Therapeutic medicines against the coronavirus infection Covid-19
Not only vaccines are being developed against the pandemic with the coronavirus SARS-CoV-2, but also medicines are being tested.
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Although the development of vaccines against the new coronavirus is proceeding at an unprecedented pace, it is unlikely that they will be available for mass vaccination as early as 2020. Hopes are therefore pinned on finding medicines to treat those already infected more quickly.
The focus is particularly on medicines that have already been approved for another disease or are at least in development. They can be converted more quickly than a completely new development.
A number of existing medicines are currently being tested for their suitability against the corona disease Covid-19. They usually belong to one of the following three groups:
- Antiviral medicines originally developed for HIV, Ebola, hepatitis C, influenza, SARS or MERS (two diseases caused by other corona viruses). They are designed to block the reproduction of the viruses or prevent them from entering lung cells. An old anti-malaria medicine is also being tested; its effectiveness against viruses has only recently been discovered.
- ImmunomodulatorsThey have been developed, for example, against rheumatoid arthritis or inflammatory bowel diseases. They are designed to limit an overreacting defense reaction in the body in such a way that it do not cause any more damage than the viruses themselves.
- Medicines for lung patientsThey have been developed, for example, to treat idiopathic pulmonary fibrosis. They are intended to prevent the patient's lungs from no longer being able to supply the blood with enough oxygen.
In addition, however, there are still projects for new medicine developments.
More detailed information about the medicines and projects can be found further down on the page.
Rapid evaluation of the suitability of the medicines
Efpia: European pharmaceutical industry response to COVID-19
As the impact of COVID-19 continues to be felt across the world, the biopharmaceutical industry in Europe remains committed to global efforts to care for those affected, contain the outbreak and develop resources to tackle future outbreaks.
In several studies in which such medicines have been or are being tested for suitability in China and elsewhere, only a few dozen patients have been included; and often there is no direct comparison with patients who only receive basic medical treatment without additional medication. Such studies can be set up quickly, but often their results are inconclusive. Also, although there are many Covid-19 patients in clinics internationally, their number does not allow comprehensive testing of all the medicines that have been proposed.
The European Medicines Agency (EMA) has therefore appealed to companies and research institutions to organise joint multinational, multi-arm, controlled and randomised patient studies for their medicines, if possible:
- "Multinational" means that medical institutions in several countries are involved.
- "Multi-arm" and "controlled" means that patients are divided into groups, each of whom receives a different treatment: All receive the same basic medical treatment, but each group except one also receives one of the medicines to be tested. In the last group (the control group), however, the basic medical treatment remains the same.
- "Randomized" means that the patients willing to participate are randomly assigned to one of the groups.
According to the EMA, such studies would, compared to small studies, be more likely to lead to clear results on the suitability of medicines, which would then also allow the approval of medicines against Covid-19.
Such a study was recently initiated by the World Health Organization (WHO): In this study, called SOLIDARITY, four treatments with drugs that are eligible for re-functioning will be compared with each other and with the basic treatment alone. The study will therefore include the following "study arms" (= types of treatment), in which several thousand patients are expected to participate - randomly distributed:
- Basic treatment alone
- Basic treatment + Remdesivir (inhibitor of the RNA polymerase of the virus)
- Basic treatment + Ritonavir/Lopinavir (HIV medicine)
- Basic treatment + Ritonavir/Lopinavir (HIV medicine) + Beta-Interferon (medicine for multiple sclerosis)
- Basic treatment + Chloroquine or Hydroxychloroquine (both are malaria drugs)
Medical institutions in Argentina, Bahrain, Canada, France, Iran, Norway, Switzerland, Spain, South Africa, Thailand, India and other countries will participate in the study. A monitoring board will regularly review interim results of the study and terminate study arms in which patients are no better (or even worse) off than in the control group. It is also possible to add further arms to the study, in which other additional treatments will then be tested. Detailed information on the study can be found in the ISRCT registry.
In parallel, the DISCOVERY study with a very similar structure has started in the EU and UK, coordinated by the French research organisation INSERM. It is expected to involve 3,200 patients from Germany, Belgium, France, Luxembourg, the Netherlands, Spain, Sweden and the UK. Instead of chloroquine, the similar malaria medicine hydroxychloroquine will be used. The selected beta interferon is interferon beta-1A.
Another major study has been launched by doctors from Oxford University in the UK, called RECOVERY. The following study arms are planned:
- Basic treatment alone
- Basic treatment + Ritonavir/Lopinavir (HIV medicine)
- Basic treatment + Beta-Interferon (multiple sclerosis medicine)
- Basic treatment + dexamethasone (cortisone derivative for damping the immune system)
- Basic treatment + hydroxychloroquin (malaria medicine)
Initially, however, only arms 1, 2 and 4 were started, and additional study arms can be added if further medicines are to be tested.
Large clinical trials of Covid-19 therapy with selected medicines are also being organised from the USA, including the Adaptive COVID-19 Treatment Trial (ACTT), for which the National Institutes of Health (NIH) are responsible. Around 75 medical institutions worldwide are expected to participate in the trials, including those in the EU and UK. The trial has initially started with two arms:
- Basic treatment alone
- Basic treatment + remdesivir (inhibitor of the RNA polymerase of the virus)
However, it is planned to add further arms to the study.
In several cases, companies provide large quantities of their medicines for these studies. For example, Sandoz, the generics division of Novartis, has agreed to provide 130 million doses of hydroxychloroquine for clinical trials and facilities, including 30 million doses for a US trial. Sanofi also supplies hydroxychloroquine for studies. Merck supplies interferon beta-1a for the DISCOVERY trial and the SOLIDARITY trial.
SWR2 FORUM: Fight against Corona - When will medicines and vaccines be available?
Radio discussion with Dr. Siegfried Throm (vfa Managing Director Research), Prof. Dr. Rolf Hilgenfeld (German Centre for Infection Research) and Volkart Wildermuth (science journalist)
For the recording of the show in german language please clickHERE.
Examples of medicines whose repurposing is being tested or considered
This overview is updated continuously. It makes no claim to completeness.
Remdesivir was originally developed by Gilead Sciences to treat Ebola infections (against which it has not proven effective). It has shown efficacy against MERS viruses in the laboratory. Now the medicine is being tested with this active ingredient in several studies against SARS-CoV-2.
CytoDyn tests whether its antibody Leronlimab is effective against the coronavirus. Against HIV and tripel-negative breast cancer this medicine is already being tested in trials. Now a phase II study on Covid-19 has been applied for.
AbbVie has provided another HIV medicine with the active substance combination Lopinavir / Ritonavir for testing as a Covid-19 therapeutic.Studies with patients are ongoing in various parts of the world, with the medicine being tested either alone or in combination with a beta interferon (e.g. interferon beta-1a) or the inhalable alpha interferon novaferon from Beijing Genova Biotech. Novaferon is approved in China for the treatment of hepatitis B.
The company Ascletis Pharma combines ritonavir with a medicine approved in China for hepatitis C with the active ingredient Danoprevir. Studies are underway.
Studies with favipiravir (= favilavir) have also been and are being conducted in China and Thailand. The medicine with favipiravir from FUJIFILM Toyama Chemical has so far only been approved for influenza therapy (in Japan and China) and is only intended for second-line therapy in Japan (when other influenza medicines are not or insufficiently effective). According to media reports, Chinese authorities have described the medicine as effective against Covid-19, but the manufacturer continues to classify its medicine as "under study" with regard to Covid-19.
ATR-002, a kinase inhibitor from Atriva Therapeutics in Tübingen (Germany) is also being developed against influenza. The company is now testing preclinically whether the substance is also able to inhibit the proliferation of SARS-CoV-2.
APEIRON Biologics (Vienna) will test the medicine APN01 in a clinical study with patients (Phase II) in Germany, Austria and Denmark. It originated in SARS research and has since been tested in patient studies for other lung diseases. It blocks a molecule on the viruses that they need to enter lung cells and also helps prevent lung damage caused by inflammatory reactions.
Chloroquine has actually become known as an active ingredient in antimalarial medicines, but has been little prescribed in recent years. However, it is now known that the active substance can also be used antivirally. Following positive laboratory tests against SARS-CoV-2, Chinese researchers have now also reported that Chloroquine has been shown to be effective in a clinical trial. Bayer has subsequently ramped up production of its original medicine containing chloroquine.
Malaria medicines with the similar active ingredient hydroxychloroquine are also currently being tested in studies. Novartis has pledged to support these efforts and, if regulatory approvals are granted at the end of May, to make up to 130 million doses of this medicine available for use worldwide. Sanofi will also make available an antimalarial medicine containing this active ingredient.
Camostat mesilate is not actually an antiviral active ingredient in its current field of application - a medicine with this substance has been approved in Japan to treat pancreatitis. However, researchers from a German consortium of research institutions led by the German Primate Centre in Göttingen have discovered that, in the laboratory, it inhibits an enzyme of lung cells that is essential for the penetration of SARS CoV-2 viruses. They therefore plan to test it in clinical trials.
The active ingredient Brilacidin from Innovation Pharmaceuticals was also not originally developed to combat viruses. Instead, it is currently being tested for the treatment of inflammatory bowel diseases and inflammation of the oral mucosa. However, it is expected to be able to attack the outer envelope of the SARS-CoV-2 virus. This is currently being tested in cell cultures.
After encouraging laboratory tests, the Spanish company PharmaMar wants to test its medicine with plitidepsin in a study against Covid-19. The medicine, which is actually approved in Australia and South East Asia for the treatment of multiple myeloma (a form of bone marrow cancer), inhibits viral replication to a considerable extent because it blocks the EF1A protein required for this purpose in the affected cells.
One group of medicines does not fight viruses directly, but instead promotes the body's own virus defence: interferons. They are variants of the body's own messenger substances that are produced genetically. Biochemists divide these messenger substances into several subgroups, of which the alpha and beta interferons are important against SARS-CoV-2:
- Alpha-Interferons: In a series of studies with Covid-19 patients, medicines with the active ingredients interferon alpha-1b, interferon alpha-2b (from the Cuban company BioCubaFarma and the Cuban-Chinese company Changchun Heber Biological Technology), peg-interferon-alpha-2a (produced by Roche), peg-interferon-alpha-2b or novaferon (from the Chinese company Genova Biotech) were used alone or in addition to other medicines. In some cases, the respective alpha-interferon was administered in inhalable form. All these medicines have, at least in some countries, been approved for the treatment of certain viral infections, for example hepatitis B or C. BioCubaFarm has indicated that it can supply large quantities of its medicine worldwide.
- Beta-Interferons: Medicines containing interferon beta-1a and interferon beta-1b are currently being tested in trials against Covid-19. The German company Merck is making its interferon beta-1a medicine available for a larger study by the INSERM institute in France. Neither medicine has been approved for antiviral therapy in the EU, but in laboratory tests interferon beta-1a was able to stop the multiplication of the related SARS viruses. For an inhalable form of interferon-beta-1a, the British company Synairgen has received approval for a study with Covid-19 patients.
Pfizer is currently testing other antiviral agents in the laboratory, which the company has already developed for the treatment of other viral diseases. If one or more of these substances prove successful in laboratory tests, Pfizer would subject them to the relevant toxicological tests and start testing them on humans at the end of 2020. MSD is also currently investigating which of its antiviral agents could be effective against SARS-CoV-2. Novartis is investigating which of its own products and substances from its own medicine discovery library could be suitable for treating covid-19 patients, either as an antiviral or in some other way (see below). Janssen (division of Johnson & Johnson) also tests its antiviral agents in the laboratory.
Downregulating immune modulators
Immune reactions are generally desirable in infected persons; they must not be so excessive that they cause more damage to the lungs than they help.
For this reason, several projects aim to curb excessive immune reactions in severely ill patients.
Sanofi and Regeneron are therefore testing their immune modulator sarilumab in a study with affected Covid-19 patients. This interleukin-6 antagonist is approved for rheumatism therapy.
Roche is testing its interleukin-6 antagonist tocilizumab in patients suffering from severe pneumonia caused by covid-19. The medicine is already approved for the treatment of rheumatoid arthritis. Chinese physicians have also been testing it for several weeks in severely infected patients.
Chinese physicians are also testing the immunomodulator fingolimod with patients. Fingolimod was developed and is approved by Novartis for the treatment of multiple sclerosis.
The company Swedish Orphan Biovitrum plans to test the immune modulators Anakinra and Emapalumab in a clinical study. Observations by Italian doctors provided the impetus. Anakinra is approved (in the EU and elsewhere) for the treatment of rheumatoid arthritis and the inflammatory diseases CAPS and Still's syndrome; Emapalumab is approved in the USA for the treatment of the inflammatory disease haemophagocytic lymphohistiocytosis.
The Jena-based company InflaRX is currently developing the immunomodulatory drug IFX-1 for the treatment of various inflammatory diseases. Several studies with patients have already been conducted. InflaRx is now investigating in a study in the Netherlands whether it can also help patients suffering from severe Covid-19. The active ingredient is a monoclonal antibody.
Novartis also considers the janus kinase inhibitor ruxolitinib to be promising for attenuating excessive immune responses. Ruxolitinib is approved for the treatment of certain cancers.
In Canada, colchicine is being tested in a clinical trial as a remedy for excessive immune reactions, led by the Montreal Heart Institute. The medicine is approved for gout (and in some countries also for pericarditis).
In a broader sense, one can also count sodium metaarsenite (NaAsO2) among the immune modulators, because it dampens the production of certain messenger substances of the immune system (the cytokines), which can trigger intensive immune reactions. The South Korean company Komipharm has thus developed a medicine against tumour-associated pain (project name PAX-1-001). It has now applied for clinical trials to test the medicine in Covid-19 patients.
Medicines for lung patients
Chinese researchers want to test a medicine from Roche with the active ingredient pirfenidone, which has already been approved for patients with idiopathic pulmonary fibrosis. This medicine counteracts the scarring of damaged lung tissue.
The Canadian company Algernon Pharmaceuticals is planning to test the suitability of its medicine NP-120 with the active ingredient ifenprodil. Ifenprodil is now patent-free and approved in Japan and South Korea for the treatment of neurological diseases. Algernon has been developing a medicine against idiopathic pulmonary fibrosis with this active ingredient for some time.
The Viennese biotech company Apeptico intends to test its active substance solnatide against acute lung failure (ARSD) for suitability for Covid-19 patients with severe lung damage. It is hoped that the substance will restore the tightness of membranes in lung tissue.
The US company Bioxytranis also currently developing a medicine with the active substance BXT-25 for patients with ARDS.It is expected to improve oxygen uptake in a damaged lung and help patients who otherwise can only be supplied with sufficient oxygen via an artificial lung. The company would like to test its medicine with a partner for critically ill patients with Covid-19.
In the USA, Bellerophon Therapeutics' ventilator was approved for use in relieving respiratory distress in Covid-19 patients by adding some nitric oxide to the air they breathe. This gas, which is produced by the body itself as a messenger substance, can dilate the blood vessels in the lungs through muscle relaxation. This procedure already showed positive effects during the SARS epidemic.
A growing number of projects are also trying to develop new medicines against Covid-19. Again, three types of projects can be distinguished:
- Projects for antibodies for passive immunization
- Existing early-stage projects for antiviral medicines
- Projects for the new development of suitable active substances
Here are some examples of projects in these areas:
Antibodies for passive immunization
An already old medical method of fighting pathogens is to inject patients with antibodies from the blood serum of people (or animals) who have already survived the disease. Emil von Behring's diphtheria antiserum from 1891 already had this effect, even though nobody knew anything about antibodies at that time. Another example is the syringes used for the passive immunisation ("passive vaccination") of people who might have contracted tetanus because they are not vaccinated against it. Recently, several Ebola medicines with such antibodies have also shown high efficacy in trials.
For this reason, most of the projects for the new development of medicines against SARS-CoV-2 also focus on the blood fluid of former Covid-19 patients, the so-called "convalescent serum" or "convalescent plasma" (both serum and plasma contain no blood cells, with serum having been cleared of certain coagulants as well). It is hoped that some of the antibodies contained therein are capable of rendering SARS-CoV-2 unable to reproduce in the body.
In the simplest case, patients should receive direct infusions with the blood plasma (checked for harmlessness) of former Covid-19 patients or freshly derived antibodies. For example, the Hannover Medical School (MHH), the Heart and Diabetes Center NRW in Bad Oeynhausen, the University Hospitals of Cologne and Münster and the Frankfurt Institute for Transfusion Medicine and Immunohaematology are planning to take this approach. Initially, however, the procedure will be tested in a study with volunteers before it is applied more widely as a therapy. In New York and other parts of the USA this method is also to be practiced in a manner specified by the FDA.
Instead, the companies, Takeda (Japan) and Grifols (Spain), want to extract antibodies from such plasma and use them to produce a medicine for infusion, a polyclonal anti-SARS-CoV-2 hyperimmunoglobulin (H-IG). Grifols plans to produce its H-IG preparation in the USA.
Other companies and research groups in the world also follow the same basic idea, but go a step further biotechnologically: They also start from convalescent serum, but pick out the most suitable antibodies and then "copy" them with biotechnological means in order to produce a medicine. One of these projects is being pursued by the Swedish Karolinska Institute. Another is being pursued by the companies AbCellera and Lilly, which have announced that within months a medicine will be developed with the most effective of more than 500 antibodies obtained, which can be tested on patients.
AstraZeneca (UK), Celltrion (South Korea) and Amgen with Adaptive Biotechnologies (USA) are also working to develop a drug in this way.
A consortium of research institutes in the USA within the framework of the DARPA Pandemic Preparedness Platform as well as a cooperation project of the companies Ethris and Neurimmune (Planegg near Munich and Switzerland) go one step further. In the end, their respective medicines will not contain copies of the most effective antibodies from convalescent plasma itself, but instead the genes for them - in the form of mRNA. Those who are injected with this mRNA produce the antibodies in their own bodies for a while and are protected. The advantage of this procedure is that it will probably be possible to produce large quantities of medicine doses more quickly than if the antibodies had to be produced biotechnologically. The disadvantage is that so far there is no other medicine that works in this way. The project of the U.S. consortium is led by James Crowe, Vanderbilt University, Tennessee, among others, who received the Future Insight Prize of the German company Merck in 2019 for his pioneering work in this field. The medicine planned by Ethris and Neurimmune has the special feature that the mRNA is to be inhaled so that the antibodies are formed close to the site of attack of the viruses.
Several projects for new medicines vary the "convalescent serum" approach. For example, Vir Biotechnology has previously extracted antibodies from the blood serum of patients who survived a SARS infection in 2003. The company is now working with the US institutes NIH and NIAID to test whether they too are able to stop the proliferation of SARS-CoV-2.
For the biotechnological production of "copies" of these antibodies, Vir Biotechnology is cooperating with the US company Biogen and the Chinese company WuXi Biologics. Imperial College London is also working with partners on an antibody therapy based on antibodies from the blood serum of former SARS patients.
Scientists from the University of Utrecht (Netherlands) have also studied antibodies from the blood serum of SARS convalescents from 2003. They found an antibody that can inhibit the proliferation of SARS-CoV-2 in culture. It will now be further tested.
Regeneron is running a similar project: The company is testing a medicine with the monoclonal antibodies REGN3048 and REGN3051 in a Phase I study with volunteers. These antibodies were developed for the treatment of MERS coronavirus, which is related to SARS-CoV-2.
Boehringer Ingelheim is also working with the German biotech company Yumab and other partners on an antibody medicine against Covid-19. However, the company does not analyse convalescent plasma, but uses laboratory methods (phage display) to create specific artificial antibodies that can, for example, interrupt the binding of the virus to human cells.
A consortium of teams from the University of Ghent, the Flemish Institute for Biotechnology, the University of Austin (Texas) and the German Primate Center in Göttingen has developed an antibody that can block SARS-CoV-2 in the laboratory. It was composed of several antibody parts (including a single-domain antibody obtained with the help of a lama).
Existing early-stage projects for antiviral medicines
A research team at the University of Lübeck (Germany) is pursuing a different approach. It has been developing so-called alpha-ketoamides as antiviral agents against corona and enteroviruses (which are responsible for oral thrush, among other things) for years. In laboratory tests, new experimental agents inhibit the multiplication of these viruses. One of them, called "13b", is optimized against corona viruses. It is now to be tested in cell cultures and with animals and, in the case of positive results, will be tested in human studies together with a pharmaceutical company.
Projects for the new development of suitable active substances
A number of large pharmaceutical companies have joined forces to develop new therapeutic medicines (as well as vaccines and diagnostics) against Covid-19. As a first step, they will make available their proprietary collections of molecules for which some data on safety and mode of action are already available. These will be tested by the "Covid-19 Therapeutics Accelerator" facility established by the Gates Foundation, Wellcome Foundation, and Mastercard. For molecules that are considered promising, tests with animals are to begin within two months. The company group includes BD, bioMérieux, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Eli Lilly, Gilead Sciences, GSK, Janssen (Johnson & Johnson), MSD, Merck, Novartis, Pfizer and Sanofi.
The German company AiCuris, which specialises in anti-infectives, has also announced that it will test its own substances for suitability against SARS-CoV-2.
The companies Vir Pharmaceuticals and Alnylam Pharmaceuticals are pursuing a different plan. They have announced their intention to develop so-called siRNA medicines that block the virus by making some of its genes non-functional. The approach is called gene silencing. The South Korean company OliX Pharmaceuticals is also working on a substance of this type against SARS-CoV-2.
Every medicine must be tested to see if it is suitable for treating people with Covid-19. This also applies to medicines that have already been approved for other patients or have been extensively tested. The regulatory authorities must then be able to test each medicine for efficacy, tolerability and technical quality based on the results. However, the regulatory authorities have indicated that they will give priority to both the approval procedures for clinical trials and the approval procedures for successfully tested medicines. Companies will also be able to submit marketing authorisation applications "chapter by chapter", which will further accelerate the examination by the authorities.
However, the experience and resources of companies that have been developing and selling medicines for many years will also be essential for the rapid introduction of suitable medicines into patient care. For example, the company Pfizer has offered to contribute its comprehensive experience with studies, approval procedures and production process development as well as its production capacity to cooperations with smaller companies that develop corona medicines. The company will also make laboratory methods, which it has developed for its own corona research, available to all on an "open source" basis.
Which is what?
Coronavirus: This is the generic term for a family of viruses that infect humans or animals. It also includes the pathogens that cause SARS in 2002/2003, MERS and several forms of the common cold.
SARS-CoV-2: The causative agent of 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 is infected with SARS-CoV-2 falls ill. Those who show symptoms after infection with the new pathogen suffer from the respiratory disease Covid-19, which is named after "coronavirus disease" and the year of its first appearance, 2019.