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 currently 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]

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, 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]

Studies[]

Chloroquine/Hydroxychloroquine[]

Chloroquine is an anti-malarial medication that is also used against some auto-immune diseases. On 18 March, the WHO announced that chloroquine and the related hydroxychloroquine would be among the four drugs studied as part of the Solidarity clinical trial.[9] On 19 March, 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.[10] New York Governor Andrew Cuomo announced that New York State trials of chloroquine and hydroxychloroquine would begin on 24 March.[11]

On 28 March, the FDA authorized the use of hydroxychloroquine sulfate and chloroquine phosphate under an Emergency Use Authorization (EUA).[12] The treatment has not been approved by the FDA's clinical trials process and is authorized under the EUA only as an experimental treatment for emergency use in patients who are hospitalized but are not able to receive treatment in a clinical trial.[13][12] The CDC has said that "the use, dosing, or duration of hydroxychloroquine for prophylaxis or treatment of SARS-CoV-2 infection" are not yet established.[14] Doctors have said they are using the drug when "there's no other option".[15] 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.[15][16]

In May, a multinational study of 96,032 people hospitalized with COVID-19 found that use of hydroxychloroquine or chloroquine (with or without an antiviral drug) provided no benefit, but instead increased the risk of heart arrhythmias and death.[17] 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.[18] 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".[19] 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.[20] A Veterans Affairs study released results showing that people treated with hydroxychloroquine were more likely to die than those who received no drug treatment at all.[21]

Drugs used for treatment of infectious diseases may also be considered for use for post-exposure prophylaxis. On May 22 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.[22] British researchers are studying whether the drug is effective when used for prevention. 10,000 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.[23]

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.[24][25] The WHO had enrolled 3,500 patients from 17 countries in the Solidarity trial.[24]

Favipiravir[]

Chinese clinical trials in Wuhan and Shenzhen claimed to show favipiravir was "clearly effective".[26] 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.[27] 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).[28]

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.[29] The Italian Medicines Agency reminded the public that the existing evidence in support of the drug is scant and preliminary.[30] 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.[31] According to the South China Morning Post, Shinzo Abe has made overtures to the Trump administration about purchasing the drug.[32]

The drug may be less effective in severe cases of illness where the virus has already multiplied. It may not be safe for use by pregnant women or those trying to conceive.[27]

Interferon beta[]

IFN-β will be included in the international Solidarity Trial in combination with the HIV drugs Lopinavir and Ritonavir.[33] as well as the REMAP-CAP [34]

Finnish biotech firm Faron Pharmaceuticals continues to develop INF-beta for ARDS and is currently involved in worldwide initiatives[which?] against COVID-19, including the Solidarity trial.[35]UK biotech firm Synairgen started conducting trials on IFN-β, a drug that was originally developed to treat COPD.[9]

Lopinavir/ritonavir[]

One study of lopinavir/ritonavir (Kaletra), a combination of the antivirals lopinavir and ritonavir, concluded that "no benefit was observed".[36][37] 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.[38]

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.[9]

Remdesivir[]

Remdesivir was created and developed by Gilead Sciences as a treatment for Ebola virus disease and Marburg virus infections.[39]

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.[40][41]

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.[42] 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.[43][42][44] 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.[42] 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.[42] The agreement between Gilead and five generic pharmaceutical companies in India and Pakistan will help make the medicine for 127 countries.[citation needed]

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, US) and three with no control (Italy, US, US).[45]

Oral vitamin D[]

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.[46] Most trials have the design of studying COVID-19-infected people who are vitamin D deficient.[46] 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.[47] 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.[48]

Azithromycin[]

New York State began trials for the antibiotic azithromycin on 24 March 2020.[49]

Hydroxychloroquine combined with zinc and an antibiotic[]

Because zinc has properties as a cofactor in the immune response for producing antibodies during viral infections,[50] it is being included among multiple-agent "cocktails" for investigating potential treatment of people hospitalized with COVID-19 infection.[51] One such cocktail is hydroxychloroquine combined with zinc (as a sulfate, 220 mg per day for 5 days, a zinc dose 20 times higher than the reference daily intake level)[50] and an approved antibiotic, either azithromycin or doxycycline in a Phase IV trial in New York State.[52]

Zinc deficiency – which decreases immune capacity to defend against pathogens – is common among elderly people, and may be a susceptibility factor in viral infections.[50] The mechanism for any potential benefit of including zinc in a cocktail treatment for recovery from severe viral infection is unknown.[50][51]

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.[53]

Ciclesonide was identified as a candidate antiviral in an in vitro drug screening assay done in Korea.[54]

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.[55][56]

Colchicine[]

Researchers from the Montreal Heart Institute in Canada are currently studying the role of colchicine in reducing inflammation and pulmonary complications in patients suffering from mild symptoms of COVID‑19.[57] The study, named COLCORONA, is recruiting 6000 adults aged 40 and over who were diagnosed with COVID‑19 and experience mild symptoms not requiring hospitalization.[57][58] Women who are pregnant or breastfeeding or who do not have an effective contraceptive method are not eligible.[58]

Anticoagulants[]

Several 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.[59] A multicenter study on 300 patients researching the use of enoxaparin sodium at prophylaxis and therapeutic dosages was announced in Italy on 14 April.[60]

Famotidine[]

Famotidine has been suggested as a treatment for COVID-19,[61]

[62] and a clinical study is currently underway.[63]

Dipyridamole[]

Dipyridamole is proposed as a treatment for COVID-19,[61][62] and a clinical trial is currently underway.[64]

Sildenafil[]

Sildenafil is proposed as a treatment for COVID-19,[61][62] and a phase 3 clinical trial is currently underway.[65]

Fibrates[]

Fenofibrate and bezafibrate have been suggested for treatment of life-threatening symptoms of COVID-19.[61][62]

Cimetidine[]

Cimetidine has been suggested as a treatment for COVID-19.[61][62]

Niclosamide[]

Niclosamide was identified as a candidate antiviral in an in vitro drug screening assay done in Korea.[54]

nanoFenretinide[]

Fenretinide was identified as a candidate antiviral in an in vitro drug screening assay done in Korea.[54]. NanoFenretinide is nanoparticle sized fenretinide and repurposed oncology drug approved to enter the clinic for a lymphoma indication "Phase 1 Trial of ST-001 nanoFenretinide in Relapsed/Refractory T-cell Non-Hodgkin Lymphoma - Full Text View - ClinicalTrials.gov". clinicaltrials.gov.</ref>. Fenretinide's clinical safety profile also makes it an ideal candidate in combination regimens.

Drugs by class[]

Antiviral drugs[]

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.[66]

Antiparasitics[]

Antibiotics[]

Some antibiotics that have been identified as potentially re-purposable as COVID‑19 treatments:[74][75]

Immunologicals[]

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

References[]

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Further reading[]

External links[]