Covid-19: update on treatments

More than 150 million cases identified (by Johns Hopkins University, in the United States, which is the reference) and more than 3.2 million deaths. At the beginning of May, it was the balance sheet of Covid-19 across the world. In some countries, such as Brazil or India, the curves are flying away, while in others, the situation is improving. One of the factors of these developments is often the scale of the vaccination campaign on which many governments rely to loosen the stranglehold on health measures. To do this, they have several products, the most famous of which are those of Pfizer-BioNTech, Modern, Astrazeneca and Janssen (the four authorized in France). Thus, at the end of April, more than 1 billion doses of Covid-19 vaccines had been injected in the world.

However, vaccination is only one way to fight the pandemic, another lies in antiviral treatments to cure those infected, or at least reduce the severity of the disease. A year ago, various molecules, often repositioned (recommended for another pathology, but tested against the new coronavirus) have been in the spotlight. Few are authorized today, apart from dexamethasone (recommended by the WHO and the High Council of Public Health in France). But research continues, always more actively. Which substances are the most promising?

Monoclonal antibodies

One of the avenues explored is that of monoclonal antibodies: derived from the same line of producing cells, often modified B lymphocytes (for example fused with cancer cells to take advantage of their capacity to divide indefinitely), they all recognize the same part, or epitope, of an antigen.

This production method in vivo, complex, in fact very expensive treatments, at several thousand euros per dose. The AstraZeneca company, already known for its vaccine, has developed AZD7442, a combination of two monoclonal antibodies (AZD8895 and AZD1061) obtained from the plasma of two patients who have recovered from an infection with SARS-CoV-2. Initially isolated by a team from Vanderbilt University in Nashville, United States, these two molecules target the RBD domain, the part of the S protein of the coronavirus that binds to the ACE2 receptor of the infected cell. The modification of a few amino acids in the sequence of antibodies prolongs their lifespan in the organism and reduces the risks of a still unexplained phenomenon known as “facilitation of infection by antibodies” (ADE for English antibody-dependant enhancement) when antibodies favor the virus: according to the most plausible hypothesis, the antibody would associate with a cell, but also with the virus, which could thus more easily infect this cell. The association will be tested as part of the European Discovery trial led by Inserm, which aims to find a treatment against Covid-19. Concerning 1,240 patients across Europe, this phase III clinical trial, with others in progress (Provent, Strom Chaser, Tackle, Activ-2 and Activ-3), will seek to assess the benefit of AZD7442 preventive and curative.

REGN-COV2 is another combination of monoclonal antibodies, offered by the company Regeneron, in partnership with the Roche laboratory. It had its quarter of an hour of fame when it was administered in October 2020 to the former President of the United States, Donald Trump. Again, the two antibodies, casirivimab and imdevimab were isolated from recovered patients. April 12, 2021, the results of the phase III study reported an 81% reduction in symptomatic infections in uninfected subjects treated with this cocktail of antibodies. In addition, in patients, the product accelerated the disappearance of symptoms. According to its designers, this treatment would also be effective against the various variants that have emerged around the world. The European Medicines Agency (EMA) authorized REGN-COV2 on February 26, 2021 for patients at risk of severe disease. Germany, then France, did the same in the following weeks and ordered several thousand doses.

Among the other monoclonal antibodies developed against Covid-19, we can mention the VIR-7831, developed by the companies Vir Biotechnology, in San Francisco, and GSK, in London, as well as the cocktail of two antibodies (bamlanivimab and etesevimab) both manufactured by the company Eli Lilly, in Indianapolis. VIR-7831, first isolated in 2003 in a person cured of severe acute respiratory syndrome (SARS), is said to reduce participants’ risk of hospitalization or death by 85%. As for the association, it would reduce the risk of hospitalization and death by 87%. Etesevimab would bind to a different epitope than bamlanivimab and neutralize variants of the coronavirus having mutations in the epitope recognized by bamlanivimab. The EMA has been evaluating this association since March 11, while the French Medicines Safety Agency (ANSM) temporarily authorized bamlanivimab alone in February 2021.

Inside EMA’s eye

The EMA is also reviewing regdanvimab (or CT-P59), a monoclonal antibody developed by South Korean company Celltrion which would neutralize SARS-CoV-2 by also binding to the RBD domain of the S protein. The molecule would be effective even against various variants, especially those with the D614G mutation, appeared in early 2020 and now dominant in the world. These three antiviral treatments evaluated by the EMA, are part with seven other monoclonal antibodies of a long and more important list of drugs closely monitored by the agency. They are 57 in number.

What do we find in this potential pharmacopoeia? On April 27, 2021, the EMA announced that it had started evaluating olumiant (baricitinib), an immunosuppressant commonly prescribed for rheumatoid arthritis and eczema, in hospitalized patients and on life support.

This molecule inhibits enzymes called Janus kinases (JAK 1 and JAK 2) which help trigger inflammation and also promote internalization of the virus in cells during infection. In doing so, baricitinib may reduce the severity of SARS-CoV-2 infection. This is what showed Volker Lauschke and colleagues from the Karolinska Institute, Stockholm, Sweden: mortality in the group that received the molecule was 71% lower than in the control group.

CROI and the way

Another promising case of repositioning, the molnupinavir (EIDD-2801 or MK-4482) , historically indicated for influenza, has been shown to be successful in phase II trials.

The results were presentedat the International Conference on Retroviruses and Opportunistic Infections (CROI) held in March 2021. Discovered in the early 2000s by researchers at Emory University, Atlanta, USA, who were researching antivirals against the hepatitis C virus, this nucleoside derivative introduces errors during the replication of viral RNA by targeting the RNA polymerase of the microorganism: the new RNAs produced are dysfunctional and unsuitable for the manufacture of new viruses. The molecule is currently being tested in a phase III trial conducted by Merck and Ridgeback Bio laboratories. The drug would drastically reduce or even suppress the viral load in a few days.

At the same CROI, the encouraging results aboutanother molecule have been announced. They concern AT-527, a compound developed by the American laboratory Atea Pharmaceuticals, which also disrupts the RNA polymerase of SARS-CoV-2 by mimicking a nucleotide (guanosine) , one of the building blocks of RNA.

In collaboration with the Roche laboratory, phase II trials are underway.

Studies of nitazoxanide are more advanced, since the results of a phase III trialhave been announced on April 14, 2021 . The compound, originally developed by the Romark laboratory in Florida, against intestinal parasites (Cryptosporidium parvum and Giardia lamblia), reduced the hospitalization rate by 79% and the rate of progression to severe disease by 85% in participants compared to the placebo group.

The antiviral properties of nitazoxanide (which becomes tizoxanide in the body) are linked to anticytokine activities, in particular interleukin-6, and therefore anti-inflammatory, as well as to a reduction in certain functions of the mitochondria called upon by the infection and to the inhibition of certain proteins of the virus, in particular the protein denoted N, the one around which the RNA is wound in the microorganism.

And in France ?

Let’s continue with beta interferon, a substance naturally produced by the body to fight in the front line against various aggressors, such as viruses and cancer cells.

Studies from the start of the pandemichad shown that a significant decrease in this production is associated with the development of severe forms of Covid-19. Therefore, administering it as soon as possible, upon diagnosis, would it improve the patient’s prognosis? This is what a test on 700 patients that has just started in France as part of the Coverage clinical trial will have to answer. Thus, the severe forms would be alleviated.

Let’s finish this panorama with clofoctol (Octofen), an antibiotic long used in the treatment of respiratory tract and mouth infections.

Its possible indication against SARS-CoV-2 was demonstrated after screening thousands of compounds. After a few twists and turns, the Institut Pasteur de Lille announced on April 13, 2021 the imminent start of tests for the molecule against Covid-19 as part of the Therapide project, which received from the Committee to this national piloting of therapeutic trials (Capnet) the label of “national research priority”. Little is yet known about the mechanism, but the compound’s affinity for proteins binding to messenger RNAs, and therefore possibly to the SARS-CoV-2 genome, may be a key component of the antiviral action of clofoctol. .

The few examples detailed here are among the most successful and the most encouraging to hope one day to treat Covid-19. No one can yet say whether any of them will keep their promises. However, they only represent the tip of a very large iceberg bringing together tens of thousands of publications on potential drugs. That no one crosses all the barriers that constitute the tests and clinical trials prior to any commercialization would be the height of bad luck …

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