Therapeutic medicines against coronavirus infection Covid-19

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

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

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

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

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

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

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

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

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

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

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

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

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

On the other hand, the company Aptarion biotech's aptamer is being developed for immune attenuation (see below).

A DARPin (Designed Ankyrin Repeat Protein) is a synthetic protein whose structure is derived from ankyrins. It consists of multiple repeating units that can recognize and bind antigens, but are much smaller and more stable than antibodies. With Ensovibep (MP0420), the Swiss company Molecular Partners partnered with Novartis to develop a compound against SARS-CoV-2 that prevents severe deaths in hamsters. It is now being tested in a Phase IIa study with patients following a Phase I tolerability study. It will also subsequently be tested in Phase II/III trials, including under the U.S. ACTIV-3 protocol.

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

Smaller agents that can easily penetrate cells (so-called small molecules) are the primary agents considered for blocking viral replication within cells. These are usually produced by chemical synthesis. Many agents under investigation (including the only one approved to date) were originally developed to treat a different viral infection.

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

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

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

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

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

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

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

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

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

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

A different plan is being pursued by the companies that want to combat SARS-CoV-2 by means of gene silencing. This approach involves preventing certain genes from being used to replicate the virus. Vir Pharmaceuticals and Alnylam Pharmaceuticals (both U.S.) want to achieve this using so-called siRNA agents. The South Korean company OliX Pharmaceuticals is also working on a compound of this type. Germany's Biotech Secarna and China's Guangzhou's Sun Yatsen University aim to achieve gene silencing using an antisense oligonucleotide - a molecule from a related class of compounds.

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

Several antimalarial medicines with the active ingredients chloroquine and hydroxychloroquine have also not proven effective. After positive laboratory tests against SARS-CoV-2, they were first tested in trials in China, and later in other countries. However, the results of several studies indicated that the medicines did not have a positive risk-benefit balance, and often even made the situation worse. Therefore, the chlorquine/hydroxychloroquine study arm in the WHO SOLIDARITY trial was halted and an interim emergency approval for hydroxychloroquine in the United States was rescinded.

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

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

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

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

Anticoagulant low-molecular-weight heparins (such as those otherwise injected into patients after certain operations) have already proven effective against the risk of thrombosis. Their use is therefore also recommended by the relevant therapy guideline (and does not require a separate Covid-19 approval). Specifically, the low-molecular-weight heparin enoxaparin has previously been tested in a number of trials. It was originally developed by a predecessor company of Sanofi. The structurally similar Tinzaparin as well as unfractionated heparin and the similarly anticoagulant Bivalirudin are also being tested in trials. Bivalirudin was developed by The Medicines Company, which is now part of Novartis. A previously unapproved anticoagulant, the heparin derivative dociparstat, is also being tested by the Chimerix company in Covid-19 patients in a Phase II/III study. According to a study by the Hasso Plattner Institute for Digital Health and the Icahn School of Medicine in New York, treatment with anticoagulants does indeed improve survival in severely ill Covid-19 patients.

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

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

After retrospective comparisons indicated a potential benefit of acetylsalicylic acid (ASA), this agent is also now being tested in a clinical trial as a therapy for hospitalized covid-19 patients. ASA is approved for the prophylaxis of heart attacks and strokes, among other indications.

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

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

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

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

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

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

One has already been approved for this purpose: Because an effective attenuation of immune reactions and thus reduction of mortality in severely ill patients succeeded in a study in the UK with dexamethasone, a cortisone derivative with a known anti-inflammatory effect: there, dexamethasone was able to reduce the risk of death in patients requiring oxygen or even artificial respiration by a fifth or a third. A corresponding extension of approval was recommended by the EMA in September 2020. Therapy improvements have also been achieved in studies with the related cortisone derivatives hydrocortisone and methylprednisolone.

But beyond that, numerous other medicines are in trials:

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

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

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

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

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

Blockade of CCR receptors on immune cells is another approach:

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

Also being tested in the U.S. is fosamatinib from Rigel Pharmaceuticals in a phase III trial. This SYK inhibitor (inhibitor of splenic tyrosine kinase) can dampen certain immune responses, including the formation of network-like structures of DNA and proteins - NETs - by certain white blood cells. This mechanism is part of the innate immune defense. Misdirected immune responses involving the formation of NETs contribute significantly to the dangerousness of the severe stage a covid 19 disease because they promote the formation of thromboses. This was discovered at the University of Nuremberg-Erlangen and elsewhere.

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

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

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

Sanofi and Denali Therapeutics are testing the immunomodulator DNL758 in a phase Ib trial with Covid-19 patients. This inhibitor of RIPK1, a molecule from an immune-related signaling pathway, has been in trials against various inflammatory diseases since 2018.

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

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

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

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

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

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

Immune cells (macrophages and dendritic cells) are used by the Israeli company Enlivex to dim the immune system back down in the event of a cytokine storm. Its cell therapy Allocetra was already in development for sepsis before the pandemic. After successful trials in Phase I and II studies, a Phase III trial is planned.

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

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

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

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

One of the medicines being tested for maintaining lung function contains the active ingredient Aviptadil, a synthetic version of the naturally occurring molecule VIP found in humans. The Swiss company Relief Therapeutics has approval for it in the EU for the treatment of acute respiratory distress syndrome (ARDS) and sarcoidosis, but has not yet brought it to market in Germany. Among other things, the active ingredient has an anti-inflammatory effect and presumably protects certain lung cells (alveolar type 2 cells) from viral attack. They are a preferred target of SARS-CoV-2 and are particularly important for maintaining lung function. The company NeuroRx conducted following positive laboratory data with support from Relief Therapeutics in the U.S. a Phase II/III study with severely ill Covid-19 patients (symptoms of severe lung failure; ventilated). Patients recovered more quickly from respiratory symptoms under intravenous therapy. Now NeuRx plans to apply for Emergency Use Authorization from the FDA. Relief Therapeutics has also begun a Phase II trial in with an inhalable formulation of the drug in collaboration with AdVita Lifescience of Gundelfingen, Germany. The goal here is also to prevent acute respiratory distress syndrome in Covid-19 patients.

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

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

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

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

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