COVID-19 drug repurposing research: Difference between revisions

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====Controversy====
====Controversy====
{{See also|Surgisphere#COVID-19 controversy}}
{{See also|Surgisphere#COVID-19 controversy}}
Due to safety concerns and evidence of [[Arrhythmia|heart arrhythmias]] leading to higher death rates, the WHO suspended the hydroxychloroquine arm of the multinational [[Solidarity trial]] in late May 2020.<ref name="who-suspend">{{Cite web|title=WHO Director-General's opening remarks at the media briefing on COVID-19 – 25 May 2020|url=https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---25-may-2020|publisher=World Health Organization|date=2020-05-25|access-date=2020-05-27}}</ref><ref>{{Cite news|title=WHO pauses hydroxychloroquine coronavirus trial over safety concerns|url=https://globalnews.ca/news/6983283/who-hydroxychloroquine-trial/|work=Global News|publisher=The Associated Press|authors=Maria Cheng, Jamey Keaten|date=2020-05-25|access-date=2020-05-27}}</ref><ref>{{Cite news|title=Coronavirus: WHO halts trials of hydroxychloroquine over safety fears|url=https://www.bbc.com/news/health-52799120|work=BBC News Online |date=2020-05-25|access-date=2020-06-04}}</ref> The WHO had enrolled 3,500 patients from 17 countries in the Solidarity trial.<ref name=who-suspend/> 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.<ref name="stat1">{{cite web |url=https://www.statnews.com/2020/06/02/top-medical-journals-raise-concerns-about-data-in-two-studies-related-to-covid-19/ |title=Top medical journals raise concerns about data in two studies related to Covid-19 | first1 = Matthew | last1 = Herper | first2 = Andrew | last2 = Joseph | name-list-format = vanc |date=June 2, 2020 |website=[[Stat (website)|Stat]] |access-date=June 4, 2020}}</ref><ref>{{cite journal |last1=Servick |first1=Kelly |title=A mysterious company’s coronavirus papers in top medical journals may be unraveling |journal=Science |date=2 June 2020 |doi=10.1126/science.abd1337 }}</ref><ref>{{cite web |url=https://www.theguardian.com/science/2020/may/28/questions-raised-over-hydroxychloroquine-study-which-caused-who-to-halt-trials-for-covid-19 |title=Questions raised over hydroxychloroquine study which caused WHO to halt trials for Covid-19 |author=Melissa Davey |date=May 28, 2020 |website=The Guardian |access-date=June 4, 2020}}</ref> The authors of the study corrected errors in the data later but initially remained firm on their conclusions.<ref name="stat1"/> Subsequently, a retraction of the study by three of its authors was published by ''The Lancet'' on 4{{nbsp}}June, 2020.<ref>{{cite journal |last1=Mehra |first1=Mandeep R |last2=Ruschitzka |first2=Frank |last3=Patel |first3=Amit N |title=Retraction—Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis |journal=The Lancet |date=June 2020 |volume=395 |issue=10240 |pages=1820 |doi=10.1016/S0140-6736(20)31324-6 |pmid=32511943 |pmc=7274621 }</ref> 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.<ref>{{cite news |url=https://www.bbc.com/news/health-52929916 |title=Coronavirus: Influential study on hydroxychloroquine withdrawn |date=June 5, 2020 |website=BBC News Online |access-date=June 5, 2020}}</ref><ref>{{cite news | last1=Boseley | first1=Sarah | last2=Davey | first2=Melissa | name-list-format = vanc | title=Covid-19: Lancet retracts paper that halted hydroxychloroquine trials | website=[[The Guardian]] | date=4 June 2020 | url=http://www.theguardian.com/world/2020/jun/04/covid-19-lancet-retracts-paper-that-halted-hydroxychloroquine-trials | access-date=4 June 2020}}</ref>
Due to safety concerns and evidence of [[Arrhythmia|heart arrhythmias]] leading to higher death rates, the WHO suspended the hydroxychloroquine arm of the multinational [[Solidarity trial]] in late May 2020.<ref name="who-suspend">{{Cite web|title=WHO Director-General's opening remarks at the media briefing on COVID-19 – 25 May 2020|url=https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---25-may-2020|publisher=World Health Organization|date=2020-05-25|access-date=2020-05-27}}</ref><ref>{{Cite news|title=WHO pauses hydroxychloroquine coronavirus trial over safety concerns|url=https://globalnews.ca/news/6983283/who-hydroxychloroquine-trial/|work=Global News|publisher=The Associated Press|authors=Maria Cheng, Jamey Keaten|date=2020-05-25|access-date=2020-05-27}}</ref><ref>{{Cite news|title=Coronavirus: WHO halts trials of hydroxychloroquine over safety fears|url=https://www.bbc.com/news/health-52799120|work=BBC News Online |date=2020-05-25|access-date=2020-06-04}}</ref> The WHO had enrolled 3,500 patients from 17 countries in the Solidarity trial.<ref name=who-suspend/> 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.<ref name="stat1">{{cite web |url=https://www.statnews.com/2020/06/02/top-medical-journals-raise-concerns-about-data-in-two-studies-related-to-covid-19/ |title=Top medical journals raise concerns about data in two studies related to Covid-19 | first1 = Matthew | last1 = Herper | first2 = Andrew | last2 = Joseph | name-list-format = vanc |date=June 2, 2020 |website=[[Stat (website)|Stat]] |access-date=June 4, 2020}}</ref><ref>{{cite journal |last1=Servick |first1=Kelly |title=A mysterious company’s coronavirus papers in top medical journals may be unraveling |journal=Science |date=2 June 2020 |doi=10.1126/science.abd1337 }}</ref><ref>{{cite web |url=https://www.theguardian.com/science/2020/may/28/questions-raised-over-hydroxychloroquine-study-which-caused-who-to-halt-trials-for-covid-19 |title=Questions raised over hydroxychloroquine study which caused WHO to halt trials for Covid-19 |author=Melissa Davey |date=May 28, 2020 |website=The Guardian |access-date=June 4, 2020}}</ref> The authors of the study corrected errors in the data later but initially remained firm on their conclusions.<ref name="stat1"/> Subsequently, a retraction of the study by three of its authors was published by ''The Lancet'' on 4{{nbsp}}June, 2020.<ref>{{cite journal |last1=Mehra |first1=Mandeep R |last2=Ruschitzka |first2=Frank |last3=Patel |first3=Amit N |title=Retraction—Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis |journal=The Lancet |date=June 2020 |volume=395 |issue=10240 |pages=1820 |doi=10.1016/S0140-6736(20)31324-6 |pmid=32511943 |pmc=7274621 }}</ref> 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.<ref>{{cite news |url=https://www.bbc.com/news/health-52929916 |title=Coronavirus: Influential study on hydroxychloroquine withdrawn |date=June 5, 2020 |website=BBC News Online |access-date=June 5, 2020}}</ref><ref>{{cite news | last1=Boseley | first1=Sarah | last2=Davey | first2=Melissa | name-list-format = vanc | title=Covid-19: Lancet retracts paper that halted hydroxychloroquine trials | website=[[The Guardian]] | date=4 June 2020 | url=http://www.theguardian.com/world/2020/jun/04/covid-19-lancet-retracts-paper-that-halted-hydroxychloroquine-trials | access-date=4 June 2020}}</ref>


The WHO decided to resume the trial on 3{{nbsp}}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".<ref>{{cite web |url=https://www.statnews.com/2020/06/03/who-resuming-hydroxychloroquine-study-for-covid-19/ |title=WHO resumes hydroxychloroquine study for Covid-19, after reviewing safety concerns |author=Andrew Joseph |date=June 3, 2020 |website=[[Stat (website)|Stat]] |access-date=June 4, 2020}}</ref><ref>{{cite web |url=https://www.independent.co.uk/news/health/coronavirus-hydroxychloroquine-trials-trump-who-lancet-a9546836.html |title=Coronavirus: WHO re-starts hydroxychloroquine trials amid controversy over published research |author=Shaun Lintern |date=June 3, 2020 |website=The Independent |access-date=June 4, 2020}}</ref>
The WHO decided to resume the trial on 3{{nbsp}}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".<ref>{{cite web |url=https://www.statnews.com/2020/06/03/who-resuming-hydroxychloroquine-study-for-covid-19/ |title=WHO resumes hydroxychloroquine study for Covid-19, after reviewing safety concerns |author=Andrew Joseph |date=June 3, 2020 |website=[[Stat (website)|Stat]] |access-date=June 4, 2020}}</ref><ref>{{cite web |url=https://www.independent.co.uk/news/health/coronavirus-hydroxychloroquine-trials-trump-who-lancet-a9546836.html |title=Coronavirus: WHO re-starts hydroxychloroquine trials amid controversy over published research |author=Shaun Lintern |date=June 3, 2020 |website=The Independent |access-date=June 4, 2020}}</ref>

Revision as of 21:48, 10 September 2020

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]

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, have been researched as COVID‑19 treatments, with some moving into clinical trials.[6][7][8]

In a statement to the journal Nature Biotechnology in February 2020, US 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

A large-scale, randomized controlled trial named the RECOVERY Trial was set up in March 2020, in the UK 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 testing five repurposed drugs and also convalescent plasma. The trial enrolled more than 11,500 COVID-19 positive participants in the U.K by June 2020.[9][10][11]

By the end of June 2020, the trial had published findings regarding hydroxychloroquine and dexamethasone.[11][12] It has also announced results for lopinavir/ritonavir which are yet to be published.[13]

Studies

Chloroquine and hydroxychloroquine

US President Donald Trump said he had been taking hydroxychloroquine.

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 multinational Solidarity clinical trial.[14] On 19 March, US 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.[15] New York Governor Andrew Cuomo announced that New York State trials of chloroquine and hydroxychloroquine would begin on 24 March.[16]

On 28 March, the US Food and Drug Administration (FDA) authorized the use of hydroxychloroquine sulfate and chloroquine phosphate under an Emergency Use Authorization (EUA).[17][18] The treatment has not been approved by the FDA's clinical trials process.[18] 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.[18][19][17] 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.[20] Doctors have said they are using the drug when "there's no other option".[21] 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.[21][22]

On 15 June, 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".[23][24][25][26]

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.[27] 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".[28] 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.[29] 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.[30][31]

A chloroquine tablet

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.[32][33][34]

In June, 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]

A multicenter, randomized, open-label, three-group, controlled trial of 667 participants in Brazil found no benefit from using hydroxychloroquine, alone or with azithromycin, to treat mild-to-moderate COVID‑19.[35]

In late July, the U.S President Donald Trump once again promoted the use of the drug contradicting various public health officials, including Dr. Fauci.[36]

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,[37] it is being included among multiple-agent "cocktails" for investigating potential treatment of people hospitalized with COVID‑19 infection.[38] 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)[37] and an approved antibiotic, either azithromycin or doxycycline – began in May as a Phase IV trial in New York State.[39] However, caution was recommended about the combination of chloroquine or hydroxychloroquine with CYP3A4 inhibitors, such as azithromycin,[29] a treatment combination found to be ineffective for preventing death in hospitalized people with COVID‑19.[40] 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.[41]

Zinc deficiency – which decreases immune capacity to defend against pathogens – is common among elderly people, and may be a susceptibility factor in viral infections.[37] 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.[37][38]

Prophylaxis

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 human trials have suggested that hydroxychloroquine may decrease the duration of both viral shedding and symptoms if the drug is administered early.[42]

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.[43]

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.[44][45][46] The WHO had enrolled 3,500 patients from 17 countries in the Solidarity trial.[44] 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.[47][48][49] The authors of the study corrected errors in the data later but initially remained firm on their conclusions.[47] Subsequently, a retraction of the study by three of its authors was published by The Lancet on 4 June, 2020.[50] 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.[51][52]

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".[53][54]

Dexamethasone

A vial of dexamethasone for injection

Dexamethasone is a corticosteroid medication in use for multiple conditions such as rheumatic problems, skin diseases, asthma and chronic obstructive lung disease among others.[55] 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.[56]

On 16 June, the Oxford University RECOVERY Trial issued a press release announcing 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; it did not benefit patients who did not require respiratory support. The researchers estimated that treating 8 patients on ventilators with dexamethasone saved one life, and treating 25 patients on oxygen saved one life.[12] Several experts called for the full dataset to be published quickly to allow wider analysis of the results.[57][58] A preprint was published on June 22[59] and the peer-reviewed article appeared on July 17.[60]

Based on those preliminary results, dexamethasone treatment has been recommended by the US National Institutes of Health (NIH) for patients with COVID-19 who are mechanically ventilated or who require supplemental oxygen but are not mechanically ventilated. The NIH recommends against using dexamethasone in patients with COVID-19 who do not require supplemental oxygen.[61] In July 2020, the World Health Organization (WHO) stated they are in the process of updating treatment guidelines to include dexamethasone or other steroids.[62]

The Infectious Diseases Society of America (IDSA) guideline panel suggests the use of glucocorticoids for patients with severe COVID-19; where severe is defined as patients with oxygen saturation (SpO2) ≤94% on room air, and those who require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).[63] The IDSA recommends against the use of glucocorticoids for those with COVID-19 without hypoxemia requiring supplemental oxygen.[63]

In late July 2020, the European Medicines Agency (EMA) started reviewing results from the RECOVERY study arm that involved the use of dexamethasone in the treatment of patients with COVID-19 admitted to the hospital to provide an opinion on the results. It focused particularly on the potential use of the drug for the treatment of adults with COVID-19.[64]

In September 2020, the WHO released updated guidance on using corticosteroids for COVID-19.[65] The WHO recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of people with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence).[65] The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID-19 (conditional recommendation, based on low certainty evidence).[65]

Favipiravir

Chinese clinical trials in Wuhan and Shenzhen claimed to show that favipiravir was "clearly effective".[66] 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.[67] 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).[68]

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.[69] The Italian Medicines Agency reminded the public that the existing evidence in support of the drug is scant and preliminary.[70] 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.[71] According to the South China Morning Post, Shinzo Abe has made overtures to the Trump administration about purchasing the drug.[72] On 30 May, the Russian Health Ministry approved a generic version of favipiravir named Avifavir, after the Russian Direct Investment Fund claimed it had proved highly effective in the first phase of clinical trials.[73][74][75]

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.[67]

Lopinavir/ritonavir

One study of lopinavir/ritonavir (Kaletra), a combination of the antivirals lopinavir and ritonavir, concluded that "no benefit was observed".[76][77] 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.[78] On 29 June, the chief investigators of the UK RECOVERY Trial reported that there was no clinical benefit from use of lopinavir-ritonavir in 1,596 people hospitalized with severe COVID-19 infection over 28 days of treatment. The results are yet to be published.[13]

There are criticisms within the scientific community about directing resources to repurposing drugs specifically developed for HIV/AIDS because such drugs are unlikely to be effective against a virus lacking the specific HIV-1 protease they target.[2] The WHO included lopinavir/ritonavir in the international Solidarity trial.[14]

Remdesivir

Remdesivir was created and developed by Gilead Sciences as a treatment for hepatitis C,[79] and was subsequently repurposed for Ebola virus disease and Marburg virus infections.[80]

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.[81][82]

On 1 May, the US 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.[83] Severe COVID‐19 is defined as patients with oxygen saturation (SpO2) ≤94% on room air, and those who require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO), a heart‐lung bypass machine.[84][85] Distribution of remdesivir under the EUA will be controlled by the US government for use consistent with the terms and conditions of the EUA.[83] Gilead will supply remdesivir to authorized distributors, or directly to a US government agency, who will distribute to hospitals and other healthcare facilities as directed by the US Government, in collaboration with state and local government authorities, as needed.[83] The agreement between Gilead and five generic pharmaceutical companies in India and Pakistan will help make the medicine for 127 countries.[86] On 15 June, 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.[87]

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.[88]

On 25 June, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended granting a conditional marketing authorization for remdesivir for the treatment of COVID-19 in adults and adolescents from twelve years of age with pneumonia who require supplemental oxygen.[89][90][91] The brand name will be Veklury.[89][90]

On 29 June, the U.S Department of Health & Human Services announced that it had agreed to buy 500,000 doses of the drug for use in hospitals across the country through September 2020. This represents 100% of Gilead's projected production for July and 90% each for the months of August and September. The department secretary Alex Azar stated in a press release, "President Trump has struck an amazing deal to ensure Americans have access to the first authorized therapeutic for COVID‑19."[92][93]

The European Union granted remdesivir a conditional marketing authorization on 3 July, with an indication for the treatment of COVID‑19 in adults and adolescents (aged twelve years and older with body weight at least 40 kg) with pneumonia requiring supplemental oxygen.[94]

In July 2020, remdesivir was provisionally approved for use in Australia for use in adults and adolescents with severe COVID‑19 symptoms who have been hospitalized.[95]

On 28 August 2020, the FDA broadened the Emergency Use Authorization (EUA) for remdesivir to include all hospitalized patients with suspected or laboratory-confirmed COVID-19, irrespective of the severity of their disease.[96][97][98]

Remdesivir/baricitinib

In May 2020, the National Institute of Allergy and Infectious Diseases (NIAID) started the Adaptive COVID-19 Treatment Trial 2 (ACTT 2) to evaluate the safety and efficacy of a treatment regimen consisting of remdesivir plus baricitinib 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.[99][100][101]

Remdesivir/interferon beta-1a

In August 2020, the NIAID started the Adaptive COVID-19 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.[100][102]

GS-441524

GS-441524 is the nucleoside of the ProTide remdesivir. It has been shown to cure cats infected with Feline infectious peritonitis (FIP), a feline form of coronavirus with a 96% cure rate.[103][104] 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.[105][80][106][107][unreliable medical source?] Some researchers have suggested its utility as a treatment for COVID‑19,[108][109][110][111][112] noting easier synthesis, lack of first-pass metabolism in the liver, greater hydrophilicity and triphosphate formation in cell types irrespective of expression CES1 and CTSA, the enzymes required to bioactivate remdesivir.

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, the US) and three with no control (Italy, the US and, the US).[113]

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.[114] As of August 27, 2020, a first result of a randomized treatment trial was released, and was favorable.[115]

Most trials have focused on studying infected people who are vitamin D deficient.[114] 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.[116] 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.[117]

The first clinical trial of one group randomized to usual care only (hydroxychloroquine with azithromycin and sometimes ceftriaxone), and compared with a group receiving a form of vitamin D (calcifediol) in addition to usual care, found far less admission to intensive care and no deaths in the vitamin D group. The sample size in this pilot study was small, yet the group receiving vitamin D had such better results that the differences were statistically significant.[118]

Other drugs

Drug Research
Anticoagulants Several anticoagulants have been tested in Italy, with Low-molecular-weight heparin being widely used to treat patients, prompting the Italian Medicines Agency to publish guidelines on its use.[119] A multicenter study on 300 patients researching the use of enoxaparin sodium at prophylaxis and therapeutic dosages was announced in Italy on 14 April.[120]
APN01 A 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.[121][122]
Artesunate/pyronaridine It was announced on 3 April 2020 that pyronaridine and artesunate, the main components of a new ACT antimalarial drug sold under the brand name Pyramax,[123] showed an inhibitory effect on SARS-CoV-2 in vitro tests using Hela cells. Pyramax showed a virus titer inhibition rate of 99% or more after 24 hours, while cytotoxicity was also reduced.[124] A preprint published in July 2020 reported that pyronaridine and artesunate exhibit antiviral activity against SARS-CoV-2 and influenza viruses using human lung epithelial (Calu-3) cells.[125] It is currently in phase II clinical trial in South Korea.[126][127][128]
Azithromycin New York State began trials for the antibiotic azithromycin on 24 March 2020.[129]
Bucillamine On 31 July 2020, the U.S. Food and Drug Administration (FDA) authorized Revive Therapeutics to proceed with a randomized, double-blind, placebo-controlled confirmatory Phase III clinical trial protocol to evaluate the safety and efficacy of bucillamine in patients with mild-moderate COVID-19.[130]
Budesonide Patients already prescribed inhaled corticosteroids have been observed to develop less serious illness when diagnosed with COVID-19, despite often having conditions such as asthma that might be thought to lead to more serious illness.[131][132] UK-Australia trial underway as of June 2020 examining the drug as an early-intervention treatment for COVID-19, results expected in September 2020.[133]
Ciclesonide Japan'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.[134]

Ciclesonide was identified as a candidate antiviral in an in vitro drug screening assay done in South Korea.[135]

Cimetidine Has been suggested as a treatment for COVID-19.[136][137]
Colchicine Researchers 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.[138] The study, named COLCORONA, is recruiting 6000 adults 40 and older who were diagnosed with COVID‑19 and experience mild symptoms not requiring hospitalization.[138][139] Women who are pregnant or breastfeeding or who do not have an effective contraceptive method are not eligible.[139]
Dipyridamole Is proposed as a treatment for COVID‑19,[136][137] and a clinical trial is underway.[140]
EIDD-2801 A drug developed to treat influenza. It is in Phase II trials as a treatment for COVID-19.[141][142]
Famotidine Has been suggested as a treatment for COVID-19,[136][137][unreliable source?] and a clinical study is underway.[143]
Fibrates Fenofibrate and bezafibrate have been suggested for treatment of life-threatening symptoms of COVID-19.[136][137][144]
Heparin Scientists have identified an ability of Heparin to bind to the spike protein of the SARS-CoV-2 virus, neutralising it, and proposed the drug as a possible antiviral.[145]
Ibuprofen A 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.[146][147]
Influenza vaccine A clinical cohort study in Brazil found that COVID-19 patients who received a recent influenza vaccine needed less intensive care support, less invasive respiratory support, and were less likely to die.[148]
Interferon beta IFN-β 1b have been shown in an open label randomised controlled trial in combination with lopinavir/ ritonavir and ribavirin to significantly reduce viral load, alleviate symptoms and reduce cytokine responses when compared to lopinavir/ ritonavir alone.<Lancet 2020;395(10238):1695-1704> IFN-β will be included in the international Solidarity Trial in combination with the HIV drugs Lopinavir and Ritonavir.[149] as well as the REMAP-CAP[150]

Finnish biotech firm Faron Pharmaceuticals continues to develop INF-beta for ARDS and is involved in worldwide initiatives[which?] against COVID‑19, including the Solidarity trial.[151] UK biotech firm Synairgen started conducting trials on IFN-β, a drug that was originally developed to treat COPD.[14]

Ivermectin Ivermectin is one of an increasing number of compounds found to inhibit SARS-CoV-2 in vitro without a defined mechanism of action. Plasma levels following oral administration appear too low to inhibit replication. An early-April preprint claimed benefits of Ivermectin, but it was based on questionable hospital data from Surgisphere and was withdrawn at the end of May. It led to government agencies in Latin America recommending Ivermectin as a treatment of COVID-19; these recommendations were later denounced by the regional WHO office.[152] As of July, ivermectin was being studied in 19 ongoing and 18 planned clinical trials.[153] A June 10 preprint reported on an observational retrospective study of hospitalized COVID-19 patients in Florida and found a significantly lower mortality in those who had received Ivermectin.[154]
Mavrilimumab Is a human monoclonal antibody that inhibits human granulocyte macrophage colony-stimulating factor receptor (GM-CSF-R).[155][156] 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.[157]
nanoFenretinide nanoFenretinide is nanoparticle sized fenretinide and repurposed oncology drug approved to enter the clinic for a lymphoma indication.[158] It was identified as a candidate antiviral in an in vitro drug screening assay done in South Korea.[135] Fenretinide's clinical safety profile also makes it an ideal candidate in combination regimens.[citation needed]
Niclosamide It was identified as a candidate antiviral in an in vitro drug screening assay done in South Korea.[135]
Sildenafil Is proposed as a treatment for COVID-19,[136][137] and a Phase III clinical trial is underway.[159]
Tocilizumab In 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.[160] 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.[161]

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.[162] Roche announced on July 29 that its randomized double-blind trial of tocilizumab for the treatment of pneumonia in Covid patients had shown no benefits.[163]

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.[164]

Antiparasitics

Antibiotics

Some antibiotics that have been identified as potentially re-purposable as COVID‑19 treatments:[175][176]

Immunologicals

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

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Further reading

External links