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.

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.

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:

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:

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:

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.

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.

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:

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.

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 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:

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

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:

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.

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:

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.

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:

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

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

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:

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.

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:

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:

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: