Approved Therapeutics for a Novel Pandemic: Drug Repurposing to Treat COVID-19

Since it was originally reported in December 2019, the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for causing coronavirus disease-2019 (COVID-19) has proliferated around the world, causing a global pandemic that is responsible for over 18 million confirmed cases and over 690,000 deaths worldwide.¹ Its high degree of transmissibility combined with the lack of an approved efficacious vaccine or widely available treatment has prompted scientists globally to create an immediate solution.

Pharmaceutical Development vs. Drug Repurposing

Drug development is a lengthy, arduous process comprising an array of research, financial, logistical, and manufacturing challenges,  and such a long-term undertaking is not optimal to face the immediate needs associated with fighting a global pandemic. As SARS-CoV-2 continues to spread, clinical trials are ongoing to derive a definitive solution. As of early August, there were over 2,000 ongoing and completed studies listed on the World Health Organization’s (WHO) International Clinical Trials Registry Platform.² The National Institute of Health’s (NIH) website, ClinicalTrials.gov, shows over 2,800 additional COVID-19 studies in various stages, with over 60 of them funded by the U.S. federal government.² The race to develop a vaccine, as well as novel therapeutics that can treat patients with varying and wide-ranging degrees of symptoms and complications, are ongoing. However, there is another branch of research focused on the repurposing of drugs that have already been tested, approved, and deemed safe in humans, and these drugs are being redeployed to treat patients with COVID-19. 

While individual repurposed drugs may not provide substantial clinical benefits in the fight against COVID-19, carefully combined cocktails and combination therapies could be effective, provided the right combinations are found and demonstrated to be effective. One limitation of phenotypic screens is the low potency of hit compounds as single agents, as their maximum tolerated dose is often subtherapeutic for the desired impact. This is one reason that combination therapies are being explored — if two or more drugs act on different cellular pathways involving viral replication with minimal redundancy, the dosage levels of each drug can be reduced and the chances of efficacy increased.³ 

Another factor that is fueling research into the repurposing of approved drugs is cost. The average cost of new drug development exceeds $1 billion,² and a new drug can take over 10 years to advance from discovery to market availability²; as such, repurposing may be a more prudent immediate strategy. It is important to note that there has been no drug to date that has been proven efficacious to treat SARS-CoV-2; however, research continues and has been prioritized by a number of companies. Hydroxychloroquine dominated the conversation around drug repurposing and was covered extensively in the media before ultimately proving ineffective against COVID-19. However, there are a multitude of other drugs being evaluated as potential treatment options for SARS-CoV-2 and its potentially devastating effects.

Umifenovir

Broad-spectrum antiviral agents (BSAA) have been touted as good drug repurposing candidates, as they combat viral replicative mechanisms and host interactions to target two or more viral families.³  Umifenovir is a small indole–derivative molecule that can block virus entry into target cells while simultaneously inhibiting the synthesis of viral RNA.⁴ It stimulates the immune system via induction of serum interferon and activation of phagocytes, and it is already licensed for prophylaxis and treatment of influenza.⁴ Research has shown that umifenovir can be an efficient inhibitor of SARS-CoV-2 in vitro, but a higher dose may be needed to achieve equal suppression in vivo, and little is known about its clinical efficacy owing to a lack of large-scale randomized, controlled trials (RCTs).⁴ 

Lopinavir–ritonavir

Lopinavir–ritonavir is an approved BSAA combination designed to inhibit HIV from replicating by binding to the protease.³ Ritonavir is combined with lopinavir to increase its plasma half-life by inhibiting the cytochrome P450.⁵ An RCT was conducted involving 199 hospitalized adult patients with confirmed SARS-CoV-2 infection. Ninety-nine patients were administered lopinavir–ritonavir, and 100 patients received standard care. However, treatment with lopinavir–ritonavir did not produce a distinguishable difference in time to clinical improvement or mortality rate among the two groups; the results after 28 days were similar, with a 19.2% mortality rate for the lopinavir–ritonavir patients and a 25% mortality rate for the control group. Additionally, treatments were stopped early in 13 patients due to adverse events.⁵  Most notably, the drugs are known to cause increased nausea, diarrhea, and increased risk for liver damage, all of which could exacerbate complications of COVID-19.⁷ Despite the findings in this study, additional trials are underway, including one that adds IFN-β and ribavirin to the lopinavir–ritonavair combination and appears to demonstrate reductions in time of viral shedding, time to alleviation of symptoms, and length of hospital stay for adult patients suffering from mild symptoms.⁷ To date, no clinical benefit has been observed with the administration of lopinavir–ritonavir in favor of standard care.⁷

Remdesivir

Gilead’s remdesivir is another BSAA garnering significant attention and headlines as a treatment option for patients with COVID-19. It is a viral RNA-dependent RNA polymerase inhibitor and is being utilized for COVID-19 patients suffering from mild to moderate symptoms.³ Remdesivir has been studied in an RCT for Ebola and demonstrated an antiviral effect,³ and it exhibits inhibitory activity against SARS-CoV and Middle East respiratory syndrome (MERS-CoV).⁶ Remdesivir was identified early in the pandemic as a promising repurposing candidate for treatment of COVID-19 due to its ability to inhibit SARS-CoV-2 in vitro, in addition to findings in nonhuman primate studies, which showed that it reduced lung virus levels and lung damage in MERS-CoV cases within 12 hours of inoculation.⁶ Although it has not been deemed efficacious, in a double-blind, randomized, placebo-controlled trial of intravenous remdesivir, it did seem to reduce the recovery duration of hospitalized adults by about four days when compared to the placebo group, with an average recovery time of 11 days rather than 15. 

Favipiravir

Favipiravir is a derivative of pyrazinecarboxamide that was initially approved for therapeutic antiviral activity against influenza. It targets RNA-dependent RNA polymerase enzymes, which are necessary for the transcription and replication of viral genomes.⁸ It inhibits the replication of influenza A and B and has demonstrated promise in the treatment of avian influenza as well, so it may be an alternative option for influenza strains resistant to neuramidase inhibitors.⁸ It was previously studied as a repurposed drug to treat Ebola and Lassa and is now being evaluated for COVID-19. The preliminary results of an open-label, controlled study to examine the effects of favipiravir compared with lopinavir–ritonavir reported significant clinical differences for patients receiving favipiravir, as they appeared to have faster viral clearance and better chest imaging after 14 days.⁹ However, conditions did not allow for the randomization of patients to receive either standard care or one of the experimental drugs,⁹ so efficacy could not be established and further research is necessary. 

Dexamethasone

Dexamethasone is a corticosteroid similar to a natural hormone produced by the adrenal glands and is used to replace the endogenous chemical when the body does not make enough.¹⁰ It relieves inflammation and is often prescribed to treat certain forms of arthritis; skin, blood, kidney, eye, thyroid, and intestinal disorders; severe allergies and asthma; and some forms of cancer.¹⁰ Corticosteroids may reduce immune-mediated lung injury and reduce progression to respiratory failure and death.¹¹ A randomized, controlled, open-label, adaptive platform trial was conducted, treating hospitalized COVID-19 patients with dexamethasone for up to 10 days, and comparing them to patients receiving standard care. The study showed that the overall mortality rate for patients taking dexamethasone was 21.6%, compared with 24.6% for patients receiving standard care after 28 days. These findings proved that there is no overall significant clinical benefit.¹¹ However, the study found that, among patients receiving invasive mechanical ventilation, dexamethasone reduced the mortality rate by one-third.¹¹ For patients suffering from hypoxaemia — which if it manifests, usually occurs five to seven days into the illness — dexamethasone proved beneficial when administered seven or more days into the symptomatic phase.¹² 

Nafamostat and Camostat

Nafamostat and camostat are synthetic protease inhibitors of trypsin, prostasin, matriptase, and plasma kallikrein.¹³ They are approved in Japan to treat chronic pancreatitis and postoperative reflux esophagitis.¹³ Camostat was found to block the entry of SARS-CoV in vitro by inhibiting the serine protease TMPRSS2, and researchers believe both nafamostat and camostat could have similar effects in inhibiting SARS-CoV-2.⁷ They have both been found to block cell entry for SARS-CoV-2 in vitro, although one preprint study reported that nafamostat inhibited viral cell entry at a rate roughly 15 times higher than camostat.⁷ Both drugs are in phase II and III clinical trials in the United States and Japan. These trials will reveal camostat’s effect on viral load and the time to clinical improvement after treatment with nafamostat.⁷

Nitazoxanide 

The FDA-approved antiparasitic drug nitazoxanide has shown antiviral activity against viral infections such as coronaviruses, influenza, hepatitis C virus, hepatitis B virus, and others, potentially making it a BSAA.¹⁴ In vitro inhibition of SARS-CoV-2 by nitazoxanide at low micromolar concentrations has been observed, and nitazoxanide also suppresses the production of cytokines, demonstrating a potential to mitigate a COVID-19–induced cytokine storm.¹⁴ Furthermore, the reported efficacy of nitazoxanide to promote bronchodilation in highly contracted airways may be beneficial in alleviating COVID-19-associated symptoms. 

Tocilizumab, Sarilumab, and Bevacizumab

A retrospective study of around 200 COVID-19 patients with severe symptoms found that many of them had elevated levels of the inflammatory cytokine IL-6.⁷ It is thought that cytokine-release syndrome is involved in worsening already severe reactions to the virus, causing acute respiratory distress syndrome (ARDS) even as viral loads diminish.⁷ A variety of drugs that block different cytokines are being tested in clinical trials, including tocilizumab and sarilumab, which are typically administered to treat rheumatoid arthritis. Both of these drugs are monoclonal antibody antagonists of the IL-6 receptor. ⁷ The results of an RCT of tocilizumab appear to be promising, although the data has yet to be published. Preliminary results from a phase II study of sarilumab show some positive trends from drug administration in patient groups categorized as “critical,” but negative results in patients categorized as “severe” (those requiring oxygen supplementation but not intubation).⁷ The third phase of that trial is testing only higher doses of the drug among patients in the critical group.

Recruitment is underway for clinical trials to test bevacizumab, a monoclonal antibody directed against the signaling protein vascular endothelial growth factor (VEGF) in a variety of cancer treatments.⁷ The drug inhibits the growth of blood vessels that feed tumors. By suppressing VEGF, this drug can also potentially reduce vascular permeability, decreasing the amount of fluid entering the lungs of patients with COVID-19 who are suffering from ARDS.⁷

Ivermectin

Ivermectin is widely used for the treatment and control of several neglected tropical diseases.¹⁵ It has an excellent safety profile, with more than 2.5 billion doses distributed over the last 30 years, and its potential to reduce malaria transmission by killing mosquitoes is under evaluation in several trials around the world.¹⁵ Ivermectin inhibits the in vitro replication of some positive, single-stranded RNA viruses, including dengue virus, Zika virus, and yellow fever virus.¹⁵ Ivermectin is believed to work by binding and destabilizing cell-transport proteins involved in nuclear entry.⁷ In an observational multicenter study with 1,400 patients that is currently under review, treatment with ivermectin was associated with a lower death rate (7% versus 21% in the control group) and shorter hospital stays.¹⁵ Fewer intubated patients died in the ivermectin group (7% versus 21%). However, it is also believed that levels of ivermectin with meaningful clinical significance against SARS-CoV-2 may not be achieved without potentially toxic increases in dosing levels.¹⁵ Further research and testing are needed to determine the possibilities of efficacy for ivermectin as treatment for COVID-19 patients. 

Tempering Expectations

Given the costs, development timelines, and logistical challenges associated with drug discovery and production juxtaposed with the urgency to find efficacious therapeutics to combat SARS-CoV-2, it is not surprising to see a surge in drug repurposing studies around the world. While the drugs referenced in this article are among the best known on the market and are in various phases of clinical trials, there are myriad other possible treatments being studied, including drug classes that span antibodies, antivirals, anti-parasitics, antibiotics, corticosteroids, and immunologicals.

While scientists are working to fast-track an efficacious vaccine, the fact remains that an average vaccine taken from the preclinical phase requires a development timeline of 10.71 years and has a market entry probability of 6%.¹⁶ Although there is much hope and some promising drug development activity, as well as universal commitment to successfully suppress the SARS-CoV-2 pandemic and more research being conducted on this than any other health crisis in the world, expectations must be tempered, as this is a novel virus with much scrutiny both from the public as well as the medical and scientific communities. 

References

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2. ClinicalTrials.gov. U.S. National Library of Medicine. Aug. 2020. Web. 

3. Senanayake, Suranga L. “Drug Repurposing Strategies for COVID-19.” National Center for Biotechnology Information, U.S. National Library of Medicine. 25 Mar. 2020. Web. 

4. Huang, Dong; Yu, He; Wang, Ting; Yang, Huan; Yao, Rong; Zongan, Liang. “Efficacy and Safety of Umifenovir for Coronavirus Disease 2019 (COVID-19): “A Systematic Review and Meta-Analysis.” Wiley Online Library. 3 Jul. 2020. Web. 

5. Bin, Cao et al. “A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19.” The New England Journal of Medicine. 7 May. 2020. Web. 

6. Beigel, John H., et al.”Remdesivir for the Treatment of COVID-19—Preliminary Report.” The New England Journal of Medicine. 22 May. 2020. Web. 

7. Shaffer, Leah. “15 Drugs Being Tested to Treat COVID-19 and How They Would Work.” Nature Medicine. 15 May. 2020. Web.

8. “Favipiravir.” National Center for Biotechnology Information. Aug. 2020. Web.

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10. “Dexamethasone.” The American Society of Health-System Pharmacists. Aug. 2020. Web.

11. Horby, Peter; Lim, Wei Shen; Emberson, Jonathan; Mafham, Marion; Bell, Jennifer; Linsell, Louise; et al.”Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report.” medRxiv. 22 Jun. 2020. Web.

12. Johnson, Raymond M. “Dexamethasone in the Management of COVID-19.” BMJ Publishing Group Ltd. 3 July. 2020. Web.

13. Rossi, Franesco; Capuano, Annalisa; Scavone, Cristina; Brusco, Simona; Bertini, Michele. “Current Pharmacological Treatments for COVID-19: What’s Next?” British Pharmacological Society. 24 Apr. 2020. Web.

14. Mahmoud, Dina; Shitu, Zayyanu; Mostafa, Ahmed. “Drug Repurposing of Nitazoxanide: Can it be an Effective Therapy for COVID-19?” Springer Nature. 28 July. 2020. Web.

15. Chaccour, Carlos; Hammann, Felix; Ramón-Garcia, Santiago; Rabinovich, N. Regina. “Ivermectin and COVID-19: Keeping Rigor in Times of Urgency.” National Center for Biotechnology Information, US National Library of Medicine. 16 Apr. 2020. Web.

16. Pronker, Esther; Weenen, Tamar; Commandeur, Harry; Claassen, Eric; Osterhaus, Albertus. “Risk in Vaccine Research and Development Quantified.” PLOS One. 20 Mar. 2013. Web.