Drug repositioning (also known as drug repurposing, re-profiling, re-tasking, or therapeutic switching) is the repurposing 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.

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 potential COVID-19 treatments, with some moving 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".

Background Outbreaks of novel emerging infections such as COVID-19 pose unique challenges to discover treatments appropriate for clinical use, given the small amount of time available for drug discovery. Since the process of developing and licensing a new drug for COVID-19 was expected to pose a particularly long delay, researchers have been probing the existing compendium of approved antivirals and other drugs as a cost-effective strategy in the meantime. In early 2020 hundreds of hospitals and universities began their own trials of existing safe drugs with repurposing potential against COVID-19.

Drug repurposing usually requires three steps before taking the drug across the development pipeline: recognition of the right drug; systematic evaluation of the drug effect in clinical models; and estimation of usefulness in phase II clinical trials.

One approach used in repositioning is to look for drugs that act through virus-related targets such as the RNA genome (i.e. remdesivir). Another approach concerns drugs acting through polypeptide packing (i.e. lopinavir).

The rush to publish papers about the pandemic resulted in some scandals of inaccurate scientific publications. Some early studies reporting the efficacy of hydroxychloroquine and remdesivir convinced drug agencies such as Food and Drug Administration (FDA) and European Medicines Agency to approve the off-label use by issuing Emergency Use Authorizations which were later revoked as new evidence showed these drugs have no effect on the course of COVID-19. These false-positive results can be explained in terms of the base-rate fallacy and the rapid changes in clinical guidance regarding COVID-19 treatment could have been avoided if mechanistic evidence for and against repurposing candidates were carefully assessed and the standard evidence amalgamation tools such as meta-analysis were routinely applied.

Monoclonal antibodies Monoclonal antibodies under investigation for repurposing include anti-IL-6 agents (tocilizumab) and anti-IL-8 (BMS-986253). (This is in parallel to novel monoclonal antibody drugs developed specifically for COVID-19.)

Mavrilimumab is a human monoclonal antibody that inhibits human granulocyte macrophage colony-stimulating factor receptor (GM-CSF-R). 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.

In January 2021, the UK National Health Service issued guidance that the immune modulating drugs tocilizumab and sarilumab were beneficial when given promptly to people with COVID-19 admitted to intensive care, following research which found a reduction in the risk of death by 24%.

Tocilizumab

Anticoagulants Medications to prevent blood clotting have been suggested for treatment, and anticoagulant therapy with low-molecular-weight heparin appears to be associated with better outcomes in severe COVID-19 showing signs of coagulopathy (elevated D-dimer). 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.

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.

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

The anticoagulant dipyridamole is proposed as a treatment for COVID-19, and a clinical trial is underway.

Antidepressants Many antidepressants have anti-inflammatory properties. An observational study in Paris area hospitals found that COVID-19 patients admitted to the hospital who were already taking an antidepressant had 44% less risk of intubation or death. The potential mechanisms how fluvoxamine and fluoxetin are contributing to prevent the development of severe respiratory symptoms of COVID-19 by protecting the type 2 lung alveolar cells have been summarized in a review in March 2022.

Fluvoxamine

In October 2021, the TOGETHER trial, a large clinical trial in Brazil, reported that treating high-risk outpatients with an early diagnosis of COVID-19 with 100 mg fluvoxamine twice daily for 10 days reduced by up to about 65% the risk of hospitalization. The effect was reduced to about 32% with low adherence, possibly due to intolerance. There was also a reduction in the number of deaths by up to about 90% with high adherence. The drug was studied because of its anti-inflammatory effects, but the mechanism of action against COVID-19 remains uncertain.

On 16 December, the NIH found that use of fluvoxamine did not impact incidence of covid-related hospitalizations and considered the evidence insufficient to recommend either for or against the drug.

On 23 December, under very low certainty evidence, the Ontario clinical practice guideline suggested considering the drug to treat mildly ill patients within 7 days of symptom onset.

In May 2022, based on a review of available scientific evidence, the US Food and Drug Administration (FDA) declined a request to issue an Emergency Use Authorization (EUA) for fluvoxamine to treat COVID-19, saying that the data were not sufficient to conclude that it may be effective in treating non-hospitalized people with COVID-19 to prevent serious illness or hospitalization. University of Minnesota professor David Boulware, who filed the EUA application, said that the standard that they were holding for fluvoxamine was a different standard than the other big pharma trials, with Paxlovid and molnupiravir and the monoclonals.

Antioxidants

Acetylcysteine (NAC) Acetylcysteine was considered as a possible treatment for COVID-19.

Antiparasitics The idea of repurposing host-directed drugs for antiviral therapy has experienced a renaissance. In some cases the research has highlighted fundamental limitations to their use for the treatment of acute RNA virus infections. Antiparasitics that have been investigated include chloroquine, hydroxychloroquine, mefloquine, ivermectin, and atovaquone.

Chloroquine and hydroxychloroquine

Ivermectin

Antivirals Research is focused on repurposing approved antiviral drugs that have been previously developed against other viruses, such as MERS-CoV, SARS-CoV, and West Nile virus. These include favipiravir, remdesivir, ribavirin, triazavirin, and umifenovir.

The combination of artesunate/pyronaridine was found to have an inhibitory effect on SARS-CoV-2 in vitro tests using Hela cells. Artesunate/pyronaridine showed a virus titer inhibition rate of 99% or more after 24 hours, while cytotoxicity was also reduced. 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. It is in phase II clinical trial in South Korea and in South Africa.

Molnupiravir is a drug developed to treat influenza. It is in Phase III trials as a treatment for COVID-19. In December 2020, scientists reported that the antiviral drug molnupiravir developed for the treatment of influenza can completely suppress SARS-CoV-2 transmission within 24 hours in ferrets whose COVID-19 transmission they find to closely resemble SARS-CoV-2 spread in human young-adult populations. A clinical trial, which has not as of 1 October 2021 been peer reviewed, suggests molnupiravir taken orally can reduce the risk of hospitalization and prevent death in patients diagnosed with COVID-19. The drug needs to be given early to be effective.Covid antiviral pill can halve risk of hospitalisation BBCCovid antiviral pill halves hospitalisations and deaths, maker says The Guardian As of 1 January 2022, Molnupiravir has been approved for emergency use against COVID-19 in the United Kingdom, India, and the United States.

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

Protease inhibitors, which specifically target the protease 3CLpro, are being researched and developed in the laboratory such as CLpro-1, GC376, and Rupintrivir.

Coronaviruses species possess an intrinsic resistance to ribavirin.

Sofosbuvir/daclatasvir is a drug combination developed to treat hepatitis C. In October 2020, a meta-analysis found a significantly lower risk of all-cause mortality with the drug combination when given to hospitalized patients.

Favipiravir Favipiravir is an antiviral drug approved for the treatment of influenza in Japan. There is limited evidence suggesting that, compared to other antiviral drugs, favipiravir might improve outcomes for people with COVID-19, but more rigorous studies are needed before any conclusions can be drawn.

Chinese clinical trials in Wuhan and Shenzhen claimed to show that favipiravir was "clearly effective". Of 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 that there was no change in how many patients in each group progressed to more advanced stages of illness that required treatment with a ventilator.

On 22 March 2020, 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 Pharmaceutical Agency reminded the public that the existing evidence in support of the drug is scant and preliminary.

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.

In June 2020, India approved the use of a generic version of favipiravir called FabiFlu, developed by Glenmark Pharmaceuticals, in the treatment of mild to moderate cases of COVID-19.

On 26 May 2021, a systematic review found a 24% greater chance of clinical improvement when administered in the first seven days of hospitalization, but no statistically significant reduction in mortality for any of the groups, including hospitalized patients and those with mild or moderate symptoms.

Lopinavir/ritonavir