Treatment and Vaccination: A European COVID-19 success story

The focus is particularly on medicinal products that have already been approved for another disease or are at least in development. Repurposing them can succeed faster than a basic new development.

A number of existing drugs are currently being tested for their suitability for corona disease Covid-19. They usually belong to one of the following three groups:

However, there are still projects for new drug developments .

Gaining clarity quickly about the suitability of the medication

In a number of studies in which such medication was and is being tested for suitability in China and elsewhere, only a few dozen patients were involved; and there is often no direct comparison with patients who only receive basic medical treatment without additional medication. Such studies can be set up quickly, but their results are often ambiguous. There are also many Covid-19 patients in clinics internationally, but not so many that it can be used to comprehensively test all drugs that are currently proposed.

The European Medicines Agency ( EMA) has therefore appealed to companies and research institutions to organize multinational, multi-armed, controlled and randomized patient studies for their medicines as possible:

Such studies, according to the EMA, would be more likely to lead to clear results on the suitability of drugs compared to small studies, which would then also allow the drugs against Covid-19 to be approved.

The World Health Organization (WHO) recently announced such a study : this study, called SOLIDARITY, is intended to compare four treatments with medicinal products that are eligible for a functional change with each other and with the pure basic treatment. The study will therefore have the following “study arms” (= types of treatment) in which several thousand patients are expected to participate – randomly distributed:

Medical institutions from Argentina, Iran and South Africa are to participate in the study. A monitoring board will regularly review interim results of the study and end study arms in which the patients are no better (or even worse) than in the control group. It is also possible to add more arms to the study, in which other additional treatments are then tried out.

At the same time, the DISCOVERY study started in Europe and the UK with a very similar structure, coordinated by the French research organization INSERM. 3,200 patients from Germany, Belgium, France, Luxembourg, the Netherlands, Spain, Sweden and the UK are to take part. Instead of chloroquine, the similar malaria drug hydroxychloroquine should be used.

Remdesivir was originally developed by Gilead Sciences against Ebola infections (against which it has not been proven), but has been shown to be effective against MERS viruses in the laboratory. The drug with this active ingredient is now being tested in several studies against SARS-CoV-2.

CytoDyn is testing whether its antibody drug Leronlimab is effective against the coronavirus. It has been developed for a long time against HIV and triple-negative breast cancer, for which it has already been tested in studies. A phase II trial for Covid-19 is now pending.

AbbVie has another HIV drug with the combination of active ingredients lopinavir / ritonavirmade available for testing as a Covid-19 therapeutic. Studies with patients are ongoing, including a study in which patients also inhale Novaferon from Beijing Genova Biotech . This alpha interferon is approved in China for the treatment of hepatitis B. The drug is now to be tested in large studies worldwide.

The company Ascletis Pharma combines ritonavir instead with an approved in China for hepatitis C drug with the active ingredient Danoprevir . Studies are ongoing.

In China, the company Zhejiang Hisun Pharmaceutical Clinical studies on Covid-19 therapy with an antiviral drug containing the active ingredient favilavir approved. So far, favilavir has only been approved for flu therapy (in Japan and China).

Also actually against flu is in development ATR-002 , a kinase inhibitor of the company Atriva Therapeutics in Tübingen. The company is now examining whether the active ingredient can also inhibit the proliferation of SARS-CoV-2.

APEIRON Biologics (Vienna) and the University of British Columbia want the drug APN01test that has emerged from SARS research and has already been tested in patient studies against other lung diseases. It blocks a molecule on the surface of the lung cells that the viruses use as a target for entry into the cells.

Chloroquine has actually become known as an active ingredient in malaria medication, but has only been prescribed very little in recent years. However, it is now known that the active ingredient can also be used antivirally. After positive laboratory tests against SARS-CoV-2. Chinese researchers meanwhile also got the news that chloroquine has proven to be effective in a clinical study. The Bayer company then restarted the production of its original preparation with chloroquine. Studies on

malaria drugs with the similar active ingredient hydroxychloroquine are also currently being examined. The company Novartis has agreed to support these efforts and to provide in the case of positive decisions by the regulatory authorities in late May up to 130 million dosage units thereof for the treatment of people worldwide. Also, Sanofi to provide a malaria drug with this drug available.

From the previous field of application, Camostat Mesilat is actually not an antiviral agent – a drug with it has been approved in Japan for inflammation of the pancreas. However, researchers from a German consortium of research institutions led by the German Primate Center in Göttingen have found that it inhibits an enzyme from lung cells in the laboratory that is essential for the penetration of the SARS-CoV-2 viruses. You are therefore planning to test it in clinical studies.

Also the active ingredient Brilacidin from the company Innovation Pharmaceuticalswas not originally developed against viruses. Rather, it is currently being tested for the treatment of inflammatory bowel diseases and inflammation of the oral mucosa. However, it is expected that it can attack the outer envelope of the SARS-CoV-2 virus. This is currently being examined in cell cultures.

The Spanish company PharmaMar wants to test its drug with plitidepsin in a study against Covid-19 after encouraging laboratory tests. The drug, which is actually approved in Australia and Southeast Asia for the treatment of multiple myeloma (a form of bone marrow cancer), has to inhibit the virus multiplication because it blocks the necessary protein EF1A in the affected cells.

Pfizer is currently testing additional antiviral agents in the laboratory that the company has previously developed for the treatment of other viral diseases. If one or more of them prove themselves in laboratory tests, Pfizer would subject them to the relevant toxicological tests and begin testing with humans at the end of 2020. Also, MSD currently investigating which of its antiviral drugs against SARS-CoV-2 could be effective. Novartis is investigating which of its own products and which substances from its own substance library for drug development could also be suitable for the treatment of Covid 19 patients – be it as an antiviral drug or be it in a different way (see below).

Immune reactions are fundamentally desirable in infected people; they just mustn’t be so excessive that they cause more damage than help in the lungs.
For this reason, excessive immune reactions in seriously ill patients are to be dampened in several projects.

Sanofi and Regeneron are therefore testing their immune modulator sarilumab in a study with affected Covid-19 patients. This interleukin-6 antagonist is approved for rheumatism therapy.

Roche is testing its interleukin-6 antagonist tocilizumabwith Covid-19 patients who have severe pneumonia. The drug is already approved for the treatment of rheumatoid arthritis. Chinese doctors have also been testing it on patients infected with swine for a few weeks.

Chinese doctors are also testing the fingolimod immunomodulator with patients. It was developed by Novartis for the therapy of multiple sclerosis and is approved for it.

In Canada, colchicine is being tested in a clinical trial to treat excessive immune responses, led by the Montreal Heart Institute . The drug is approved against gout (and in some countries also against pericarditis).

In a broader sense you can alsoSodium metaarsenite (NaAsO ₂ ) is one of the immune modulators because it dampens the production of certain messenger substances of the immune system (the cytokines), which can trigger intensive immune reactions. The South Korean company Komipharm has developed a drug for tumor-associated pain (project name PAX-1-001). It has now requested clinical trials to test the drug on Covid-19 patients .

Chinese researchers want to test a Roche drug with the active ingredient pirfenidone that has already been approved for patients with idiopathic pulmonary fibrosis. This medication counteracts the scarring of damaged lung tissue .

The Canadian company Algernon Pharmaceuticals plans to test its drug NP-120 with the active ingredient Ifenprodil for suitability. Ifenprodil is now patent-free in Japan and South Korea against neurological diseases. Algernon has been developing a drug against idiopathic pulmonary fibrosis with this active ingredient for some time.

The Viennese biotech company Apeptico wants its active ingredient Solnatideagainst current lung failure (ARSD) for suitability for Covid-19 patients with severe lung damage. It is intended to restore the tightness of membranes in the lung tissue.

The US company Bioxytran is also currently developing a drug with the active ingredient BXT-25 for patients with ARDS. It is expected to improve oxygen uptake in a damaged lung and help patients who can only be adequately supplied with oxygen via an artificial lung. The company also wants to try out its drug with a partner for seriously ill patients with Covid-19.

A growing number of projects are also trying to develop new drugs against Covid-19. There are three types of projects:

Here are some examples of projects from these areas:

Antibodies for passive immunization

One of the old methods of medicine to combat pathogens is to inject patients with antibodies from the blood serum of people (or animals) who have already survived the disease. The diphtheria antiserum by Emil von Behring from 1891 already had this effect, even if nobody knew anything about antibodies at the time. Another example is the syringes for passive immunization (“passive vaccination”) of people who may have been infected with tetanus because they have not been vaccinated against it. Recently, several antibody-containing Ebola medications have also been shown to be highly effective in studies.

Most of the projects for the development of new drugs against SARS-CoV-2 therefore focus on the blood serum of former Covid 19 patients, the so-called “convalescent serum”. The hope is that some of the antibodies it contains will be able to render SARS-CoV-2 unable to reproduce in the body.

This rationale is followed by a project by the Takeda company : Within the framework of the TAK-888 project, the aim is to obtain an antibody mixture from the blood plasma of people who have recovered from Covid-19 (or later from people who have been vaccinated against Covid-19). Such a mixture is called anti-SARS-CoV-2 polyclonal hyperimmune globulin (H-IG) ; the treatment with “passive immunization”.

Other companies and research groups in the world also follow this basic idea, but go one step further in terms of biotechnology: They also start with convalescent serum, but pick out the most suitable antibodies and then “copy” them with biotechnical means to produce a drug. One of these projects is being pursued by the Swedish Karolinska Institute . Another company, AbCellera and Lilly , has announced that within months the most effective of more than 500 antibodies obtained will be used to develop a drug that can be tested on patients. Also AstraZeneca (UK) , Celltrion (South Korea) and (according to media reports) Boehringer Ingelheim and the German Center for Infection Research (DZIF) are working to develop a drug in this way.

A consortium of research institutions in the USA goes one step further as part of the DARPA Pandemic Preparedness Platform. In the end, their drug should not contain copies of the most effective antibodies from convalescent plasma itself, but instead the genes for it – in the form of mRNA. Anyone who gets injected with this mRNA produces the antibodies themselves in his body for a while and is protected. The advantage of this procedure: It is probably possible to produce large quantities of drug doses faster than if you had to produce the antibodies biotechnologically. The disadvantage: So far, there is no other drug that works like this. The project is led, among others, by James Crowe, Vanderbilt University, Tennessee, who received the Future Insight Prize from the German company Merck in 2019 for his pioneering work in this field .

Several projects for new drugs vary the “convalescent serum” approach. Thus Vir Biotechnology previously antibodies from the blood serum of patients recovered which have recovered from SARS infection of 2003. The company is now examining with the US institutes NIH and NIAID whether they are also able to stop the multiplication of SARS-CoV-2. Vir Biotechnology is cooperating with the US company Biogen and the Chinese company WuXi Biologics for the biotechnological production of “copies” of these antibodies .

Scientist from the University of Utrecht (Netherlands) also tested antibodies from the blood serum of SARS convalescents from 2003. They found an antibody that can inhibit the proliferation of SARS-CoV-2 in culture. It should now be tested further. Regeneron is  running a similar project : The company is testing a drug with the monoclonal   ntibodies REGN3048 and REGN3051 in a phase I study with volunteers. These antibodies were developed to treat the MERS coronavirus, which is related to SARS-CoV-2. Existing projects in early stages for antiviral drugs A research team at the University of Lübeck is pursuing another path

For years it has been developing so-called alpha-ketoamides as antiviral agents against corona and enteroviruses (which are responsible for mouth rot among other things). In laboratory tests, new experimental substances inhibit the multiplication of these viruses. One of them, called “13b”, is optimized against corona viruses. It is now to be tested in cell cultures and with animals and, in the event of positive results, to be tested in studies with humans together with a pharmaceutical company.

New drug development projects

A number of large pharmaceutical companies have teamed up to develop new therapeutic drugs (such as vaccines and diagnostics) against Covid-19. In a first step, they will make their own collections of molecules available, for which some data on safety and mode of action are already available. These are to be tested by the “Covid-19 Therapeutics Accelerator” facility, which was launched by the Gates Foundation, Wellcome and Mastercard. For molecules classified as promising, tests with animals should also begin within two months. The group of companies includes BD, bioMérieux, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Eli Lilly, Gilead, GSK, Janssen (Johnson & Johnson), MSD, Merck, Novartis, Pfizer and Sanofi.

The companies are pursuing a different planVir Pharmaceuticals and Alnylam Pharmaceuticals . You have announced that you will develop so-called siRNA agents that block the virus by causing some of its genes to stop working. The approach is called gene silencing.