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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Although the development of vaccines against the new coronavirus is proceeding at an unprecedented pace, hopes are also pinned on finding medicines to treat those already infected. The focus is particularly on medicines that have already been approved for treating another disease or are at least in development. This is because converting them can succeed more quickly than a fundamentally new development. Pharmaceutical researchers speak of "repurposing" medicines. In the case of Covid-19, these medicines usually belong to one of the following four groups:

In addition, there are projects for repurposing medicines from other medicine groups as well as projects for developing new medicines, see below. There you will also find more detailed information on some of the repurposing projects.

It is not simply a question of whether or not the medicines are effective against covid-19, but more specifically at what stage of the disease they are of use. Medicines that are helpful in the early stages (mild infection without breathing problems) might be ineffective or even harmful in patients with severe pneumonia - or vice versa. For example, depressant immunomodulators are probably only appropriate in patients with severe pneumonia, whereas they would adversely weaken viral defenses in mild disease. Some medicines may not be therapeutic at all, but protect against infection. All this must also be taken into account when news of a failure with a medicine spreads.

The only way to clarify which medicines are truly useful against Covid-19 is with clinical trials involving volunteers. However, the first such 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 any additional medicine. Such studies could be set up quickly, but their results were inconclusive.

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

Such trials, the EMA argues, are more likely to produce clear results on the suitability of medicines compared to small trials; results that would then allow the medicines to be approved for Covid-19. They can be designed in such a way that "study arms" (i.e. types of treatment within the study) can be terminated along the way or new ones can be added.

IMI's five-year CARE (Corona Accelerated R&D in Europe) project was launched in mid-August 2020. It involves 37 contributors from the EU, China, the UK, Switzerland and the US. Coordinated by VRI-Inserm and the companies Janssen and Takeda, this consortium is researching and developing agents against Covid-19, namely antibodies that neutralise the virus and small molecule compounds that are designed to act directly against the virus. It is also investigating the feasibility of repurposing existing medicines (approved or in development for other diseases) against Covid-19. This IMI projecthas a volume of €77.7 million (EU funds plus cash and in-kind contributions from pharmaceutical companies).

An overview of all ongoing projects for medicines and vaccines against COVID-19 is maintained by the US Milken Institute. Further information on some of them can be found here; however, the vfa list does not claim to be complete.

Remdesivir was originally developed by Gilead Sciences against Ebola infections (against which it has not proven effective), but has also shown efficacy against MERS viruses in the laboratory. In several clinical trials, the medicine was able to shorten the duration of illness by several days in study participants at certain stages of the disease. As a result, the Covid 19 treatment received emergency use approval in the US, approval in Japan and, in July, conditional approval in the EU, among others. However, in a multinational study conducted by WHO (the SOLIDARITY trial, see below), preliminary results indicate that no such effect was observed. How this discrepancy is to be understood is currently being investigated; it may turn out that the disease stages in which the medicine has an effect need to be defined even more precisely.
Demand for the medicine is high worldwide; the EU has also ordered larger quantities. But the manufacturer has licensed several other companies to produce and distribute their own remdesivir medicines for certain regions of the world.

Favipiravir (= Favilavir) from FUJIFILM Toyama Chemical initially only had approval for influenza therapy (in Japan and China) and is only intended for second-line therapy in Japan (when other influenza medicines are not effective or not effective enough). After appropriate studies, a medicine based on it from the Russian company Khimrar was approved in Russia for Covid-19 therapy. Fujifilm Toyama Chemical now also intends to apply for an extension of approval in Japan following positive study results: In a study with patients who were not severely ill with pneumonia, the time until the symptoms disappeared or the viral load fell below the detection limit was reduced by an average of several days with the medicine. However, the Japanese medicine authorities classify the evidence for the medicine as "inconclusive". Pregnant and breastfeeding women are not allowed to take the medicine.

Molnupiravir (= MK-4482) was also initially developed by MSD for influenza therapy, but did not make it to the approval stage. Now, after positive trials with ferrets and phase I results with volunteers, it is being tested in phase II/III trials with outpatients and inpatients of Coivd-19.

Also actually in development against influenza is ATR-002, a kinase inhibitor (more precisely, an MEK inhibitor) from the company Atriva Therapeutics in Tübingen with antiviral and immunomodulatory effects. At the beginning of January 2021, testing will begin in a Phase II study with hospitalized patients with moderate to severe Covid-19 in Germany and other countries.

Atea Pharmaceuticals (USA) originally developed the chemosynthetic agent AT-527 (a purine nucleotide derivative that inhibits RNA polymerases) against hepatitis C viruses (and reached Phase II there). The company is now testing AT-527 in a Phase II trial against SARS-CoV-2 in collaboration with Roche (Switzerland).

APEIRON Biologics (Vienna) is testing the medicine alunacedase alfa (= APN01 or rhsACE2) in a clinical trial with patients (phase II ) in Germany, Austria and Denmark. The active substance - a genetically engineered, soluble form of the human angiotensin-coverting enzyme 2 - originated in SARS research and has in the meantime already been tested in patients with other lung diseases. It blocks a molecule on the viruses that they need to invade lung cells and also helps to prevent lung damage caused by inflammatory reactions. Results are only available from one case study so far.

In contrast, an older HIV medicine with the active ingredient combination lopinavir / ritonavir has not proven effective against covid-19. Among other things, it was tested in the SOLIDARITY Trial (see below).

Some medicines do not fight viruses directly, but are designed to strengthen the body's own defence against viruses. One of these is being developed by the German company AiCuris: its stimulating immunomodulator contains parapoxviruses and was originally developed for the treatment of hepatitis B; it has already completed a phase I trial with patients for this purpose. Now it is to be tested with some asymptomatic corona patients in anticipation of an enhanced immune response.

Already tested in several trials is a group of other immune modulators: 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 of importance against SARS-CoV-2:

Results to date with beta interferons have been equivocal. In some trials, they appeared to reduce the risk of needing ventilation and, on average, shortened hospital stays. However, in the WHO SOLIDARITY trial (see below), they did not appear to benefit patients. It is possible that the effectiveness of these medicines is highly dependent on the stage of disease at which they are administered.

Severe covid-19 infection not only affects the lungs, but can also have effects on the heart, kidneys, and other organs. In addition, blood clots have been found post-mortem 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.

Anticoagulant low-molecular-weight heparins are being used to counter the risk of thrombosis in Covid-19, and the low-molecular-weight heparin enoxaparin in particular is being tested in a number of trials. It was originally developed by Sanofi and is approved, among other things, for the prophylaxis of venous thromboembolic disease in patients with respiratory failure or severe infection and limited mobility, but also for the treatment of certain forms of acute coronary syndrome. The structurally similar tinzaparin as well as unfractionated heparin are also being tested in trials; this is in preparation for bivalirudin, which is also an anticoagulant. A previously unapproved anticoagulant, the heparin derivative dociparstat, is also being tested by the company 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 that are structurally unrelated to heparin are also being tested. These include edoxaban, a direct oral factor Xa inhibitor that is being considered as an adjunct to low molecular weight heparin. Also being tested is rivaroxaban from the same class of compounds, manufactured by Bayer, which is approved for the treatment of acute coronary syndrome (ACS), among other conditions, to see if it can be used to prevent cardiac complications in Covid 19 patients.

After retrospective comparisons indicated a possible benefit of acetylsalicylic acid (ASA), ASA is now also being tested in a clinical trial as a therapy for hospitalized Covid 19 patients. ASA is approved for the prophylaxis of heart attacks and strokes, among other things.

Clot-dissolving medicines are also being tested, including the active ingredients alteplase and tenecteplase (Boehringer Ingelheim).

Several medical facilities are testing whether antihypertensive medicines in the sartan 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 examining whether this class of antihypertensive medicines (as well as the class of ACE inhibitors) may actually pose dangers to Covid-19 patients.

An analysis of medical records in the USA by a health insurance company suggests that older Covid 19 patients who were taking medicines from the ACE inhibitor class as continuous therapy independently of this condition required hospital treatment less frequently. For this reason, a clinical trial is now planned in which patients who do not yet have the disease (and who are not currently using an ACE inhibitor) will take either a low-dose ACE inhibitor or placebo. The aim is to find out whether the different medication has an effect on the course of the disease in participants who later develop Covid-19. In another study, the ACE inhibitor ramipril is being tested specifically in hospitalized Covid-19 patients. To date, ACE inhibitors have been approved to lower high blood pressure and prevent atherosclerosis.

AstraZeneca is conducting a trial to see if dapagliflozin can prevent serious 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 studies it has also been shown to prevent the development of heart failure.

GSK's ambrisentan (an endothelin receptor antagonist) is approved for the treatment of pulmonary arterial hypertension; it dilates the lung vessels and thus improves oxygen uptake into the blood, among other things. The medicine will now be tested in the TACTIC-E trial (see above) in combination with dapagliflozin against Covid-19.

CSL Behring, on the other hand, is currently developing garadacimab (a factor XIIa inhibitor) as a medicine for hereditary angioedema. It is now also testing this medicine for suitability against lung failure in severe Covid-19 disease.

Immune responses are generally desirable in infected individuals; they just must not be so excessive that they do more harm than good in the lungs. Such an excessive immune reaction is called a "cytokine storm" because large amounts of messenger substances called cytokines are released. Several Covid 19 therapy projects are therefore aimed at dampening such an immune reaction with a suitable immunomodulator.

A study conducted in the UK with dexamethasone, a cortisone derivative with a known anti-inflammatory effect, showed that dexamethasone effectively reduced the risk of death in patients requiring oxygen or even artificial respiration by one fifth or one third. The EMA recommended a corresponding extension of approval in September 2020. The related cortisone derivatives hydrocortisone and methylprednisolone have also been shown to improve therapy in studies.

The Jena-based company InflaRx is currently developing the medicinevilobelimab (IFX-1) for the treatment of various inflammatory diseases, among others; several studies with patients have already been conducted. In its trial for Covid-19 therapy, Phase III within a Phase II/III trial has started in September 2020 - in the Netherlands, Germany and Peru. It is being tested whether vilobelimab can also help people severely affected by Covid-19. The active substance is a monoclonal antibody and specific inhibitor of C5a, a component of the complement system, which in turn is part of the human immune system.

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

And UCB is also testing a C5 inhibitor with patients with severe covid-19 disease. The compound, zilucoplan, has been in development for myasthenia gravis (Phase III), immune-mediated necrotizing myopathy (IMNM), amyotrophic lateral sclerosis (ALS) and other complement-associated diseases. For the new project, the company is collaborating within the COVID R&D Alliance.

Similarly, the C3 inhibitor AMY-101 interferes with the complement system. Amyndas Pharmaceuticals is also testing this compound in Covid-19 patients with severe pneumonia.

Inconsistent study results have been reported from Covid-19 treatment of patients with pneumonia treated with Roche 's interleukin-6 antagonist tocilizumab: While fewer patients required ventilation or died in some, other studies failed to find this benefit. A study of critically ill patients, on the other hand, found a reduction in the risk of death.

The same applies to the interleukin-6 antagonist sarilumab from Sanofi: with it, too, the risk of not surviving the disease was reduced in a study with seriously ill patients.

Following positive results in a smaller study, a medicine that directly targets interleukin-6 is now also being tested in the Phase III SILVAR study with severely ill patients: siltuximab from EUSA Pharma. The medicine contains an interleukin-6 neutralising antibody and is approved for the treatment of multicentric Castleman's disease, a form of lymph node tumour.

Novartis is conducting a clinical trial of its immunomodulator canakinumab (an interleukin-1 beta blocker) in many countries, including Germany. The medicine 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 ACTIV-5 trial in the US is also testing risankizumab, which binds interleukin-23 and is approved for the treatment of the autoimmune disease psoriasis.

The TNF-alpha inhibitor adalimumab, which is approved for rheumatoid arthritis and other conditions, is also being tested in patients with the aim of preventing the disease from progressing to a severe or critical stage. This ties in with the observation that patients on continuous therapy with adalimumab for autoimmune disease show milder disease progression when infected with SARS-CoV-2. Sandoz adalimumab is being used in the UK AVID-CC trial.

Another TNF-alpha inhibitor to be tested is infliximab, which is part of the ACTIV-1 Trial conducted by the US National Institutes of Health (NIH). The Janssen company is providing it for this purpose.

The monoclonal antibody lenzilumab from Humanigen (USA) is also one of the agents that dampen the immune system. It inhibits GM-CSF, the granulocyte-macrophage colony-stimulating factor. This protein belongs to the cytokines. The effect of the antibody is currently being investigated in a phase III 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 against rheumatoid arthritis; however, approval for this is still pending.

Bristol Myers Squibb's Abatacept inhibits full activation of T cells and is already approved for 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 ingredient Leronlimab from CytoDyn is a CCR5 antagonist, it blocks a receptor on the surface of certain immune cells. In a phase II trial, it was shown to improve the health of mild to moderate Covid-19 patients. The manufacturer then conducted a Phase III trial in patients with severe disease and applied to the FDA for emergency use approval. Until a decision is made, new patients with severe symptoms at the hospitals that participated in the trial can be treated with Leronlimab. The company is also testing whether Leronlimab will improve late symptoms in Covid 19 patients who have had the infection for a long time. The antibody Leronlimab has long been developed for the treatment of HIV and triple-negative breast cancer, for which it is already being tested in trials. However, its efficacy against HIV is not based on attenuating immunomodulation, but on the fact that the active substance prevents the AIDS viruses from gaining access to the immune cells that they would otherwise infect.

Also targeting CCR5, but additionally targeting the receptor CCR2, is cenicriviroc. This is a compound that is currently being developed and tested in trials by AbbVie against other diseases, but it has not yet been approved. The company is now making it available for testing with Covid-19 patients as part of the National Institutes of Health's ACTIV-1 Trial in the US. A Phase II trial was conducted at the Charité Hospital in Berlin.

Merck of Germany will test M5049, a TLR7/8 inhibitor-type immunomodulator, in a trial of hospitalized Covid-19 patients in the U.S. and Brazil. It has been previously tested by the company against various immune diseases. To date, there is no approved medicine in this medicine class.

Another attenuating immunomodulator is MSD's MK-7110 (CD24Fc). This substance was originally developed for the treatment of graft-versus-host disease and has already been successfully tested in a phase II trial. Since September, a phase III trial has also been investigating whether it can also be used to effectively protect hospitalized Covid 19 patients from excessive immune reactions. Structurally, MK-7110 is an artificial protein fused from the "foot part" of an antibody and a piece of the cell surface protein CD24. It targets the innate immune system and inhibits the release of cytokines.

Also being tested in the US is fosamatinib from Rigel Pharmaceuticals. This SYK inhibitor (inhibitor of splenic tyrosine kinase) can dampen certain immune responses, including the formation of network-like structures of DNA and proteins - the NETs - by certain white blood cells. This mechanism is part of the innate immune defence. The medicine has so far been approved for the treatment of chronic immune thrombocytopenia (platelet deficiency). Misdirected immune reactions with the formation of NETs contribute significantly to the dangerousness of the severe stage of a Covid-19 disease because they promote the formation of thromboses. This was discovered at the University of Nuremberg-Erlangen, among others.

Amgen is testing apremilast, a phosphodiesterase IV inhibitor (PDE4 inhibitor), in hospitalized Covid19 patients as part of the COMMUNITY study. The medicine is approved for the oral treatment of psoriasis and psoriatic arthritis. For the new project, the company is collaborating within the COVID R&D Alliance.

Lanadelumab, an anti-callikrein antibody from Takeda that has not yet been approved, is also designed to dampen immune reactions. The company is testing it in hospitalized Covid 19 patients as part of the same COVID R&D Alliance COMMUNITY trial. The medicine is also designed to counteract fluid accumulation in the lungs.

Lanadelumab, an anti-Kallikrein antibody from Takeda, is also thought to dampen immune responses. It was developed for the treatment of the rare heriditary angioedema and has been tested in trials, but has not yet been approved. The company is testing it in hospitalized Covid 19 patients as part of the COVID R&D Alliance 's COMMUNITY trial. The medicine is also designed to counteract fluid accumulation in the lungs.

The US/German company Immunic Therapeutics is testing its immunomodulator IMU-838 in two Phase II trials in hospitalized Covid 19 patients (once as monotherapy, once in combination with oseltamivir). As a selective oral inhibitor of the enzyme DHODH (dihydroxyorotate dehydrogenase), the compound inhibits metabolism in activated T and B cells, which slows down the immune response. IMU-838 has little effect on other immune cells. The medicine was previously in development as a treatment for relapsing-remitting multiple sclerosis and other autoimmune diseases. It has also shown activity in cell cultures against AIDS, hepatitis C and influenza A viruses.

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

The companies Lilly and Incyte are testing their Janus kinase inhibitor baricitinib (sometimes in combination with remdesivir) in hospitalized covid-19 patients. It has so far only been approved for rheumatoid arthritis. In one study, the administration of both medicines shortened the recovery time compared to remdesivir alone. Very severely ill patients benefited more than patients with milder symptoms. In the US, combination therapy has been approved for emergency use in patients with Covid-19. A study on the treatment with baricitinib alone has not yet been completed. German hospitals are also involved in testing baricitinib against Covid-19.

In one study, the recovery time of hospitalized Covid-19 patients could be shortened even further with the combination of Remdesivir and Baricitinib than with Remdesivir 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 types of cancer and is also being tested for graft-versus-host disease, which also involves an excessive immune response.

Also in development as an anticancer medicine is opaganib from RedHill (Israel). This sphingosine kinase-2 (SK2) inhibitor has shown anti-inflammatory but also antiviral effects in preclinical studies. This could be helpful for the treatment of covid-19-related pneumonia. The medicine has been made available in Italy through a hardship program and will be tested for its suitability.

Also in development as a cancer medicine is opaganib from Israeli/US company RedHill Biopharma. This sphingosine kinase-2 (SK2) inhibitor has shown anti-inflammatory but also antiviral activity in pre-clinical studies. This could be helpful for the treatment of covid-19-related pneumonia. The medicine has been tested in a Phase II trial in the US. Initial analyses of the study show positive results.

Acalabrutinib, a Brutontyrosine kinase inhibitor from AstraZeneca, was also developed for cancer therapy and has approval for the treatment of certain leukemias in the US. Now the company is testing it to dampen excessive immune responses in covid-19.

Zanubrutinib is also a Brutontyrosine kinase inhibitor that was originally developed for one 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 an agent against excessive immune responses; one of these is being led by the Montreal Heart Institute, for example. The agent is now also to be tested in the adaptive multi-arm recovery trial in the UK. The medicine is approved for gout (and in some countries also for pericarditis). In a smaller trial in Greece, the medicine has accelerated the recovery of severely ill Covid 19 patients.

Immune cells (macrophages and dendritic cells) are used by Israeli company Enlivex to dumb down the immune system in the event of a cytokine storm. Its cell therapy Allocetra was already in development against sepsis before the pandemic. After successful testing with a small number of patients, a phase II trial is planned.

EDP1815 from Evelo Biosciences is a completely new type of immunomodulator. It contains a naturally occurring human intestinal bacterium isolated from the small intestine of a donor. Messenger substances from EDP1815 can dampen the production of certain cytokines from the intestine without also down-regulating the production of type 1 interferons, which boost viral defenses. The medicine is being developed for autoimmune diseases such as psoriasis and atopic dermatitis, but is now also being tested in the UK in the Tactic-E trial against Covid-19 (see below).

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

Canadian company Algernon Pharmaceuticals is testing its medicineNP-120 (ifenprodil) for suitability in critically ill COVID-19 patients who require oxygenation. Ifenprodil is now approved off-patent in Japan and South Korea for neurological diseases. Algernon has been developing a medicine for idiopathic pulmonary fibrosis with this compound for some time.

The Viennese biotech company Apeptico plans to test its active substance Solnatide against acute respiratory distress syndrome (ARSD) for suitability for Covid-19 patients with severe lung damage. It is intended to restore the tightness of membranes in lung tissue.

Boehringer Ingelheim is also working on a medicine that will be used in cases of acute respiratory distress syndrome in Covid-19 to maintain the functionality of the lungs: BI 764198, an inhibitor of receptor potential cation channel 6 (TRPC6). It was developed and tested for the treatment of another disease up to and including Phase I before the pandemic. Now a Phase II trial with Covid 19 patients is to begin.

Boehringer Ingelheim is also conducting a phase III study in patients to determine whether nintedanib, a medicine already approved for the treatment of other forms of pulmonary fibrosis, is also effective against the lung scarring (fibrosis) that can occur with Covid-19.

The US company Bioxytran is currently developing a medicine 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 would otherwise only be able to receive adequate oxygen via an artificial lung. The company would also like to test its medicine with a partner for seriously ill patients with Covid-19.

The peptide substance FX06 from the Viennese company MChE/F4-Pharma is expected to be effective against leaks in the blood vessels of the lungs and other organs caused by Covid-19. A clinical trial 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 to relieve respiratory distress in Covid-19 patients by adding some nitric oxide to the air they breathe. This gas, which the body itself produces as a messenger, can dilate blood vessels in the lungs by relaxing muscles. This approach already showed positive effects during the SARS epidemic.

Some medicines for which repurposing has been proposed do not fall into any of the aforementioned categories. They are being tested because they are nevertheless expected to have an antiviral or immunodampening effect. Some medicines could also be sorted into several of the above categories at the same time with equal justification.

The Heidelberg-based company Apogenix is testing its medicine with the active substance Asunercept, a CD95L inhibitor, in phase II trials in Russia, Spain, Vienna, Cologne and London in hospitalised Covid 19 patients. The medicine is actually in development for the treatment of various cancers in which it helps the immune system fight cancer; it does not yet have regulatory approval. In COVID-19 patients, it counteracts the death of lung epithelial cells, among other things.

Medicines containing camostat or nafamostat have approval in Japan for the treatment of pancreatitis. However, researchers from a German consortium of research institutions led by the German Primate Center in Göttingen have found that in the laboratory they inhibit an enzyme of lung cells (the transmembrane serine protease 2) that is essential for the invasion of the SARS-CoV-2 viruses. Several clinical trials with both medicines are now underway worldwide with Covid-19 patients. The German Federal Ministry of Education and Research (BMBF) is funding a project in which nafamostat, which has a 50-fold stronger antiviral effect, is to be tested in intravenous administration; the development of a nasal spray with the active substance is also planned.

Innovation Pharmaceuticals ' active ingredient brilacidin is currently being tested for the treatment of inflammatory bowel diseases and inflammation of the oral mucosa. However, it is expected that it can also attack the outer envelope of the SARS-CoV-2 virus. This is currently being tested in cell cultures.

Following encouraging laboratory tests, the Spanish company PharmaMar is testing its medicine with plitidepsin in a trial against Covid-19. The medicine, which is actually approved in Australia and Southeast Asia for the treatment of multiple myeloma (a form of bone marrow cancer), must inhibit viral replication because it blocks the necessary protein EF1A in the affected cells.

Scientists at the Universities of Würzburg and Münster were able to show that the antidepressant fluoxetine can inhibit viral replication in cell cultures because it inhibits an enzyme in body cells (acid sphingomyelinase); this intervention in turn interferes with viral replication in these cells. This is similarly true of the medicines amidarone and imipramine. Clinical studies to test the therapeutic effect are still pending.

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

The tapeworm medicine niclosamide is known to enhance cellular "waste processing" (autophagy). This process is reduced in cells infected with SARS-CoV-2. In laboratory experiments at the Charité hospital in Berlin, it was possible to reduce viral replication with the medicine - as with the active substances spermidine (an endogenous substance) and MK-2206 (an active substance against breast cancer). There are no study results yet.

Another medicine being tested is famotidine (an H2 blocker), which is approved for the treatment of gastric acid-related diseases. In Covid 19 patients, however, it is used in doses nine times higher than those approved. The background to this is evidence from the analysis of Chinese medical records, which suggests that patients taking famotidine may have a lower risk of dying from Covid-19.

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

The use of another antimalarial agent is being promoted, particularly in Africa: Artemisinin. It is otherwise part of antimalarial combination medicines that are taken as tablets. Against Covid-19, it is used as a drink. At the Max Planck Institute in Potsdam and other research institutions, the efficacy of the active substance against SARS-CoV-2 is being systematically researched in laboratory trials.

A growing number of projects are also trying to develop new medicines against Covid-19. Three types of projects can be distinguished here:

Here are some examples of projects from these areas:

These 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) that have already survived the disease in question. Emil von Behring's diphtheria antiserum of 1891 already worked in this way, even though no one knew more precisely at the time what antibodies it contained. Another example are the injections for passive immunization of people who might have contracted tetanus via an injury. Recently, several Ebola medicines with such antibodies have also shown high efficacy in studies.

Most projects to develop 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 clotting substances have been removed). Groups of projects can be distinguished according to the type of approach:

1. Direct transfer of antibodies from convalescents
In the simplest case, patients receive infusions directly with a blood plasma donation (checked for safety) from former Covid 19 patients or with freshly obtained antibodies. This is already practiced in Germany at some clinics as a curative trial; and in many places geneses are invited to donate plasma (for example by the German Red Cross). In parallel, this therapy is being tested in a study with volunteers. Also in other countries plasma is collected (for example in Austria) and this therapy is practiced, e.g. in the USA. However, convincing therapy successes have not been published so far.

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

2. Antibody preparations from reconvalent plasma
Instead, some companies want to extract antibodies from such plasma and use them to produce a medicine for infusion, called polyclonal anti-SARS-CoV-2 hyperimmunoglobulin (H-IG). Such a medicine has the advantage over convalescent plasma that the 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 test its medicine in a clinical trial starting in October, together with the National Institute of Allergy and Infectious Diseases (NIAID) of the US.

Grifols (Spain) is also developing an H-IG medicine. It plans to then produce this in the US. A clinical trial is planned.

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

3. Preparations with "copied" antibodies from convalescent plasma
Other companies and research groups around the world are following the same basic idea, but have gone one step further: they have selected the most suitable antibodies from convalescent sera and "copied" them using biotechnological means in order to produce them in large quantities using cell cultures and use them to produce a medicine. The most advanced projects are those of the US companies Lilly and Regeneron: both have received emergency use authorisation for one of their antibody medicines in the USA on the basis of phase II studies.

Lilly is collaborating with AbCellera (Canada) on the development of the monoclonal antibody Bamlanivimab (= LY-CoV555). The phase II BLAZE-1 trial in patients at risk with mild or moderate disease delivered positive interim results, the basis for emergency approval in the United States. Now Lilly is starting the Phase III BLAZE-2 trial in the outpatient setting, which means Covid-19 patients living at home or in retirement homes.
For the large-scale production of the medicine, Lilly is cooperating with the US company Amgen and the South Korean company Samsung BioLogics. In view of the high international demand for medicines of this type on the one hand and the initially limited production quantities on the other, Lilly has drawn up principles for itself for the most responsible supply possible, which include a focus on high-risk patients and other aspects as well as a graduated pricing system. In addition to this project, Lilly is also developing another antiviral antibody with Shanghai Junshi Biosicences (China ): etesevimab (JS016, LY-CoV016)for outpatient treatment.

Regeneron's emergency-approved antibody medicineREGN-COV2 contains the monoclonal antibodies casirivimab and imdevimab. This cocktail is based on analysis of antibodies from transgenic mice (see below) and recovered Covid-19 patients. REGN-COV2 is currently being tested in a Phase II/III trial in outpatients following initial positive data. REGN-COV2 also demonstrated antiviral effects in the treatment of hospitalized Covid19 patients. These initial trial data are being reviewed in the UK RECOVERY study of at least 2000 inpatients. In addition, a Phase III trial is underway in which volunteers are receiving it for prevention. Following a notice from the Data Monitoring Board responsible for a patient study, Regeneron will not proceed with the trial in ventilator-dependent patients. Regeneron received support from the U.S. government for large-scale production.

In addition, Regeneron has developed the triple antibody combination REGN-EB3, which will also be tested in trials.

AstraZeneca (UK) has also developed a medicine with two genetically engineered antibodies derived from antibodies found in convalescent plasma by US Vanderbilt University. They have been modified to 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 treatment and prevention of covid-19. Lonza will participate in production at a US site.

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). Interim results from the therapy trial indicate a reduction in recovery time and less frequent progression of the disease to a more severe stage in patients with mild to moderate symptoms. Celltrion intends to apply for emergency approval in South Korea.

In Germany, a consortium consisting of the University Hospital of Cologne, the University of Marburg, the German Center for Infection Research (DZIF) and Boehringer Ingelheim is developing the medicine BI 767551, whose monoclonal antibody active ingredient is derived from an antibody derived from convalescent plasma. In a phase I/IIa study, both an application by injection and by inhalation are currently being tested.

The CORAT consortium also relies on a similar approach, using the laboratory method "phage display" to identify suitable human antibodies. The consortium includes the Braunschweig-based biotech company Yumab, the Helmholtz Centre for Infection Research (Braunschweig), the Technical University of Braunschweig and the University of Tübingen. The antibody COR-101 developed by Yumab has been available in sufficient quantities since mid-November for a clinical trial that is scheduled to begin in early 2021.

Also in Germany, the Berlin Charité, the German Center for Neurodegenerative Diseases (DZNE) and the biotech company Miltenyi Biotec are working on such a medicine. Positive results from trials with animals are available.

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

Another company active in this field BeiGene (China). It is testing neutralising antibodies under licence which have been derived from convalescent patients by the company Singlomics Biopharmaceuticals and are being produced by genetic engineering.

Other antibodies that neutralize the Covid 19 virus in laboratory tests were developed by researchers from Tsinghua University in Beijing and the company Brii Biosciences. The antibody duo BRII-196 and BRII-198 are now being tested in the US ACTIV-3 trial.

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

Another project of this type is being pursued by the Karolinska Institute in Sweden.

In contrast to the projects mentioned so far, the company Aridis is developing a medicine with a recombinant antibody (AR-711) for inhalation; it is intended to be particularly effective in the respiratory tract.

4. Medicines with genes for antibodies from convalescent plasma
A consortium of research institutions 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. In the end, their respective medicines will not contain copies of the most effective antibodies from convalescent plasma itself, but instead the genes for them - in the form of mRNA. Those who are injected with this mRNA produce the antibodies themselves in their bodies for a while and are protected. The advantage of this approach is that it is probably possible to produce large doses of medicines more quickly than if the antibodies had to be produced biotechnically. The disadvantage: So far, there is no other medicine that works in this way. The project of the US consortium 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. 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 with copied antibodies from SARS or MERS convalescent plasma
Several projects for new medicines extend the "convalescent plasma" approach to diseases whose pathogens are closely related to the SARS-CoV2 virus and carry structurally similar proteins on their surface. For example, Vir Biotechnology analysed antibodies from the blood serum of individuals taken in 2003 after they had survived 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 being tested with patients in a Phase II/III trial (as part of the ACTIV-3 protocol funded by the US National Institutes of Health (NIH)). Vir Biotechnology is cooperating with GSK for the clinical trials and with Biogen (USA) and WuXi Biologics (China) for the production of the antibodies.

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 Utrecht University (Netherlands) have also studied antibodies against SARS, but these were produced from transgenic mice. They found an antibody that could inhibit the replication of SARS-CoV-2 in culture. In this antibody, rodent-typical parts were then replaced with human sections. This antibody, now called "human 47D11", is being further developed by Utrecht University in collaboration with the companies AbbVie and Harbour BioMed and the Erasmus Medical Center. The antibody is currently being tested in a Phase I study for tolerability and dissemination in the body.

6. Preparations with antibodies from laboratory animals or from the computer

Another variant of the same basic principle is not to look at antibodies from geneses at all, but to obtain suitable antibodies with laboratory animals or by synthetic means. These can then be biotechnically produced, 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 Trianni company (Erlangen), use genetically modified mice as a source of suitable antibodies.

In turn, parts of an artificial anti-SARS-CoV-2 antibody generated by a consortium of the University of Ghent, the Flemish Institute for Biotechnology, the University of Austin (Texas) and the German Primate Center in Göttingen originate from an antibody produced with the help of a llama.

The University of Pittburgh (USA) also used a llama, but to obtain a special type of antibody: Nanobodies, which are much smaller than ordinary antibodies. A medicine developed on this basis using genetically engineered nanobodies against covid-19 is soon to be tested in clinical trials. Nanobodies have the advantage that they are easier to produce than ordinary antibodies and can be stored at room temperature for longer periods of time. They are also being considered for a medicine for inhalation.

Formycon, a biotech company based in Martinsried, Germany, took another approach: it specifically combined an antibody part with the human protein ACE2 to create the molecule FYB207, which attaches itself to lung cells instead of the virus. Once these are blocked, the strategy goes, viruses can no longer enter and replicate. Laboratory tests confirm this approach. However, a trial with patients is still pending.

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

IAVI and the Wellcome Trust have launched an appeal to governments, organisations and industry to provide access to antibody medicines against Covid-19 worldwide, including in poorer countries.

A research team at the University of Lübeck is pursuing a different path. For years, it has been developing so-called alpha-ketoamides as antiviral agents against corona and enteroviruses (which are responsible for oral thrush, among other things). In laboratory tests, new experimental active 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, will be tested in trials with humans together with a pharmaceutical company.

Research groups at the Universities of Mainz, Giessen and Würzburg have invented active substances that can paralyse an enzyme of SARS-CoV-2 (a protease) that the virus needs to replicate. They now need to be tested further before they can be trialled with humans.

A number of major 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 facility, set up by the Gates Foundation, the Wellcome Trust and Mastercard. Animal testing is then expected to begin within two months for molecules deemed promising. The group of companies includes BD, bioMérieux, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Lilly, Gilead, GSK, Janssen (Johnson & Johnson), MSD, Merck, Novartis, Pfizer and Sanofi.

Molecular Partners and Novartis are developing two protein-based antiviral medicines (called MP0420 and MP0423) that are designed to attach to viruses in a similar way to antibodies, preventing them from replicating. This type of protein, originally developed at the Universtiäts Zürich, is called DARPins. So far, they have not been tested with humans.

A different plan is being pursued by companies that want to combat SARS-CoV-2 by means of gene silencing. This approach involves preventing certain genes from being used to replicate the virus. Vir Pharmaceuticals and Alnylam Pharmaceuticals (both USA) want to achieve this with the help of so-called siRNA agents. The South Korean company OliX Pharmaceuticals is also working on an active substance of this kind. The German biotech Secarna and China's 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 a good idea to conduct trials of several medicines in the same study; then the same group of patients receiving only a basic treatment serves as a control for all other study "arms" with experimental medicines. Patients willing to participate are randomly allocated to the arms.

One particularly large trial of this type is being conducted by the World Health Organization (WHO) for the inpatient treatment of Covid-19 patients, the SOLIDARITY Trial. It currently has only the following study arms:

But there were other study arms initially, but they 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, including Germany, are participating in the study. The German part of the study is coordinated by the German Center for Infection Research (DZIF) and the German Center for Lung Research (DZL). Detailed information on the study can be found in the ISRCTNregistry.

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

Another large study, called the RECOVERY Trial, is taking place in UK hospitals with hospitalized patients, led by physicians at Oxford University. It currently has the following study arms:

Large clinical trials of Covid-19 therapy with selected medicines are also being organised from the US, including the Adaptive COVID-19 Treatment Trial (ACTT), for which the National Institutes of Health (NIH) is responsible. Around 75 medical institutions worldwide are expected to participate, 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 large trials are being conducted in the UK: TACTIC-E and TACTIC-R; led by Cambridge University Hospitals NHS Foundation Trust and funded by the pharmaceutical companies involved.

TACTIC-E currently has the following arms:

TACTIC-R currently has the following arms:

In several cases, companies are providing large quantities of their medicines for these trials. For example, Merck is providing interferon beta-1a for the DISCOVERY Trial and the SOLIDARITY Trial.

Every medicine must be tested to see whether it is suitable for treating people with covid-19. This also applies to medicines that have already been approved for other patients or have been extensively tested. Regulatory authorities must then be able to assess each medicine for efficacy, tolerability and technical quality based on the results. However, the regulatory authorities have signalled that they will prioritise both the approval procedures for clinical trials and the approval procedures for successfully tested medicines. Companies will also be able to submit applications for approval on a "chapter-by-chapter" basis, which will further accelerate the review by the authorities.

Essential to getting appropriate medicines into patient care quickly, however, will be the experience and resources that companies that have been developing and selling medicines for years can bring to the table. For example, Pfizer has offered to bring its extensive experience with trials, regulatory approval processes and manufacturing process development, as well as its production capacity, to collaborations with smaller companies developing Corona medicines. The company will also make laboratory methods it has developed for its own Corona research available to all on an "open source" basis.