Therapeutic medicines against coronavirus infection Covid-19
Thanks to intensive R&D activities by companies, several therapeutic medicines have already been approved against the SARS-CoV-2 infection Covid-19. Other medicines are in trials: some new, some already approved for other diseases. Here is an overview.
Although the development of therapeutics against covid-19 is largely taking longer than that of the first vaccines, it is also proceeding far more rapidly than is usually the case in the drug industry.
The approved Covid-19 drugs
This table shows which therapeutic drugs have been approved or submitted for approval.
First fundamentally new drugs received approval less than two years after the start of the project; typically, ten years or more are required. The rapid pace is due in part to prioritization within companies and speedy study approval processes in many countries.
Drugs of different types are needed, depending on disease stage and complications. Most fall into one of the following five groups:
- Antiviral medicines. They are designed to prevent viruses from entering or replicating in body cells.
- Cardiovascular medicines. They are intended to protect the blood vessels, heart, and other organs from complications caused by covid 19 disease (especially thrombosis).
- Attenuating immunomodulators. They are intended 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.
- Medicines for lung function. They are intended to help the lungs maintain their function during the acute infection and then regenerate with as little consequence as possible.
- Medicines against long covid, i.e. persistent symptoms after the actual covid 19 disease has subsided.
It should be borne in mind that drugs that are helpful in the early stages (infection without respiratory problems) may be ineffective or even harmful in patients with severe pneumonia - and vice versa. This should be kept in mind when news spreads about a success or failure with a drug.
Currently, more than 460 different drugs are being tested to see if they can be helpful against covid-19 in one way or another, according to U.S. association BIO. As of Dec. 14, 2022, it counted 205 antiviral and 263 other therapeutic drugs in development. Most of these agents are already approved for another disease, or at least were in development against it before the pandemic. Repurposing them ("repurposing") is usually faster than basic new development. Increasingly, however, the drugs in clinical trials include those whose development did not begin until 2020 or later.
Further information on some therapeutic drugs (some in trials, some approved) 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 drugs can prevent this by intercepting the viruses even before they enter cells; or they block the multiplication process in the cells; or they strengthen the body's own virus defense.
1.1 Antiviral drugs that prevent viruses from entering cells
SARS-CoV-2 viruses primarily use cells in the respiratory tract to replicate. They attempt to invade these when they are freshly inhaled. However, the SARS-CoV-2 viruses that then develop in these cells also look for new respiratory tract cells immediately after their cell exit. However, they presumably only succeed in penetrating cells that carry (firmly anchored) the molecule ACE2 on their surface. They bind to this molecule (however, some research teams are investigating whether another molecule can also take over the role of ACE2). Formation in most SARS-CoV-2 viruses also required another cell surface-anchored molecule: TMPRSS2 (pronounced "Tempress Two"), a serine protease-type enzyme. However, the omicron variants of SARS-CoV-2 do not need TMPRSS2.
Fighting infections with antibodiesGenetic
antiviral antibodies are new, but the approach is old: for more than 100 years, patients with certain infectious diseases or poisonings have been injected or infused with antibodies, but these come directly from the blood serum of humans or animals that have survived the disease in question. Emil von Behring's diphtheria antiserum of 1891 already worked in this way. Well-known are the injections for people who might have contracted tetanus.
Most projects in which viruses are to be intercepted are based on antiviral antibodies produced by genetic engineering. The model for these is usually antibodies from the blood plasma of former corona patients - antibodies that have contributed to a successful recovery. Researchers select antibodies that are particularly effective in blocking viruses in the laboratory, modify them specifically (e.g., to extend their residence time in the organism), and then produce them genetically in large quantities using cell cultures. Other companies and research groups have developed their antibodies using variants of this strategy. Sometimes they combine two different antibodies in one drug. A tabular overview of all ongoing projects for SARS-CoV-2 neutralizing antibodies and related drug molecules is provided by the Antibody Society.
The EU has granted marketing authorization for four antibody drugs: For a combination drug with casirivimab + imdevimab from Roche / Regeneron (for prevention and therapy), a monopreparation with regdanvimab from Celltrion (for therapy), for another monopreparation with sotrovimab from GSK / Vir Biotechnology (for therapy) and for another combination drug from AstraZeneca with tixagevimab and cilgavimab (for prophylaxis and therapy). Previously, for several drugs, it had developed recommendations for national drug authorities seeking to regulate early use in their own countries. In the U.S., emergency approvals were issued for several antibody drugs.
Several companies and research groups are working on drugs using nanobodies instead of ordinary antibodies. That's the name given to sections of smaller antibodies capable of binding to foreign proteins that are produced by llamas and alpacas (called heavy chain antibodies). They are easier to produce than human antibodies and (unlike the latter) can also be stored at room temperature for longer periods.
- For example, parts of an artificial anti-SARS CoV-2 antibody generated by a consortium from Ghent University, the Flemish Institute for Biotechnology, the University of Austin (Texas), and the German Primate Center in Göttingen came from an antibody produced using a llama.
- The University of Pittburgh (USA) developed Nanobody-21, a drug for inhalation. In studies with hamsters, 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 pending.
- Belgian company ExeVir Bio has unveiled the drug XVR012, which has been effective in neutralizing numerous SARS-CoV-2 variants in preclinical studies. This contains the nanobody XVR013 and a fusion protein into which two other nanobodies have been incorporated. Both bind to the spike protein of SARS-CoV-2.
- 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, Germany. 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 drugs; with the single nanobodies possibly being administered by inhalation. Clinical trials are underway.
A consortium of research institutions in the USA within the framework of the DARPA Pandemic Preparedness Platform as well as a cooperation project of the companies Ethris and Neurimmune (Planegg near Munich and Switzerland) go one step further. In the end, their respective drugs will not contain copies of the most effective antibodies from convalescent plasma itself, but instead the genes for them - in the form of mRNA. Those who are injected with this mRNA produce the antibodies themselves in their bodies for a while and are protected (if everything goes according to plan). The advantage of this approach is that it is probably possible to produce large quantities of drug doses more quickly than if the antibodies had to be produced biotechnically. The handicap: So far, there is no other drug that works this way. The U.S. consortium's project is led by James Crowe, Vanderbilt University, Tennessee, among others, who received the Future Insight Prize from the German company Merck in 2019 for his pioneering work in this field. The drug planned by Ethris and Neurimmune has as a special feature that the mRNA is to be inhaled, so that the antibodies are formed close to the site of attack of the viruses.
Drugs with human-derived antibodies
Several projects have attempted to process antibodies directly from the blood plasma of former Covid-19 sufferers into highly concentrated drugs; so-called polyclonal anti-SARS-CoV-2 hyperimmunoglobulin (H-IG) preparations. However, the CoVIg-19 Plasma Alliance, in which several plasma preparation companies had joined forces, had to abandon its project after negative study results. The same happened to Grifols (Spain).
Not only classical antibodies and nanobodies, but also molecules of a completely different structure 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 thus prevent the virus from entering a cell and replicating 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:
- A research team from the University of Bonn and the caesar research center has created an aptamer from DNA that binds to non-infectious model viruses and prevents them from coming into contact with cells in laboratory tests. 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.
The company's aptamer, Aptarion Biotech, on the other hand, is being developed for immune dampening (see below).
A DARPin (Designed Ankyrin Repeat Protein) is a laboratory-designed protein whose structure is derived from ankyrins. Like an antibody, a DARPin can recognize and bind a specific antigen, but it is much smaller and more stable than an antibody.
- With Ensovibep (MP0420), the Swiss company Molecular Partners and Novartis developed a DARPin active ingredient against SARS-CoV-2. After positive results with hamsters, it also proved its worth in the phase II EMPATHY trial in outpatients, in whom it significantly reduced the risk of hospitalization. According to laboratory studies published in a preprint, the compound is also effective against the omicron variant. However, the compound showed no therapeutic benefit in patients with advanced stage Covid-19 in the ACTIV-3 study.
The Scottish company Elasmogen and the University of Minnesota (USA), on the other hand, are relying on a type of molecule formed by sharks 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.
Another route to active substances that bind to the viruses is to take the natural binding partner as a model, ACE2:
- A team at the University of Oregon is relying on mRNA in lipid nanoparticles to enable cells to make soluble ACE2 themselves.
- Formycon, a company based in Planegg-Martinsried, Germany, is pursuing a similar strategy together with the University of Munich. For its active ingredient FYB207, it has genetically combined unanchored ACE2 with an antibody fragment. Laboratory tests confirm that it can bind to viruses and prevent them from entering cells. Testing with volunteers is planned.
In contrast, APEIRON Biologics (Vienna, Austria) is no longer testing a drug that contained the part of ACE2 that protrudes from the cell (called alunacedase alfa [= APN01 or rhsACE2]) as the genetically engineered active ingredient.
The U.S. Scripps Research Institute has found yet another way to prevent SARS-CoV-2 from binding to ACE2. The special trick is that the viruses themselves deliver the active ingredient that thwarts the binding. This substance, known as NMT5 (structurally related to memantine), first binds to SARS-CoV-2, from where it then alters ACE2 by chemical transfer of nitro groups in such a way that docking of SARS-CoV-2 is no longer possible. The advantage of this is that ACE2 outside of virus-affected body regions is not affected. The project is still in the laboratory stage.
Inhibition of the serine protease TMPRSS2, which must participate in the binding of SARS-CoV-2 to ACE2, also promises to prevent the viruses from entering the body. Several compounds are capable of doing this in the laboratory. Clinical trials are now underway worldwide with some of them:
- RedHill Biopharma is testing upamostat (RHB-107) (originally developed by Heidelberg Pharmaceuticals for cancer) in a Phase II/III trial with Covid-19 patients who have mild or moderate symptoms. Positive interim results are available.
- Camostat is also being tested in several Phase III trials, following partially positive results in smaller studies. The combination of camostat + niclosamide is being clinically tested by the Charité Research Organization 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 also funding a project to test nafamostat, which has a 50-fold stronger antiviral effect, in intravenous administration; the development of a nafamostat nasal spray is also planned. In China and Switzerland, namafostat is also being tested in studies with Covid-19 in the advanced disease stage; however, the antiviral properties of the active ingredient are not likely to be the main focus there.
- In a clinical trial at the University Hospital of Ciudad Real (Spain), the duration of treatment in hospitalized patients was shortened by inhaling aprotinin. Aprotinin inhibits TMPRSS2 and other proteases.
- A research team at the Washington School of Medicine in St. Louis (USA) has developed the compound MM3122, which blocks TMPRSS2 in the laboratory. Further development is planned in collaboration with ProteXase Therapeutics.
- At the University of Sherbrooke, Cornell University and the University of British Columbia, another TMPRSS2 inhibitor, N-0385, has been developed. A nasal spray with it has been shown to be effective in animal studies. Development is planned as a preventive and as a therapeutic drug.
- For pentarlandir, see below.
However, it is also possible to throttle the formation of the serine protease TMPRSS2. Something like this is possible with antiandrogens - i.e. active ingredients that were actually developed for prostate cancer therapy - such as proxalutamide from Kintor Pharmaceutical (China). However, the study results on this are inconclusive and also overshadowed by criticism of the conduct of a study in Brazil. In a study conducted mainly in the United States, proxalutamide reduced the risk of hospitalization. In contrast, another study could not identify any benefit from proxalutamide.
1.2 Antiviral drugs 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 chemically and synthetically. Many active substances under investigation were originally developed against other viral infections.
The purpose of the agents is to block one of the many processes that a SARS-CoV-2 virus initiates after entering a cell. Some serve to copy the viral genome; others ensure the production of various viral proteins and other components.
1.2.1 Preventing the formation of copies of the viral genome
The viral genetic material consists of one strand of RNA. One of the viral enzymes involved in the formation of copies of it is RNA-dependent RNA polymerase. An active agent can prevent its formation:
- Sachi Bioworks (USA) has developed the antisense molecule SBCoV202, which blocks the starting point for the reading (translation) of the viral RNA to form the polymerase, and has successfully tested it in animals with partners at the Universities of Colorado and New York. More specifically, SBCoV202 is a nanoligomer with a peptide nucleic acid attached to a gold nanoparticle.
Several agents can also interfere with the activity of RNA-dependent RNA polymerase:
- One such agent is remdesivir (a nucleotide analog) from Gilead Sciences. Remdesivir became the first drug to receive a conditional EU marketing authorization 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 as well as 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 drug's benefit in September 2021. To improve global availability, Gilead Sciences has licensed several companies in Egypt, India and Pakistan to produce their own remdesivir drugs and distribute them in 127 countries.
- Capsules containing a second RNA polymerase inhibitor, molnupiravir from MSD (called Merck & Co., Inc., in the U.S.) and Ridgeback Biotherapeutics (invented at Emory University), underwent an approval process at the EMA from November 2021 to February 2023 (preceded by about a month-long rolling review ), with the goal of recommending approval for outpatient therapy for Covid-19 patient:ing. However, the EMA then opposed approval. However, MSD and Ridgeback have announced their intention to seek a review of the decision. The drug has already been approved in the UK since Nov. 4, 2021. The active ingredient was originally invented for flu therapy, but has not yet been fully tested for this purpose.
- According to laboratory experiments, kinetin (MB-905) can lead to defective RNA synthesis by RNA polymerase in a similar way to molnupiravir. This was found by Brazilian researchers from the Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz) and the National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN) and the Center for Technological Development in Health (CDTS). Because the compound is already in clinical trials against another disease, they expect MB-905 to soon be in trials against Covid-19 as well.
- Chinese companies Henan Genuine Bio and Fosun Pharma have tested Azvudine, a drug originally developed against HIV (and approved for that purpose in China), against Covid-19 with positive results. The drug is a nucleoside analog and blocks the RNA-dependent RNA polymerase of various viruses. It has received conditional approval in China.
- The Chinese company Ascletis also has a corresponding inhibitor, ASC10, in development. It can be taken orally. It is currently being tested in a Phase I trial.
- Another development is VV116. The active ingredient is a nucleoside analog that inhibits RNA polymerase. VV116 can also be taken orally. There are already positive results from a phase III trial. Numerous Asian companies and institutions are involved in its development: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, the Wuhan Institute of Virology, Chinese Academy of Sciences; Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Central Asian Center of Drug Discovery and Development, Chinese Academy of Sciences / China-Uzbekistan Medicine Technical Park, Lingang Laboratory, Vigonvita Life Sciences Co, Ltd, and Junshi Biosciences.
- Tempol (MBM-02) from Adamis Pharma (USA) interferes with viral RNA polymerase activity in a different way: it oxidizes iron-sulfur compounds that the polymerase requires. In addition, it reduces the formation of cytokines in laboratory tests and thus also has an immunosuppressive or anti-inflammatory effect. The orally ingestible active ingredient is being tested in a Phase II/III study.
Covid-19-related development of the RNA polymerase inhibitor AT-527 from Atea Pharmaceuticals/Roche and the RNA polymerase inhibitor favipiravir from FUJIFILM Toyama Chemical did not continue.
The viral enzyme helicase Nsp13 is also needed to form new copies of the viral genome. The German company Eisbach Bio developed the active ingredient EIS-10700, which blocks this enzyme. It also inhibits helicases of other coronaviruses in the laboratory. A phase I trial with it has already been planned for 2021, but has not yet started. The EisCor_2 project is supported by the BMBF with almost 8 million euros.
1.2.2 Blockade of proteases involved in the formation of other viral components
Another target is an enzyme of SARS-CoV-2 called major protease (Mpro) or 3CL protease. It participates in the formation of proteins for new viruses. Several companies and research groups are developing drugs against it:
- Pfizer received approval in the EU on Jan. 28, 2022, for a drug containing the new active ingredient nirmatrelvir (= PF-07321332) in combination with ritonavir for the outpatient treatment of high-risk patient:ing. Now Pfizer is testing the drug with minors 6 years and older and is working on a lower-dose dosage form for children younger than 6. The company is allowing generic manufacturers to produce the drug to supply 95 poorer countries, based on an agreement with the Medicines Patent Pool. Pfizer itself produces the drug in Freiburg i. Br. in Germany and elsewhere.
- Shionogi (Japan), in collaboration with Hokkaido University (Japan), has developed Ensitrelvir (S-217622), an orally ingestible agent that blocks the main protease. It has shown positive results in outpatient therapeutic use in a Phase III study and has received regulatory approval in Japan. In parallel, it is also being tested in a Phase III trial for prevention.
- SyneuRx International (Taiwan) is currently testing a drug called "pentarlandir" with the active ingredient SNB01 from a biological source with Covid 19 patients in the early stages of the disease. Following positive positive results, including variant coverage, a Phase III trial is planned. The compound inhibits the main protease and additionally TMPRSS2.
- Enanta Pharmaceuticals (USA) has developed EDP-235, an oral, once-daily compound to inhibit the major protease. The drug has produced positive results in a Phase I trial. The goal is not only therapeutic but also prophylactic use.
- Frontier Biotechnologies (China) is developing a drug with the active ingredient FB2001, which must be administered intravenously. A phase I trial in the U.S. has produced positive results. A phase II/III trial has started.
- Pfizer (USA) has developed yet another inhibitor of the major protease: Lufotrelvir (PF-07304814). The compound, unlike Pfizer's first protease inhibitor, does not require additives to be effective long enough. Positive results from Phase I testing have already been published.
- Sorrento Therapeutics (USA) is testing the newly developed oral agent STI-1558 in Phase I trials. It too inhibits the main protease, but in addition also inhibits cathepsin L, which impedes viral entry into cells. In laboratory experiments, the compound was also shown to be very effective against the omicron variant. The agent can be used without concomitant use of ritonavir or other agents.
- Ascletis Pharma (China) also has an orally ingestible compound, ASC11, in preclinical development against the major protease. The company has been granted an IND in the USA, so that Phase I can now begin. Among other things, this will clarify whether ASC11 needs to be boosted with ritonavir as a comedication or not.
- Novartis (Switzerland) is also working on one or more orally ingestible major protease inhibitors.
- Proteros Biostructures (Planegg, Germany) is collaborating with Arbutus Biopharma and X-Chem (both USA) to develop new compounds that target the major protease. They have found the first series of drug candidates.
- 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 oral thrush, 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 is to be tested in cell cultures and with animals and, in the event of positive results, will be tested in human trials together with a pharmaceutical company.
- 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 based on an analysis technique in which the main protease was brought into contact with small organic substances (so-called molecular fragments). The project is still in the laboratory stage.
- 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 agents developed for other purposes. From their laboratory tests, calpeptin and pelitinib emerged as candidates that are now being further investigated in preclinical studies. Neither substance has yet been approved against any disease in Germany.
- The Fastcure Consortium with its initiator Innophore (Graz, Austria) is pursuing the same goal. It is using bioinformatics methods to analyze already marketed drugs to determine whether they contain structurally suitable active ingredients.
- A research team from the University of Chicago (USA) and other research institutions in the USA and France, screening 1,900 drugs, determined that masitinib can inhibit the main protease. A drug containing this active ingredient is already approved for certain mast cell tumors in dogs; there it acts as a tyrosine kinase inhibitor. The French company AB Science is now testing the compound in a Phase II trial in patients with mild to moderate symptoms.
However, SARS-CoV-2 also has a second protease-type enzyme, papain-like protease (PLpro). It is also involved in the formation of viral components and represents an interesting target:
- Research groups at the universities of Mainz, Giessen and Würzburg have invented active substances that can paralyze this enzyme. They now need to be tested further before they can be tried out with humans.
- Research teams from New York and the University of Texas found that the oral agents simeprevir, paritaprevir, and vaniprevir, which are already approved for hepatitis C therapy, also block PLpro and work synergistically with remdesivir in cell cultures to prevent SARS-CoV-2 from replicating far better than remdesivir alone can.
- Researchers at the German Electron Synchrotron DESY were able to identify three plant-derived natural products that block PLpro: Hydroxyethylphenol, Hydroxybenzaldehyde, Methyldihydroxybenzoate.
1.2.3 Blockade of other cellular components involved in virus replication
The RNA-DRUGS research group of the Universities of Frankfurt a.M., Marburg and Munich (LMU) is working on small-molecule inhibitors that attach directly to viral RNA in the cell and thus prevent it from controlling viral replication. The project is funded by the German innovation agency SPRIN-D, where it has already reached the second funding stage.
Another target is MEK, a kinase-type enzyme in human cells whose functionality SARS-CoV-2 requires 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 with hospitalized patients with moderate to severe covid-19 in Germany and other countries. In the laboratory, the compound is also effective against the Omikron variant. 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.
Another strategy for combating the virus is to disrupt a metabolic pathway in the infected cells that is essential for viral replication but 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 2-deoxy-D-glucose was effective against viral replication in cell culture experiments.
Innovation Pharmaceuticals ' compound brilacidin can prevent SARS-CoV-2 replication 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 fast track status to Brilacidin to accelerate development and testing of the compound.
Following encouraging laboratory tests, the Spanish company PharmaMar is testing its drug with plitidepsin in a clinical 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 human protein eEF1A, which is necessary for this purpose, in the affected cells.
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. This also applies in the same way to the active ingredients amiodarone and imipramine. The active ingredient fluvoxamine, also an ASM inhibitor approved for depression, simultaneously has a high affinity for the sigma-1 receptor (S1R). 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. In contrast, another study saw no effect. Other studies with fluvoxamine and fluoxetine are currently ongoing.
Moleculin has WP1122 in development, a prodrug of 2-deoxyguanosine. It has shown antiviral activity in the laboratory and was recently tested in a Phase I study with volunteers.
The off-patent tapeworm drug niclosamide enhances cellular "garbage processing" (autophagy). This process is throttled 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 did the active ingredients spermidine (an endogenous substance) and MK-2206 (an active ingredient against breast cancer). Meanwhile, Covid-19 therapy with niclosamide is being tested in a number of phase II trials with patients, either as monotherapy (e.g. in a trial by Union Therapeutics) or in combination with camostat (Charité Research Organization). A study on the suitability of the compound for prophylaxis is ongoing in the UK.
A different plan is being pursued by companies seeking to combat SARS-CoV-2 using 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 using so-called siRNA agents. The South Korean company OliX Pharmaceuticals is also working on an active ingredient of this type. German biotech Secarna and China's Guangzhou's Sun Yatsen University want to achieve gene silencing using an antisense oligonucleotide - a molecule from a related class of compounds.
By 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. The active ingredient ivermectin, which is approved for the control of mites and parasitic nematodes, has also not proven effective. The initial results of smaller studies were initially inconsistent; ultimately, it became apparent that there was probably no relevant therapeutic efficacy.
Several antimalarial drugs containing the active ingredients chloroquine and hydroxychloroquine also failed to prove effective. After positive laboratory tests against SARS-CoV-2, they were first tested in China and later in trials in other countries. However, the results of several studies indicated that the drugs did not have a positive risk-benefit balance, often even worsening the situation. 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.
However, in Phase III trials with patients in the early stages of the disease is another antimalarial drug with the active ingredient combination pyronaridine + artesunate. The project is being advanced by Quran-based Shin Poong Pharmaceuticals. The company has also initiated a phase IIefficacy trialagainst the omicron variant.
1.3 Antiviral drugs that boost immune defenses
Some drugs do not fight viruses directly, but are designed to boost the body's immune defenses against viruses.
One of these is being developed by the German company AiCuris: its stimulatory immunomodulator contains parapoxviruses and was originally developed for the treatment of hepatitis B; it has also already completed a Phase I study 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 have been 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 submit a marketing authorization application in India for the compound already used to treat hepatitis C.
- Peginterferon Lambda is also still being tested. It has been tested in a Phase II trial in Canada. Patients treated with the active ingredient experienced a faster reduction in viral load and an earlier resolution of symptoms than control patients. A phase III trial is being planned. This interferon, like other interferons, activates an antiviral immune response; however, it essentially becomes active for this purpose only in certain cells of the lung, liver and intestine. Targeting action 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.
1.4 Antiviral drugs with a different mode of action
Takeda has found in laboratory experiments that a drug approved for angioedema, Icatibant, can reduce viral replication by 90% after fresh infection. The drug decreases the concentration of the bradykinin receptor b2, which is elevated in covid-19 infections. The drug will now be tested further.
The company Sanotize has successfully tested a nasal spray containing nitric oxide in trials. In these, it lowered the risk of symptomatic infection when used shortly after exposure. On top of that, it could be used for prevention.
Teams from Hannover Medical School, the DZIF and the University of Giessen are working together on another approach to develop new drugs against corona viruses. Instead of taking a specific target structure in the virus or host cell or a specific mode of action as a starting point, they are testing a large number of archived chemical compounds in the laboratory to see if they can block virus replication. Only when a substance shows corresponding efficacy do they investigate its mechanism of action.
A team at the Gladstone Institute in the United States is using mRNA-based therapeutic interfering particles (TIPs) to inhibit viral replication. These particles contain short non-coding mRNA segments and, after intranasal administration, can "attack" cells like viruses. In cells, the introduced mRNA does not give rise to new particles, but in the case of true infection with SARS-CoV-2 or other RNA viruses, it competes with them for cellular resources needed for virus replication. The result, certainly in animal studies, is reduced viral shedding in treated individuals. Studies with humans are planned.
Researchers from the University Medical Center Göttingen, the German Primate Center and the University of Veterinary Medicine Hannover are working on a"CRISPR/Cas13-mediated Antiviral Therapy" (the project title) against SARS-CoV-2 under the direction of Prof. Dr. Elisabeth Zeisberg, Göttingen. The goal is to destroy SARS-CoV-2 using special gene scissors in infected cells based on the CRISPR/Cas13 system. They are introduced into lung epithelial cells using harmless adeno-associated AAV-2 viruses. They do not affect the cells themselves. However, in combination with a special combination of crRNAs directed against SARS viruses, they prevent the proliferation of SARS-CoV-2. This approach has already proven successful in the petri dish and in hamsters. The project is funded by the innovation agency SPRIN-D; it has already reached the second funding stage there.
Covid-19 infection often brings blood clots in various organs as a complication. In addition, the infection may involve effects on the heart and kidneys. A number of approved cardiovascular drugs 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 guideline (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 studies. 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 efficacy 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 achieve 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 edoxaban from Daiichi Sankyo, rivaroxaban from Bayer and apixaban from Bristol Myers Squibb / Pfizer, three direct oral Factor Xa inhibitors that are 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 ingredient is to be tested as part of the ACTIV-4 study program. Binding to the AT1 receptor is expected to restore lung function and help prevent the formation of thromboses.
Clot-dissolving drugs are also being tested. Among others, Boehringer Ingelheim is testing such a drug with the active ingredient alteplase.
With regard to combating pulmonary and cardiac complications, various medical facilities are testing antihypertensive drugs 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 U.S. by a health insurance company indicates that older Covid 19 patients who were taking drugs from the ACE inhibitor class as continuous therapy independently of this condition required inpatient treatment less frequently. 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. The aim is to investigate 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, in turn, 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 reactions are generally desirable in infected individuals; they 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 quantities of messenger substances called cytokines are released. In some patients, this occurs. Several Covid 19 therapy projects therefore aim to dampen such a reaction with suitable agents - they are called anti-inflammatories or immunomodulators.
One has already been approved for this purpose: In a study in the UK, dexamethasone, a cortisone derivative with a known anti-inflammatory effect, effectively weakened immune reactions and thus reduced mortality in severely ill patients: Dexamethasone was able to reduce the risk of death in patients requiring oxygen or even artificial respiration by one fifth or one third. A corresponding approval extension was recommended by the EMA 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 drugs 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. A phase II/III trial with ventilated patients with severe Covid-19 disease showed indications of a reduction in mortality in its phase III part, the significance of which, however, was uncertain or uncertain depending on the evaluation method. On 04/04/2023, the company received emergency approval for the drug in the United States. The active ingredient is a specific inhibitor of complement component C5a. The German Ministries of Education & Research and of Health support the project.
- Both Alexion and the University of Cambridge (UK) are testing another C5a inhibitor in Covid-19 patients with severe pneumonia: ravulizumab. The drug is approved to treat the rare paroxysmal nocturnal hemoglobinuria (PNH).
- The Berlin-based company Aptarion Biotech is developing an L-aptamer to inhibit C5a. This molecule, called AON-D21, can limit the immune response according to tests to date. Supported by 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 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 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, the Sobi company received a recommendation from the EMA on Dec. 16, 2021, to extend the approval for a drug containing the active ingredient anakinra. The active ingredient blocks (as an IL-1-alpha/beta receptor antagonist) the messenger effect of interleukin-1. The drug is already approved (in combination with methotrexate) for the treatment of rheumatoid arthritis; also for the treatment of cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever and Still's disease.
- Also submitted to the EMA for a marketing authorization extension is a medicine containing tocilizumab from Roche. This agent prevents interleukin-6 (IL-6) from taking effect. The drug already has approval for other inflammatory diseases and as an adjunctive medication for certain cancer therapies, and has now been tested in numerous trials with hospitalized Covid 19 patients. In the U.S., tocilizumab received emergency approval for use in covid-19 patients in June 2021.
- The ACTIV-5 trial in the U.S. is also testing risankizumab, which binds interleukin-23 and is approved to treat the autoimmune disease psoriasis.
- In the Czech Republic (Charles University and BIOCEV Research Center), BAZE-X1, the first inhalable dosage form of bazedoxifene, was developed. The active ingredient, which is contained in drugs for osteoporosis, blocks interleukin-6. The drug is currently being tested in a Phase II trial.
Another possibility being tested is to prevent immune cells from communicating by means of the messenger substance TNF-alpha:
- 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 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 U.K. AVID-CC trial.
- Infliximab is another TNF-alpha inhibitor being tested as part of the ACTIV-1 Trial of 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 targeted immune dampening is the blockade of the messenger substance GM-CSF, which belongs to the cytokines:
- This is possible with the help of 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 U.S. FDA has initially declined to grant emergency approval in the United States on the basis of the available data, but has invited the company to submit further data.
- Interim results from a Phase II/III trial of 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.
- Also being tested is Izana Bioscience's GM-CSF inhibitor namilumab, which has so far only been studied in patients with rheumatoid arthritis and other autoimmune diseases.
Furthermore, targeted immune dampening by inhibiting the full activation of T cells is being attempted. This is possible with abatacept from Bristol Myers Squibb. Its drug is already approved for 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 an essential role in this process. The CATCOVID study is now testing 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 funded 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 against other diseases, but has not yet received regulatory 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 United States. A Phase II trial has also been conducted at the Charité Hospital in Berlin, Germany.
- However, the company CytoDyn has not yet been able to improve therapy with its CCR5 antagonist Leronlimab in trials with Covid-19 patients. However, the company is also testing whether Leronlimab also 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 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 receiving 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 defense against newly invaded pathogens. However, in cases of severe pneumonia caused by Covid-19, they may contribute to immune overreaction. Canadian company Edesa Biotech has achieved positive results with its TLR4 inhibitor EB05 in a phase II trial of 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 defense. Misdirected immune responses involving 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.
The US company MediciNova is testing another oral PDE4 inhibitor, ibudilast, in hospitalized patients at risk of disease escalation. A Phase II trial yielded positive results; and a Phase II/III trial was approved in Canada in February 2023. The company is also developing its drug for other inflammatory and neurodegenerative diseases.
Lanadelumab, an anti-Kallikrein antibody from Takeda, is also designed to dampen immune responses. It was developed to treat the rare heriditary angioedema and has been tested in trials, but has not yet received regulatory approval. The company is testing it in hospitalized Covid 19 patients as part of the COVID R&D Alliance 's COMMUNITY trial. The drug is additionally designed to counteract fluid accumulation in the lungs.
The U.S./German company Immunic Therapeutics is testing the inhibition of viral replication in the laboratory with a combination of vidofludimus calcium (IMU-838, a selective oral inhibitor of the enzyme DHODH ]dihydroxyorotate dehydrogenase]) and N4-hydroxycytidine (NHC) and has licensed rights from the University Hospital of Göttingen. The active ingredient vidofludimus calcium slows down metabolism in activated T and B cells (which dampens the immune response), but has little effect on other immune cells. IMU-838 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.
A Texas research team tested OP-101 from Ashvattha Therapeutics (USA), a hydroxyl-polyamidoamine-dendrimer-N-acetylcysteine conjugate that dampens activated macrophages, in a Phase IIa trial with hospitalized patients. Blood values indicate that inflammatory processes could be dampened in this way.
A Janus kinase inhibitor is also being tested: tofacitinib. It is already approved for certain autoimmune diseases. Tofacitinib has been successfully tested in hospitalized Covid 19 patients. Lilly, on the other hand, has withdrawn its marketing authorization application to the EU for its Janus kinase inhibitor baritinib.
Actually in development as a cancer drug is opaganib from the Israeli/US company RedHill Biopharma. This sphingosine kinase 2 (SK2) inhibitor has shown anti-inflammatory but also antiviral activity in preclinical studies. This could be useful for the treatment of covid-19-related pneumonia. The drug has been tested in a Phase II trial in the United States, with positive results. It is believed that the drug achieves its efficacy by interfering with the multiplication cycle of SARS-CoV-2 in several ways at once.
Drugs 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 'sacalabrutinib has approval for the treatment of certain leukemias. 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 of abivertinib. The drug targets mutated forms of Brutontyrosine kinase and the receptor EGFR. The company has been testing the drug against NSCLC-type lung cancer for some time.
Colchicine has been and continues to be tested in over 25 clinical trials as a means of combating excessive 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 agent was tested in the adaptive multi-arm Recovery Trial (UK). There, 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.
Like colchicine, sabizabulin interferes with the assembly of microtubules in cells. However, unlike colchicine, this agent was found to substantially reduce death rates in moderately to severely ill Covid 19 patients in a Phase III trial at interim analysis; the trial was subsequently terminated prematurely. However, after a subsequent application for emergency approval with the FDA was unsuccessful, another Phase III trial is now to be conducted. U.S.-based Veru has developed and clinically tested the drug for the treatment of refractory prostate and breast cancer, and is also leading its trial against Covid-19. The drug's immune-suppressing efficacy may be due to the fact that it inhibits the proliferation of certain immune cells. In addition, however, the drug also has an antiviral effect in the laboratory. This, in turn, could be related to the fact that viruses also use microtubules for transport within the cell, as a kind of "monorail." If the microtubules cannot be formed properly, this is prevented. An ETF review of the drug has been underway at the EMA since late July. ETF reviews are used to make recommendations on a drug that has not yet been approved for use in a medical emergency and for which national authorities want to grant a special use authorization until it can be used on a completely regular basis after approval.
The French company Inotrem has been testing the peptide drug nangibotide in a Phase II trial of Covid 19 patients in intensive care, with positive results (including a reduction in mortality by day 28). Nangibotide inhibits TREM-1, a receptor on certain immune cells. The company is considering a regulatory filing for the U.S. and EU based on Phase II results, according to a media report.
Immune cells (macrophages and dendritic cells) are used by Israeli company Enlivex to dumb down the immune system in the event of a cytokine storm. Its cell therapy Allocetra was already in development against sepsis before the pandemic. After successful testing in Phase I and II trials, a Phase III trial is planned.
Proteo Biotech (Germany) will test the genetically engineered version of an immunosuppressive human protein in a clinical trial to determine whether it can prevent severe disease progression and organ complications due to an excessive immune response in COVID-19 patients. The project is funded by the German Federal Ministry of Education and Research (BMBF).
rnatics (Germany) will test an inhalable drug for the treatment of inflammatory lung injury in Covid-19 in a clinical trial. The drug inhibits certain microRNA in macrophages, which has an inflammation-increasing effect in affected individuals. This project is also funded by the German Federal Ministry of Education and Research (BMBF).
EDP1815 from Evelo Biosciences is a completely new type of immunomodulator. It contains the naturally occurring human intestinal bacterium Prevotella histicola which was 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 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's apabetalone 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 in 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 multiple 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 manufacturer now plans to conduct a Phase III trial to determine whether the drug can prevent 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 immune suppressing drugs mentioned 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, which like dexamethasone is structurally related to the natural hormone cortisone, was tested. Indeed, the results of the STOIC trial with 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 a faster recovery on average. The drug will now be tested in a phase III trial.
The vital task of the lungs is to ensure gas exchange 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. Subsequently, it is essential for recovery that the lungs can regenerate with functional tissue and not just scar tissue.
One of the drugs 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 approval for this 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 protects certain lung cells (alveolar type 2 cells) from viral attack. These are a preferred target of SARS-CoV-2 and are particularly important for maintaining lung function. NeuroRx, with the support of Relief Therapeutics in the U.S., conducted a Phase II/III study in severely ill Covid-19 patients (symptoms of severe lung failure; ventilated) following positive laboratory data. Patients recovered more quickly from respiratory symptoms under intravenous therapy. NeuRx subsequently filed for Emergency Use Authorization with the FDA. A long-term study (1-year follow-up) of patients:in with severe pre-existing conditions indicated that VIP improved their survival by 60%. However, in another study in severely ill Covid 19 patients, aviptadil did not show efficacy. Relief Therapeutics has also started a Phase II trial with an inhalable formulation of the drug in collaboration with AdVita Lifescience in Saarbrücken, Germany. Here, too, the aim is to prevent acute respiratory distress syndrome in Covid 19 patients.
Canadian company Algernon Pharmaceuticals is testing its drug 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 developing a drug with this active ingredient for some time for idiopathic pulmonary fibrosis, a disease characterized by increasing shortness of breath.
Vienna-based biotech company Apeptico plans to test its active ingredient Solnatide against acute respiratory distress syndrome (ARSD) for suitability in intensive care Covid-19 patients with severe lung damage. This project is funded by the EU with one and a half million euros. Munich's 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 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 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.
Protection against inflammation and fibrotic changes in the lungs of Covid-19 patients by the endogenous protein angiotensin-(1-7) was reported by a research team from the University of Ulm. Angiotensin-(1-7) can stop the action 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 angiotensin-(1-7) production. The STAMINA-Cov19 project, coordinated by Explicat Pharma in Hohenbrunn, Germany, now aims to develop an inhalable version of angiotensin-(1-7) 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. More details can be found in the section on Long Covid therapy.
Apogenix, a Heidelberg-based company, is testing its drug with the active ingredient Asunercept, a CD95L inhibitor, in Phase II trials in Russia, Spain, Vienna, Cologne and London in hospitalized Covid 19 patients. It has produced positive results in the phase II ASUNCTIS trial in moderately to severely ill patients. A Phase III trial is in preparation. The drug has been in development for some time for the treatment of various cancers in which it supports the immune system's defense against tumors; it has not yet been approved. In Covid 19 patients, one of its effects is to counteract the death of lung epithelial cells.
Direct Biologics has successfully used exosomes derived from bone marrow cells in patients with ARDS in a Phase II trial.
Long covid is a collective term for the complaints that quite a few people suffer from after they have actually survived covid 19 disease. It does not seem to matter whether Covid-19 has taken a mild or severe course in them. Because the physical basis of many of these complaints is still unclear, research groups and companies are relying on basing their projects for effective therapies on hypotheses and chance observations rather than on a solid understanding of disease processes at the molecular level. It is also likely that the different types of long covid are not always based on the same disease processes - that there are in fact several different diseases involved that require different treatments. Hypotheses include, for example, that SARS-CoV2 viruses remaining in the body interfere with important processes. Another hypothesis is that during the acute infection, the immune system of affected individuals began to produce antibodies against the body's own tissues (so-called autoantibodies), and that these now cause inflammatory reactions and malfunctions in the blood vessel walls.
Despite this extremely difficult starting situation for pharmaceutical researchers, companies and institutes have launched a number of projects to help people with one or another long covid symptom. In these, they are testing drugs that were actually intended to treat other diseases; some of them have already been approved for this other application, but some other drugs are still being tested against them.
One symptom reported by many of those affected is persistent exhaustion (fatigue), sometimes also with severe concentration disorders ("brain fog"), without any physical causes identifiable with previous diagnostics. This has been known for some time in medicine from people suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or fibromyalgia. A number of drugs are being tested with the aim of overcoming the symptoms:
- These include the drug AXA1125 from Axcella Therapeutics (USA). It consists of a mixture of six natural amino acids and interferes with metabolic regulation in the mitochondria, according to the company. Positive results are available from a phase IIa study. A Phase IIb and III placebo-controlled trial based on this has been approved in the U.S. and is expected to begin soon. The drug was originally developed for liver disease; testing against this has not yet been completed.
- The U.S. company Resolve Therapeutics is testing infusions of RSLV-132 (a fusion protein of RNase and antibody truncation) in a phase II trial; this has already reached full enrollment since November 2022. The compound is in parallel development against Lupus Erythematosus and Sjögren's Syndrome. Underlying the approach is evidence that viral RNA and RNA-containing autoantibodies in the brains of affected individuals may play a role in Long Covid.
- Charité Berlin plans to test a drug already approved for the treatment of heart failure in a clinical trial called VERI-LONG with affected individuals.
- Charité Berlin is also testing an immunoadsorption procedure for the same purpose in a clinical trial, using a TheraSorb column from Miltenyi Biotec to remove autoantibodies from patients' blood.
- In individual healing trials, positive effects were also seen in "Brain Fog" with the use of naltrexone; an active ingredient against opiod effects. Now, drugs with this active ingredient are also being tested in clinical trials for this application. Among other things, their use with transdermal patches is being considered.
- The company AIM ImmunoTech (USA) is testing the efficacy of an approved drug with the active ingredient rintatolimod as part of an expanded access program for patients with ME/CFS that is also open to Long Covid patients. According to the manufacturer, the drug activates the Toll-like receptor TLR-3 in airway epithelial cells. Structurally, it is double-stranded RNA with mismatched poly I : poly C12U.
- The company GeNeuro (headquartered in Switzerland with research laboratories in France) is testing whether temelimab can reduce fatigue and cognitive impairment in a Phase II trial in Switzerland since November 2022. The temelimab antibody binds the harmful W-ENV protein, which is detectable in some patients with long covid; accordingly, only W-ENV-positive patients are recruited for the study. The European Investment Bank is involved in funding.
- The University of Erlangen conducted individual curative trials in three Long Covid patients with the active substance BC 007 from Berlin Cures. This active ingredient (it is a DNA-based aptamer) has been developed for the treatment of patients with heart disease who have formed antibodies against the body's own proteins (certain receptors), resulting in circulatory disturbances in the heart, among other things. According to the manufacturer, various symptoms(fatigue, memory and concentration disorders, lost sense of taste) improved in those individually treated with Long Covid. Berlin Cures is preparing a Phase II study with more than 100 patients with Long Covid with a clinical trial service provider, according to media reports, and has submitted an application for approval of the study. Funding for the study has been secured, according to management.
- A possible cause of Long Covid symptoms could be SARS-CoV-2 viruses remaining in the body. For this reason, several studies are being conducted in the U.S. to test whether the antiviral combination of nirmatrelvir + ritonavir, which was actually developed for acute therapy in the early phase of the infection, can help at least some of those affected. Pfizer is involved in the PAXLC and STOP-PASC phase II trials, while Duke University is responsible for the PASC phase III trial. Fatigue relief is only one of several efficacy criteria in the trials.
- With the same goal, Virios Therapeutics (USA), in collaboration with the Bateman Horne Center (Salt Lake City, USA), is testing a combination of the antiviral agent valacyclovir and the anti-inflammatory agent celecoxib. The results of the Phase I trial are expected to be presented during 2023. The idea behind the project is that reactivation of Epstein-Barr viruses latently present in patients could be the cause of fatigue and cognitive disorders.
- CBD-rich cannabis will also be tested in a study to determine whether it is effective against fatigue in long covid patients. Its efficacy on pain symptoms, depression, sleep quality, resting heart rate, oxygen saturation, activity levels and other parameters will also be assessed.
Pain in various parts of the body is another symptom experienced by some Long Covid patients (as well as those with fibromyalgia). A drug is also being tested for this:
- It is the drug TNX-102 SL (= cyclobenzaprine HCl in a sublingual tablet) from the company Tonix Pharmaceuticals. It is being tested in a phase II trial against Long Covid. At the same time, a phase III clinical trial is already underway in patients with fibromyalgia.
Other projects focus on combating inflammation and other disease processes in the respiratory tract:
- The company Oncotelic Therapeutics (USA) is testing its active ingredient OT-101, an antisense molecule that blocks the formation of the neurotransmitter TGF-β2, against the long covid syndrome "respiratory distress. The compound is also being tested for the treatment of patients with various types of cancer (which produce TGF-β2 in excess).
- Spanish physicians are conducting a Phase III trial to determine whether some respiratory symptoms in Long Covid can be treated with a drug approved for the treatment of asthma and hay fever containing the active ingredient montelukast.
- Similarly, Canadian physicians are testing another drug approved (in Japan) for asthma in a Phase II/III trial. It contains the active ingredient ibudilast.
- Humanetics Corportion (USA) is conducting an ongoing phase II trial to determine whether genistein (formulated as an oral suspension of nanoparticles) can improve respiratory problems and reduced physical performance. Genistein (pronounced "Ge-ni-ste-in") in a plant-based estrogen, some of which is available as a dietary supplement.
- To combat 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. Trial testing of the active ingredient - initially against idiopathic pulmonary fibrosis - has started in 2022. The project is funded by the state of Bavaria.
- The University of Chicago is already testing a drug already approved for other forms of pulmonary fibrosis with sirolimus in a phase II/III trial with Long Covid patients.
One project aims to help people who suffer from a disturbed or largely lost sense of smell as a result of a covid 19 infection:
- 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 monitored, as vitamin A must not be overdosed.
In other projects against long covid, it has not yet been published which symptoms are to be addressed as a priority:
- Panacell Biotech, a South Korean company and research institute, plans to test natural killer cells, exosomes and brown adipose-derived stem cells against Long Covid symptoms in clinical trials. It is not yet known on which paramenters efficacy will be measured.
(1) 12 years old and weighing at least 40 kg, and with pneumonia requiring supplemental oxygen (low- or high-flow oxygen therapy or other noninvasive ventilation at the start of therapy)
Worldwide access to Covid-19 medicines.
The drugs are needed wherever people have Covid-19. On Sept. 30, the Bill and Melinda Gates Foundation and 16 pharmaceutical and diagnostics companies countered concerns about focusing solely on the needs and opportunities of the developed world in developing such drugs with the statement "Commitments to Expanded Global Access for COVID-19 Diagnostics, Therapeutics, and Vaccines." Signatories commit to developing innovations for patients worldwide, working toward affordability and rapid availability for all countries, supporting mechanisms for fair global resource allocation, and building confidence in Covid-19 medicines and diagnostics by making safety the highest requirement for every product.
Which is which.
Coronavirus: it is the generic term for a family of viruses that affect humans or animals. The causative agents of SARS in 2002/2003, MERS and several forms of the common cold are also included.
SARS-CoV-2: The pathogen causing the current pandemic was given this name in February 2020, and is often simply called "novel coronavirus." The abbreviation stands for Severe Acute Respiratory Syndrome-Coronavirus-2.
Covid-19: Fortunately, not every person who contracts SARS-CoV-2 becomes ill. Those who show symptoms after contracting the new pathogen suffer from the respiratory disease Covid-19, which derives its name from "coronavirus disease" and the year it first appeared, 2019.