COVID-19 drug repurposing research
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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.
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".
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 in the United Kingdom, the 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 is an interleukin 6 inhibitor authorized for use in several conditions, including rheumatoid arthritis, giant cell arteritis, systemic juvenile idiopathic arthritis and severe cytokine release syndrome. Its use has been studied in several trials.
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. 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.
It is part of the RECOVERY Trial in the UK. Hoffmann–La Roche and the WHO have also launched separate trials for its use in severe cases. 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.
The REMAP‑CAP study in the UK found that tocilizumab was beneficial in adults with severe COVID‑19, who were critically ill and receiving respiratory or cardiovascular organ support in an intensive care setting, when this was started within 24 hours of the need for organ support. The use of tocilizumab and its place in therapy have been updated by UK NICE in January 2021.
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. These include favipiravir, remdesivir, ribavirin, triazavirin, and umifenovir.
It was announced on 3 April 2020 that artesunate/pyronaridine, the main components of a new ACT antimalarial drug sold under the brand name Pyramax, 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. 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 currently in phase II clinical trial in South Korea and in South Africa.
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.[unreliable medical source?] 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.
Molnupiravir is a drug developed to treat influenza. It is in Phase II 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.
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.
In March 2020, the main protease (3CLpro) of the SARS-CoV-2 virus was identified as a target for post-infection drugs. The enzyme is essential for processing the replication-related polyprotein. To find the enzyme, scientists used the genome published by Chinese researchers in January 2020 to isolate the main protease. Protease inhibitors approved for treating human immunodeficiency viruses (HIV) – lopinavir and ritonavir – have preliminary evidence of activity against the coronaviruses, SARS and MERS. As a potential combination therapy, they are used together in two Phase III arms of the 2020 global Solidarity project on COVID‑19. A preliminary study in China of combined lopinavir and ritonavir found no effect in people hospitalized for COVID‑19.
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. 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. The WHO included lopinavir/ritonavir in the international Solidarity trial.
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.
A study published in October 2020 screening those FDA approved drugs which target SARS-CoV-2 spike (S) protein proposed that the current unbalanced combination formula of lopinavir might in fact interfere with the ritonavir's blocking activity on the receptor binding domain-human angiotensin converting enzyme-2 (RBD-hACE2) interaction, thus effectively limiting its therapeutic benefit in COVID-19 cases.
Remdesivir, sold under the brand name Veklury, is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences. It is administered via injection into a vein. During the COVID-19 pandemic, remdesivir was approved or authorized for emergency use to treat COVID‑19 in around 50 countries. Updated guidelines from the World Health Organization in November 2020 include a conditional recommendation against the use of remdesivir for the treatment of COVID-19.
Remdesivir was originally developed to treat hepatitis C, and was subsequently investigated for Ebola virus disease and Marburg virus infections before being studied as a post-infection treatment for COVID-19.
The most common side effect in healthy volunteers is raised blood levels of liver enzymes (a sign of liver problems). The most common side effect in people with COVID‑19 is nausea. Side effects may include liver inflammation and an infusion-related reaction with nausea, low blood pressure, and sweating.
Remdesivir is a prodrug that is intended to allow intracellular delivery of GS-441524 monophosphate and subsequent biotransformation into GS-441524 triphosphate, a ribonucleotide analogue inhibitor of viral RNA polymerase.international nonproprietary name (INN) while the development code name was GS-5734.
Chloroquine and hydroxychloroquine
Chloroquine and hydroxychloroquine are anti-malarial medications also used against some auto-immune diseases. Chloroquine, along with hydroxychloroquine, was an early failed experimental treatment for COVID-19. They are not effective for preventing infection.
Several countries initially used chloroquine or hydroxychloroquine for treatment of persons hospitalized with COVID‑19 (as of March 2020), though the drug was not formally approved through clinical trials. From April to June 2020, there was an emergency use authorization for their use in the United States, and was used off label for potential treatment of the disease. On 24 April 2020, citing the risk of "serious heart rhythm problems", the FDA posted a caution against using the drug for COVID‑19 "outside of the hospital setting or a clinical trial".Their use was withdrawn as a possible treatment for COVID‑19 infection when it proved to have no benefit for hospitalized patients with severe COVID-19 illness in the international Solidarity trial and UK RECOVERY Trial. On 15 June, the FDA revoked its emergency use authorization, stating that it was "no longer reasonable to believe" that the drug was effective against COVID-19 or that its benefits outweighed "known and potential risks". In fall of 2020, the National Institutes of Health issued treatment guidelines recommending against the use of hydroxychloroquine for COVID-19 except as part of a clinical trial.
In vitro, ivermectin has antiviral effects against several distinct positive-sense single-strand RNA viruses, including SARS-CoV-2. Subsequent studies found that ivermectin could inhibit replication of SARS-CoV-2 in monkey kidney cell culture with an IC50 of 2.2–2.8 μM. Based on this information, however, doses much higher than the maximum approved or safely achievable for use in humans would be required for an antiviral effect. Aside from practical difficulties, such high doses are not covered by current human-use approvals of the drug and would be toxic, as the antiviral mechanism of action is considered to operate via the suppression of a host cellular process, specifically the inhibition of nuclear transport by importin α/β1.
In November 2020, a systematic review found weak evidence of benefit when ivermectin is used as an add-on therapy for people with non-severe COVID-19. A randomized controlled trial (RCT) of 24 patients with non-severe COVID-19 and no risk factors found no difference in PCR-positive nasal swabs nor in viral load between patients who received ivermectin and those given placebo, thus failing the primary outcome of the study. Merck, the company from which the drug originated, has said that there is no good evidence ivermectin is plausible or effective as a drug used against COVID-19, and that attempting such use may be unsafe.
As of January 2021[update], the U.S. National Institutes of Health COVID-19 Treatment Guidelines state that the evidence for ivermectin is too limited to allow for a recommendation for or against its use. Ivermectin is not approved by the U.S. Food and Drug Administration (FDA) for anti-viral use. Additional evidence from RCTs and dose-response studies are needed. At least 45 such trials were listed as of January 2021.
It was reported in June 2020 that despite the absence of high-quality evidence to suggest any efficacy, use of ivermectin for prevention or treatment of early-stage COVID-19 has become increasingly widespread especially in Latin America, raising concerns about self-medication, safety, and the feasibility of future clinical trials. In response, the Brazilian Health Regulatory Agency, Brazilian Society of Infectious Diseases, and Brazilian Thoracic Society all issued position statements in July or January 2021 advising against the use of ivermectin for this purpose. Furthermore, the government of Peru rescinded a previous recommendation for the use of ivermectin (alongside azithromycin and hydroxychloroquine) in hospitalized patients, although as of January 2021 it is still prescribed for outpatient use.
In March 2021, both the FDA and the European Medicines Agency (EMA) issued guidance that ivermectin should not be used to treat or prevent COVID-19. After reviewing the evidence on ivermectin the EMA said that "the available data do not support its use for COVID-19 outside well-designed clinical trials". Ivermectin is not authorized for use to treat COVID-19 within the European Union. In the United Kingdom the national COVID-19 Therapeutics Advisory Panel determined that the evidence base and plausibility of ivermectin as a COVID-19 treatment were insufficient to pursue further investigations. The WHO say that ivermectin should not be used to treat COVID-19 except in a clinical trial.
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.
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. as well as the REMAP-CAP 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. UK biotech firm Synairgen started conducting trials on IFN-β, a drug that was originally developed to treat COPD.
In September 2020, a meta-analysis study published by the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group found hydrocortisone to be effective in reducing mortality rate of critically ill COVID-19 patients when compared to other usual care or a placebo.
The use of corticosteroids can cause a severe and deadly "hyperinfection" syndrome for people with strongyloidiasis, which may be an underlying condition in populations exposed to the parasite Strongyloides stercoralis. This risk can be mitigated by the presumptive use of ivermectin before steroid treatment.
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. Dexamethasone is only helpful in people requiring supplemental oxygen. Following an analysis of seven randomized trials, the WHO recommends the use of systemic corticosteroids in guidelines for treatment of people with severe or critical illness, and that they not be used in people that do not meet the criteria for severe illness.
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. 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 and the peer-reviewed article appeared on July 17.
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 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.
In September 2020, the WHO released updated guidance on using corticosteroids for COVID-19. 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). The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID-19 (conditional recommendation, based on low certainty evidence).
In September 2020, the European Medicines Agency (EMA) endorsed the use of dexamethasone in adults and adolescents (from twelve years of age and weighing at least 40 kg) who require supplemental oxygen therapy. Dexamethasone can be taken by mouth or given as an injection or infusion (drip) into a vein.
Administration of this inhaled steroid early in the course of COVID-19 infection has been found to reduce the likelihood of needing urgent medical care and reduced the time to recovery. More studies are on-going. In April 2021, budesonide was approved by authorities in the UK for off-label use to treat COVID-19 on a case-by-case basis.
Ciclesonide, an inhaled corticosteroid for asthma, was identified as a candidate antiviral in an in vitro drug screening assay done in South Korea. It has been used for treatment of pre-symptomatic COVID-19 patients and is under-going clinical trials.
Supplementation with micronutrients, including vitamin C, has been suggested as part of the supportive management of COVID-19, as levels of vitamin C in serum and leukocytes are depleted in the acute stage of infection owing to increased metabolic demands. The use of high-dose intravenous vitamin C has been studied. According to ClinicalTrials.gov, there are at least 34 ongoing clinical trials including vitamin C, which have completed or are recruiting people, hospitalized and severely ill with COVID‑19.
During the COVID-19 pandemic, there has been interest in vitamin D status and supplements, given the significant overlap in the risk factors for severe COVID-19 and vitamin D deficiency. These include obesity, older age, and Black or Asian ethnic origin, and it is notable that vitamin D deficiency is particularly common within these groups.
The National Institutes of Health (NIH) COVID-19 Treatment Guidelines stated in July 2020 that "there are insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19."
The general recommendation to consider taking vitamin D supplements, particularly given the levels of vitamin D deficiency in Western populations, has been repeated. As of February 2021[update], the English National Institute for Health and Care Excellence (NICE) continued to recommend small doses of supplementary vitamin D for people with little exposure to sunshine, but recommended that practitioners should not offer a vitamin D supplement solely to prevent or treat COVID‑19, except as part of a clinical trial.
Multiple studies have reported links between pre-existing vitamin D deficiency and the severity of the disease. Several systematic reviews and meta-analyses of these show that vitamin D deficiency may be associated with a higher probability of becoming infected with COVID-19, and have clearly demonstrated there are significant associations between deficiency and a greater severity of the disease, including relative increases in hospitalization and mortality rates of about 80%. The quality of some of the studies included and whether this demonstrates a causal relationship has been questioned.
Many clinical trials are underway to assess the use of oral vitamin D and its metabolites such as calcifediol for prevention or treatment of COVID‑19 infection, especially in people with vitamin D deficiency.
The effects of oral vitamin D supplementation on the need for intensive care unit (ICU) admission and mortality in hospitalized COVID-19 patients has been the subject of a meta-analysis. A much lower ICU admission rate was found in patients who received vitamin D supplementation, which was only 36% of that seen in patients without supplementation (p<0.0001). No significant effects on mortality were found in this meta-analysis. This analysis was limited by heterogenicity in the studies, but these findings indicate a potential role for vitamin D in improving COVID-19 severity with more robust data being required to substantiate any effects on mortality.
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.
Some antibiotics that have been identified as potentially re-purposable as COVID‑19 treatments, including teicoplanin, oritavancin, dalbavancin, monensin, and azithromycin. New York State began trials for the antibiotic azithromycin on 24 March 2020.
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 the antirheumatic agent bucillamine in patients with mild-moderate COVID-19.
The oral JAK inhibitor baricitinib is also being studied for COVID-19 treatment. In November 2020, the FDA granted emergency use authorization for baricitinib to be given to certain people hospitalized with suspected or confirmed COVID-19 (specifically, adults and children two years of age or older requiring supplemental oxygen, mechanical ventilation, or ECMO), but only in conjunction with remdesivir. In a single clinical trial, this combination therapy was shown to have a small, but statistically significant effect on patient outcomes compared to administration of remdesivir alone.
In 2021, the importance of drug repurposing for COVID-19 led to the establishment of broad-spectrum therapeutics. Broad-spectrum therapeutics are effective against multiple types of pathogens. Such drugs have been suggested as potential emergency treatments for future pandemics.
Histamine H2 receptor antagonists are under investigation. Cimetidine has been suggested as a treatment for COVID-19. Famotidine has been suggested as a treatment for COVID-19, and a clinical study is underway.
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. The study, named COLCORONA, was recruiting 6000 adults 40 and older who were diagnosed with COVID‑19 and experienced mild symptoms not requiring hospitalization. Women who were pregnant or breastfeeding or who did not have an effective contraceptive method were not eligible. The trail results are favorable, but inconclusive.
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.
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.
nanoFenretinide is nanoparticle sized fenretinide and repurposed oncology drug approved to enter the clinic for a lymphoma indication. It was identified as a candidate antiviral in an in vitro drug screening assay done in South Korea. Fenretinide's clinical safety profile also makes it an ideal candidate in combination regimens.
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Recommendation 4. Among hospitalized patients with severe* COVID-19, the IDSA guideline panel suggests glucocorticoids rather than no glucocorticoids. (Conditional recommendation, Moderate certainty of evidence)
Remark: Dexamethasone 6 mg IV or PO for 10 days (or until discharge if earlier) or equivalent glucocorticoid dose may be substituted if dexamethasone unavailable. Equivalent total daily doses of alternative glucocorticoids to dexamethasone 6 mg daily are methylprednisolone 32 mg and prednisone 40 mg.
Recommendation 5. Among hospitalized patients with COVID-19 without hypoxemia requiring supplemental oxygen, the IDSA guideline panel suggests against the use of glucocorticoids. (Conditional recommendation, Low certainty of evidence)
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