Therapeutic medicines against coronavirus infection Covid-19

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

Major efforts are underway to develop even more effective medicines to treat people infected with the new coronavirus. Medicines of different types are needed. Most fall into one of the following four groups:

  1. Antiviral medicines. They are designed to prevent 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 disease.
  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 designed to help the lungs maintain their function during acute infection and then regenerate with as little consequence as possible.

1. Antivirale medicines

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

1.1 Antiviral medicines designed to intercept viruses while they are still in the upper respiratory tract

Ideally, it would be possible to catch the viruses in the upper respiratory tract long before they reach the lungs. That's why some companies and research groups are looking into using nasal sprays to catch SARS-CoV-2 viruses:

  • The company SaNOtize tested a nasal spray for its ability to kill coronaviruses in the nose before infection occurs. Called NONS (Nitric Oxide Nasal Spray), the spray contains nitric oxide (NO), which is already used as part of heart surgery. The spray significantly reduced viral loads in infected individuals within the first 24 hours of use, according to the manufacturer in a Phase II study in the UK. The company plans to seek regulatory approval in several countries.
  • The Australian company Starpharma claims for a nasal spray containing the active ingredient SPL7013 (a dendrimer) that it was able to prevent SARS-CoV-2 from entering cells in cell culture experiments. SPL7013 has been commercially available in approved products for some time. However, its efficacy has not yet been confirmed by clinical trials
  • Nasal sprays containing Iota-carrageenan (from red algae) have been commercially available for years as a medical product for the prevention and treatment of colds. Argentine researchers report in a pre-publication, non-peer-reviewed paper that this actually reduced the risk of infection in a placebo-controlled study with hospital staff. Another study by Austrian company Marinomed on this in the UK is ongoing; laboratory results on its product have already been published by the company.
  • The Swiss company APR Applied Pharma Research plans to test a nasal spray containing 0.005 percent hypochlorous acid in nanoparticles with volunteers.
  • Ursapharm (Saarbrücken, Germany), Cebina (Vienna, Austria), and the University of Pécz (Hungary) have begun testing nasal sprays containing azelastine with volunteers. Such nasal sprays are approved for allergy therapy; however, the compound also allowed SARS-CoV-2 to be combated in the laboratory.

Marinomed is also testing in a clinical study whether the active ingredient Iota-carrageenan administered as an inhalation solution improves the situation of corona patients treated as outpatients.

1.2 Antiviral medicines designed to prevent 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) (firmly anchored) on their surface. ACE2 is the actual binding site.

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

  • A corresponding medication has been developed by APEIRON Biologics (Vienna); the unanchored ACE2 in it has been named Alunacedase alfa (= APN01 or rhsACE2). In a clinical phase II trial in critically ill patients in Germany, Austria, and Denmark, a reduction in ventilator days and lowered viral load was observed; therefore, further investigation is planned in a US phase II trial. The compound originated in SARS research and has since been tested against other lung diseases.
  • The company Formycon from Planegg-Martinsried is also pursuing this strategy. However, for its compound FYB207, it has still genetically combined the unanchored ACE2 with an antibody section. Laboratory tests confirm this approach. A trial with volunteers is planned starting in Q4 2021.

Inhibition of the serine protease TMPRSS2 also promises to prevent viral invasion. This is possible with the agents Camostat, Nafamostat und Upamostat. Clinical trials with these agents are now underway in Covid-19 patients worldwide:

  • In one of these, being conducted by the Charité Research Organization in Berlin, the combination Camostat + niclosamide is being clinically tested.
  • The German Federal Ministry of Education and Research (BMBF) is funding an project in which the 50-fold stronger antiviral nafamostat is to be tested in intravenous administration; the development of a nasal spray with the active substance 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 study in Covid-19 patients who have mild or moderate symptoms.

Emergency approvals have already been granted for several antibody medicines in the US. And the EMA is already reviewing several of these medicines in a rolling review (i.e., an approval process in which application dossiers are submitted one at a time); these are medicines from Lilly, Regeneron/Roche, Celltrion, and GSK/Vir Biotechnology. In addition, it is developing recommendations for these medicines for national drug regulatory agencies that already want to give these medicines special approval for use in their own countries.

Here is information on some of the projects involving antiviral antibodies:

  • In developing the antibodies Bamlanivimab and Etesivimab, Lilly is collaborating with AbCellera (Canada) and Shanghai Junshi Biosicences (China). In the phase II BLAZE-1 trial, bamlanivimab did not show significant improvement in patients at risk with mild or moderate disease. In contrast, viral load decreased more rapidly with combination therapy than with placebo. In a phase III trial, the combination drug reduced the development of severe symptoms from 1.95% (placebo) to 0.5% (active drug). Of those treated with the antibodies, all survived; four people in the placebo group died. The figures match an earlier phase III trial, which had seen about a 70% reduction in hospitalization and mortality. In the EU, the combination is in a rolling review process for accelerated approval. At German university hospitals, bamlanivimab (monotherapy) is used with special approval according to the indication (high-risk patient, mild to moderate symptoms, no oxygen supplementation). Used preventively in residents and caregivers in nursing homes and assisted living facilities (phase III study BLAZE-2), it reduced the risk of diseaseaccording to the manufacturer by up to 80%. Similarly, in the phase II BLAZE-4 trial, the combination with Vir Biotechnology/GSK's VIR-7831 antibody reduced viral load by 70% compared with placebo. For large-scale production of the medicines, Lilly is collaborating with Amgen (U.S.) and Samsung BioLogics (South Korea). In view of the high demand and the limited production volumes for the time being, Lilly has worked out principles for itself to supply as responsibly as possible, including a tiered pricing system in addition to a focus on high-risk patients and other aspects.
  • Regeneron's antibody medicines REGN-COV2 contain the monoclonal antibodies casirivimab and imdevimab. They are derived from studies of antibodies from transgenic mice and former Covid-19 patients. The collaboration partner is Roche, which is expected to supply the EU and others. In a Phase II/III study of outpatients, REGN-COV2 reduced both hospitalization and mortality by 70 percent, even at lower doses than initially tested. REGN-COV2 also showed antiviral effects in treating hospitalized Covid19 patients. These initial trial data are being reviewed in the UK RECOVERY trial with hospitalized patients, designed with at least 2000 patients. - A Phase III study further tested 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, only after three weeks without this therapy. - According to an additional Phase III study, the drug also helps asymptomatic subjects with fresh infection: according to a Phase 3 study, it reduced viral load by 90% and the risk of developing symptoms by about half. Following a notice from the Data Monitoring Board, which is responsible for a patient study, Regeneron will not continue testing in ventilator-dependent patients. For large-scale production, Regeneron received support from the US 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 medicines: its antibody is called Regdanvimab (CT-P59). It is currently being tested to determine whether it is suitable for therapy (phase II/III) and posure prophylaxis (phase III). Interim results from the therapy trial suggest a reduction in recovery time and less frequent progression of disease to a more severe stage in patients with mild to moderate symptoms. A rolling review has begun for Celltrion's medicines at the EMA. The company intends to apply for emergency approval in South Korea.
  • The antibody Sotrovimab = VIR-7831 from Vir Biotechnology/GSK is modeled on an antibody from the blood of a person who contracted SARS in 2003. It is currently being tested with patients in the COMET-ICE phase II/III trial, among others (under the ACTIV-3 protocol, sponsored by the US National Institutes of Health [NIH]). According to preliminary results, the antibody reduces hospitalizations and deaths by 85%. GSK then applied to the FDA for emergency approval. The companies also began a rolling submission to the EMA and provided it with interim results for a recommendation to member states and plan to submit a marketing authorization application. The companies Biogen (USA) and WuXi Biologics (China) are involved in the production of the medicines.
  • Celltrion (South Korea) has also developed such a medicines: its antibody is called Regdanvimab (CT-P59). It is currently being tested to determine whether it is suitable for therapy (phase II/III) and posure prophylaxis (phase III). Interim results from the therapy trial suggest a reduction in recovery time and less frequent progression of disease to a more severe stage in patients with mild to moderate symptoms. A rolling review has begun for Celltrion's medicines at the EMA. The company intends to apply for emergency approval in South Korea.
  • AstraZeneca (UK) has developed a medicine with two genetically engineered antibodies derived from antibodies found by the US Vanderbilt University in the plasma of two healthy patients. They were modified to remain in the blood longer than ordinary antibodies. The medicines are called AZD7442. Following positive interim results, it is now being tested in a phase III trial (ACTIV-3), first in sufferers with mild symptoms and later also in hospitalized patients, to determine whether it is suitable for treating covid-19. The Lonza company will participate in production at a U.S. site.
  • A combination drug with two antibodies (SARS-CoV-2 mAb Combo) is also being worked on by Bristol Myers Squibb with The Rockefeller University. The antibodies have been optimized for long residence times in the body. Clinical trials, in which the medicines will be administered partly intravenously and partly subcutaneously, began in January 2021.
  • The CORAT consortium relies on a similar approach, using the laboratory method "phage display." The consortium includes Braunschweig-based CORAT, Yumab, the Helmholtz Center for Infection Research (Braunschweig), the Technical University of Braunschweig and the University of Tübingen. Since April, the antibody COR-101 has been tested in a phase Ib/II study with volunteers. COR-101 was designed so that the antibody can be administered even when a further increase in inflammation needs to be avoided
  • Also in Germany, the Berlin-based Charité, the German Center for Neurodegenerative Diseases (DZNE) and the biotech company Miltenyi Biotec are working on such a medicine. Positive results from experiments with animals are available
  • In Germany, a consortium of the Uniklinik Köln, the University of Marburg, the German Center for Infection Research (DZIF), and the Boehringer Ingelheim company is also developing medicines with the antibody BI 767551, which was derived from convalescent plasma. The special feature: The ongoing Phase I/IIa trial is testing both injection and inhalation application.
  • The company Aridis is also developing a medicines with a recombinant antibody for inhalation (AR-711).
  • Another antibody derived from convalescent plasma is being developed by Memo Therapeutics and Northway Biotechpharma (Switzerland and Lithuania). Clinical trials have not yet begun.
  • Another company active in the field BeiGene (China). It is testing under license neutralizing antibodies copied from convalescent patients by the company Singlomics Biopharmaceuticals, which are produced by genetic engineering.
  • Other antibodies that neutralize the Covid-19 virus in laboratory tests were developed by researchers from Tsinghua University in Beijing and the company Brii Biosciences. The antibody duo BRII-196 and BRII-198 have now been tested in the U.S. ACTIV-3 trial, but failed to meet the trial objective in hospitalized patients. The study will now investigate whether the antibodies have positive effects in less severely ill patients treated as outpatients. The drug is also being tested in Hong Kong.
  • A three-antibody cocktail of this type is also being developed at Tel Aviv University (Israel). So far, positive laboratory results have been obtained.
  • Another project of this type is being pursued by the Swedish Karolinska Institut.
  • The Imperial College London is working with partners on another antibody therapy starting from antibodies derived from the blood serum of former SARS patients.
  • Scientists at University of Utrecht (Netherlands), for example, have also studied antibodies to SARS; however, 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. Now called "human 47D11," this antibody is being further developed by Utrecht University jointly with the companies AbbVie and Harbour BioMed, as well as the Erasmus Medical Center. The antibody is currently being tested in a Phase I trial for tolerability and dissemination in the body.
  • Researchers from 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) gene-modified mice as a source of suitable antibodies.

Several companies and research groups are working on medicines using nanobodies instead of ordinary antibodies. That's the name of smaller antibodies produced by llamas and alpacas. They are easier to make than ordinary antibodies and (unlike them) can be kept at room temperature for longer periods of time.

Not only classical antibodies and nanobodies, but also molecules of a completely different design can be used to bind proteins and thus alter or suppress their function. Researchers are specifically looking for such artificial binders that attach to SARS-CoV-2 and thereby prevent the virus from entering and replicating in a cell. 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 it against SARS-CoV-2:

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

On the other hand, the company Aptarion biotech's aptamer 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 partnered with Novartis to develop a compound against SARS-CoV-2 that prevents severe deaths in hamsters. It is now being tested in a Phase IIa study with patients following a Phase I tolerability study. It will also subsequently be tested in Phase II/III trials, including under the U.S. ACTIV-3 protocol.

In turn, the Scottish company Elasmogen and the University of Minnesota (USA) are relying on a type of molecule that sharks make 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 primary agents considered for blocking viral replication within cells. These are usually produced by chemical synthesis. Many agents under investigation (including the only one approved to date) were originally developed to treat a different viral infection.

One way to prevent replication is to block RNA polymerase with an inhibitor:

  • So Remdesivir was originally developed by Gilead Sciences against Ebola infections, against which it did not prove effective. However, the drug showed efficacy against MERS viruses in the laboratory. In several clinical trials, the medicines were able to shorten the duration of illness by several days in patients at certain stages of the disease. As a result, the Covid-19 treatment drug received emergency use approval in the U.S., approval in Japan and, in July, conditional approval in the EU, among others. About half of all Covid 19 patients hospitalized in the U.S. - as of January 2021 - receive remdesivir. However, no such effect was observed in the WHO multinational SOLIDARITY Trial. How to understand this discrepancy is currently being investigated; it may show that the disease stages in which the drug has an effect need to be defined more precisely. The current data has been summarized by the RKI. The manufacturer has granted licenses to several other companies at once to produce and distribute their own Remdesivir medicines for certain regions of the world.
  • Favipiravir, another RNA polymerase inhibitor, from FUJIFILM Toyama Chemical, initially had approval only for influenza therapy (in Japan and China) and is only for second-line therapy in Japan, i.e., when other influenza drugs are not effective or insufficiently effective. After appropriate studies, a medicines based on it from the Russian company Khimrar was approved in Russia for Covid-19 therapy. Fujifilm Toyama Chemical now also plans to apply for expansion of approval in Japan following positive study results.The drug was shown to shorten the time it takes for symptoms to subside or viral loads to fall below the detection limit by an average of several days in a study of patients who were not severely ill with pneumonia. However, Japanese drug authorities classify the evidence for the drug as "inconclusive". A Phase III study is reviewing the effects of favipiravir. In February 2021, the analysis of nine trials in a meta-analysis found that while favipiravir may provide benefit to newly hospitalized patients, it may not reduce mortality in those with mild to moderate disease.
  • The third RNA polymerase inhibitor, Molnupiravir (= MK-4482), was also initially developed by MSD for influenza therapy, but has not yet made it to regulatory approval there. Now it is being tested with Ridgeback Biotherapeutics in a Phase III study with high-risk patients who have had symptoms for 5 days or less but are not hospitalized. MSD has entered into licensing agreements with five Indian generic manufacturers so that the drug can be made available quickly in large quantities if successful.
  • The fourth RNA polymerase inhibitor is called AT-527. Atea Pharmaceuticals (USA) originally developed this synthetic chemical (a purine nucleotide derivative) against hepatitis C viruses (and reached Phase II there). Now, together with Roche (Switzerland), the company is testing AT-527 in a Phase II trial against SARS-CoV-2. A Phase III trial in outpatients is also planned.

Another target is an enzyme of SARS-CoV-2 called major protease or 3CL protease. It participates in the formation of finished viruses in infected cells:

  • Pfizer is testing new antiviral agents PF-07321332 and PF-07304814 in the U.S. in Phase I studies. Both molecules block the major protease in cell cultures.
  • 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 said 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, named "13b", is optimized against coronaviruses. It will be tested in cell cultures and with animals and, if positive, will be tested in human trials in collaboration with a pharmaceutical company.
  • Research teams at the German Electron Synchrotron (DESY) and at the Bernhard Nocht Institute for Tropical Medicine (both in Hamburg) investigated whether there might also be inhibitors of the main protease among agents developed for other purposes. From their laboratory trials, Calpeptin and Pelitinib emerged as candidates that are now being further investigated in preclinical studies. Neither compound has yet been approved against any disease in Germany.

However, SARS-CoV-2 also possesses a second enzyme of the protase type: "papain-like protease" (PLpro). It, too, represents an interesting target:

Some components of viruses must reach the nucleus after entering a cell. They use microtubules - a type of "monorail" that is part of the cell's skeleton - as a means of transport from the cell membrane to the nucleus. The synthetic chemical Veru-111 from Veru 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 cancers and will be evaluated in a phase III trial for potential effect in hospitalized high-risk Covid-19 patients.

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

  • An inhibitor of this enzyme is ATR-002, developed by Atriva Therapeutics in Tübingen, Germany. Testing began in early 2021 in a Phase II study of hospitalized patients with moderate-to-severe covid-19 in Germany and other countries. ATR-002 was originally developed as an influenza drug. It has immunomodulatory activity in addition to antiviral activity.

The drug Brilacidin from the company Innovation Pharmaceuticals can prevent the proliferation of SARS-CoV-2 in cell cultures. It also inhibits the formation of interleukins and tumor necrosis factor alpha, which are essential in stimulating an inflammatory response. It is currently being tested in a Phase II trial involving hospitalized Covid-19 patients. It also has anti-bacterial activity. The FDA granted brilacidin fast track status to accelerate development and testing of the compound.

Spanish company PharmaMar is testing its drug with Plitidepsin in a trial against Covid-19 after encouraging laboratory tests. The medicines, which are actually approved in Australia and Southeast Asia for the treatment of multiple myeloma (a form of bone marrow cancer), are thought to inhibit viral replication by blocking the protein EF1A, which is needed for this purpose, in infected cells.

Scientists at 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. This is similarly true of the drugs Amiodarone and Imipramine. The drug fluvoxamine, also an ASM inhibitor approved for depression, simultaneously has a high affinity for the sigma-1 receptor (S1R). This in molecule exerts many functions, including regulating the production of cytokines during an immune response. In preclinical tests, fluvoxamine had been found to decrease cytokine production typical of severe sepsis, thereby increasing survival. In a first study with symptomatic covid-19 patients, the agent showed a positive effect. An observational study in employees at a horse racing stable in California after a massive corona outbreak also ended with this result. Several Phase II trials of fluvoxamine and fluoxetine are currently underway.

Already approved elsewhere, namely for mites and parasitic nematodes (river blindness), are medicines containing Ivermectin. The drug was developed decades ago by MSD (called Merck in the US). It is being tested in trials to see if it can help Covid 19 patients. Two evaluations of results from several studies each concluded that the drug can reduce the rate of hospitalizations and lower the risk of death. In contrast, another such meta-analysis saw no such effect. In a placebo-controlled study of younger patients in Colombia, the treatment also produced no benefit. MSD assesses the results to date for Covid-19 therapy negatively. The EMA advises against using imvermectin outside of clinical trials. However, in Czech Republic, the drug is used with special permission.

The tapeworm drug niclosamide, developed many years ago by the Bayer company, enhances the cell's own "garbage processing" (autophagy). This process is throttled in cells infected with SARS-CoV-2. In laboratory experiments at the Berlin Charité, the agent has been shown to lower viral replication - as it has with spermidine (an endogenous substance) and MK-2206 (an anti-breast cancer agent). Meanwhile, therapy of Covid-19 patients with niclosamide in combination with camostat is being tested in a phase II trial conducted by the Charité Research Organization in Berlin.

A different plan is being pursued by the 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 U.S.) want to achieve this using so-called siRNA agents. The South Korean company OliX Pharmaceuticals is also working on a compound of this type. Germany's Biotech Secarna and China's Guangzhou's Sun Yatsen University aim to achieve gene silencing using an antisense oligonucleotide - a molecule from a related class of compounds.

By contrast, an older HIV medicines with the lopinavir/ritonavir drug combination has not proven effective against covid-19. It had been tested in the SOLIDARITY Trial, among other trials.

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 first tested in trials in China, and later in other countries. However, the results of several studies indicated that the medicines did not have a positive risk-benefit balance, and often even made the situation worse. Therefore, the chlorquine/hydroxychloroquine study arm in the WHO SOLIDARITY trial was halted and an interim emergency approval for hydroxychloroquine in the United States was rescinded.

The use of another antimalarial agent is being promoted, particularly in Africa: Artemisinin. It is otherwise part of antimalarial combination drugs taken as tablets. Against covid-19, it is used as a drink. At the Max Planck Institute Potsdam and other research institutions, the compound's effectiveness against SARS-CoV-2 is being systematically studied in laboratory trials. WHO now also wants to test artemisinin in its SOLIDARITY Trial.

1.3 Antiviral medicines that boost immune defenses


Some medicines do not fight viruses directly, but are designed to boost the body's immune defenses. One of these is being developed by the German company AiCuris: Its stimulatory immunomodulator contains parapoxviruses and was originally developed to treat hepatitis B; it has also already completed a Phase I trial with patients for that purpose. It will now be tested with some asymptomatic corona patients in anticipation of an enhanced immune response.

Already tested in several trials is a group of other immune modulators: the 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 various alpha and beta interferons have so far shown no benefit for Covid-19 therapy. Only interferon alpha-2b (PegIFN) was shown to be helpful in the Phase III PegiHep trial, prompting manufacturer Zydus Cadila to file an registration application in India for the compound already used to treat hepatitis C. Also still further along in trials is peginterferon lambda. It has been tested in Canada in a Phase II study. In patients treated with the drug, viral load decreased faster and symptoms disappeared sooner than in control patients. A Phase III trial is being planned. First described in 2002, this interferon, like other interferons, activates an antiviral immune response. However, unlike other molecules in the class, it becomes active primarily in certain cells of the lung, liver and intestine because these cells have the appropriate receptor. These organs are targeted by SARS-CoV-2. Targeting there could reduce or avoid side effects in other organs that can be triggered by inteferons. The compound is also being developed by Eiger BioPharmaceuticals to treat the viral disease hepatitis D.

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

Anticoagulant low-molecular-weight heparins (such as those otherwise injected into patients after certain operations) have already proven effective against the risk of thrombosis. Their use is therefore also recommended by the relevant therapy guideline (and does not require a separate Covid-19 approval). Specifically, the low-molecular-weight heparin enoxaparin 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 the similarly anticoagulant Bivalirudin 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 Chimerix company in Covid-19 patients in a Phase II/III study. 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 survival in severely ill Covid-19 patients.

The efficacy of heparin-derived agents is unlikely to be due to anticoagulation. This is because studies have shown that SARS-CoV-2 also possesses binding sites for the heparin-like cell attachments that help the virus achieve its first cell contact even before it goes to ACE2. Heparin agents can prevent this.

However, anticoagulants 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 now being tested in a clinical trial as a therapy for hospitalized covid-19 patients. ASA is approved for the prophylaxis of heart attacks and strokes, among other indications.

Clot-busting medicines are also being tested, including those with the active ingredients Alteplase and Tenecteplase (Boehringer Ingelheim).

As for combating pulmonary and cardiac complications, several medical institutions are testing antihypertensive agents from the sartan class. These include telmisartan, valsartan, losartan, and candesartan. However, an Irish study is also examining whether this class of antihypertensive drugs (as well as the class of ACE inhibitors) may actually pose risks to covid-19 patients.

An analysis of medical records in the United States by a health insurer suggests that elderly covid-19 patients who took medicines from the ACE inhibitor class as continuous therapy independently of this condition required hospitalization less often. Therefore, a clinical trial is now planned in which patients who have not yet developed the disease (and who are not currently using an ACE inhibitor) will take either a low-dose ACE inhibitor or placebo. Research will be conducted to determine whether the different medication affects disease progression in participants who later develop covid-19. In a different study, the ACE inhibitor ramipril is being tested specifically in hospitalized covid-19 patients. To date, ACE inhibitors have been approved to lower hypertension and prevent atherosclerosis.

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

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

3. Attenuating immunomodulators


Immune responses are generally desirable in infected individuals; they just must not be so excessive that they do more harm than good in the lungs. Such an excessive inflammatory or immune reaction is called a "cytokine storm" because large amounts 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 attenuation of 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 a fifth or a third. A corresponding extension of approval was recommended by the EMA in September 2020. Therapy improvements have also been achieved in studies with the related cortisone derivatives hydrocortisone and methylprednisolone.

But beyond that, 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.

  • These include vilobelimab (IFX-1), in development at Jena-based InflaRx for the treatment of various inflammatory diseases, among others. With Covid-19 patients, Phase III within a Phase II/III study has started in September 2020 - in the Netherlands, Germany and Peru. The compound is a specific inhibitor of complement component C5a.
  • 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 medicines are approved for the treatment of the rare paroxysmal nocturnal hemoglobinuria (PNH).
  • UCB is testing another C5 inhibitor with patients with severe covid-19 disease. The compound, Zilucoplan, has been in development for myasthenia gravis (Phase III), immune-mediated necrotizing myopathy (IMNM), amyotrophic lateral sclerosis (ALS), and other complement-associated diseases. For the new project, UCB is collaborating as part of the COVID R&D Alliance.
  • Similarly, the C3 inhibitor AMY-101 interferes with the complement system. Amyndas Pharmaceuticals is also testing this agent in Covid-19 patients with severe pneumonia.

Another thrust is to block communication between immune cells by messengers from the interleukin group:

  • inconsistent study results have been reported from the Covid-19 treatment of patients with pneumonia treated with Roche's interleukin-6 antagonist tocilizumab, which is approved for the treatment of inflammatory conditions. Whereas the EMPACTA trial of hospitalized patients but who did not require oxygen was found to reduce the risk of death and the need for ventilation, the COVACTA trial did not. A trial of tocilizumab in combination with Gilead's redesivir (REMDACTA trial) in patients with severe pneumonia also showed the treatment had no effect. An study of critically ill patients again found a reduction in the risk of death.
  • The same is true of Sanofi's interleukin-6 antagonist Sarilumab: it, too, was found to reduce the risk of not surviving the disease in a study with critically ill patients.
  • A drug that directly targets interleukin-6 is also now being tested in the Phase III SILVAR trial with critically ill patients, following positive results in a smaller study: siltuximab from EUSA Pharma. The medicines contains an interleukin-6 neutralizing antibody and is approved for the treatment of multicentric Castleman disease, a form of lymph node tumor.
  • Novartis is conducting a clinical trial of its immunomodulator canakinumab (an interleukin-1 beta blocker) in many countries, including Germany. The medicines are approved for the treatment of several autoimmune diseases-including various periodic fever syndromes, Still's syndrome, systemic juvenile idiopathic arthritis-and gouty arthritis.
  • The ACTIV-5 trial in the United States is also testing risankizumab, which binds interleukin-23 and is approved to treat the autoimmune disease psoriasis.

Blockade of immune cell communication using the messenger TNF-alpha is also being tested as a treatment option:

  • The TNF-alpha inhibitor adalimumab, which is approved for rheumatoid arthritis and other conditions, is also being tested with patients with the goal of preventing progression of the disease to a severe or critical stage. This kicks off 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 AVID-CC trial in the U.K.
  • Another TNF-alpha inhibitor being tested isinfliximab, as part of the ACTIV-1 Trial conducted by the U.S. National Institutes of Health (NIH). The Janssen company is providing it for this purpose. WHO is also planning to trial this agent, as part of its SOLIDARITY trial.

Another approach to targeted immune dampening is to block the messenger GM-CSF, which is a cytokine:

  • This is possible with the help of the monoclonal antibody Lenzilumab from Humanigen (USA). Its efficacy was studied in a phase III study. In the study, patients treated with it had a better chance of being treated without ventilation. The company has announced regulatory filings in the U.S., U.K., and EU.
  • The same mode of action is shared by Otilimab. This antibody is also being tested by GSK in a study of Covid 19 patients. Otilimab was originally developed by Morphosys and then tested against rheumatoid arthritis; however, approval for it is pending.
  • Also being tested is the GM-CSF inhibitor Namilumab from Izana Bioscience, for which there have so far been studies only in patients with rheumatoid arthritis and other autoimmune diseases.

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

Blockade of CCR receptors on immune cells is another approach:

  • Blocking the CCR5 and CCR2 receptors is Cenicriviroc from AbbVie. The company has developed the drug for other diseases but does not yet have approval. The company is now making it available for testing with Covid-19 patients as part of the National Institutes of Health's ACTIV-1 Trial in the United States. A phase II trial was conducted at Charité Berlin.
  • However, the CytoDyn company has so far not been able to improve therapy with the CCR5 antagonist Leronlimab in studies with Covid 19 patients. However, the company is also testing whether leronlimab also improves late effects in former Covid-19 patients.

The German company Merck is testing M5049, a TLR7/8 inhibitor-type chemical synthetic immunomodulator, in a study of hospitalized Covid-19 patients in the United States, Brazil, and the Philippines. It has been previously tested by the company against various immune diseases. To date, there is no approved medicine in this class of drugs.

Also being tested in the U.S. 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 - NETs - by certain white blood cells. This mechanism is part of the innate immune defense. Misdirected immune responses involving the formation of NETs contribute significantly to the dangerousness of the severe stage a covid 19 disease because they promote the formation of thromboses. This was discovered at the University of Nuremberg-Erlangen and elsewhere.

Amgen is testing apremilast, a phosphodiesterase IV inhibitor (PDE4 inhibitor), in hospitalized Covid 19 patients as part of the COMMUNITY study. The medicines are approved for the oral treatment of psoriasis and psoriatic arthritis. For the new project, the company is collaborating as part of the COVID R&D Alliance.

Also expected to dampen immune responses is lanadelumab, an antikallikrein antibody from Takeda. It was developed for the treatment of rare heriditary angioedema and has been tested in trials, but does not yet have regulatory approval. The company is testing it in COMMUNITY trial of the COVID R&D Alliance in hospitalized Covid 19 patients. The medicines are additionally expected to counteract fluid buildup in the lungs.

The U.S./German company Immunic Therapeutics is testing its immunomodulator IMU-838 in two phase II studies with hospitalized Covid-19 patients (once as monotherapy, once in combination with oseltamivir). The drug is a selective oral inhibitor of the enzyme DHODH (dihydroxyorotate dehydrogenase). It slows metabolism in activated T and B cells (which dampens the immune response) but has little effect on other immune cells. Preliminary data from clinical studies with patients suggest that IMU-838 may reduce mortality as well as the need for ventilation. The medicine was previously in development as a treatment 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 in trials 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 to treat autoimmune diseases and has already been tested with psoriasis patients for this purpose. Now, however, a Phase II trial with Covid-19 patients is also in the works.

Lilly and Incyte have been testing their Janus kinase inhibitor baricitinib (in part, combination with remdesivir) in hospitalized Covid 19 patients. It has so far only been approved for rheumatoid arthritis. In an study, administration of both medicines shortened recovery time compared with remdesivir alone. Very severely ill patients benefited more markedly than patients with milder symptoms. In an study, the combination of remdesivir and baricitinib shortened the recovery time of hospitalized covid-19 patients even further than remdesivir alone. In the U.S., the combination therapy has been approved for emergency use in patients with Covid-19. A marketing authorization application has been submitted in the EU for monotherapy.

Also in development as an anticancer drug is opaganib from the Israeli/US company RedHill Biopharma. This sphingosine kinase 2 (SK2) inhibitor has shown anti-inflammatory, as well as antiviral, activity in preclinical studies. This could be useful for the treatment of covid-19-related pneumonia. The medicines have been tested in a Phase II study in the United States. Initial analyses of the study show positive results.

Also, Acalabrutinib, a Bruton tyrosine kinase inhibitor from AstraZeneca, was developed for cancer therapy and has approval for the treatment of certain leukemias. Now the company is testing it to dampen excessive immune responses in Covid-19 in a clinical trial.

Zanubrutinib is also a Bruton tyrosine kinase inhibitor that was originally developed for one type of cancer (mantle cell lymphoma). Now it is being tested by the Chinese company BeiGene in patients with severe covid-19 infection.

In more than 25 clinical trials, Colchicine has been and continues to be tested as a treatment for exaggerated immune responses. In a larger study at the Montreal Heart Institute, called COLCORONA, it was used to reduce rates of hospital admissions and 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 dim the immune system back down in the event of a cytokine storm. Its cell therapy Allocetra was already in development for sepsis before the pandemic. After successful trials in Phase I and II studies, a Phase III trial is planned.

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

Apabetalone from Resverlogix 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 as well as virus-triggered damage to heart muscle. The manufacturer announced a clinical trial in Covid-19 patients. Apabetalone is an epigenetic agent that indirectly causes certain genes to be increased or decreased in activity in cells.

The Berlin-based company Aptarion biotech is working on an aptamer (an L-aptamer) for immune attenuation in covid-19, for which it has funding approval from the BMBF. While the aforementioned immune-suppressing medicines are or will be tested almost exclusively in severely ill patients, a British study tested whether they could also help patients with a previously mild course in outpatient treatment. Specifically, an asthma inhaler containing the active ingredient budesonide was tested, which, like dexamethasone, is structurally related to the natural hormone cortisone. Indeed, results from the STOIC study involving 146 participants suggest that the drug can reduce the risk of severe disease progression. The larger PRINCIPLE Trial, with 2617 people aged 50 and older who tested positive, showed faster recovery on average. The medicines will now be tested in a phase III trial.

4. Medicines for lung function

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 this can no longer be done adequately. Subsequently, it is 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 naturally occurring molecule VIP found in humans. The Swiss company Relief Therapeutics has approval for it 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 ingredient has an anti-inflammatory effect and presumably protects certain lung cells (alveolar type 2 cells) from viral attack. They are a preferred target of SARS-CoV-2 and are particularly important for maintaining lung function. The company NeuroRx conducted following positive laboratory data with support from Relief Therapeutics in the U.S. a Phase II/III study with severely ill Covid-19 patients (symptoms of severe lung failure; ventilated). Patients recovered more quickly from respiratory symptoms under intravenous therapy. Now NeuRx plans to apply for Emergency Use Authorization from the FDA. Relief Therapeutics has also begun a Phase II trial in with an inhalable formulation of the drug in collaboration with AdVita Lifescience of Gundelfingen, Germany. The goal here is also to prevent acute respiratory distress syndrome in Covid-19 patients.

It is now being tested in studies by Relief Therapeutics and NeuroRx (USA) in COVID-19 patients with acute respiratory failure who are receiving intensive care. Initial tests showed that ventilated Covid-19 patients improved rapidly and significantly. The drug received emergency approval from the FDA.

Canadian company Algernon Pharmaceuticals is testing its medicines ifenprodil (NP-120) for suitability in critically ill Covid-19 patients who require oxygenation. A Phase III trial has begun. The drug binds to the GluN2B receptor. It is thought to prevent the harmful overactivation of the immune system. Ifenprodil is approved off-patent in Japan and South Korea for neurological diseases. Algernon has been using this compound to develop a medicine for idiopathic pulmonary fibrosis, a disease characterized by increasing shortness of breath.

Vienna-based biotech Apeptico plans to test its Solnatide compound for acute respiratory distress syndrome (ARSD) for suitability in intensive care Covid-19 patients with severe lung injury. This project is funded by the EU with one and a half million euros. The Munich LMU Klinikum is leading the clinical trial. In Austria, severely ill patients can be treated with Solnatide as part of a hardship program. Solnatide is a synthetic peptide that is inhaled. It activates a sodium channel in the cells of the lung tissue, thereby helping to restore the tightness of membranes there.

It is intended to restore the tightness of membranes in lung tissue.

The peptide compound FX06 from the Vienna-based company MChE/F4-Pharma is also intended to serve this purpose. A clinical trial is in preparation. The medicines were developed to treat other vascular diseases, for which they have already been tested in clinical trials.