Tocilizumab, molnupiravir, Calquence, dexamethasone, Anakinra, monoclonal antibodies… Covid therapies – under rolling review or now given – are only starting to come up after over a year in the pandemic and groping research to find THE drug that will settle a score with the virus. Supportive therapies are now only enabling to prevent a deterioration of cases once at the hospital or ahead of time to avoid intubation.
And the research offsets vaccines’ since it has moved a lot in a short period of time. And for good reason: several produces are already on the market since the beginning of the year and given everywhere across the world to prevent from new more contaminating and deadlier variants from breaking out. But why is looking for a therapy more difficult than for a vaccine?
A complex virus to fight
First of all, we must say that to fight the virus, we need to know the structure and its weaknesses. This is how, in January 2020, a team of Institut Pasteur scientists managed to sequence the genome, detailing the composition and flaws to fight against. Coronaviruses are “RNA viruses, but very singular, they truly are outside this family of RNA viruses because they have very long genomes: 30,000 nucleotides”, Aix-Marseille University lecturer-researcher and biologist Isabelle Imbert told in March 2020 in a CNRS podcast.
She went on: “generally, RNA viruses are 10,000 to 12,000-nucleotide long, so the fact they have a much longer genome makes it will make the system more difficult”. A superior number of nucleotides involving there are more replication proteins, enabling the virus to reproduce itself. And a “much more complex playground”, the scientist said, making the search for an effective inhibitor therapy more difficult.
“Their weak spot is their dependent-RNA polymerase RNA activity”, the biologist adds. She goes on: “Targeting this enzymatic activity has widely proven itself in the world of virology since now, we can cure patients suffering from the hepatitis C virus (another RNA virus, editor’s note), with a drug particularly aiming at this dependent-RNA polymerase RNA activity (an enzyme synthetizing RNA molecules by copying the RNA, editor’s note)”. She concludes: “Managing to understand how the Covid polymerase works will make it a target of choice, an information that can be collected by people working in developing the inhibitor”.
The vaccine’s strength: its mechanism
Why has a vaccine been found so fast but not a cure? Because studying coronaviruses is not new: in 2003, a virus close to Covid broke out, aka the SRAS-COV1. A “first cousin” working in a similar way and for which vaccines were already under rolling review, but fewer therapies: “these viruses are narrowly linked and belong to the coronavirus family we have been studying for a while”, Nancy university hospital infectious disease specialist Pr. Christian Rabaud said in December 2020.
He went on: “On their surface, they have similar proteins and use the same to attach to the cells and enter them to infect them. The most important one being the Spike protein, that is now the target of most vaccines being developed”. The search for vaccine has been adapted to this new virus. Add to this an almost unlimited financing to develop the vaccine and you quickly get a reliable and effective product, but depending on searchers and clinical trial outcomes.
Whether it involves an mRNA vaccine, or a viral vector vaccine, the global mechanism is the same: inciting the creation of antibodies in the organism before contamination so, once the virus has entered one’s body, is eliminated before it can replicate. As for therapies, they work differently from one disease to the other, as they attack the virus differently, once by developing in the organism, hence the difficulty to quickly find one, unless you are lucky.
Creating a new therapy from A to Z takes time…
Another subject about the look for a therapy: “looking and developing drugs takes a long time”, Geneva University Global Health Institute Head and Epidemiologist Pr. Antoine Flahault explains to Atlantico. He goes on: “Developing new molecules is very long, we think it takes about ten years, and we are only eighteen months in the pandemic!”.
The strategy used to buy time is about “repositioning old molecules, prescribes for other diseases, on the therapy for COVID-19”, the professor adds, “whether because these molecules have an antiviral power on infected cells in the lab, or for their anti-inflammatory properties, knowing COVID-19 severe complications are often linked to the inflammatory storm of the infected organism”.
But this strategy has limits: “It is clear the repositioning strategy has not been successful so far, and little molecules have shown clear benefits for patients, excluding, as we have reported with dexamethasone”, Flahault explains as well.
Where is the look for a therapy at?
Although looking for a therapy takes a while, some molecules have already delivered results. For instance, dexamethasone, an anti-corticoid, has delivered very encouraging result on secondary inflammation of the lungs because of Covid, the famous “cytokine shock”. A molecule treating a symptom – the one leading to respiratory distress and in most cases death – giving time to the body to fight the virus on its own.
Another promising therapy is based on monoclonal antibodies, now approved by the European regulator to help and cure the disease in hospital Covid units. But the problem is these therapies are very expensive, hence the necessity to keep looking for other ways to fight the disease.
More drugs have entered to will be rolling reviews. For instance, we can think of Xav-19, a polyclonal antibody developed by Nantes biotech Xenothera: “Our product is now in phase 3 of the clinical trials. If everything goes well, it could be approved and used from this Fall", Xenothera CEO Odile Duvaux told our peers from Le Monde.
The research yet aims at being optimistic: “Today, we know how to fix damages caused by the virus better, for instance, using dexamethasone, an anti-inflammatory, but there is no therapy on the market yet directly attacking the virus. Research has improved a lot though, and we hope to see several drugs developed in the next six months”, Aix-Marseille University CNRS Head of Research Bruno Canard told Le Monde.
This is good news, then, drugs will join the vaccine arsenal.
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Covid: vaccines and therapies available or still being reviewed
