Repurposing of drugs against SARS-CoV-2.

In addition to the development of new drugs against the coronavirus, tests are also being carried out at the same time to determine whether developed drugs, some of which have already been approved, can be repurposed in the fight against the virus.

In addition to the development of new drugs against the coronavirus, tests are being carried out to determine whether it is possible to "repurpose" drugs against SARS-CoV-2. This article gives an insight into the strategies used by virologists.

Supportive Care - How SARS-CoV-2 is currently treated.

Why the spectrum in infected persons can range from no symptoms to mild to moderate or even severe symptoms has not been conclusively clarified at present. Obviously, age, the general immune status, also in connection with ongoing immunosuppressive medication, and certain previous illnesses play a role.
We know that the infected body defends itself against the SARS-CoV-2 pathogen early on in the course of an infection. This is followed by an immune reaction, which can be very "violent" or "exuberant" in individual cases at a later stage of the infection. This reaction can cause a real cytokine or chemokine storm in the body through the massive release of messenger substances such as cytokines or chemokines. As a result, the state of health of the infected person can deteriorate significantly.
Therefore, moderate to severe symptoms make hospital admission mandatory. However, no specific anti-SARS-CoV-2 antiviral drugs are currently available to effectively and sustainably combat an infection. Physicians currently have only supportive care, or symptomatic treatment, as a treatment option for COVID-19 sufferers, according to state-of-the-art (current state of development).

The antiviral treatment.

A specific, antiviral medication is probably more advisable in an earlier phase of the infection. The antiviral effect can inhibit the further spread of the virus in the body and also thereby prevent the later complications caused by violent immune reactions. However, an adaptive ("acquired") immune cell-based immune response is always necessary to "clear" virus-infected cells, because the immune system can distinguish virus-infected cells from non-virus-infected cells.
(Note: This is a fundamental finding for which Rolf Zinkernagel and Peter Doherty were awarded the Nobel Prize in Medicine 24 years ago (1996)).

The normal case: the development of new drugs.

In an online communication, the Association of Research-Based Pharmaceutical Companies has shown in great detail which development steps and time span it takes to develop a new ("de novo") drug. Thus, the average drug development is stated to take more than 13 years until approval.[1].

The rapid "drug development".

We are currently in an absolute emergency situation. There is not enough time for the development of new drugs.

Repurposing.

Repurposing", changing the purpose, is the use of medicines that have already been used against other diseases (see under Strategy point 5. and 6.).
The "scientific" order of the day is to test drugs that have already been developed and, for the most part, approved for the treatment or therapy of other RNA viruses for their effectiveness against SARS-CoV-2. Not in self-experiments, but in controlled clinical trials. If successful, an antiviral drug can be expected to become available quickly.

These, usually already approved, antiviral drug candidates have had the basic, non-clinical safety testing (note: which is always required to detect adverse effects of an agent before human use) done, in addition to the availability of safety profiles through human use, but, in a different context!

Kalil 2020, and we would agree, believes that the rapid and simultaneous combination of supportive care or symptomatic treatment and the use of antiviral drugs in randomised clinical trials (RCTs) is the only way to develop effective and safe treatments for COVID-19.[2].

Principle strategies for pharmaceutical intervention.

Scientists around the world are working hard to change the situation of not having an antiviral SARS-CoV-2 drug available as soon as possible. Different strategies are being considered to develop these needed drugs.

Principle strategies for pharmaceutical intervention, drug development of SARS-CoV-2 infection, are based on:

    1. Based on detailed knowledge of the SARS-CoV-2-specific genome and its specifically encoded proteins.[3][4][5].
    2. Based on knowledge of the form of virus infection, virus entry and the way the virus replicates and knowledge already gained on SARS-CoV in vitro.[6][7].
    3. Basis of computer-based molecular interaction models.[8].
    4. Based on in vitro findings of already approved substances now in the context of SARS-CoV-2.[9].
    5. Basis of using previously known drugs approved for a different viral infection (viral infections that are also due to RNA viruses). This approach is referred to in science as "repurposing".[10][11].
    6. Basis of using previously known drugs that have been clinically proven for a different viral infection but have not been approved. This approach is also a "repurposing" approach[12].
    7. Based on the clinical information available to date on the treatment of SARS-CoV/ MERS-CoV[13][14].
    8. Based on the evidence that SARS-CoV-2 infection leaves an immunity (In a preliminary uncontrolled case series of five critically ill patients with COVID-19 and ARDS (acute respiratory distress syndrome), the administration of convalescent plasmas (plasma preparations from people who have recovered from COVID-19), which probably contained neutralising antibodies, improved their clinical status.
      However, the limited sample size, the size and the study design preclude a definitive conclusion on the potential efficacy of this treatment, as these observations need to be evaluated in clinical trials. In addition, all patients were treated experimentally with lopinavir/ritonavir and/or interferon alpha-1ß and or favipiravir[15]).(Note: See Table 2 (NCT04292340, first clinical trial with convalescent plasmas). (The numbering of the strategies are random).
PRIORITY.

In their 2006 report, Stockmann and colleagues summarised and assessed results of a systematic review of evidence from publications on various non-SARS-specific antiviral therapies during the 2002 and 2003 pandemics. This report also includes specific criteria to look for large apparent beneficial effects, adverse or poor outcomes, or evidence of potential benefit that could be used to prioritise future activities for research on SARS treatments[16].

Just as then, no specific antivirals or licensed vaccines are currently available to combat SARS-CoV-2. Moreover, the SARS pandemic in 2002 and 2003 was ultimately halted by conventional control measures, including travel restrictions and patient isolation.[17].

(Note: At the time of infectiousness of a SARS patient relative to the time of onset of symptoms, one could also contribute to the containment of infection in SARS patients via symptoms by measuring elevated temperature, as SARS patients developed obvious symptoms such as fever prior to the onset of infectiousness[18]).

Also at that time, repurposing strategies were used (as explained in strategy nos. 5 and 6), since - as reported - no specific anti-SARS drugs were available at the time of the SARS pandemic in 2002 and 2003.

Tested in clinical trials in a different context: REMDESIVIR - CHLOROQUIN - FAVIPIRAVIR.

With Remdesivir, we now have an antiviral drug that was developed to combat Ebola. Although it has not yet been approved, it has nevertheless been tested in clinical trials (see strategy no. 6). Remdesivir, an inhibitor of the RNA replication enzyme (RNA-dependent RNA polymerase, "RdRP"), was shown to inhibit SARS-CoV-2 virus infection of a human cell line (human liver cancer Huh-7 cells)[19].

Chloroquine, an approved, widely used anti-malarial and autoimmune drug, has recently been considered as a potential "broad spectrum" antiviral drug. Chloroquine is known to cause an increase in endosomal pH. Endosomes are cellular compartments responsible for the modification of proteins and distribution of proteins in the cell. It could therefore also block viral replication. Physiological pH is required for virus-cell fusion. An acidic environment could inhibit this. Furthermore, it was shown in Vero E6 cells that the so-called glycosylation (the "attachment of sugar molecules to proteins) of cellular receptors of SARS-CoV is disturbed.[20]. These in vitro studies provide a first and hopeful indication of the usefulness of testing drugs in controlled clinical trials for their efficacy against SARS-CoV-2 in humans for safety and efficacy.

Favipiravir (T-705), a guanine analogue (Note: A base analogue, which when "incorporated" inhibits nucleic acid amplification) approved for influenza treatment can effectively inhibit the RNA-dependent RNA polymerase of some RNA viruses such as for influenza, Ebola, yellow fever, chikungunya, norovirus and enterovirus, as well as in a recent study its activity against 2019-nCoV (now SARS-CoV-2) was reported in vitro, in Vero E6 cells[21].

However, the fact that an antiviral agent works in a cell culture does not mean that it will also help infected humans. For this, controlled clinical studies are needed, which have already been started, as shown in tables 1 and 2.

Already approved in another context: LOPINAVIR/RITONAVIR (Kaletra), CAMOSTAT MESILATE.

Two other possible drugs for "repurposing" are Keletra and Camostat Mesilate. They have in common that they are already i) approved drugs. Kaletra, is a combination preparation of lopinavir and ritonavir[22]which is used for the treatment of HIV infection. Camostat Mesilate is a drug approved in Japan for the treatment of inflammation of the pancreas.[23].
Both drugs inhibit proteases. These are enzymes that cut a protein or a protein chain. This can inhibit virus-specific proteins that are needed for their multiplication.

How CAMOSTAT MESILATE works.

A membrane-bound human cellular protease ("TMPRSS2") involved in SARS-CoV-2 virus entry into the cell can also be inhibited by camostat mesilates. This mechanism of action was demonstrated by Hofmann et al. in 2020 through cell culture model experiments. It was also shown that sera from patients who had undergone SARS-CoV-2 gave evidence of neutralising antibodies against the SARS-CoV-2-S (spike) protein.[24](Note: The SARS-CoV-2-S protein is the "matching key" for the "cellular lock", the human ACE-2 receptor (angiotensin-converting enzyme-2) and thus the virus entry (infection) of humans can be explained). This inhibition mechanism was explained by Mr. Pöhlmann as follows:

Mr Pöhlmann - as co- and corresponding author in Hoffmann et al., 2020 - has told RDN: "To trigger a disease, viruses basically have to enter the body's cells. For this purpose, the novel coronavirus SARS-CoV-2 carries a protein on its surface that assumes the function of a kind of key (the "spike protein"), explains Stefan Pöhlmann, head of the Department of Infection Biology at the German Primate Center. "However, this key only functions when it is split into two parts." This is exactly what the protease TMPRSS2 does. This means: without activation by the protein, the virus has no chance of infecting lung cells. "The drug binds to the active centre of the enzyme (the protease TMPRSS2) and blocks it," explains Pöhlmann. "So far, however, it has not been used in connection with coronavirus infections in humans"[25].

High risk warning.

As reported on RND online, "the French drug safety authority advises against the drugs hydroxychloroquine and Kaletra. Both the malaria drug and the HIV drug can cause serious side effects such as heart disorders. No drug is yet known that could help against Covid-19. Furthermore, the French authority has stressed that under no circumstances should the drugs be taken as self-medication or on prescription from a local doctor. In this context, it calls for everyone's responsibility to avoid unnecessary hospitalisation due to misuse of these drugs"[26].
A list of likely drug interactions with experimental therapies of COVID-19 has been published by the Liverpool Drug Interaction Group (LDIG) (based at the University of Liverpool, UK) in collaboration with University Hospital Basel (Switzerland) and Radboud UMC (The Netherlands) to continuously assess the risks for the use of experimental agents in the treatment of COVID-19[27].

Outlook.

The rapid and simultaneous combination of supportive care or symptomatic treatment and use of antiviral drugs in randomised clinical trials (RCTs) is the only way to develop effective and safe treatments for COVID-19 and for any other future outbreak[28]. This means that an experimental therapeutic approach with repurposing drugs in the course of compassionate use should only be used in extreme emergencies, if at all.

(Note: Compassionate use therapy or "individual curative attempt" of a particularly seriously ill patient is the responsibility of the treating physician, who may administer an unauthorised medicinal product for the patient to be treated, for which there is sufficient evidence of the efficacy and safety of the medicinal product. The practitioner must notify the competent authority of this use.[29]).

Tables 1 to 3 show clinical trials currently registered (in the USA and Europe) (as of 31.3.2020) to investigate the safety and efficacy of some "repurposing" drugs. The tables show a selection of "antiviral" drugs and not the full spectrum of registered clinical trials, which also address approaches for the therapy of immunopathological reactions but also for the improvement of COVID-19, supportive care.

TABLES.

Table 1: EU Clinical Trials Register: (Query: antiviral and COVID-19, 5 hits; SARS-CoV-2, 15 hits), 31.03.2020
https://www.clinicaltrialsregister.eu/ctr-search/search?query=antiviral+COVID-19

EUDRA CT NUMBER ANTI-VIRAL DRUG (COVID-19) START STUDY
2020-001010-38 Chloroquine 2020-03-23
2020-001243-15 New antiviral drug 2020-03-26
2020-000842-32 Remdesivir 2020-03-18
2020-001023-14 IFNβ-1a for nebulisation 2020-03-17
2020-000841-15 Remdesivir 2020-03-18
2020-001281-11 Hydroxychloroquine 2020-03-30
2020-000982-18 different anti-viral drugs 2020-03-26
22020-001200-42 Camostat Mesilate 2020-03-30
2020-001052-18 Investigational Therapeutics 2020-03-25

list is not exhaustive!

Table 2: ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world.
https://clinicaltrials.gov/ (Query: COVID-19 and antiviral) 59 hits, 31.03.2020

Clin Trials.gov. Identifyer: ANTI-VIRAL DRUG (COVID-19) START STUDY
NCT04292899 Remdesivir 2020-03-06
NCT04292730 Remdesivir 2020-03-15
NCT04321616 Different antiviral drugs 2020-03-26
NCT04307693 Hydroxychloroquine 2020-03-11
NCT04292340 Convalescent plasma 2020-02-01
NCT04252664 Remdesivir 2020-02-12
NCT04323345 Natural Honey treatment 2020-03-25
NCT04261907 ASC09/Ritonavir and Lopinavir/Ritonavir 2020-02-07
NCT04257656 Remdesivir 2020-02-06
NCT04303299 Various Combination of Protease Inhibitors, Oseltamivir, Favipiravir, and Hydroxychloroquine 2020-03-15
NCT04261270 ASC09/Ritonavir Compound Tablets and Ritonavir 2020-02-01
NCT04321174 Lopinavir/ritonavir 2020-03-30

list is not exhaustive!

Table 3: ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world. - Summary -

Synonyms Research Results* Entire Database**
COVID-19 239 studies 239 studies
SARS CoV-2 69 studies 69 studies
...2019-nCoV 36 studies 36 studies
2019 novel coronavirus 16 studies 16 studies
severe acute respiratory syndrome coronavirus 2 4 studies 4 studies

Number of studies in the search results containing the term or synonym
Number of studies in the entire database containing the term or synonym

Conclusion. Repurposing.

Guo et al., 2020 have recently presented a review of the "repurposing" drug candidates (but also on the origin and transmission of the virus) that is worth reading[30].
We are well on our way to having anti-SARS-CoV-2/ COVID-19 therapeutics available relatively quickly. We believe that the antiviral medication will "make the race" and be available more quickly than the vaccine, which has also been longed for.

Current status. Repurposing.
Supportive therapies:

Supportive therapy is also time-critical in the course of an infection. A first phase after infection (a protective immune defence phase) is followed by a second phase. This second phase is a destructive phase driven by inflammatory processes ("an immunopathological phase", as described above). Shi et al., 2020 suggest a range of supportive medication, including immune system supportive ("adjuvant") measures, such as the administration of pegylated INF (interferon)-alpha or antisera and - among others - vitamin B3 in the early phase.

Shi, Y., Wang, Y., Shao, C. et al. COVID-19 infection: the perspectives on immune responses. Cell Death Differ (2020). https://doi.org/10.1038/s41418-020-0530-3, https://www.nature.com/articles/s41418-020-0530-3, Accessed 17 APR 2020.

"Repurposing" medicines:
Remdesivir. Repurposing.

18 April 2020: The FAZ reported the first treatment successes with Remdesivir in monkeys. It also reported that random clinical trials with Remdesivir have already taken place in several countries. According to the report, the drug showed great efficacy in corona patients in a hospital in Chicago, which is participating in the clinical trials. The previously unapproved drug Remdesivir was also used to treat Ebola. The Federal Institute for Drugs and Medical Devices (BfArM) approved a so-called hardship programme at the beginning of April, in which severely affected Corona patients - outside of a clinical trial - may be treated with Remdesivir in hospital, although there is no official approval yet.
https://www.faz.net/-ivn-9ylkx. Accessed 18 APR 2020.

Chloroquine. Repurposing.

The online edition of the Deutsches Ärzteblatt reports on 14 APR 2020: "COVID-19: Smaller study with chloroquine discontinued due to complications".
(https://www.aerzteblatt.de/nachrichten/111958/COVID-19-Kleinere-Studie-mit-Chloroquin-wegen-Komplikationen-abgebrochen?rt=d843a216383cf7b8adfaeea584f3d62e.Accessed 16 APR 2020.)

Citing Canadian Medical Association Journal (2020;doi: 10.1503/cmaj.200528, there was a warning of dangers of QTc prolongation in the ECG, where a study was stopped in Brazil because it resulted in fatal arrhythmias or heart muscle weakness (medRxiv 2020; doi: 10.1101/2020.04.07.20056424).

Medscape (Christine Soares) provided an overview of ongoing clinical trials on 14 APR 2020: "Reasons for Hope: The Drugs, Tests, and Tactics That May Conquer Coronavirus".
https://www.medscape.com/viewarticle/928608?src=wnl_edit_tpal&uac=304334DV&impID=2347734&faf=1#vp_4.Accessed 17 APR 2020.

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      24. 24]Op cit 5.
      25. 25]Ibid.
      26. 26]RND Redaktionsnetzwerk-2: "Severe side effects: French authority warns against chloroquine as Covid-19 drug" (31.03.2020). https://www.rnd.de/gesundheit/corona-medikament-chloroquin-als-covid-19-medikament-hat-nebenwirkungen-3X3L56MO3UIBDVJPBLOZW4MAEU.html. Accessed 31.03.2020.
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      28. 28]Op cit 2.
      29. 29]EMA: Compassionate Use: https://www.ema.europa.eu/en/human-regulatory/research-development/compassionate-use. Accessed 1.4.2020.
      30. 30]Op cit 22.

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Persons to the article.

Dr Ralf Hess

Principal Consultant IVD

Dr. Ralf Hess studied biology at the Albert-Ludwigs-University of Freiburg, where he also completed his doctorate at the Institute of Virology. Dr. Hess has many years of experience in the development of medical devices and medicinal products and their combination, in laboratory analysis and quality assurance. The quality expert has set up, implemented and maintained QM systems in accordance with ISO and GxP for various areas of application. The customer service portfolio ranges from manufacturers of classical and biological drugs, medical device companies and vaccine manufacturers to immunohistochemical, immunological, molecular biological and serological diagnostic laboratories. Dr. Hess works worldwide as an auditor in the GxP/ISO area and has many years of experience in FDA remediation projects and the regulatory development of combination products (drug device products).
Dr. Ralf Hess supports Entourage as Principal Consultant IVD.

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