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. This is one line of scientific research which is being pursued to develop safe and effective COVID-19 treatments. Other research directions include the development of a COVID-19 vaccine and convalescent plasma transfusion.

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.

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".

## RECOVERY Trial

Main articles: 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.

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

## Studies

### Chloroquine and hydroxychloroquine

See also: Chloroquine#COVID-19, 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 multinational Solidarity clinical trial. 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. New York Governor Andrew Cuomo announced that New York State trials of chloroquine and hydroxychloroquine would begin on 24 March.

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). The treatment has not been approved by the FDA's clinical trials process. 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. 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. Doctors have said they are using the drug when "there's no other option". 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.

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".

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. 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". 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. 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.

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.

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.

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.

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

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

#### 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.

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.

#### 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. The WHO had enrolled 3,500 patients from 17 countries in the Solidarity trial. 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. The authors of the study corrected errors in the data later but initially remained firm on their conclusions. Subsequently a retraction of the study by three of its authors was published by *The Lancet* on 4 June, 2020. 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.

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".

### Dexamethasone

See also: Dexamethasone#COVID-19

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

On 16 June 2020, 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. Several experts called for the full dataset to be published quickly to allow wider analysis of the results. A preprint was published on June 22.

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. In July 2020, the World Health Organization (WHO) stated they are in the process of updating treatment guidelines to include dexamethasone or other steroids.

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). The IDSA recommends against the use of glucocorticoids for those with COVID-19 without hypoxemia requiring supplemental oxygen.

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. Focusing particularly on the potential use of the drug for the treatment of adults with COVID-19.

### Favipiravir

See also: Favipiravir#COVID-19
Chinese clinical trials in Wuhan and Shenzhen claimed to show that favipiravir was "clearly effective". 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. 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).

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. The Italian Medicines Agency reminded the public that the existing evidence in support of the drug is scant and preliminary. 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. According to the South China Morning Post, Shinzo Abe has made overtures to the Trump administration about purchasing the drug. On 30 May 2020, 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.

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.

### Lopinavir/ritonavir

One study of lopinavir/ritonavir (Kaletra), a combination of the antivirals lopinavir and ritonavir, concluded that "no benefit was observed". 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. On 29 June 2020, 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.

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

### Remdesivir

See also: Remdesivir#COVID-19
Remdesivir was created and developed by Gilead Sciences as a treatment for hepatitis C, and was subsequently repurposed for Ebola virus disease and Marburg virus infections.

During 2020, several clinical trials were underway. 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.

On 1 May 2020, 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. 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. Distribution of remdesivir under the EUA will be controlled by the US government for use consistent with the terms and conditions of the EUA. 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. The agreement between Gilead and five generic pharmaceutical companies in India and Pakistan will help make the medicine for 127 countries. 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.

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.

On 25 June 2020, 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 12 years of age with pneumonia who require supplemental oxygen. The brand name will be Veklury.

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."

The European Union granted remdesivir a conditional marketing authorization on 3 July 2020, with an indication for the treatment of COVID‑19 in adults and adolescents (aged 12 years and older with body weight at least 40 kg) with pneumonia requiring supplemental oxygen.

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.

#### 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.. 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. Some researchers have suggested its utility as a treatment for COVID‑19, 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).

#### 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. Most trials have the design of studying COVID‑19-infected people who are vitamin D deficient. 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. 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.

## Drugs by class

#### 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.

* Favipiravir
* Remdesivir
* Ribavirin
* Triazavirin
* Umifenovir

#### Antiparasitics

* Chloroquine
* Hydroxychloroquine
* Mefloquine
* Ivermectin
* Atovaquone

#### Antibiotics

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

* Teicoplanin
* Oritavancin
* Dalbavancin
* Monensin
* Azithromycin

#### Immunologicals

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

* Type I Interferons (Interferon-β, peginterferon alpha-2a and -2b)
* Anti-IL-6 agents (Tocilizumab)
* Anti-IL-8 (BMS-986253)

## Further reading

* "Coronavirus Disease 2019 Treatment: A Review of Early and Emerging Options". *Open Forum Infectious Diseases* **7** (4): ofaa105. April 2020. . . . //www.ncbi.nlm.nih.gov/pmc/articles/PMC7144823/.
* Zimmer, Carl (30 April 2020). "Old Drugs May Find a New Purpose: Fighting the Coronavirus". https://www.nytimes.com/2020/04/30/health/coronavirus-antiviral-drugs.html.
* "Rapid repurposing of drugs for COVID-19". *Science* **368** (6493): 829–830. May 2020. . .
* "Repurposing of drugs for Covid-19: a systematic review and meta-analysis". *medRxiv*. June 2020. .

## External links

* "COVID-19 therapeutics tracker". https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-therapeutics-tracker.
* "STAT's Covid-19 Drugs and Vaccines Tracker". https://www.statnews.com/feature/coronavirus/drugs-vaccines-tracker/#treatments.
* "Coronavirus Drug and Treatment Tracker". https://www.nytimes.com/interactive/2020/science/coronavirus-drugs-treatments.html.
* "JHMI Clinical Recommendations for Available Pharmacologic Therapies for COVID-19". https://www.hopkinsguides.com/hopkins/ub?cmd=repview&type=479-1155&name=14\_538747\_PDF.