Therapeutic medicines against coronavirus infection Covid-19

Existing medicines are being tested and new ones invented to combat the SARS-CoV-2 pandemic. Two have already been approved, and others are to follow in the coming months.

  1. Antiviral medicines. They are designed to prevent the viruses from entering or replicating in body cells.
  2. Cardiovascular medicines. They are intended to protect blood vessels, the heart and other organs from complications caused by COVID-19.
  3. Dampening immunomodulators. They are designed to limit the body's immune responses in the advanced stages of the disease so that they do not cause more damage than the viruses themselves.
  4. Medicines for lung function. They are intended to help the lungs to maintain their function during the acute infection and to regenerate afterwards with as few consequences as possible.
  5. Medicines for long covid, i.e. persistent symptoms after the actual Covid 19 disease has subsided.

It should be borne in mind that medicines that are helpful in the early stages (infection without breathing problems) may be ineffective or even harmful in patients:with severe pneumonia - and vice versa. This should be borne in mind when news of success or failure with a drug spreads.

Currently, more than 634 different medicines are being tested to see if they can be helpful against covid-19 in one way or another, according to the U.S. association BIO. As of Nov. 30, 2021, it counted 268 antiviral medicines and 366 other therapeutic medicines in development. Most of these medicines are already approved for another disease, or at least were in development against it before the pandemic. Repurposing them is usually quicker than basic new development. Increasingly, however, the medicines in clinical trials also include those whose development only began in 2020.

Further information on some of the medicines in trials is provided below. It is not possible to go into all of them because of the large number.

Viruses can only replicate in cells. Antiviral medicines can therefore prevent virus replication in several ways: they can intercept the viruses before they enter their target cells; they can block the replication process in the cells; or they can strengthen the body's own virus defence.

1.1 Antiviral medicines designed to intercept viruses already in the upper respiratory tract

Ideally, SARS-CoV-2 viruses could be intercepted in the upper respiratory tract. Companies and research groups are looking into whether nasal sprays can do this:

  • Nasal sprays containing iota carrageenan from red algae have been on the market for years as a medicinal product for colds. Argentine researchers reported in an advance publication without peer review that they were able to reduce the risk of SARS-CoV-2 infection in a placebo-controlled study with hospital staff. Another study on this in the UK by Austrian company Marinomed is ongoing. Marinomed is also investigating whether the active ingredient can also be usefully administered by inhalation or as carrageenan pastilles.
  • The Australian company Starpharma claims that a nasal spray containing the active ingredient SPL7013 (a dendrimer) was able to prevent SARS-CoV-2 from entering cells in cell culture experiments. SPL7013 has been on the market in approved products for some time. However, efficacy against SARS-CoV-2 has not yet been confirmed in clinical studies.
  • Ursapharm (Saarbrücken), Cebina (Vienna) and the University of Pécz (Hungary) are testing a nasal spray containing azelastine (an antihistamine) with volunteers. Such nasal sprays are approved for allergy therapy; however, the active substance was also able to combat SARS-CoV-2 in the laboratory. Results of a phase II study at the University Hospital of Cologne (84 volunteers) indicate that azelastine can increase the decrease of the viral load in the upper respiratory tract within one week.
  • The company SaNOtize tested whether a nasal spray can kill coronaviruses in the nose. It contains a nitric oxide (NO) releasing solution. The spray significantly reduced the viral load of infected individuals within the first 24 hours of use in a phase II trial in the UK, according to the manufacturer. A Phase III trial in Canada is planned.

1.2 Antiviral medicines that stop viruses from entering cells

Once the SARS-CoV-2 viruses have made it to the cells of the respiratory tract, they invade where they can. However, they only succeed in doing so in cells that carry the molecules ACE2 and TMPRSS2 (a serine protease; pronounced: "Tempress Two") on their surface. ACE2 represents the actual binding site.

One strategy to prevent the viruses from penetrating is therefore to administer large quantities of unanchored ACE2 molecules; these then "stick" to the binding sites of the viruses:

  • APEIRON Biologics (Vienna) has developed a corresponding drug; the unanchored ACE2 in it is called alunacedase alfa (= APN01 or rhsACE2). In a phase II clinical trial with critically ill patients, a reduction in ventilation days and a lowered viral load were observed; therefore, further investigation is planned in the phase II ACTIV-4d RAAS trial in the USA. The active substance originates from SARS research and has in the meantime already been tested against other lung diseases.
  • The Planegg-Martinsried-based company Formycon is also pursuing this strategy. For its active substance FYB207, however, it has combined the unanchored ACE2 genetically with an antibody section. Laboratory tests confirm this approach. A trial with volunteers is planned from Q4 2021.

Inhibition of the serine protease TMPRSS2 also promises to prevent viral invasion. Some active substances are capable of doing this. Clinical trials with some of them are now underway worldwide:

  • Camostat is being tested in several phase III trials, following partially positive results in smaller studies. A combination of Camostat + niclosamide is being clinically tested by the Charité Research Organisation in Berlin. A study led by the Korean company Daewoong Pharmaceuticals was not very conclusive because many participants did not take the drug (as well as the placebo for comparison) as intended.
  • The German Federal Ministry of Education and Research (BMBF) is funding a project in which the 50-fold more antivirally active nafamostat is to be tested in intravenous administration; the development of a nafamostat nasal spray is also planned.
  • RedHill Biopharma was testing upamostat (RHB-107) (originally developed by Heidelberg Pharmaceuticals) for cancer, but has now begun a Phase II/III trial in Covid 19 patients who have mild or moderate symptoms.
  • A research team at the Washington School of Medicine in St. Louis (USA) has developed the compound MM3122, which blocks TMPRSS2. Further development is planned in collaboration with the company ProteXase Therapeutics.

However, it is also possible to reduce the formation of the serine protease TMPRSS2. This is achieved by antiandrogens - substances that were actually developed for prostate cancer therapy - such as proxalutamide from Kintor Pharmaceutical (China). In a clinical trial, proxalutamide actually reduced the mortality of hospitalized Covid 19 patients by over 90 percent; the duration of clinical treatment was also significantly shortened. The trial were conducted in Brazil at a time when gamma variant was highly prevalent. A phase III trial with outpatients is currently underway, another (this time with men only) has been approved, and a third with inpatients is imminent.

  • Lilly is collaborating with AbCellera (Canada) and Shanghai Junshi Biosicences (China) on the development of the antibodies Bamlanivimab and Etesivimab. In a phase III trial, the combination product reduced the development of severe symptoms from 1.95% (placebo) to 0.5% (active substance). Of those treated with the antibodies, all survived; four died in the placebo group. The numbers match an earlier phase III trial that had seen about a 70% reduction in hospitalization and mortality. However, in theEU, a rolling review process for approval was cancelled. Used preventively in residents and caregivers in nursing homes and assisted living facilities (Phase III study BLAZE-2), it reduced the risk of disease by up to 80%, according to themanufacturer. For large-scale production, Lilly is cooperating with Amgen (USA) and Samsung BioLogics (South Korea). In view of the high demand and the initially limited production quantities, 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.
  • Regeneron and Roche 's REGN-COV2 antibody drug contains the monoclonal antibodies casirivimab and imdevimab. They are derived from studies of antibodies from transgenic mice and former Covid 19 patients. In a phase II/III study of outpatients, REGN-COV2 reduced both hospitalization and mortality by 70 percent. REGN-COV2 also demonstrated antiviral effects in the treatment of hospitalized Covid19 patients. These initial trial data are being tested in the UK RECOVERY study of hospitalized patients, which will enroll at least 2,000 patients. - A phase III trial was also conducted to test the efficacy of REGN-COV2 for prevention. Subjects were uninfected members of a household in which one person had been found to have the virus. In those who became infected, symptoms disappeared after an average of one week with REGN-COV2, and only after three weeks without this therapy. - According to an additional phase III study, the compound also helped asymptomatic subjects with fresh infection: it reduced viral load by 90% and the risk of developing symptoms by about half. For large-scale production, Regeneron received support from the U.S. government. In addition, Regeneron has developed the triple antibody combination REGN-EB3, which will also be tested in trials.
  • Celltrion (South Korea) has also developed such a drug: its antibody is called Regdanvimab (CT-P59). The drug has been tested in a phase II/III trial for therapy and a phase III trial for post-exposure prophylaxis. Results of the therapy trial showed a reduction in recovery time and less frequent progression of the disease to a more severe stage in patients with mild to moderate symptoms.
  • The antibody Sotrovimab = VIR-7831 from Vir Biotechnology/GSK is modelled on an antibody from the blood of a person who contracted SARS in 2003. It is currently being tested in patients in the COMET-ICE Phase II/III study (as part of the ACTIV-3 protocol, funded by the US National Institutes of Health [NIH]). Preliminary results indicate that the antibody reduces hospitalizations and deaths by 85%. GSK subsequently received emergency approval from the FDA, and the EMA issued an assessment for EU countries to use the drug ahead of approval. The companies also began a rolling submission to the EMA. Biogen (US) and WuXi Biologics (China) are involved in the production of the drug.
  • AstraZeneca (UK) is developing the drug AZD7442 with genetically engineered antibodies tixagevimab and cilgavimab. They are derived from antibodies identified at Vanderbilt University Medical Center (USA) from healthy patients, but have been modified to remain active in the blood for longer. In a phase III trial, the drug was shown to reduce the risk of severe disease or death in Covid 19 outpatients. AZD7442 is also currently being tested (PROVENT trial) to determine whether it is suitable for prophylaxis. For prophylaxis, AstraZeneca has also initiated a rolling review for its drug with the EMA. In laboratory tests, AZD7442 also neutralized delta variant viruses. The company Lonza will participate in production at a US site.
  • Bristol Myers Squibb is also working with The Rockefeller University on a two-antibody combination product(SARS-CoV-2 mAb Combo). The antibodies have been optimized for long residence times in the body. Clinical trials in which the drug is administered partly intravenously and partly subcutaneously began in January 2021.
  • The CORAT consortium relies on a comparable approach, using the laboratory method "Phage Display" for antibody generation. The consortium includes Braunschweig-based CORAT Therapeutics, Yumab, the Helmholtz Centre for Infection Research (Braunschweig), TU Braunschweig and the University of Tübingen, among others. Since April, the antibody COR-101 has been tested in a phase Ib/II trial with volunteers. COR-101 was designed in such a way that the antibody can also be administered when a further increase in inflammation must be avoided. Financial support of up to 12.7 million euros is provided by the BMBF and the state of Lower Saxony. Yumab and the University of Braunschweig were awarded the Lower Saxony Innovation Prize for the development of the antibody. In the laboratory, the antibody also binds to the delta variant of SARS-CoV-2.
  • Also in Germany, the Charité hospital in Berlin , the German Centre for Neurodegenerative Diseases (DZNE) and the biotech company Miltenyi Biotec are working on such a drug. Positive results from experiments with animals are available.
  • The company Aridis is developing AR-712, a drug for inhalation with the two recombinant antibodies AR-711 and AR-720 for non-hospitalised patients. AR-711 was shown to be very effective in tests by the CoVIC consortium. According to Aridis, it ranks in the top 10% in three different neutralization tests that 350 antibodies have undergone to date. When tested in mice, AR-711 landed in the top five out of 75 antibodies tested. It also inhibits Delta and Delta Plus variants.
  • Another antibody derived from convalescent plasma is being developed by 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 under license neutralizing antibodies that have been derived from convalescent patients by the company Singlomics Biopharmaceuticals and are produced by genetic engineering.
  • Other antibodies that neutralize the Covid 19 virus in laboratory tests have been developed by researchers at Beijing Tsinghua University and the company Brii Biosciences. The antibody duo BRII-196 and BRII-198 was tested in the US ACTIV-3 and ACTIV-2 trials. Based on positive results from ACTIV-2, Brii filed for emergency approval in the US for the outpatient treatment of Covid-19 patients.
  • The monoclonal antibody ADG20, which was developed by the US company Adagio, has been tested in the phase II/III EVADE trial since May 2021 in several locations worldwide with different prevalence levels. The trial is analyzing the suitability of the antibody for both prevention and treatment. In addition, ADG20 is being tested in the STAMP trial in high-risk patients who have mild or moderate symptoms. Adagio is collaborating with India's Biocon Biologics to manufacture the antibody and bring it to market in Asia.
  • A three-antibody cocktail of this type is also being developed at Tel Aviv University in Israel. Positive laboratory results have been obtained so far.
  • Another project of this kind is being pursued by the Karolinska Institute in Sweden.
  • Imperial College London is working with partners on another antibody therapy based on antibodies from the blood serum of former SARS patients.
  • Scientists at Utrecht University in the Netherlands, for example, 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.
  • 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 gene-modified mice as a source of suitable antibodies.
  • A team from the EPF Lausanne and the University Hospital Lausanne has obtained the antibody P5C3 from the blood of a Covid-19 patient, which neutralises all currently known coronavirus variants in laboratory tests and protects hamsters against Covid-19. In collaboration with a start-up company, the antibody will be genetically engineered and tested in a clinical trial.

Several companies and research groups are working on medicines using nanobodies instead of ordinary antibodies. This is the name given to smaller antibodies produced by llamas and alpacas. They are easier to produce than human antibodies and (unlike these) can also be stored at room temperature for longer periods.

  • For example, 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 Center in Göttingen are derived from an antibody produced with the help of a llama.
  • The University of Pittburgh (USA) developed Nanobody-21, a drug for inhalation. In studies with hamsters, the Nanobody prevented severe symptoms and significantly reduced the number of virus particles in the animals' airways, even at low concentrations.
  • A research group at Ohio State University (USA) has developed two nanobodies that target a site on the spike protein of SARS-CoV-2 that is inaccessible to ordinary antibodies because of their size. A clinical trial is still pending.
  • Scientists at the University of Bonn and the Bonn-based company DiosCURE have developed further antiviral nanobodies. A drug containing the nanobodies DIOS-202 and DIOS-203 is expected to enter clinical trials before the end of 2021. Both bind to the spike proteins of the virus, but at different sites.
  • Three nanobodies that bind to the spike protein of SARS-CoV-2 (including alpha, beta, gamma and delta variants) at different sites have been developed by a research team at the Max Planck Institute for Biophysical Chemistry in Göttingen. Fusion proteins consisting of two or three of these nanobodies bind even more strongly. The researchers classify both the single nanobodies and the combinations as interesting options for medicines; with the single nanobodies possibly being administered by inhalation. Clinical trials are underway.

Not only classical antibodies and nanobodies, but also completely differently constructed molecules can be used to bind proteins and thus alter or suppress their function. Researchers are specifically looking for such artificial binders that attach themselves to SARS-CoV-2 and thus prevent the virus from entering a cell and multiplying there. Several molecules that meet these criteria have now been identified; structurally, they belong to the aptamers, the DARPins and the VNARs.

An aptamer is a short, synthetic, single-stranded DNA or RNA that can fold into a three-dimensional structure that attaches to a protein. The following companies are developing them against SARS-CoV-2:

  • Berlin Cures has developed the aptamer BC 007 for the treatment of patients with heart disease who develop autoantibodies against heart muscle cells. It has already been tested in phase II trials. However, in the laboratory it also binds to SARS-CoV-2, thereby preventing the virus from entering a cell. Clinical trials are planned.
  • A research team from the University of Bonn and the caesar Research Centre has created an aptamer from DNA that binds to non-infectious model viruses in laboratory experiments and prevents them from coming into contact with cells. They call it SP6. Subsequent experiments will test whether this also applies to real SARS-CoV-2 viruses. Those involved hope that their research will result in a nasal spray that can intercept viruses.

Aptamer from the company Aptarion Biotech, on the other hand, is being developed for immune attenuation (see below).

A DARPin (Designed Ankyrin Repeat Protein) is a synthetic protein whose structure is derived from ankyrins. It consists of multiple repeating units that can recognize and bind antigens, but are much smaller and more stable than antibodies. With Ensovibep (MP0420), the Swiss company Molecular Partners and Novartis developed a compound against SARS-CoV-2 that prevents severe deaths in hamsters. Following a Phase I tolerability study, it was tested in the ACTIV-3 trial with hospitalized patients, but did not prove successful there. However, development for outpatients in earlier stages of the disease (Phase II/III EMPATHY study) is ongoing.

The Scottish company Elasmogen and the University of Minnesota (USA) are again relying on a type of molecule that sharks produce instead of antibodies - but which serve the same purpose in their case. They are called VNARs (variable new-antigen receptors). Their VNARs directed against the spike protein of SARS-CoV-2 are still in the laboratory stage.

1.3 Antiviral medicines that block intracellular replication

Smaller agents that can easily penetrate cells (so-called small molecules) are the main candidates for blocking viral replication within cells. These are usually produced chemically-synthetically. Many active substances under investigation were originally developed against other viral infections.

One way to prevent replication is to block a viral enzyme called RNA-dependent RNA polymerase. It is essential for viral replication because it generates the genetic material for the newly emerging viruses:

  • The active ingredient Remdesivir (a nucleotide analogue) from Gilead Sciences has this effect. Remdesivir became the first medicine to receive a conditional marketing authorisation in the EU in July 2020 for the treatment of certain Covid 19 patients:at least(1) . Currently, remdesivir is approved in approximately 50 countries worldwide. Clinical studies show that remdesivir can shorten recovery time and slow disease progression. Real-world studies involving 50,000 patients also show that treatment with Remdesivir can reduce mortality. The Federal Joint Committee (G-BA; the self-governing body of the German healthcare system) positively assessed the benefit of the drug in September 2021. To improve global availability, Gilead Sciences has licensed several companies in Egypt, India and Pakistan to produce their own remdesivir medicines and distribute them in 127 countries.
  • Capsules containing a second RNA polymerase inhibitor, molnupiravir from MSD (called Merck & Co., Inc. in the US) and Ridgeback Biotherapeutics (invented at Emory University), have been in a marketing authorisation process with the EMA since 23 Nov 2021, following a rolling review since 25 Oct 2021, with the aim of gaining approval for outpatient treatment of Covid 19 patient:in. In the UK, the drug has already been approved since 04.11.2021; in the USA, an emergency approval has been applied for since 11.10.2021. The drug was originally invented for flu therapy, but has not yet been fully tested for that purpose. The companies have reported interim results from a phase III trial of Covid-19 sufferers; it showed a halving of the number of patients in whom disease progression forced hospitalisation. MSD has entered into licensing agreements with five Indian generic drug manufacturers so that the drug can be made available quickly in large quantities if successful. In addition, MSD has entered into a Voluntary Licensing Agreement with the Medicines Patent Pool (MPP) to further facilitate global access to medicines based on Molnupiravir. The company explained: "Under the terms of the agreement, MPP, through the license granted by Merck, will be permitted to further license non-exclusive sublicenses to manufacturers ("MPP License") and diversify the manufacturing base for the supply of quality-assured or WHO-prequalified molnupiravir to countries covered by the MPP License, subject to local regulatory authorization. Merck, Ridgeback Biotherapeutics and Emory University will not receive royalties for sales of molnupiravir under this agreement for as long as COVID-19 remains classified as a Public Health Emergency of International Concern by the World Health Organization."
  • Favipiravir, another RNA polymerase inhibitor, from FUJIFILM Toyama Chemical, had approval for influenza therapy (in Japan and China), and in Japan only for second-line therapy, i.e. when other influenza medicines are not or insufficiently effective. After appropriate studies, a drug 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 drug. However, the Japanese drug authorities classify the evidence for the drug as "inconclusive". The effect of Favipiravir is being tested in a phase III trial. In February 2021, a meta-analysis review of nine studies found that while favipiravir may provide benefit to newly hospitalized patients, it failed to reduce mortality in those with mild to moderate disease.

The Covid-19-related development of the RNA polymerase inhibitor AT-527 by Atea Pharmaceuticals and Roche will not be continued.

Another target is an enzyme of SARS-CoV-2 called major protease or 3CL prote ase. It participates in the formation of finished viruses in infected cells. Several companies and research groups are developing medicines against it:

  • Pfizer tested PF-07321332, a new drug invented in 2020, in a phase III trial in combination with ritonavir with patient:in outpatients. The company reported positive trial results on 11/5/2021, filed for emergency approval in the U.S. on 11/16/2021, and announced additional regulatory filings. The company allows production of the drug by generic manufacturers to supply 95 poorer countries, based on an agreement with the Medicines Patent Pool.
  • Also directed against this main protease are so-called alpha-ketoamides, which a research team at the University of Lübeck has been developing for years. They are supposed to be effective against corona and enteroviruses (which are responsible for mouth rot, among other things). In laboratory tests, new experimental agents inhibit the multiplication of these viruses. One of them, called "13b", is optimized against coronaviruses. It will be tested in cell cultures and with animals, and if the results are positive, it will be tested in human trials in collaboration with a pharmaceutical company.
  • Shionogi (Japan), in collaboration with Hokkaido University (Japan), has developed the orally ingestible drug S-217622, which blocks the main protease. It has shown positive results preclinically and in a phase I trial. It is currently being tested in a phase II/III trial in outpatients.
  • Frontier Biotechnologies (China) is developing a drug containing FB2001, which must be administered intravenously. The drug is currently being tested in a phase I trial in the USA; a phase II/III trial is being planned.
  • Research teams at the German Electron Synchrotron (DESY ) and the Bernhard Nocht Institute for Tropical Medicine (both in Hamburg) investigated whether inhibitors of the main protease might also exist among medicines developed for other purposes. From their laboratory experiments, calpeptin and pelitinib emerged as candidates that are now being further investigated in preclinical studies. Neither substance has yet been approved for use against any disease in Germany.
  • In the STOP-CORONA project, researchers from Helmholtz-Zentrum Berlin, the synchrotron radiation source BESSY II, the University of Lübeck and the University of Würzburg are developing active substances against the main protease on the basis of an analysis technique in which the main protease is brought into contact with small organic substances (so-called molecular fragments). The project is still in the laboratory stage.
  • A research team from the University of Chicago (USA) and other research institutions in the USA and France, screening 1,900 medicines, have determined that masitinib can inhibit the main protease. A drug containing this active ingredient is already approved for the treatment of certain mast cell tumours in dogs; there it acts as a tyrosine kinase inhibitor.

However, SARS-CoV-2 has a second protase-type enzyme: "papain-like protease" (PLpro). This also represents an interesting target:

  • Research groups at the Universities of Mainz, Giessen and Würzburg have invented medicines that can inhibit this enzyme. They now need to be tested further before they can be tested on humans.
  • Research teams from New York and the University of Texas found that the medicines simeprevir, paritaprevir and vaniprevir, which are already approved for hepatitis C therapy and can be taken orally, also block PLpro and, in cell cultures, synergistically with remdesivir, prevent the proliferation of SARS-CoV-2 far better than remdesivir alone can.

The German company Eisbach Bio is working on blocking viral replication in cells by blocking another enzyme: the helicase Nsp13 of SARS-CoV-2. This enzyme contributes to the replication of the virus' genetic material in infected cells, which is necessary for the formation of new viruses. Eisbach Bio's compound EIS-10700 also blocks helicases of other coronaviruses in the laboratory. A Phase I trial with this is planned for Q3 2021. The EisCor_2 project is supported by the BMBF with almost 8 million euros.

Another target is MEK, a kinase-type enzyme in human cells, whose functionality is required by SARS-CoV-2 for its replication:

  • One inhibitor of this enzyme is zapnometinib (ATR-002), developed by Atriva Therapeutics in Tübingen, Germany. In early 2021, testing began in a phase II trial involving hospitalized patients with moderate to severe covid-19 in Germany and other countries. Zapnometinib was originally developed for influenza. It inhibits viral replication and also prevents the immune system from overshooting. Thus, it could be used in the early as well as in the late phase of an infection. The BMBF is supporting the project with 11.4 million euros.

Some components of viruses must reach the nucleus after entering a cell. As a means of transport from the cell membrane to the nucleus, they use microtubules - a kind of "monorail" that is part of the basic structure of the cell. Veru 's chemical synthetic Veru-111 destroys the components of microtubules (alpha- and beta-tubulins). This also triggers a strong anti-inflammatory effect. Veru-111 has been developed and clinically tested against refractory prostate and breast cancer and will be tested in a phase III trial for a potential effect in hospitalized high-risk Covid-19 patients.

Another strategy to combat the virus is to disrupt a metabolic pathway in the infected cells that is essential for viral replication and is not vital for the cell itself. Research teams in Frankfurt a.M. and Kent, among others, are working on this. Disrupting the pentose phosphate pathway with the help of benfooxythiamine plus thiamine 2-deoxy-D-glucose was effective against viral replication in cell culture experiments.

Innovation Pharmaceuticals ' compound brilacidin can prevent SARS-CoV-2 from replicating in cell cultures. It also inhibits the formation of interleukins and tumour necrosis factor alpha, which are key factors in stimulating an inflammatory response. It is currently being tested in a Phase II trial with hospitalized Covid-19 patients. On top of that, it works against bacteria. The FDA granted fast track status to Brilacidin to accelerate the development and testing of the compound.

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

Scientists at the Universities of Würzburg and Münster discovered that the antidepressant fluoxetine can inhibit viral replication in cell cultures by stopping an enzyme called "acid sphingomyelinase" (ASM) there. The same is true for the medicines amiodarone and imipramine. The drug fluvoxamine, also an ASM inhibitor approved for depression, has a high affinity for the sigma-1 receptor (S1R) at the same time. This in the molecule exerts many functions, including regulating the production of cytokines during an immune response. After preclinical testing and smaller studies with symptomatic Covid-19 patients, the compound also showed a positive effect in a larger study. Other studies with fluvoxamine and fluoxetine are currently ongoing.

Quite a few studies have also been conducted with ivermectin, an agent approved for the control of mites and parasitic nematodes. But the results have been mixed, often showing no therapeutic effect, for example in a placebo-controlled trial in younger patients in Colombia. The WHO and the EMA advise against using ivermectin outside of clinical trials. The COVRIIN expert group at the German Robert Koch Institute (RKI) also assesses it this way in a publication dated 19.11.2021.

A study in which ivermectin is currently being further investigated for suitability is the British PRINCIPLE study with Covid 19 patients in outpatient treatment.

The off-patent tapeworm drug niclosamide enhances cellular "waste processing" (autophagy). This process is reduced in cells infected with SARS-CoV-2. In laboratory experiments at the Charité hospital in Berlin, the drug was able to reduce viral replication - as was also the case with the active substances spermidine (an endogenous substance) and MK-2206 (an active substance against breast cancer). In the meantime, Covid-19 therapy with niclosamide is being tested in several phase II trials with patients, either as a monotherapy (e.g. in a trial by Union Therapeutics) or in combination with Camostat (Charité Research Organisation). A study on the suitability of the active substance for prophylaxis is underway in the UK.

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

Several antimalarial medicines with the active ingredients chloroquine and hydroxychloroquine have also not proven effective. After positive laboratory tests against SARS-CoV-2, they were initially 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, often even worsening the situation. 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 malaria 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 effectiveness of the active substance against SARS-CoV-2 is being systematically researched in laboratory trials. The WHO now also wants to test artemisinin in its SOLIDARITY Trial.

1.4 Antiviral medicines that boost the immune response

Some medicines do not fight viruses directly, but are intended to strengthen the body's own viral defences.

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. It is currently being tested in a study with Covid 19 patients.

A group of other immunomodulators 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, beta and lambda interferons were considered against SARS-CoV-2:

  • However, studies with different alpha and beta interferons have so far shown no benefit for Covid-19 therapy. Only interferon alpha-2b (PegIFN) proved to be helpful in the Phase III PegiHep study, which is why the manufacturer Zydus Cadila submitted an application for approval of the active substance, which is already used to treat hepatitis C, in India.
  • Peginterferon Lambda is also still being tested. It has been tested in a Phase II study in Canada. Patients treated with the drug experienced faster viral load reduction and symptom resolution than control patients. A Phase III trial is planned. This interferon, like other interferons, activates an antiviral immune response; however, it essentially only becomes active for this purpose in certain cells of the lung, liver and intestine. The targeted effect there could reduce or avoid side effects in other organs that other interferons can trigger. The compound is also being developed by Eiger BioPharmaceuticals for the treatment of the viral disease hepatitis D.
  • The German company Ethris also relies on interferon lambda. However, its drug ETH47 does not contain this messenger substance itself, but mRNA that can stimulate cells to produce it. It is to be used in the respiratory tract. A trial with patients is still pending.

Covid-19 infection often brings blood clots in various organs as a complication. In addition, the infection can bring effects on the heart and kidneys. A number of approved cardiovascular medicines are being tested or used against this.

Anticoagulant low-molecular-weight heparins (such as those usually injected into patients after certain operations) have already proven effective against the risk of thrombosis. Their use is recommended by the relevant therapy guidelines (and does not require a separate Covid 19 approval). The low-molecular-weight heparin enoxaparin in particular has previously been tested in a number of trials. It was originally developed by a predecessor company of Sanofi. The structurally similar tinzaparin, as well as unfractionated heparin and bivalirudin, which is also an anticoagulant, are also being tested in trials. Bivalirudin was developed by The Medicines Company, which is now part of Novartis. A previously unapproved anticoagulant, the heparin derivative dociparstat, is also being tested by the company Chimerix in Covid 19 patients in a Phase II/III trial. 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.

The effectiveness of heparin-derived agents is unlikely to be due to anticoagulation alone. This is because studies have shown that SARS-CoV-2 also has binding sites for the heparin-like cell attachments that help the virus make its first cell contact even before it moves to ACE2. Heparin agents can prevent this initial docking.

However, anticoagulants that are structurally unrelated to heparin are also being tested. These include Daiichi Sankyo's edoxaban, Bayer's rivaroxaban and Bristol Myers Squibb/Pfizer's apixaban, three direct oral factor Xa inhibitors already approved for other thrombotic diseases.

After retrospective comparisons indicated a potential benefit of acetylsalicylic acid (ASA), this agent is also being tested in a clinical trial in hospitalized Covid 19 patients. ASA is approved for the prevention of heart attacks and strokes, among other things.

The active ingredient TRV027 from Trevena (USA), which binds to the AT1 receptor, is also expected to have a preventive effect against thrombosis. The active substance is to be tested as part of the ACTIV-4 study programme. Binding to the AT1 receptor is expected to improve lung function and help prevent the formation of thromboses.

Clot-dissolving medicines are also being tested. Among others, Boehringer Ingelheim is testing such a drug with the active ingredient alteplase.

As far as combating lung and heart complications is concerned, various medical institutions are testing blood pressure-lowering medicines from the class of sartans. 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 risks 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 disease 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.

GSK 'sambrisentan (an endothelin receptor antagonist) is approved for the treatment of pulmonary arterial hypertension; it dilates the lung vessels, improving oxygen uptake into the blood, among other benefits. The drug 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 drug for hereditary angioedema. It is now also testing this drug for suitability against lung failure in severe Covid-19 disease.

Immune responses are generally desirable in infected patients, but they should not be so excessive that they do more harm than good in the lungs. Such an excessive inflammatory or immune reaction is called a "cytokine storm" because large quantities of messenger substances called cytokines are released. In some patients, this occurs. Several projects on Covid 19 therapy are therefore aimed at dampening such a reaction with suitable agents - they are called anti-inflammatories or immunomodulators.

One has already been approved for this purpose: Because an effective weakening of the immune reactions and thus reduction of mortality in severely ill patients succeeded in a study in the UK with dexamethasone, a cortisone derivative with a known anti-inflammatory effect: there, dexamethasone was able to reduce 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; and Germany and many other countries have granted it (the drug has national approvals, not a central EU approval). Treatment improvements have also been achieved in studies with the related cortisone derivatives hydrocortisone and methylprednisolone.

But in addition, numerous other medicines are in trials:

Several are designed to defuse Covid-19 by dampening a part of the immune system called the complement system.

  • This includes vilobelimab (IFX-1), which is being developed by the Jena-based company InflaRx for the treatment of various inflammatory diseases. Phase III within a Phase II/III study has started with Covid-19 patients in September 2020 - in the Netherlands, Germany and Peru. The compound is a specific inhibitor of the complement component C5a. The German Ministries of Education & Research and Health support the project.
  • The company Alexion as well as the University of Cambridge (UK) are testing another C5a inhibitor in Covid-19 patients with severe pneumonia: Ravulizumab. The drug is approved for the treatment of the rare paroxysmal nocturnal haemoglobinuria (PNH).
  • The Berlin-based company Aptarion Biotech is developing an L-aptamer to inhibit C5a. This molecule, called AON-D21, can limit the immune reaction according to tests carried out so far. With the support of the BMBF to the tune of 5.3 million euros, AON-D21 is being tested for safety and tolerability in Covid-19 patients (Accelerate-D21 study).
  • UCB is testing another C5 inhibitor in patients with severe Covid-19 disease. The compound zilucoplan has been in development for some time against myasthenia gravis (Phase III), immune-mediated necrotizing myopathy (IMNM), amyotrophic lateral sclerosis (ALS) and other complement-associated diseases. For the new project, UCB is collaborating within the COVID R&D Alliance.
  • The C3 inhibitor AMY-101 interferes with the complement system at a similar site. Amyndas Pharmaceuticals is also testing this compound in Covid-19 patients with severe pneumonia.

Another thrust is to block communication that immune cells by means of the messengers interleukin-1, interleukin-6 and interleukin-23 (IL-1, IL-6 and IL-23). From an initial larger number of projects, the following in particular have emerged:

  • Following positive study results, Sobi submitted an application to the EMA to extend the marketing authorisation for a drug containing the active ingredient anakinra for the treatment of certain Covid 19 patients. The drug is already approved (in combination with methotrexate) for the treatment of rheumatoid arthritis and for the treatment of cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever and Still's disease.
  • Also submitted to the EMA for a marketing authorisation extension is a medicine containing Roche's tocilizumab. This drug prevents interleukin-6 (IL-6) from taking effect. The medicine is already approved for other inflammatory diseases and as an adjunct to certain cancer therapies, and has now been tested in numerous trials in hospitalised Covid 19 patients. In the US, tocilizumab received emergency approval for use in covid-19 patients in June 2021.
  • The ACTIV-5 trial in the US is also testing risankizumab, which binds interleukin-23 and is approved to treat the autoimmune disease psoriasis.

Another possibility being tested is to prevent immune cells from communicating by means of the messenger TNF-alpha:

  • 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 kt on the observation that patients on continuous therapy with adalimumab for autoimmune disease show milder disease progression when infected with SARS-CoV-2. Sandoz's adalimumab is being used in the UK AVID-CC trial.
  • Another TNF-alpha inhibitor being tested is infliximab, which is part of the ACTIV-1 Trial conducted by the US National Institutes of Health (NIH). The company Janssen is providing it for this purpose. The WHO is also using infliximab as part of its SOLIDARITY trial; as a single infusion.

Another approach for a targeted immune attenuation is the blockade of the messenger substance GM-CSF, which belongs to the cytokines:

  • This is possible with the monoclonal antibody lenzilumab from Humanigen (USA). Its efficacy was investigated in a phase III trial. In the study, patients treated with this antibody had a better chance of being treated without ventilation. The US FDA has initially rejected emergency approval in the USA on the basis of the available data, but has invited the company to submit further data.
  • Interim results from a phase II/III trial with plonmarlimab, which is also directed against GM-CSF and is being developed by the company I-Mab, also point to a reduction in mortality and less need for mechanical ventilation.
  • The GM-CSF inhibitor Namilumab from Izana Bioscience, which has so far only been tested in patients suffering from rheumatoid arthritis and other autoimmune diseases, is also being tested.

Furthermore, a targeted immune attenuation by inhibiting the full activation of T-cells is attempted. This is possible with Abatacept from Bristol Myers Squibb. This drug is already approved for the treatment of rheumatoid and psoriatic arthritis. The drug is being tested in Covid 19 patients as part of the ACTIV-1 Trial of the US National Institutes of Health.

Researchers from the Berlin Institute of Health (BIH) found that cells infected with SARS-CoV-2 secrete messenger substances (chemokines) to attract immune cells, which can promote the dreaded exuberant immune response. Therefore, blocking the "receiving antennae" for chemokines on immune cells (the chemokine receptors or CCRs) is another approach:

  • According to BIH findings, the receptor CCR1 (also known as CD191) in particular plays a key role in this. The CATCOVID study is now investigating whether the CCR1 inhibitor BX471, which was previously developed by Bayer, is helpful in covid 19 patients. The Charité and the university hospitals in Leipzig and Würzburg are participating in the study. It is being financed by the BMBF with 3.7 million euros.
  • The blockade of other chemokine receptors is also being tested. For example, AbbVie's cenicriviroc blocks the receptors CCR5 and CCR2. The drug has been in development for some time for other diseases, but is still without approval. AbbVie is now making it available for testing with Covid-19 patients in the National Institutes of Health's ACTIV-1 trial in the US. A Phase II trial has also been conducted at the Charité Hospital in Berlin.
  • However, CytoDyn's CCR5 antagonist Leronlimab has so far failed to improve therapy in trials with Covid-19 patients. However, the company is also testing whether Leronlimab improves late effects in former Covid 19 patients.

Blocking the surface molecule CD3 on certain immune cells is also considered promising because it indirectly leads to the stimulation of regulatory T cells, which can dampen inflammation. Tiziana Life Sciences and FHI Clinical are therefore planning a phase II trial with hospitalized Covid 19 patients who receive the anti-CD3 antibody Foralumab intranasally.

Blockade of certain Toll-Like Receptors (TLRs) may also be effective. Toll-like receptors are molecules on cell surfaces that are normally part of an early warning system to initiate an initial defence against newly invaded pathogens. However, in the case of severe pneumonia caused by Covid-19, they may contribute to the immune overreaction.

  • Germany's Merck is testing M5049, a synthetic chemical immunomodulator that blocks TLR7/8, in a trial of hospitalized Covid 19 patients in the U.S., Brazil and the Philippines. It has been previously tested by the company against various immune diseases. To date, there is no approved drug in this class of medicines.
  • Canadian company Edesa Biotech has achieved positive results with its TLR4 inhibitor EB05 in a Phase II trial with hospitalized Covid 19 patients.

Also being tested is fosamatinib from Rigel Pharmaceuticals; in a phase III trial. 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 response. 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 covid-19 patients as part of the COMMUNITY study. The drug 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 antikallikrein antibody from Takeda, is also designed 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 drug is also designed to counteract fluid accumulation in the lungs.

US/German company Immunic Therapeutics is testing its immunomodulator IMU-838 in two Phase II trials in hospitalized Covid 19 patients (one as monotherapy, one in combination with oseltamivir). The drug is a selective oral inhibitor of the enzyme DHODH (dihydroxyorotate dehydrogenase). It slows down metabolism in activated T and B cells (which dampens the immune response), but has little effect on other immune cells. Initial data from clinical trials with patients indicate that IMU-838 can reduce mortality and the need for ventilation. The drug was previously in development for relapsing-remitting multiple sclerosis and other autoimmune diseases.

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 signaling pathway, has been tested against various inflammatory diseases since 2018.

The Swiss company MetrioPharm, which also operates laboratories in Berlin, has the immunomodulator MP1032 in development, which slows the activation of macrophages - a type of immune cell. It is intended for the treatment of autoimmune diseases and has already been tested with psoriasis patients. Now, however, a phase II trial with Covid-19 patients is also in preparation.

Several Janus kinase inhibitors are also being tested. They are already approved for the treatment of certain autoimmune diseases:

  • Lilly and Incyte have tested 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 one study, the combination of remdesivir and baricitinib reduced the recovery time of hospitalized Covid 19 patients even further than remdesivir alone. In the US, the combination therapy has been approved for emergency use in patients with Covid-19. In the EU, a marketing application has been submitted for monotherapy.
  • The Janus kinase inhibitor tofacitinib has also been successfully tested in hospitalized covid-19 patients.

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

Medicines from the class of Brutontyrosine kinase inhibitors are also being tested for their ability to dampen the immune response. They were originally developed for the treatment of cancer patients:

  • AstraZeneca's acalabrutinib has been approved for the treatment of certain leukaemias. Now the company is testing it in a clinical trial with Covid 19 patients.
  • Similarly,BeiGene's zanubrutinib is currently being tested. The company originally developed the drug for mantle cell lymphoma.
  • Sorrento Therapeutics (USA) has achieved positive results in a phase II trial with abivertinib. The drug targets mutated forms of Brutontyrosine kinase and the receptor EGFR. The company has been in the process of testing the drug for NSCLC-type lung cancer for some time.

Colchicine has been and continues to be tested in over 25 clinical trials as an agent to counteract excessive immune responses. In a major study at the Montreal Heart Institute, called COLCORONA, it was used to reduce the rate of hospital admissions and the risk of death, according to media reports. The drug also hastened the recovery of severely ill Covid-19 patients in a study in Greece. In parallel, the drug was tested in the adaptive multi-arm recovery trial (UK). The treatment failed to reduce mortality, so the colchicine portion of the trial was terminated. Colchicine dampens the activity of certain immune cells. The drug is approved for the treatment of gout and, in some countries, pericarditis.

Immune cells (macrophages and dendritic cells) are used by the Israeli company Enlivex to dampen 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 in Phase I and II trials, a Phase III trial is planned.

EDP1815 from Evelo Biosciences is a completely new type of immunomodulator. It contains the naturally occurring human intestinal bacterium Prevotella histicolaisolated 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 drug 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.

Resverlogix'sapabetalone is a BETi (bromodomain and extraterminal family inhibitor). The compound is under clinical investigation for the treatment of various diseases. In animal studies, apabetalone can prevent a fatal cytokine storm and also virus-triggered damage to the heart muscle. The manufacturer announced a clinical trial with Covid-19 patients. Apabetalone is an epigenetic agent that indirectly ensures that certain genes in cells are increased or decreased in activity.

Trimodulin is an antibody mixture (containing IgG, IgM and IgA antibodies) produced by the German company Biotest from blood plasma of healthy donors - regardless of whether they once had Covid-19 or not. It works in several ways: It counteracts attacks by the immune system on the body's own tissue (so in this respect it is immunosuppressive), but it promotes other immune system responses. A phase II trial showed a treatment benefit for a subset of Covid-19 patients treated as inpatients. The company now plans to conduct a phase III trial to determine whether the drug can protect hospitalized patients from severe respiratory failure and multiple organ failure. The German Federal Ministry of Education and Research (BMBF) is funding this project, called TRICOVID.

While the above-mentioned immunosuppressive medicines are or will be tested almost exclusively in severely ill patients, a British study tested whether they could also be used to help patients with a previously mild course of the disease in outpatient treatment. Specifically, an asthma inhaler with the active ingredient budesonide was tested, which, like dexamethasone, is structurally related to the natural hormone cortisone. Indeed, results from the STOIC trial of 146 participants suggest that the drug can reduce the risk of severe disease progression. The larger PRINCIPLE trial, with 2617 people aged 50 and over who tested positive, showed a faster recovery on average. The drug is now to be tested in a phase III trial.

The vital task of the lungs is to ensure the exchange of gases between the air we breathe and the blood. Severely ill corona patients are in danger of losing their lives if they are no longer able to do this adequately. It is then essential for recovery that the lungs can regenerate with functional tissue and not just scar tissue.

One of the medicines being tested for maintaining lung function contains the active ingredient aviptadil, a synthetic version of the molecule VIP, which occurs naturally in humans. The Swiss company Relief Therapeutics has marketing authorisation for this drug in the EU for the treatment of acute respiratory distress syndrome (ARDS) and sarcoidosis, but has not yet brought it to market in Germany. Among other things, the active substance has an anti-inflammatory effect and protects certain lung cells (alveolar type 2 cells) from viral attack. These cells are a preferred target of SARS-CoV-2 and are particularly important for maintaining lung function. NeuroRx, with the support of Relief Therapeutics, conducted a Phase II/III trial in the USA with severely ill Covid 19 patients (symptoms of severe lung failure; ventilated) following positive laboratory data. Patients recovered more quickly from respiratory symptoms with intravenous therapy. NeuRx subsequently filed for Emergency Use Authorization with the FDA. A long-term study (1-year follow-up) of patients with severe pre-existing conditions showed that VIP improved their survival by 60%. Relief Therapeutics has also started a Phase II trial with an inhalable formulation of the drug in collaboration with AdVita Lifescience in Saarbrücken, Germany. The aim here is also to prevent acute respiratory distress syndrome in Covid 19 patients.

The Canadian company Algernon Pharmaceuticals is testing its drug Ifenprodil (NP-120) for suitability in severely ill Covid 19 patients who require oxygen supply. A phase III trial has begun. The drug binds to the GluN2B receptor. It is thought that this may prevent the harmful over-activation of the immune system. Ifenprodil is approved off-patent in Japan and South Korea for the treatment of neurological diseases. Algernon has been developing a drug with this active ingredient for some time to treat idiopathic pulmonary fibrosis, a disease characterized by increasing shortness of breath.

The Viennese biotech company Apeptico wants to test its active substance Solnatide against acute respiratory distress syndrome (ARSD) for suitability for intensive care Covid-19 patients with severe lung damage. This project is funded by the EU with one and a half million euros. The Munich LMU Hospital is leading the clinical trial. In Austria, severely ill patients can be treated with Solnatide as part of a hardship programme. Solnatide is a synthetic peptide that is inhaled. It activates a sodium channel in the cells of the lung tissue, thereby helping to protect the tightness of the alveoli so that they do not fill with blood or tissue fluid.

The peptide compound FX06 from the Vienna-based company MChE/F4-Pharma is also expected to serve this purpose. It is being tested in the FX-COVID trial. Studies have previously been conducted to treat other vascular diseases with this drug.

The antibody Adrecizumab is also intended to prevent leakage from the pulmonary capillaries. It was developed by the German company Adrenomed for the treatment of sepsis and is currently being tested in clinical trials for this purpose (link: https://transkript.de/news/sepsis-antikoerper-der-adrenomed-ag-erreicht-endpunkt.html). It binds the peptide hormone adrenomedullin (ADM), which stabilizes endothelia but helps dilate blood vessels, thereby regulating blood pressure. The binding does not block the ADM, but on the contrary ensures that it can perform its task more effectively. In a recent small case study, eight Covid 19 patients, all of whom had pre-existing conditions and required invasive ventilation due to infection, were treated with the antibody. Only one patient died during the course of the study. With the support of the BMBF in the amount of 5.16 million euros, larger clinical efficacy studies can now be started.

A research team from the University of Ulm reported on the protection against inflammation and fibrotic changes in the lungs of Covid-19 patients by the endogenous protein angiotensin-(1-7). Angiotensin-(1-7) can stop the effect of another hormone (angiotensin II), which is significantly elevated in covid-19 patients and associated with high viral load and lung problems. But viral infection decreases the production of angiotensin-(1-7). In the STAMINA-Cov19 project, which is coordinated by the company Explicat Pharma in Hohenbrunn, an inhalable version of angiotensin-(1-7) is now to be developed as a drug. The project is funded by the BMBF with almost 4.2 million euros.

The drug PRS-220 from Pieris Pharmaceuticals is also directed against fibrotic changes ("scarring") in the lungs. Further details can be found in the section on Long Covid therapy.

Long covid is a catch-all term for the limitations and other symptoms experienced by some people who have actually survived covid-19 disease. They can occur after a disease with a severe course as well as after a course that is actually mild. Since the physical basis of many of these complaints is still unclear, only a few drug projects have been started so far. However, here are some examples of drug trials for one or another of the long covid symptoms:

  • For inflammation in the brain in Long Covid patients, US company Mercator is trialling its drug MD-004, which was invented as an epilepsy drug but has not yet been tested in this capacity with humans.
  • The University of Erlangen carried out individual healing trials in three Long Covid patients with the active substance BC 007 from Berlin Cures. This substance (it is an aptamer) had been developed for the treatment of patients with heart disease who had formed antibodies against the body's own proteins (certain receptors), which led to circulatory disturbances in the heart, among other places. Various symptoms(fatigue, memory and concentration disorders, lost sense of taste) improved in those affected by Long Covid. Clinical trials with BC 007 are planned.
  • Many Long Covid patients are affected by persistent fatigue. A study in the UK is testing whether the drug AXA1125 from Axzella can help these patients. It interferes with metabolic regulation in the mitochondria. It was originally developed to treat liver disease, but trials are still ongoing.
  • The company AIM plans to test the compound rintatolimod in a trial for the treatment of long covid. It activates the Toll-like receptor TLR-3 in airway epithelial cells; structurally, it is a double-stranded RNA with mismatached poly I : poly C12U.
  • Against pulmonary fibrosis (a "scarring" of the lungs) caused by Covid-19, the company Pieris (USA / Germany) is developing the inhalable drug PRS-220. Its active ingredient is an anticalin-type protein that acts as a CTGF inhibitor. Clinical trials are scheduled to begin in 2022. The project is funded by the state of Bavaria.
  • Whether a sense of smell lost or impaired as a result of Covid-19 can be regenerated by treating the nasal mucosa with vitamin A is currently being tested by the British University of East Anglia in a clinical trial. Such treatment must be medically supervised, as vitamin A must not be overdosed.

Footnotes

(1) 12 years old and weighing at least 40 kg, and with pneumonia requiring supplemental oxygen (low- or high-flow oxygen therapy or other non-invasive ventilation at the start of therapy)