COVID-19 drug repurposing research

Drug repositioning (also known as drug re-purposing, re-profiling, re-tasking, or therapeutic switching) is the re-purposing of an approved drug for the treatment of a different disease or medical condition than that for which it was originally developed.[1] This is one line of scientific research which is being pursued to develop safe and effective COVID-19 treatments.[2][3] Other research directions include the development of a COVID-19 vaccine[4] and convalescent plasma transfusion.[5]

This article is about drugs that may be repurposed for treating COVID-19. For potential COVID-19 vaccine, see COVID-19 vaccine. For potential therapeutic drugs for COVID-19, see COVID-19 drug development.

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During the pandemic, several existing antiviral medications, previously developed or used as treatments for severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV/AIDS, and malaria, were being researched as COVID‑19 treatments, with some moved into clinical trials.[6][7][8]

In a statement to the journal Nature Biotechnology in February 2020, U.S. National Institutes of Health Viral Ecology Unit chief Vincent Munster said, "The general genomic layout and the general replication kinetics and the biology of the MERS, SARS and [SARS-CoV-2] viruses are very similar, so testing drugs which target relatively generic parts of these coronaviruses is a logical step".[2]

RECOVERY Trial
Main article: RECOVERY Trial

A large-scale, randomized controlled trial named the RECOVERY Trial was set up in March 2020 in the U.K to test possible treatments for COVID-19. It is run by the Nuffield Departments of Public Health and of Medicine at the University of Oxford and is currently testing five repurposed drugs and also convalescent plasma. As of June 2020, the trial has enrolled more than 11,500 COVID-19 positive participants in the U.K.[9][10][11]

Studies

Chloroquine and hydroxychloroquine
See also: Chloroquine § COVID-19, and Hydroxychloroquine § COVID-19

Chloroquine is an anti-malarial medication also used against some auto-immune diseases. On 18 March, the World Health Organization (WHO) announced that chloroquine and the related hydroxychloroquine would be among the four drugs studied as part of the Solidarity clinical trial.[12] On 19 March, the U.S. President Donald Trump encouraged the use of chloroquine and hydroxychloroquine during a national press conference. These endorsements led to massive increases in public demand for the drugs in the United States.[13] New York Governor Andrew Cuomo announced that New York State trials of chloroquine and hydroxychloroquine would begin on 24 March.[14]

On 28 March, the U.S. Food and Drug Administration (FDA) authorized the use of hydroxychloroquine sulfate and chloroquine phosphate under an Emergency Use Authorization (EUA).[15][16] The treatment has not been approved by the FDA's clinical trials process.[16] However, the drug is authorized under the EUA as an experimental treatment for emergency use in patients who are hospitalized, but are not able to receive treatment in a clinical trial.[16][17][15] The Centers for Disease Control and Prevention (CDC) said that "the use, dosing, or duration of hydroxychloroquine for prophylaxis or treatment of SARS-CoV-2 infection" are not yet established.[18] Doctors have said they are using the drug when "there's no other option".[19] On 9 April, the National Institutes of Health began the first clinical trial to assess whether hydroxychloroquine is safe and effective to treat COVID‑19.[19][20]

On 15 June 2020, the FDA revoked the emergency use authorization for hydroxychloroquine and chloroquine, stating that although the evaluation of both these drugs under clinical trials continues, the FDA (after interagency consultation with the Biomedical Advanced Research and Development Authority (BARDA)) concluded that, based on new information and other information discussed "... it is no longer reasonable to believe that oral formulations of hydroxychloroquine (HCQ) and chloroquine (CQ) may be effective in treating COVID‑19, nor is it reasonable to believe that the known and potential benefits of these products outweigh their known and potential risks".[21][22][23][24]

On 24 April, the FDA cautioned against using the drug outside a hospital setting or clinical trial after reviewing case reports of adverse effects including ventricular tachycardia, ventricular fibrillation and in some cases death.[25] According to Johns Hopkins' ABX Guide for COVID‑19, "Hydroxychloroquine may cause prolonged QT, and caution should be used in critically ill COVID‑19 patients who may have cardiac dysfunction or if combined with other drugs that cause QT prolongation".[26] Caution was also recommended as to the combination of chloroquine and hydroxychloroquine with treatments which might inhibit the CYP3A4 enzyme (by which these drugs are metabolized). As such, combination might indirectly result in higher plasma levels of chloroquine and hydroxychloroquine, and thus enhance the risk for significant QT prolongation. CYP3A4 inhibitors include Azithromycin, ritonavir and lopinavir.[27] A Veterans Affairs study released results on 21 April suggesting COVID‑19-hospitalized patients treated with hydroxychloroquine were more likely to die than those who received no drug treatment at all, after correcting for clinical characteristics.[28][29]

A chloroquine tablet

Drugs used for treatment of infectious diseases may also be considered for use for post-exposure prophylaxis. On 22 May, The Lancet published a response to criticism of the Indian government's decision to allow chemoprophylaxis with hydroxychloroquine for some high risk persons who may have had exposure to COVID. Researchers supporting prophylactic administration of hydroxychloquine note that results from recently published human trials have suggested that hydroxychloroquine may decrease the duration of both viral shedding and symptoms if the drug is administered early.[30] British researchers are studying whether the drug is effective when used for prevention. 10,000 National Health Service (NHS) workers, along with 30,000 additional volunteers from Asia, South America, Africa, and other parts of Europe are participating in the global study. Results are expected by the end of 2020.[31]

A randomized, double-blind, placebo-controlled trial of hydroxychloroquine in 821 participants by the University of Minnesota Medical School found that it does not treat COVID‑19 infection, but the study presented limitations.[32][33][34]

In June 2020, use of hydroxychloroquine in the UK RECOVERY Trial was discontinued when an interim analysis of 1,542 treatments showed it provided no mortality benefit to people hospitalized with severe COVID‑19 infection over 28 days of observation.[11]

Combined with zinc and another antibiotic

Due to the properties of zinc as a cofactor in the immune response for producing antibodies during viral infections,[35] it is being included among multiple-agent "cocktails" for investigating potential treatment of people hospitalized with COVID‑19 infection.[36] One such cocktail – hydroxychloroquine combined with a high dose of zinc (as a sulfate, 220 mg per day for five days, a zinc dose twenty times higher than the reference daily intake level)[35] and an approved antibiotic, either azithromycin or doxycycline – began in May as a Phase IV trial in New York State.[37] However, caution was recommended about the combination of chloroquine or hydroxychloroquine with CYP3A4 inhibitors, such as azithromycin,[27] a treatment combination found to be ineffective for preventing death in hospitalized people with COVID‑19.[38] There is preliminary evidence that combining hydroxychloroquine and azithromycin for treating non-hospitalized ("outpatient") people with COVID‑19 infection with multiple comorbidities was effective, but remains under preliminary research.[39]

Zinc deficiency – which decreases immune capacity to defend against pathogens – is common among elderly people, and may be a susceptibility factor in viral infections.[35] The mechanism for any potential benefit of including zinc in a cocktail treatment for recovery from severe COVID‑19 or any viral infection is unknown.[35][36]

Controversy
See also: Surgisphere § COVID-19 controversy

Due to safety concerns and evidence of heart arrhythmias leading to higher death rates, the WHO suspended the hydroxychloroquine arm of the multinational Solidarity trial in late May 2020.[40][41][42] The WHO had enrolled 3,500 patients from 17 countries in the Solidarity trial.[40] The research surrounding this suspension, provided by a company called Surgisphere based in Chicago, came into question due to errors in the underlying data set.[43][44][45] The authors of the study corrected errors in the data later but remained firm on their conclusions.[43]

The WHO decided to resume the trial on 3 June, after reviewing the safety concerns which had been raised. Speaking at a press briefing, WHO's director-general, Tedros Adhanom Ghebreyesus stated that the board had reviewed the available mortality data and had found "no reasons to modify the trial".[46][47]

A retraction of the study by three of its authors was published by The Lancet on 4 June, 2020.[48] The authors stated that their reason behind the retraction was because Surgisphere had failed to cooperate with an independent review of the data used for the study by not allowing any such review to take place.[49][50]

Dexamethasone
A vial of dexamethasone for injection

Dexamethasone is a corticosteroid medication currently in use for multiple conditions such as rheumatic problems, skin diseases, asthma and chronic obstructive lung disease among others.[51] A multi-center, randomized controlled trial of dexamethasone in treating acute respiratory distress syndrome (ARDS), published in February 2020, showed reduced need for mechanical ventilation and mortality.[52]

In June 2020, the Oxford University RECOVERY Trial announced and then published preliminary results that the drug could reduce deaths by about a third in participants on ventilators and by about a fifth in participants on oxygen.[53] Several experts have called for the full dataset to be published quickly to allow wider analysis of the results.[54][55] The World Health Organization (WHO) states that dexamethasone should be reserved for seriously ill and critical patients receiving COVID-19 treatment in a hospital setting.[56]

Demand for dexamethasone surged after publication of the preprint.[57]

Favipiravir

Chinese clinical trials in Wuhan and Shenzhen claimed to show that favipiravir was "clearly effective".[58] 35 patients in Shenzhen tested negative in a median of 4 days, while the length of illness was 11 days in the 45 patients who did not receive it.[59] In a study conducted in Wuhan on 240 patients with pneumonia, half were given favipiravir and half received umifenovir. The researchers found that patients recovered from coughs and fevers faster when treated with favipiravir, but there was no change in how many patients in each group progressed to more advanced stages of illness (treatment with a ventilator).[60]

On 22 March, Italy approved the drug for experimental use against COVID‑19 and began conducting trials in the three regions most affected by the disease.[61] The Italian Medicines Agency reminded the public that the existing evidence in support of the drug is scant and preliminary.[62] On 2 April, Germany announced that it would purchase the drug from Japan for its stockpile, and use the military to deliver the drug to university hospitals, where the drug will be used to treat COVID‑19 patients.[63] According to the South China Morning Post, Shinzo Abe has made overtures to the Trump administration about purchasing the drug.[64]

The drug may be less effective in severe cases where the virus has already multiplied. It may not be safe for use by pregnant women or those trying to conceive.[59]

On 30 May 2020, the Russian Health Ministry approved a generic version of favipiravir named Avifavir, which proved highly effective in the first phase of clinical trials.[65][66][67]

Lopinavir / Ritonavir

One study of lopinavir/ritonavir (Kaletra), a combination of the antivirals lopinavir and ritonavir, concluded that "no benefit was observed".[68][69] The drugs were designed to inhibit HIV from replicating by binding to the protease. A team of researchers at the University of Colorado are trying to modify the drugs to find a compound that will bind with the protease of SARS-CoV-2.[70]

There are criticisms within the scientific community about directing resources to repurposing drugs specifically developed for HIV/AIDS.[2] The WHO included lopinavir/ritonavir in the international Solidarity trial.[12]

Remdesivir

Remdesivir was created and developed by Gilead Sciences as a treatment for Ebola virus disease and Marburg virus infections.[71]

During 2020, several clinical trials were underway.[7] The first randomized, placebo-controlled trial of remdesivir in China showed the drug had no clinical or virological benefits compared to the placebo group and caused adverse effects in the remdesivir-treated people, leading to early termination of the trial.[72][73]

On 1 May 2020, the U.S. Food and Drug Administration granted Gilead Emergency Use Authorization of remdesivir to be distributed and used by licensed health care providers to treat adults and children hospitalized with severe COVID‐19.[74] 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.[75][74][76] 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.[74] 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.[74] The agreement between Gilead and five generic pharmaceutical companies in India and Pakistan will help make the medicine for 127 countries.[77] 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.[78]

GS-441524

GS-441524 is the nucleoside of the phosphate pro-drug remdesivir. It has been shown to cure cats infected with Feline infectious peritonitis (FIP), a feline form of coronavirus with a 96% cure rate.[79] Studies have shown that even when remdesivir is administered, GS-441524 is the predominant metabolite circulating in serum due to rapid hydrolysis of the remdesivir pro-drugs, followed by dephosphorylation.[71][80][81] Some researchers have suggested its utility as a treatment for COVID‑19.[82]

Vitamins

Intravenous vitamin C

According to ClinicalTrials.gov, there are six ongoing clinical trials of intravenous vitamin C for people who are hospitalized and severely ill with COVID‑19; three placebo controlled (China, Canada and, U.S.) and three with no control (Italy, U.S. and, U.S.).[83]

Oral vitamin D
Oral vitamin D tablets

According to ClinicalTrials.gov, several Phase II–IV clinical trials are underway to assess the use of oral vitamin D for prevention or treatment of COVID‑19 infection, with most in preliminary stages and none completed, as of May 2020.[84] Most trials have the design of studying COVID‑19-infected people who are vitamin D deficient.[84] The rationale for these trials is based on speculation and observational reports that low vitamin D may be associated with a higher incidence and severity of this infection.[85] After adjustments were made for potential confounding factors, such as ethnicity, one study found insufficient evidence to indicate that vitamin D supplementation provided a benefit to reduce susceptibility to COVID‑19 infection.[86]

Other drugs
Drug Research
AnticoagulantsSeveral anticoagulants are being tested in Italy. Low-molecular-weight heparin is being widely used to treat patients, prompting the Italian Medicines Agency to publish guidelines on its use.[87] A multicenter study on 300 patients researching the use of enoxaparin sodium at prophylaxis and therapeutic dosages was announced in Italy on 14 April.[88]
APN01A form of angiotensin-converting enzyme 2, a Phase II trial is underway with 200 patients to be recruited from severe, hospitalized cases in Denmark, Germany, and Austria to determine the effectiveness of the treatment.[89][90]
Artesunate/pyronaridineIt was announced on 3 April 2020 that pyronaridine and artesunate, the main components of a new ACT antimalarial drug Pyramax[91], showed an inhibitory effect on SARS-COV-2 in vitro tests using Hela Cells. The Pyramax showed a virus titer inhibition rate of 99% or more after 24 hours, while cytotoxicity was also reduced[92]. However, no publication on in vitro test was made yet. Now, it is in phase II clinical trial, in South Korea.[93][94]
AzithromycinNew York State began trials for the antibiotic azithromycin on 24 March 2020.[95]
CiclesonideJapan's National Center for Global Health and Medicine (NCGM) is planning a clinical trial for Teijin's Alvesco (ciclesonide), an inhaled corticosteroid for asthma, for the treatment of pre-symptomatic patients infected with the novel coronavirus.[96]

Ciclesonide was identified as a candidate antiviral in an in vitro drug screening assay done in South Korea.[97]

CimetidineHas been suggested as a treatment for COVID-19.[98][99]
ColchicineResearchers from the Montreal Heart Institute in Canada are studying the role of colchicine in reducing inflammation and pulmonary complications in patients suffering from mild symptoms of COVID‑19.[100] The study, named COLCORONA, is recruiting 6000 adults 40 and older who were diagnosed with COVID‑19 and experience mild symptoms not requiring hospitalization.[100][101] Women who are pregnant or breastfeeding or who do not have an effective contraceptive method are not eligible.[101]
DipyridamoleIs proposed as a treatment for COVID‑19,[98][99] and a clinical trial is underway.[102]
FamotidineHas been suggested as a treatment for COVID-19,[98][99] and a clinical study is underway.[103]
FibratesFenofibrate and bezafibrate have been suggested for treatment of life-threatening symptoms of COVID-19.[98][99]
IbuprofenA trial called "Liberate" has been started in the United Kingdom to determine the effectiveness of ibuprofen in reducing the severity and progression of lung injury which results in breathing difficulties for COVID‑19 patients. Subjects are to receive three doses of a special formulation of the drug – lipid ibuprofen – in addition to usual care.[104][105]
Interferon betaIFN-β will be included in the international Solidarity Trial in combination with the HIV drugs Lopinavir and Ritonavir.[106] as well as the REMAP-CAP[107]

Finnish biotech firm Faron Pharmaceuticals continues to develop INF-beta for ARDS and is involved in worldwide initiatives against COVID‑19, including the Solidarity trial.[108] UK biotech firm Synairgen started conducting trials on IFN-β, a drug that was originally developed to treat COPD.[12]

IvermectinIvermectin is one of an increasing number of additional compounds found to inhibit SARS-CoV-2 without a defined mechanism of action. Plasma levels following oral administration appear too low to inhibit replication, however ivermectin use was associated with significantly reduced mortality in a retrospective study of 280 hospital patients, particularly in persons with severe pulmonary disease. As of June 4, ivermectin is being studied in 10 ongoing and 14 planned clinical trials. [109]
MavrilimumabIs a human monoclonal antibody that inhibits human granulocyte macrophage colony-stimulating factor receptor (GM-CSF-R).[110][111] It has been studied to see if it can improve the prognosis for patients with COVID-19 pneumonia and systemic hyperinflammation. One small study indicated some beneficial effects of treatment with mavrilimumab compared with those who were not.[112]
nanoFenretinidenanoFenretinide is nanoparticle sized fenretinide and repurposed oncology drug approved to enter the clinic for a lymphoma indication.[113] It was identified as a candidate antiviral in an in vitro drug screening assay done in South Korea.[97] Fenretinide's clinical safety profile also makes it an ideal candidate in combination regimens.
NiclosamideIt was identified as a candidate antiviral in an in vitro drug screening assay done in South Korea.[97]
SildenafilIs proposed as a treatment for COVID-19,[98][99] and a Phase III clinical trial is underway.[114]
TocilizumabIn March 2020, China approved the drug for the treatment of inflammation in COVID-19 patients but found no conclusive evidence whether the treatment is effective.[115] The Australasian Society for Clinical Immunology and Allergy recommend tocilizumab be considered as an off-label treatment for those with COVID-19 related acute respiratory distress syndrome.[116]

It is part of the RECOVERY Trial in the UK to be tested as a potential treatment,[9] while Hoffmann–La Roche and the WHO have also launched separate trials for its use in severe cases.[117]

Drugs by class

Antibody

Antivirals

Considerable scientific attention has been focused on re-purposing approved antiviral drugs that have been previously developed against other viruses, such as MERS-CoV, SARS-CoV, and West Nile virus.[118]

Antiparasitics

Antibiotics

Some antibiotics that have been identified as potentially re-purposable as COVID‑19 treatments:[127][128]

Immunologicals

Drugs with immune modulating effects that may prove useful in COVID‑19 treatment:

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