Therapeutic medicines against the coronavirus infection Covid-19

Not only vaccines are being developed against the coronavirus SARS-CoV-2 pandemic, but also existing medicines are being tested and new ones invented.

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Even though the development of vaccines against the new coronavirus is proceeding at an unprecedented speed, hopes are pinned on finding medicines to treat those already infected. The focus is particularly on medicines that have already been approved for the treatment of another disease or are at least in development. This is because they can be converted more quickly than a basic new development. Pharmaceutical researchers speak of "repurposing" the medicines. In Covid-19, these medicines usually belong to one of the following four groups:

In addition, there are also projects for repurposing medicines from other medicine groups and projects for new medicine development, see below. There you will also find more detailed information about some projects for repurposing.

It is not simply a question of whether the medicines are effective against Covid-19 or not, but more precisely at what stage of the disease are beneficial. medicines that are useful at an early stage (mild infection without breathing problems) might be ineffective or even harmful in patients with severe pneumonia - or vice versa. For example, the attenuating immunomodulators are probably only appropriate in patients with severe pneumonia, whereas in mild disease they would adversely weaken the virus defence. Some medicines may not be therapeutically applicable at all, but they do protect against infection. All this should also be taken into account when news of a medicine failure spreads.

Which medicines can really be usefully used against Covid-19 can only be clarified with clinical studies with volunteers. However, the first of these trials - in China and elsewhere - usually involved only a few dozen patients, and often there was no direct comparison with patients who received only basic medical treatment without additional medication. Such trials could be set up quickly, but their results were ambiguous.

The European Medicines Agency EMA therefore appealed to companies and research institutions at an early stage to organise multinational, multi-arm, controlled and randomised patient studies for their medicines, if possible:

Such studies, according to the EMA, are more likely to lead to clear results about the suitability of medicines compared to small studies; results that would then also allow the approval of medicines against Covid-19. They can be designed in such a way that "study arms" (i.e. types of treatment within the study) can be terminated or new ones added while on the road.

In mid-August 2020, the five-year IMI project CARE (Corona Accelerated R&D in Europe) was launched. It comprises 37 participants from the EU, China, Great Britain, Switzerland and the USA. Under the leadership of Boehringer Ingelheim, this consortium is researching and developing agents against Covid-19, namely antibodies that neutralise the virus and small molecules that are designed to act directly against the virus. It is also investigating the value of redesignating existing medicines (approved or under development for other diseases) against Covid-19. This IMI projecthas a budget of 77.7 million euros (EU funds as well as financial and in-kind contributions from pharmaceutical companies).

The US Milken Institute maintains an overview of all ongoing projects for medicines and vaccines against COVID-19. Further information on some of them can be found here; the vfa list does not claim to be complete.

Remdesivir was originally developed by Gilead Sciences to treat Ebola infections (against which it has not been proven effective), but has also shown efficacy against MERS viruses in the laboratory. In several clinical trials, the medicine has been able to reduce the duration of disease by several days in subjects at certain stages of the disease. As a result, Covid-19 received emergency use approval in the United States, approval in Japan and, in July, conditional approval in the EU. However, in a multinational study conducted by the WHO (the SOLIDARITY trial, see below), preliminary results indicate that no such effect was observed. The understanding of this discrepancy is currently being investigated and may indicate that the stages of disease at which the medicine is effective need to be further defined.
Demand for the medicine is high worldwide and the EU has also ordered larger quantities. However, the manufacturer has licensed several other companies to produce and distribute its own Remdesivir medicines for certain regions of the world.

Favipiravir (= favilavir) from FUJIFILM Toyama Chemical initially only had approval for flu therapy (in Japan and China) and is only intended for second-line therapy in Japan (when other flu medications are not or insufficiently effective). After corresponding studies, a medicine based on it from the Russian company Khimrar was approved in Russia for Covid-19 therapy. Fujifilm Toyama Chemical is now also planning to apply for an extension of the approval in Japan after positive results of the study. In the study with patients who did not suffer from severe pneumonia, the medicine reduced the time until the symptoms subside or the viral load drops below the detection limit by an average of several days. Pregnant and breastfeeding women are not allowed to take the medicine.

ATR-002, a kinase inhibitor (more precisely: a MEK inhibitor) from Atriva Therapeutics in Tübingen, is also being developed against influenza. The company has been able to show in laboratory experiments that the substance also inhibits the proliferation of SARS-CoV-2. In addition, it has an immunomodulatory effect. A clinical phase II study with inpatients treated with medium-heavy Covid-19 is now scheduled to begin in the last quarter of 2020.

APEIRON Biologics (Vienna) is testing the medicine APN01 in a clinical study with patients (Phase II) in Germany, Austria and Denmark. It originated from SARS research and has already been tested in patients with other lung diseases. It blocks a molecule on the viruses that they need to enter lung cells and also helps to prevent lung damage caused by inflammatory reactions. So far, results are only available from one case study.

However, an older HIV medicine with the active substance combination Lopinavir / Ritonavir has not proved effective against COVID-19. It had been tested in the SOLIDARITY trial (see below).

Some medicines do not fight viruses directly, but are intended to strengthen the body's own virus defence. The German company AiCuris is developing one of them: Its stimulating immunomodulator contains parapox viruses and was originally developed for the treatment of hepatitis B; it has already completed a Phase I study with patients for this purpose. It is now to be tested with some asymptomatic corona patients in anticipation of an enhanced immune response.

A group of other immune modulators has already been tested in various studies: interferons. They are genetically engineered variants of the body's own messenger substances. Biochemists divide them into several subgroups, of which the alpha and beta interferons are important against SARS-CoV-2:

Immune reactions are generally desirable in infected persons; they must not be so excessive that they cause more damage to the lungs than they help. Such an excessive immune reaction is called "cytokine storm" because large amounts of messenger substances called cytokines are released. Several projects on Covid-19 therapy therefore focus on attenuating such an immune reaction with a suitable immunomodulator.

An effective weakening of immune reactions and thus a reduction in mortality in severely ill patients was achieved in a study in the UK with dexamethasone, a cortisone derivative with a known anti-inflammatory effect: Dexamethasone was able to reduce the risk of death by one fifth and one third in patients who require oxygen or even artificial respiration. In September 2020, the EMA recommended that the approval be extended accordingly. Studies have also shown improvements in therapy with the related cortisone derivatives hydrocortisone and methylprednisolone.

The Jena-based company InflaRx is currently developing the medicineIFX-1 for the treatment of various inflammatory diseases; several studies with patients have already been conducted. InflaRx is now investigating in a Phase II/III study in the Netherlands whether it can also help patients suffering from severe Covid-19. The active ingredient is a monoclonal antibody. The company has reported positive results from the phase II part of the study program. IFX-1 is a specific inhibitor of C5a, a component of the complement system, which is part of the human immune system.

The Alexion company and the University of Cambridge (UK) are testing another C5a inhibitor in Covid-19 patients with severe pneumonia: ravulizumab. The medicine is approved for the treatment of rare paroxysmal nocturnal haemoglobinuria (PNH).

The C3 inhibitor AMY-101 intervenes in the complement system at a similar point. Amyndas Pharmaceuticals is also testing this compound in covid-19 patients with severe pneumonia.

Positive study results were reported from the treatment of patients with pneumonia with Covid-19 treated with Roche 's interleukin-6 antagonist tocilizumab: 44% fewer patients became ventilators or died. Further studies are ongoing.

A substance that is directly directed against interleukin-6 is also being tested in a study: Sìltuximab from EUSA Pharma. The medicine is approved for the treatment of multicentre Castleman's disease, a form of lymph node tumours.

Novartis is conducting a clinical trial with its immunomodulator Canakinumab (an interleukin-1-beta blocker) in many countries, including Germany. Canakinumab is approved for the treatment of several autoimmune diseases - including various periodic fever syndromes, Still's syndrome, systemic juvenile idiopathic arthritis - and gouty arthritis.

The company Swedish Orphan Biovitrum is testing the combination of the immune modulators Anakinra and Emapalumab in a clinical study in the USA and Italy. The trial was initiated by observations made by Italian doctors. The interleukin-1 receptor antagonist Anakinra is approved (including in the EU) for the treatment of rheumatoid arthritis and the inflammatory diseases CAPSCryopyrin-associated(1) and Still's syndrome; the interferon-gamma inhibitor Emapalumab has been approved in the USA for the inflammatory disease haemophagocytic lymphohistiocytosis.

The TNF-alpha inhibitor Adalimumab, which is approved for the treatment of rheumatoid arthritis, among other things, is also being tested with patients with the aim of preventing the disease from progressing to a severe or critical stage. This ties in with the observation that patients under long-term therapy with adalimumab due to an autoimmune disease show milder disease progression when infected with SARS-CoV-2. In the British study AVID-CC is used adalimumab from Sandoz.

Infliximab will be tested as another TNF-alpha inhibitor as part of the ACTIV-1 trial of the US National Institutes of Health (NIH). The company Janssen is providing the medicine for this trial.

GSK is testing its immunomodulator otilimab in a study with Covid-19 patients. This GM-CSF inhibitor was originally developed by Morphosys and then tested in rheumatoid arthritis, but has yet to be approved.

Abatacept from Bristol Myers Squibb inhibits the full activation of T cells and is already approved for use in rheumatoid and psoriatic arthritis. The medicine will be tested in Covid-19 patients as part of the US National Institutes of Health's ACTIV-1 trial.

The active substance Leronlimab from CytoDyn is a CCR5 antagonist (i.e. it blocks a receptor on the surface of certain immune cells). In a study (phase II), the health situation of mild to moderate COVID-19 patients could be improved. The manufacturer then initiated a Phase III study with severely ill patients and applied for emergency use approval from the FDA. Leronlimab has long been developed against HIV and tripel-negative breast cancer, for which it is already being tested in trials. However, its effectiveness against HIV is not based on a dampening immune modulation, but on the fact that it denies the AIDS virus access to the immune cells that would otherwise infect it.

Cenicriviroc also targets CCR5, but additionally the receptor CCR2; a substance that is currently being developed by AbbVie for the treatment of other diseases, but which has not yet been approved. The company is now making it available for testing on Covid-19 patients as part of the ACTIV-1 trial of the National Institutes of Health in the USA.

The German company Merck will test M5049, an immunomodulator of the TLR7/8 inhibitor type, in a study with hospitalized Covid-19 patients in the USA and Brazil. The company has previously tested the product against various immune disorders. To date, there is no approved medicine in this medicine class.

Fosamatinib from Rigel Pharmaceuticals (in Germany: Grifols) is also being tested in the USA. This SYK inhibitor can attenuate certain immune reactions, including the ejection of net-like defence structures - the NETs - by certain white blood cells. It is currently approved for the treatment of chronic immune thrombocytopenia. Misdirected immune reactions with the formation of NETs contribute significantly to the danger of the severe stage of Covid-19 disease, as was discovered at the University of Nuremberg-Erlangen, among others.

The US/German company Immunic Therapeutics is testing its immunomodulator IMU-838 in two Phase II studies with Covid-19 patients treated in hospital (once as monotherapy, once in combination with oseltamivir). As a selective oral inhibitor of the enzyme DHODH (dihydroxyorotate dehydrogenase), the medicine inhibits metabolism in activated T and B cells, while it hardly interferes with other immune cells. The medicine was previously in development as a treatment for relapsing forms of multiple sclerosis and other autoimmune diseases.

Sanofi and Denali Therapeutics are testing the immunomodulator DNL758 in a Phase Ib study with Covid-19 patients. This inhibitor of RIPK1, a molecule from an immune-relevant signaling pathway, has been tested against various inflammatory diseases since 2018.

The companies Eli Lilly and Incyte are testing their Januskinas inhibitor baricitinib in hospitalized Covid-19 patients. So far, it has only been approved for use in rheumatoid arthritis. In one study, the combination of remesivir and baricitinib further reduced recovery time in hospitalized covid-19 patients than remesivir alone.

Similarly, Novartis is also testing its janus kinase inhibitor ruxolitinib in studies with this patient group - with the participation of German medical institutions. Ruxolitinib is approved for the treatment of certain cancers and is also being tested for graft-versus-host disease, another form of excessive immune response.

Opaganib from RedHill (Israel) is also under development as a cancer medicine. This sphingosine kinase 2 (SK2) inhibitor has shown anti-inflammatory as well as antiviral effects in pre-clinical studies. This could be useful in the treatment of covid-19-induced pneumonia. The medicine has been made available in Italy through a hardship program and will be tested for its suitability.

Acalabrutinib, a brutontyrosine kinase inhibitor from AstraZeneca, has also been developed for cancer therapy and has been approved for the treatment of certain leukemias in the USA. The company is now testing it on Covid-19 to suppress excessive immune reactions.

Zanubrutinib is also a brutontyrosine kinase inhibitor, originally developed against a type of cancer (mantle cell lymphoma). It is now being tested by the Chinese company BeiGene in patients with severe covid-19 infection.

In about a dozen clinical trials, colchicine has been and is being tested as a remedy for excessive immune reactions; one of these trials is being led by the Montreal Heart Institute, for example. The medicine is approved for gout (and in some countries also for pericarditis). In a small study in Greece, the medicine has accelerated recovery in severely ill Covid-19 patients.

The Israeli company Enlivex uses immune cells (macrophages and dendritic cells) to dim the immune system in the case of a cytokine storm. Its cell therapy medicine Allocetra was already being developed for the treatment of sepsis before the pandemic. After successful testing with a small number of patients, a phase II study is planned.

EDP1815 from Evelo Biosciences represents a completely new type of immunomodulator. It contains a naturally occurring human intestinal bacterium isolated from the small intestine of a donor. EDP1815's messenger substances can attenuate the production of certain cytokines from the intestine without at the same time reducing the production of type 1 interferons, which strengthen the virus' defence. The medicine is being developed against autoimmune diseases such as psoriasis and atopic dermatitis, but is now also being tested in the UK in tactic-E against Covid-19 (see below).

The Canadian company Algernon Pharmaceuticals is testing its medicine NP-120 (Ifenprodil) for its suitability in critically ill Covid-19 patients who require oxygenation. Ifenprodil is now off-patent in Japan and South Korea for the treatment of neurological diseases. Algernon has been developing a medicine against idiopathic pulmonary fibrosis with this active ingredient for some time.

The Viennese biotech company Apeptico intends to test its active substance solnatide for acute lung failure (ARSD) for its suitability for Covid-19 patients with severe lung damage. It is hoped that it will be able to restore the tightness of membranes in lung tissue.

The US company Bioxytran is currently developing a medicine containing the active ingredient BXT-25 for patients with ARDS. It is expected to improve the oxygen uptake in a damaged lung and help patients who otherwise can only be supplied with sufficient oxygen via an artificial lung. The company would like to test its medicine with a partner for critically ill patients with Covid-19.

The peptide active ingredient FX06 from the Viennese company MChE/F4-Pharma is said to be effective against leaks in the blood vessels of the lung and in other organs caused by Covid-19. A clinical study is in preparation. The medicine was developed for the treatment of other vascular diseases, for which it has already been tested in clinical trials.

In the USA, Bellerophon Therapeutics ' ventilator has been approved for use in the treatment of respiratory distress in Covid-19 patients by adding some nitric oxide to the breath. This gas, which the body itself produces as a messenger substance, can dilate the blood vessels in the lungs through muscle relaxation. This procedure already showed positive effects during the SARS epidemic.

A severe Covid 19 infection not only affects the lungs, but can also affect the heart, kidneys and other organs. In addition, post mortem blood clots have been found in some Covid-19 patients. A number of approved cardiovascular medicines are being tested against such complications of the disease. Certain cardiovascular medicines may also be suitable for protecting the lungs.

Against the risk of thrombosis with Covid-19, anticoagulant low-molecular-weight heparins are used and especially the low-molecular-weight heparin enoxaparin is being tested in a series of studies. It was originally developed by Sanofi and is approved, among other things, for the prophylaxis of venous thromboembolic disease in patients with respiratory insufficiency or severe infection and limited mobility, but also for the treatment of certain forms of acute coronary syndrome. Tinzaparin, which is structurally similar to heparin, and unfractionated heparin are also being tested in trials, and preparations are underway for bivalirudin, which is also an anticoagulant. A previously unapproved anticoagulant, the heparin derivative Dociparstat, is also being tested by Chimerix in covid-19 patients. According to a study by the Hasso Plattner Institute for Digital Health and the Icahn School of Medicine in New York, treatment with anticoagulants does indeed improve the survival chances of severely ill Covid-19 patients.

Anticoagulants not structurally related to heparin are also being tested. These include edoxaban, a direct oral factor Xa inhibitor that is being considered as an additive to low-molecular-weight heparin. Rivaroxaban from the same class of medicines manufactured by BAYER, which is approved for the treatment of acute coronary syndrome (ACS), is also being tested to see whether it can prevent cardiac complications in covid-19 patients.

Various medical institutions are testing whether antihypertensive medicines from the Sartane class are helpful in overcoming pulmonary and cardiac complications of Covid-19. These include telmisartan, valsartan, losartan and candesartan. However, an Irish study is also investigating whether this class of antihypertensives (as well as the class of ACE inhibitors) may even pose risks to covid-19 patients.

An evaluation of medical records in the USA by a health insurance company indicates that older Covid-19 patients who took medicines from the class of ACE inhibitors as long-term therapy independently of this disease had to be treated less frequently in hospital. Therefore, a clinical trial is now being planned in which previously undiseased patients (who have not previously used an ACE inhibitor) will either take a low-dose ACE inhibitor or placebo. The study will investigate whether the different medication has an effect on the course of the disease in participants who will later become ill with Covid-19. In another study, the ACE inhibitor ramipril is being tested specifically in hospitalised covid-19 patients. To date, ACE inhibitors have been approved for the reduction of high blood pressure and the prevention of atherosclerosis.

AstraZeneca is investigating whether dapagliflozine can prevent the occurrence of severe complications such as organ failure in Covid-19 patients. The medicine (an SGLT inhibitor) is approved for the treatment of type 2 diabetes, but in trials it has also been shown to prevent the development of heart failure.

Ambrisentan (an endothelin receptor antagonist) from GSK is approved for the treatment of pulmonary arterial hypertension; it dilates the pulmonary vessels, thereby improving, among other things, oxygen uptake into the blood. The medicine will now be tested in the TACTIC-E trial (see above) in combination with dapagliflozine against Covid-19.

CSL Behring, in turn, is currently developing garadacimab (a factor XIIa inhibitor) as a medicine for hereditary angioedema. It is now also testing this medicine for its suitability for treating lung failure in severe covid-19 disease.

Some medicines for which repurposing is suggested cannot be classified into any of the above-mentioned categories. They are being tested because they are nevertheless expected to have an antiviral or immune-suppressing effect. Some medicines could also be classified into several of the above categories at the same time with equal justification.

One of these medicines contains the active ingredient aviptadil. The Swiss company Relief Therapeutics has been developing the medicine for several years for the treatment of acute respiratory distress syndrome (ARDS) and has already reached phase III. Among other things, the active ingredient has an anti-inflammatory effect and presumably protects a certain type of lung cell (alveolar type 2 cells), which is particularly important for maintaining lung function, against virus attack. It is now being tested in studies by Relief Therapeutics and NeuroRx (USA) in COVID-19 patients with acute lung failure under intensive care. Interim results suggest that the medicine may significantly reduce the risk of these patients not surviving the disease.

The Heidelberg-based company Apogenix is testing its medicine with Asunercept, a CD95L inhibitor, in a Phase II study in Russia and Spain in hospitalised Covid-19 patients. The medicine is actually in development for the treatment of various cancers in which it supports the immune system in fighting cancer; it has not yet received regulatory approval. In COVID-19 patients, it counteracts the death of lung epithelial cells, among other things.

Medicines with camostat or nafamostat have been approved in Japan for pancreatitis. However, researchers of a German consortium of research institutions led by the German Primate Centre in Göttingen have discovered that, in the laboratory, it inhibits an enzyme of lung cells (transmembrane serine protease 2) that is essential for the penetration of the SARS CoV-2 viruses. In the meantime, several clinical trials involving Covid-19 patients are being carried out worldwide with both medicines . The German Federal Ministry of Education and Research (BMBF) is funding a project in which nafamostat, which has a 50-fold higher antiviral effect, is to be tested in intravenous administration.

The active ingredient Brilacidin from Innovation Pharmaceuticals is currently being tested for the treatment of inflammatory bowel diseases and inflammation of the oral mucosa. However, it is also expected to be able to attack the outer envelope of the SARS-CoV-2 virus. This is currently being tested in cell cultures.

After encouraging laboratory tests, the Spanish company PharmaMar is testing its medicines with plitidepsin in a study against Covid-19, a medicine that is actually approved in Australia and Southeast Asia for the treatment of multiple myeloma (a form of bone marrow cancer), must significantly inhibit virus proliferation because it blocks the protein EF1A required for this in the affected cells.

Already approved elsewhere, namely against mites and parasitic nematodes (river blindness), are medicines containing ivermectin, an active ingredient from MSD's research. It is being tested in individual healing trials and studies to see whether it can help Covid-19 patients. A retrospective evaluation of the treatment courses of covid-19 patients with and without ivermectin (ICON Trial) at Florida International University suggests that ivermectin could reduce the risk of dying from covid-19. However, the authors of the preliminary publication, which has not yet been reviewed, point out the need for prospective studies to confirm or invalidate this. In Bangladesh, the combination ivermectin/doxycycline was tested in a clinical trial, and here too the results suggest that the combination is effective. Ivermectin is also being tested by the French company MedinCell as a possible preventive measure.

It is known from the tapeworm medicine niclosamide that it enhances the cells' own "waste processing" (autophagy). This is because this process is slowed down in cells infected with SARS-CoV-2. In laboratory experiments at the Charité hospital in Berlin, the agent was able to reduce virus replication - as was the case with the active ingredients spermidine (a substance produced naturally in the body) and MK-2206 (an active ingredient against breast cancer). There are no study results yet.

Therapy with the gastric acid-reducing medicine famotidine (an H2-blocker), which is approved for the treatment of gastric acid-related diseases, is also being tested. However, in Covid-19 patients, the dose of famotidine is nine times higher than the approved dose. This is due to evidence from the evaluation of Chinese medical records, which suggests that patients taking famotidine may have a lower risk of dying from covid-19.

At times, several antimalarial medicines have received great attention, including those containing the active ingredients chloroquine and hydroxychloroquine. After positive laboratory tests against SARS-CoV-2, they were first tested in studies in China and later in other countries. However, the results of several studies indicated that the medicines do not have a positive benefit-risk balance, at least not in patients at certain stages of the disease. For this reason, the study arm with chlorine/hydroxychloroquine was stopped in the WHO SOLIDARITY study and an interim emergency approval for hydroxychloroquine in the USA was revoked.

In Africa in particular, the use of another antimalarial agent is being promoted: artemisinin. It is otherwise part of antimalarial combination medications taken as tablets. It is used against Covid-19 drink. At the Max Planck Institute Potsdam and other research institutions, the effectiveness of the active ingredient against SARS-CoV-2 is being systematically researched in laboratory experiments.

A growing number of projects are also trying to develop new medicines against Covid-19. Here one can distinguish three types of projects:

Here are some examples of projects from these areas:

At the beginning of October, Regeneron and Eli Lilly applied for an Emergency Use Authorization in the USA for their respective antibody-based SARS-CoV-2 medicines after seeing positive interim results from initial clinical trials.

The medicines developed and produced using modern biotechnological methods are ultimately based on an already old approach to fighting pathogens. For decades, patients suffering from certain infectious diseases or poisoning have been injected or infused with antibodies from the blood serum of human donors (or animals) who have already survived the disease in question. Emil von Behring's diphtheria antiserum from 1891 already had this effect, even though no one knew more about the antibodies contained at that time. Another example is the syringes used for the passive immunisation of people who might have been infected with tetanus through an injury. Recently, several Ebola medicines with such antibodies have also shown a high efficacy in studies.

Most projects for the development of new medicines against SARS-CoV-2 therefore also focus on the blood fluid of former Covid-19 patients with their antibodies, the so-called "convalescent serum" or "convalescent plasma" (serum is plasma from which certain coagulation substances have been removed). Groups of projects can be distinguished according to the type of procedure:

1. Direct transfer of antibodies from convalescents

In the simplest case, patients receive direct infusions with a blood plasma donation (checked for harmlessness) from former Covid-19 patients or with antibodies freshly extracted from them. In Germany, this is already practiced in some hospitals as an attempt to cure; and in many places Genese are invited to donate plasma (for example, by the German Red Cross). In parallel, this therapy is being tested in a study with volunteers. Plasma is also collected in other countries (e.g. Austria) and this therapy is practiced, e.g. in the USA. Convincing therapeutic successes have not been published so far, however.

A variant of this approach is the project of the Indian Council of Medical Research (ICMR) and with the Indian company Biological E Ltd, in which the plasma of horses injected with previously inactivated SARS-CoV-2 is processed. The plasma will be tested in clinical trials as a therapeutic and prophylactic agent. The project is reminiscent of the pioneers of this form of therapy, as the first diphtheria antiserum was already produced mainly with horses.

2. Antibody preparations from convalescent plasma

Instead, some companies want to extract the antibodies from such plasma and use them to produce a medicine for infusions, called polyclonal anti-SARS-CoV-2 hyperimmunoglobulin (H-IG). Such a medicine has the advantage over convalescent plasma that its efficacy does not vary from application to application, the antibodies can be concentrated and the medicine can be easily shipped.

For such a medicine, several companies that already produce other medicines from plasma have joined forces to form the CoVIg-19 Plasma Alliance: Takeda (Japan), Biotest (Germany), Bio Products Laboratory (UK), CSL Behring (Australia), LFB (France), Octapharma (Switzerland), ADMA Biologics (USA), BioPharma Plasma (Ukraine), GC Pharma (South Korea), and Sanquin (Netherlands). The alliance will begin clinical trials of its medicine in October, together with the National Institute of Allergy and Infectious Diseases (NIAID) of the USA.

The company Grifols (Spain) is also developing an H-IG preparation. It plans to produce this in the USA. A clinical study is planned.

The Polish company Biomed Lublin is also developing such a medicine and is preparing an initial study with it.

3. Preparations containing "copied" antibodies from convalescent plasma

Other companies and research groups in the world follow the same basic idea, but go one step further: they start from convalescent serum, but pick out the most suitable antibodies and then "copy" them with biotechnological means, in order to produce them in large quantities with cell cultures and use them to make a medicine.

The most advanced are two such projects, which are being driven by the US company Lilly. For the one involving the antibody LY-CoV555, Lilly is cooperating with AbCellera (Canada). Lilly and Shanghai Junshi Biosicences (China) are jointly developing the antibody JS016. Both antibodies are already being tested with Covid-19 patients in inpatient treatment. Lilly also has a third antibody in preclinical testing. Eli Lilly is cooperating with the US company Amgen for the large-scale production of the medicine.

AstraZeneca (UK) has also developed a medicine with two genetically engineered antibodies derived from antibodies found in convalescent plasma by the US Vanderbilt University. They have been modified so that they remain in the blood longer than ordinary antibodies. The medicine is called AZD7442. Following positive interim results, it will now be tested in phase III trials to determine whether it is suitable for the therapy and prevention of Covid-19.

Celltrion (South Korea) has also developed such a medicine: CT-P59. It is currently being tested to determine whether it is suitable for therapy (phase II/III) and post-exposure prophylaxis (phase III).

Regeneron is also involved in a similar project: The company is testing the cocktail REGN-COV2 with two monoclonal antibodies in a Phase II/III study with patients and a Phase III study in which volunteers receive it for prevention. This cocktail is based on the analysis of antibodies from transgenic mice (see below) and from former Covid-19 patients. Regeneron has received support from the US government for large-scale production. Preliminary results are available.

Another company active in this field is BeiGene (China). It is testing neutralizing antibodies under license, which were copied from the company Singlomics Biopharmaceuticals convalescent patients and are produced using genetic engineering.

In Germany, the CORAT consortium is using this approach, using the laboratory method "phage display" to identify suitable human antibodies. Members of the consortium include the Braunschweig-based biotech company Yumab, the Helmholtz Centre for Infection Research (Braunschweig), the Technical University of Braunschweig and the University of Tübingen. Yumab has reported positive interim results.

Also in Germany, the Berlin Charité, the German Centre for Neurodegenerative Diseases (DZNE) and the biotech company Miltenyi Biotec are working on such a medicine. Positive results from experiments with animals have been obtained.

Another antibody derived from convalescent plasma is being developed by Memo Therapeutics and Northway Biotechpharma (Switzerland and Lithuania). Clinical trials have not yet started.

A three-antibody cocktail of this type is also being developed at the University of Tel Aviv (Israel). Positive laboratory results have been obtained so far.

The Swedish Karolinska Institute is pursuing another project of this kind.

4. Medicines with genes for antibodies from convalescent plasma

A consortium of research institutes in the USA within the framework of the DARPA Pandemic Preparedness Platform as well as a cooperation project of the companies Ethris and Neurimmune (Planegg near Munich and Switzerland) go one step further. Their respective medicines will not ultimately contain copies of the most effective antibodies from convalescent plasma itself, but rather the genes for them - in the form of mRNA. Those who are injected with this mRNA produce the antibodies in their own bodies for a while and are protected. The advantage of this procedure is that it is probably possible to produce large quantities of medicine doses more quickly than if the antibodies had to be produced biotechnologically. The disadvantage: So far, there is no other medicine that works in this way. The project of the U.S. consortium is led by James Crowe, Vanderbilt University, Tennessee, among others, who received the Future Insight Prize of the German company Merck in 2019 for his pioneering work in this field. The special feature of the medicine planned by Ethris and Neurimmune is that the mRNA is to be inhaled so that the antibodies are formed close to the site of attack of the viruses.

5. Preparations containing copied antibodies from SARS or MERS convalescent plasma

Several projects for new medicines extend the "convalescent plasma" approach to related diseases. For example, Vir Biotechnology has analyzed antibodies from the blood serum of individuals, which it removed in 2003 after surviving a SARS infection. One antibody proved to be particularly effective against SARS CoV-2 viruses; this led to further developed antibody variants, one of which, VIR-7831, is now being tested in clinical trials with patients at risk of hospitalization. Phase III trials are scheduled to begin in October. Vir Biotechnology is collaborating with GSK for clinical trials and with Biogen (USA) and WuXi Biologics (China) for antibody production.

Imperial College London is also working with partners on an antibody therapy based on antibodies from the blood serum of former SARS patients.

Scientists at the University of Utrecht (Netherlands) have also studied antibodies against SARS, but these were produced by transgenic mice. They found an antibody that can inhibit the reproduction of SARS-CoV-2 in culture. In this antibody, rodent-typical parts were then replaced by human parts. This antibody, now called "human 47D11", is now being further developed by the University of Utrecht together with the companies AbbVie and Harbour BioMed and the Erasmus Medical Center. Before it can be tested with humans, however, several laboratory tests must be carried out.

6. Preparations containing antibodies invented in the laboratory

Another variant of the same basic principle is not to look at antibodies from convalescent animals at all, but to obtain suitable antibodies with laboratory animals or by synthetic means. These can then be produced biotechnologically, processed into a medicine and infused into patients.

For example, researchers at the University of Erlangen-Nuremberg in cooperation with the Fraunhofer Institute for Cell Therapy and Immunology (Leipzig), the German Primate Center (Göttingen) and the company Trianni (Erlangen) are using genetically modified mice as a source of suitable antibodies.

An antibody obtained with the aid of a llama in turn produces parts of an artificial anti-SARS-CoV-2 antibody produced by a consortium of the University of Ghent, the Flemish Institute for Biotechnology, the University of Austin (Texas) and the German Primate Centre in Göttingen.

The biotech company Formycon, based in Martinsried near Munich, uses computer-assisted structural protein design instead of animals to invent suitable antibodies from which it then selects the most suitable ones using different test methods.

Boehringer Ingelheim in turn uses several techniques in parallel to obtain suitable antibodies, including the use of transgenic mice and computer-assisted antibody design.

The Antibody Society provides a tabular overview of all ongoing projects for SARS-CoV-2 neutralizing antibodies.

A research team at the University of Lübeck is pursuing a different approach. It has been developing so-called alpha-ketoamides as antiviral agents against corona and enteroviruses (which are responsible for oral thrush, among other things) for years. In laboratory tests, new experimental agents inhibit the reproduction 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 case of positive results, will be tested in human trials in cooperation with a pharmaceutical company.

A number of large pharmaceutical companies have joined forces to develop new therapeutic medicines (as well as vaccines and diagnostics) against Covid-19. As a first step, they will make available their proprietary collections of molecules for which some data on safety and mode of action are already available. These will be tested by the Covid-19 Therapeutics Accelerator, a facility established by the Gates Foundation, the Wellcome Trust and Mastercard. Molecules that are considered promising will be tested on animals within two months. The company group includes BD, bioMérieux, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Eli Lilly, Gilead, GSK, Janssen (Johnson & Johnson), MSD, Merck, Novartis, Pfizer and Sanofi.

Further progress has already been made by Ridgeback Biotherapeutics LP and MSD (both USA), who have tested the efficacy of the active substance EIDD-2801 against corona viruses in the laboratory and tested the compatibility with volunteers in a Phase I study. Studies with patients are to follow. MSD is also working with the Institute for Systems Biology (USA) to investigate the molecular mechanisms of SARS-CoV-2 infection.

A different plan is being pursued by the companies that want to combat SARS-CoV-2 using gene silencing. This approach prevents certain genes from being used to replicate the virus. Vir Pharmaceuticals and Alnylam Pharmaceuticals (both USA) hope to achieve this with the help of so-called siRNA agents. The South Korean company OliX Pharmaceuticals is also working on a substance of this kind. The German biotech company Secarna and the Chinese Guangzhou's Sun Yatsen University want to achieve gene silencing with the help of an antisense oligonucleotide - a molecule from a related class of medicines.

In order to gain as much knowledge as possible about treatment options with a limited number of patients, it is advisable to test several medicines in the same study; then the same patient group receiving only basic treatment will serve as a control for all other studies "poor" with experimental medicines. The patients who are willing to participate are randomly distributed among the poor - i.e. at random.

A particularly large study of this kind is being conducted by the World Health Organization WHO on the inpatient treatment of Covid-19 patients, the SOLIDARITY Trial. Although it currently only has the following study arms:

However, there were other study arms in the beginning, but these have since been shut down after the respective medicines proved to be problematic or not sufficiently effective. These are also important findings.

Medical institutions from many countries are participating in the study, including Germany. The German part of the study is coordinated by the German Centre for Infection Research (DZIF) and the German Centre for Lung Research (DZL). Detailed information on the study can be found in the ISRCTNregistry.

In parallel, the DISCOVERY study is running with a very similar structure, coordinated by the French research organisation INSERM. So far, almost exclusively French patients have been included.

Another large study is being conducted under the direction of medical doctors from the University of Oxford in the UK, called the RECOVERY Trial. It currently has the following study arms:

Large clinical trials of Covid-19 therapy with selected medicines are also being organised from the USA, including the Adaptive COVID-19 Treatment Trial (ACTT), for which the National Institutes of Health (NIH) are responsible. Around 75 medical institutions worldwide are expected to participate in the trials, including those in the EU and UK. The trial has initially started with two arms:

However, it is planned to add further arms to the study.

Two other major studies are being conducted in the UK: TACTIC-E and TACTIC-R; led by the Cambridge University Hospitals NHS Foundation Trust and funded by the participating pharmaceutical companies.

TACTIC-E currently has the following arms:

TACTIC-R currently has the following arms:

In several cases, companies provide large quantities of their medicines for these studies. Merck supplies interferon beta-1a for the DISCOVERY Trial and the SOLIDARITY Trial.

Every medicine must be tested to see if it is suitable for treating people with Covid-19. This also applies to medicines that have already been approved for other patients or that have been extensively tested. The regulatory authorities must then be able to test each medicine for efficacy, tolerability and technical quality based on the results. However, the regulatory authorities have indicated that they will give priority to both the approval procedures for clinical trials and the approval procedures for successfully tested medicines. Companies will also be able to submit marketing authorisation applications "chapter by chapter", which will further accelerate the examination by the authorities.

However, the experience and resources of companies that have been developing and selling medicines for many years will also be essential for the rapid introduction of suitable medicines into patient care. For example, the company has offered Pfizer to contribute its comprehensive experience with studies, approval procedures and production process development as well as its production capacity to cooperations with smaller companies that develop corona medicines. The company will also make laboratory methods, which it has developed for its own corona research, available to all on an "open source" basis.