivimab. The trials, however, established its safety profile.


COVID-19


Hospitalized patients

Remdesivir was approved for medical use in the United States in October 2020. The US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) approved remdesivir based on the agency's analysis of data from three randomized, controlled clinical trials that included participants hospitalized with mild-to-severe COVID19. The FDA granted approval and reissued the revised EUA to Gilead Sciences Inc. The FDA approved remdesivir based primarily on evidence from three clinical trials (NCT04280705, NCT04292899, and NCT04292730) of 2043 hospitalized participants with COVID19. The trials were conducted at 226 sites in 17 countries including the United States. In November 2020, the World Health Organization (WHO) updated its guideline on therapeutics for COVID19 to include a conditional recommendation against the use of remdesivir, triggered by results from the WHO Solidarity trial. Meanwhile, the
Public Health Agency of Canada The Public Health Agency of Canada (PHAC; ) is an agency of the Government of Canada that is responsible for public health, emergency preparedness and response, and infectious and chronic disease control and prevention. History The PHAC was f ...
's COVID19 Clinical Pharmacology Task Group recommended that remdesivir only be administered to hospitalized patients as part of a
randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...
due to limited information on risks and benefits. In January 2022, the Canadian component of the WHO Solidarity Trial reported that in-hospital people with COVID19 treated with remdesivir had 17% lower relative risk of death (18.7% versus 22.6% death rates) and 47% reduced relative risk for needing oxygen and mechanical ventilation (8.0% versus 15.0%) compared to people receiving standard-of-care treatments. In September 2022, the WHO updated their guidelines to recommend use of remdesivir for both non-hospitalized and hospitalized patients. This was based on final results from the SOLIDARITY trial that showed a reduction in mortality or progression to mechanical ventilation for non-ventilated patients.


Nonhospitalized outpatients

In January 2022, a study indicated that nonhospitalized people who were at high risk for COVID19 progression had an 87% lower risk of hospitalization or death after a 3-day course of intravenous remdesivir.


Remdesivir/baricitinib

In May 2020, the
National Institute of Allergy and Infectious Diseases The National Institute of Allergy and Infectious Diseases (NIAID, ) is one of the 27 institutes and centers that make up the National Institutes of Health (NIH), an agency of the United States Department of Health and Human Services. NIAID's mis ...
(NIAID) started the Adaptive COVID19 Treatment Trial 2 (ACTT-2) to evaluate the safety and efficacy of a treatment regimen consisting of remdesivir plus
baricitinib Baricitinib, sold under the brand name Olumiant among others, is an immunomodulatory medication used for the treatment of rheumatoid arthritis, alopecia areata, and COVID-19. It acts as an inhibitor of janus kinase (JAK), blocking the subty ...
for treating hospitalized adults who have a laboratory-confirmed SARS-CoV-2 infection with evidence of lung involvement, including a need for supplemental oxygen, abnormal chest X-rays, or illness requiring mechanical ventilation. In November 2020, the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) issued an emergency use authorization (EUA) for the drug baricitinib, in combination with remdesivir, for the treatment of suspected or laboratory-confirmed COVID19 in hospitalized people two years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or
extracorporeal membrane oxygenation Extracorporeal membrane oxygenation (ECMO) is a form of extracorporeal life support, providing prolonged cardiac and respiratory system, respiratory support to people whose human heart, heart and human lung, lungs are unable to provide an adequa ...
(ECMO). The data supporting the EUA for baricitinib combined with remdesivir are based on a randomized, double-blind, placebo-controlled clinical trial (ACTT-2), which was conducted by the National Institute of Allergy and Infectious Diseases (NIAID). The EUA was issued to Eli Lilly and Company.


Remdesivir/interferon beta-1a

In August 2020, the NIAID started the Adaptive COVID19 Treatment Trial 3 (ACTT 3) to evaluate the safety and efficacy of a treatment regimen consisting of remdesivir plus interferon beta-1a for hospitalized adults who have a laboratory-confirmed SARS-CoV-2 infection with evidence of lung involvement, including a need for supplemental oxygen, abnormal chest X-rays, or illness requiring mechanical ventilation.


Veterinary uses

In 2019, GS-441524 was shown to have promise for treating feline infectious peritonitis caused by a
coronavirus Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the comm ...
. It has not been evaluated or approved by the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(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. 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 COVID19 treatment.


References


External links

* {{Authority control Anti–RNA virus drugs Antiviral drugs COVID-19 drug development Experimental antiviral drugs Gilead Sciences Heterocyclic compounds with 2 rings Nitriles Nitrogen heterocycles Nucleotides Orphan drugs Phenol esters Phosphoramidates