key: cord-325019-hznnoxw6
authors: Benavides-Cordoba, Vicente
title: Drug Repositioning for COVID-19
date: 2020-06-30
journal: Colombia medica
DOI: 10.25100/cm.v51i2.4279
sha: 
doc_id: 325019
cord_uid: hznnoxw6

Drug repositioning is a strategy that identifies new uses of approved drugs to treat conditions different from their original purpose. With the advance of COVID-19 and the pandemic declaration; It has become the closest alternative to reduce the advance of the virus. Antimalarial, antiviral drugs, antibiotics, glucocorticoids, monoclonal antibodies, among others, are being studied; their findings, although preliminary, could establish a starting point in the search for a solution. In this review, we present a selection of drugs, of different classes and with potential activity against COVID-19, whose trials are ongoing; and as proofs of concept, double blind, add-on event-driven, would allow proposing research that generates results in less time and preserving quality criteria for drug development and approval by regulatory agencies.

The new disease caused by the coronavirus (COVID- 19) was reported in the city of Wuhan, Hubei province in China, and has spread rapidly around the world. Infected patients have been reported in 210 countries. This disease was declared as pandemic by the World Health Organization on March 12th (WHO) 1 .

SARS-CoV-2 is a positive single-stranded RNA beta-coronavirus. Like SARS and MERS, the genome encodes non-structural proteins such as chymotrypsin type 3 protease, papain-like protease, helicase, and RNA-dependent RNA polymerase; and structural proteins such as spike glycoprotein and accessory proteins 2 . So far, there are no vaccines that had been approved. However, just a few weeks after the first reports of the disease, several laboratories began investigating for a vaccine that immunizes against this virus, and approximately 37 research laboratories and academic centres are currently doing so 3 . Vaccine development already has a starting point from the knowledge gained from the SARS-CoV and MERS epidemics and the selection of antigens based on them. However, it would take several months for a vaccine to have a consistent safety profile across populations and to mimic the immune response 4 .

Another option would be to develop new molecules that allow treating the disease according to its stage; however, this process could be even slower. Furthermore, de novo drug development takes place in an environment where preclinical research findings may not be replicated 5 . Likewise, when researching new molecules in humans, it is necessary to ask several questions that could improve the designs, and avoid some failures, such as, for example, did the drug hit the target?, did the medication change the target?, what was the dose response?, and what are the characteristics of the study patients?. To answer these questions, you need financial resources and time, which in many occasions must be abundant 6 .

According to the advances in technology and knowledge of human disease, the transfer of these benefits in advance has great expectations, and moreover, the challenges of the pharmaceutical industry are great and exhausting 7 . The costs and time required for the development of a medicine have made working with the industry less attractive to researchers 8 , which is accentuated by the global economic crisis secondary to the pandemic.

Due to this, the strategy that could offer results in less time, with better levels of safety and at a lower cost is known as "Drug Repurposing". This strategy consists of identifying new uses of approved drugs different from the original therapeutic indication. 9 . This strategy differs from "Off Label" use in that it requires research and development to gain regulatory agency approval 10 . It has several advantages; first, the risk of toxicity failure is low because the drug is safe enough and has been tested in preclinical and early human studies. Second, the time is reduced since preclinical and safety studies have already been carried out, and third, the necessary resources are less 11 . These advantages can generate a quick return on investment (300 million dollars in repositioning against 2-3 trillion dollars in the study of a new molecule) and in case of failure there is less loss 12 . About 3422 medicines that have been described in human clinical trials are in the marketing phase around the world, thus, the possibility of selection is wide 13 .

Three actors have been identified in the field of repurposing: the academy, the research institutes and, of course, the pharmaceutical industry, each with its own characteristics. In academia and research institutes, there is less need for economic or commercial success, but they depend on securing resources from the state or other funder. Furthermore, the pharmaceutical industry has the complete platform to do the trials, but they are not always motivated because many countries do not recognize second-use patents 14 .

Among the diseases in which researchers are using repositioning are cancer (thalidomide, metformin, chlorpromazine, digoxin, doxycycline) [15] [16] [17] , neurodegenerative diseases such as Parkinson's (ambroxol, amantadine) 18 , viral and infectious diseases (azithromycin, mycophenolic acid) 19, 20 , asthma and allergies (ruxolitinib, imatinib, metformin) 21 , neuropathic pain (gabapentin, amitriptyline) 22 , kidney disease (levosimendan, allopurinol) 23 and cardiovascular-pulmonary disease (tadalafil, fasudil) [24] [25] [26] .

The best examples of Drug Repurposing are in the cardiovascular system, from the use of aspirin as a platelet antiplatelet 27 to the approval of Sildenafil, a drug previously used for erectile dysfunction that is now the first-line treatment in pulmonary hypertension. 28, 29 .

Since the first reports of coronavirus's infections began to be known in late 2019 in China, studies have been started with drugs approved for other diseases. To date, there are 908 studies registered at www.clinicaltrials.gov, of which 560 are intervention studies that include clinical trials of repositioning in Covid-19, mostly from China. 30 .

Chloroquine, which was initially approved for the treatment of malaria 31 , and which has been studied in approximately 400 diseases (with the first trial being carried out in 1946) 32 , was evaluated for the treatment of SARS-CoV infection in 2003 33 and now in the SARS-CoV-2 pandemic 34 . Hydroxychloroquine, a chloroquine analog, is a medicine widely used in the treatment of systemic autoimmune diseases 35 , being currently the most studied drug for treating COVID-19. Hydroxychloroquine is metabolized in the liver and is eliminated via the kidneys after 30 to 50 days. It is a 4-aminoquinolone with immunosuppressive, anti-autophagic and antimalarial properties. Although its mechanism of action is unknown, it can suppress immune function by interfering with antigen processing and presentation 36, 37 . It is a medicine with a higher risk / benefit than chloroquine and allows higher doses to be used. In COVID 19, 133 clinical trials are registered, taking different degrees of severity, ranging from prophylactic use in the general population and in health workers 38 to patients with severe acute respiratory syndrome (SARS). It is believed that, as happened with SARS-CoV, it could reduce the viral load of patients in pre and post infection stages, in addition to reducing the expression of CD154 in T cells 39 .

The results obtained so far are controversial, since on the one hand it has been reported that treatment with hydroxychloroquine did not generate additional effects to standard treatment and instead increased the risk of ventilatory support 40 , and on the other, French researchers documented that the addition of azithromycin to hydroxychloroquine treatment can generate synergistic effects by improving the elimination of the virus. It is necessary to clarify that the previously described are preliminary studies and that they require large sample sizes to generate a definitive conclusion 41 . This mixture is being studied for treating patients with and without complications (Table 1) .

Antivirals are other group of drugs being tested to combat the pandemic. In Wuhan, more than 85% of patients received medications such as Oseltamivir, Remdesivir, Ganciclovir, Lopinavir/Ritonavir and Ribavirin 42,43 . These antivirals have been combined with systemic corticosteroids and inhalation of interferon in the treatment of patients with severe complications 44 . Satisfactory results were achieved using Remdesivir, obtaining clinical improvement in 68% of patients with SARS, with a significant reduction in mortality, days of hospitalization and days of mechanical ventilation. This study was developed with patients from the United States, Japan, Italy, Austria, France, Germany, the Netherlands, Spain and Canada 45 , however, just as it happens with hydroxychloroquine, its effectiveness should be contrasted with more clinical trials and in more patients.

Immunotherapy has shown effectiveness in the treatment of infectious diseases; thus, the use of monoclonal antibodies constitutes a new stage in their prevention, due to its versatility and specificity. 46, 47 . Therapy with antibodies that bind to the angiotensin 2-converting enzyme 48, 49 . Currently there are 15 trials registered in Clinical Trials that are testing this hypothesis, using monoclonal antibodies, which are being performed only in complicated patients, none in stable patients or in prophylaxis.

Famotidine, a histamine H2 receptor antagonist; have shown effects on inmune system (50) It is currently being studied and results obtained in patients in China can generate positive expectations, currently in the United States, they are in the recruitment phase; the reduction of the mortality and its low probability of adverse effects generates an attractiveness for researchers (51, 52) . Glucocorticoids (Methylprednisolone and Dexamethasone) as monotherapy with discrete results 53 , or accompanying other medications such as thalidomide 54 ; antiinflammatories such as colchicine 55 , or drugs that do not yet have a clear mechanism of action such as pirfenidone, are being studied to be repositioned in Covid-19. China and the United States lead most of the trials, however, countries such as Italy, Spain, the United Kingdom, Canada, and Denmark 56 also participate in the search for a medicine that could change the course of a crisis that can only be compared to the world wars of the early twentieth century. With all the limitations, repositioning tests are an attractive strategy, providing the possibility of combinations that seek synergism 57 . The search for these treatments is an obligation acquired by science and public health.

There are controversies about the maximum and minimum recommendations and the essential requirements to conduct a good clinical trial of drug repositioning. The infrastructure, the preparation of products, materials, protocols, forms of reporting, databases, statistics, monitoring and reports, as well as laboratory evaluations are often insufficient 58 and their availability is reserved, a situation that is accentuated with the pandemic 59 , therefore, the maximum recommendations should be flexible when approving studies.

The COVID-19 Clinical Research Coalition initiative establishes flexible guidelines that allow research to be carried out. This initiative shows that the research agenda should not be controlled, but facilitated, for which 4 objectives are proposed: first, to facilitate rapid reviews by ethics committees and regulatory agencies; second, to facilitate permits for the importation of medicines and materials, as was done with the Ebola vaccine trials; third, to ensure simple data collection strategies sufficient to strengthen efficacy analyses; and fourth, to provide a reference framework for governments to share the results obtained before publishing in scientific journals 60 . Compliance with these objectives will allow studies to be carried out in shorter times and with enough resources to ensure quality. Thus, the Food and Drug Administration (FDA) in the United States 61 , and the INVIMA in Colombia, approved the use of hydroxychloroquine in hospitalized patients via fast track.

To move forward and generate fast and reliable results, it might be considered doing a proof of concept, double blind, add-on event-driven. In Add-On studies, one group receives the standard treatment, while the other group receive the drug to be tested in addition to the standard treatment. Using these studies, the comparison of relative or absolute efficacy could be obtained in short periods of time 62 . The FDA Recognizes Add-On designs in Cancer, Behavioural Disorders, HIV, and Heart Failure studies 63 . In this methodology processes are developed over time and results are produced that then turn into events that ultimately lead to additional results as the narrative unfolds. 64 .

Unlike most diseases, there are currently no proven treatments to treat COVID-19. Therefore, there are 183 registered studies that use placebo as a comparator of the drug to be repurposed [65] [66] [67] . The ethics committees are expected to be willing to meet the needs that the ethical conflict the placebo group generates, with enough updating to control the ethical aspects without preventing the execution of the projects. Probably there will be problems, one of them would be the entry of participants linked to the health system who could "sabotage" the study, taking Drug repositioning for COVID -19 the drug without belonging to the experimental group or trying another drug at the same time in the hope of avoiding a contagion or treating the illness.

The dissemination of these findings should be responsible, avoiding anecdotal evidence 68 . Differences in plasma concentrations of medicines from person to person could generate more adverse reactions, and therefore, rapid clinical trials but with high scientific quality should be carried out 38 . While the vaccine arrives, the repositioning of medicines will continue to be the first research strategy against this crisis that has changed the rhythm of life of humanity.

COVID-19) -events as they happen

Therapeutic options for the 2019 novel coronavirus (2019-nCoV)

Immune responses in COVID-19 and potential vaccines: lessons learned from SARS and MERS epidemic

Challenges in early clinical development of adjuvanted vaccines

Organs-on-chips at the frontiers of drug discovery

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

An analysis of the attrition of drug candidates from four major pharmaceutical companies

Drug repurposing: progress, challenges and recommendations

Drug Repositioning: Identifying and developing new uses for existing drugs

From off-label to repurposed drug in nononcological rare diseases: definition and state of the art in selected EU countries

Overcoming the legal and regulatory barriers to drug repurposing

Can you teach old drugs new tricks?

The drug repurposing hub: a nextgeneration drug library and information resource

Drug repositioning for COVID-19

Drug repurposing from the perspective of pharmaceutical companies

Drug repurposing in cancer

Drug Repurposing in anticancer reagent development

Repurposing vitamin D as an anticancer drug

Drug repurposing in Parkinson's disease

Drug repurposing for viral infectious diseases: how far are we?

Recent drug-repurposing-driven advances in the discovery of novel antibiotics

Drug repurposing to treat asthma and allergic disorders: progress and prospects

Drug repurposing for the development of novel analgesics

Drug repurposing in kidney disease

Repurposing treatments to enhance innate immunity. Can statins improve neutrophil functions and clinical outcomes in COPD?

Pleiotropic mechanisms of action of perhexiline in heart failure

Targeting Phosphodiesterase 5 as a Therapeutic Option Against Myocardial Ischaemia/Reperfusion Injury and for Treating Heart Failure

Aspirin for primary prevention of coronary disease

Sildenafil in the treatment of pulmonary hypertension. Vasc Health Risk Manag

A bibliometric review of drug repurposing

COVID 19 -List Results -ClinicalTrials.gov 2020

Malaria Chemotherapeutics Part I: History of antimalarial drug development, currently used therapeutics, and drugs in clinical development

Activity of a New Antimalarial Agent, Chloroquine (SN 7618)

Drug repositioning for COVID-19

In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine

Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies

Hydroxychloroquine: a multifaceted treatment in Lupus

Hydroxychloroquine compound summary 2020

Hydroxychloroquine: an update

Use of Hydroxychloroquine and Chloroquine during the COVID-19 pandemic: What Every Clinician Should Know

COVID-19: A Recommendation to examine the effect of hydroxychloroquine in preventing infection and progression

Clinical outcomes of hydroxychloroquine in hospitalized patients

Hydroxychloroquine and Azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Treatment of COVID-19: old tricks for new challenges

COVID-19): the epidemic and the challenges

Critical care response to a hospital outbreak of the 2019-nCoV infection in Shenzhen

Compassionate use of remdesivir for patients with severe Covid-19

Evaluation of human monoclonal antibody 80R for immunoprophylaxis of severe acute respiratory syndrome by an animal study, epitope mapping, and analysis of spike variants

Monoclonal antibodies for prophylactic and therapeutic use against viral infections

The molecular biology of coronaviruses

Perspectives on monoclonal antibody therapy as potential therapeutic intervention for coronavirus disease-19 (COVID-19)

Immunomodulatory properties of cimetidine: Its therapeutic potentials for treatment of immune-related diseases

Delivering Benefits at Speed through Real-World Repurposing of Off-Patent Drugs: The COVID-19 Pandemic as a Case in Point

New York clinical trial quietly tests heartburn remedy against coronavirus. Science; 2020

Effectiveness of glucocorticoid therapy in patients with severe novel coronavirus pneumonia: protocol of a randomized controlled trial

Thalidomide combined with low-dose glucocorticoid in the treatment of COVID-19 Pneumonia

The greek study in the effects of colchicine in COVID-19 complications prevention (GRECCO-19 Study): rationale and study design

Race to find COVID-19 treatments accelerates

Clinical trials on drug repositioning of COVID-19

Access to pathology and laboratory medicine services: a crucial gap

COVID-19: what science advisers must do now

Global Coalition to Accelerate COVID-19 Clinical research in resource-limited settings

Fact sheet for health care providers emergency use authorization (EUA) of hydroxychloroquine sulfate supplied from the strategic national stockpile for treatment of Covid-19 in certain hospitalized patients

Statistical approaches to analysis of small clinical trials

Event-driven research

Transplantation of ACE2 -mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia

Drug repositioning for COVID-19

Hydroxychloroquine versus placebo in COVID-19 patients at risk for severe disease

University Hospital, Angers

Evaluation of the efficacy and safety of sarilumab in hospitalized patients with COVID-19

Scientists identify 69 drugs to test against the Coronavirus