“Scandal”. This is how Antoine Flahault, director of the Institute of Global Health at the University of Geneva, qualifies, on Twitter, the decision of Lilly Laboratories. The American pharmaceutical company has developed the only monoclonal antibody, bebtelovimab, which remains completely effective in neutralizing the BA.4 and BA.5 sub-variants of Omicron, as shown by a recent study conducted by a team from Columbia University and published in pre-publication on the BioRxiv site. Problem: Lilly refuses to market its treatment outside the United States, where 600,000 doses have already been ordered.
Why is this important? Because the BA.4 and BA.5 sub-variants, which are more transmissible than their predecessors, have recently experienced spectacular progress in the world, to become dominant in the United States, South Africa, but also in Portugal, which sees currently an increase in confirmed cases, hospitalizations and deaths linked to Covid-19. In Switzerland, these subvariants now account for almost 50% of new transmissions, according to Christian Althaus, epidemiologist at the Institute of Social and Preventive Medicine at the University of Bern. According to the latter, 65% of the Swiss population still has immunity against BA.5, but 15% of the population could be infected by the newcomer within the next few weeks.
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Furthermore, Omicron also seems to have increased its pathogenicity, as its subvariants appeared. According to a study by the University of Tokyo, which evaluated the characteristics of the BA.4 and BA.5 subvariants, the latter would replicate more efficiently in human lung cells. In hamsters, lung lesions would be more severe during an infection with these two new sub-variants, in comparison with BA.2. Hence the importance of having effective treatments for people at high risk of developing severe forms of the disease or for immunocompromised patients.
“The Lilly company told us that it did not want to share its antibody to conduct clinical studies in Europe, nor to market doses, is indignant Antoine Flahault. This is very concerning, as we will not have an effective neutralizing antibody to treat the infected people most at risk.” The Federal Office of Public Health, for its part, had already inquired in February about the possibility of supplying bebtelovimab from Lilly, which reportedly replied “that it does not currently intend to make the drug available in outside the United States”. Negotiations are ongoing between the pharmaceutical company and the US government for the supply of additional doses under an amended purchase agreement. But nothing else.
What are the reasons for this decision? When contacted, the pharmaceutical company, which has a branch in Switzerland, replied laconically that it “continued to assess the need and demand for [son] processing in other markets.” However, hypotheses are emerging: “Lilly had launched a first generation of monoclonal antibodies directed against SARS-CoV-2, but this treatment very quickly lost effectiveness against new variants, explains Alexandra Calmy, infectious disease specialist at the University Hospitals of Geneva ( HUG). Is it possible that the company was burned by this experience and no longer wishes to invest as much in this therapeutic field? It is very difficult for us as doctors not to have a drug that seems to retain efficacy against BA.4 and BA.5.”
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In fact, as Antoine Flahault reminds us, most of the monoclonal antibodies put on the market fell into oblivion one after the other, collateral victims of the different variants of SARS-CoV-2. “As soon as mutations on the spike protein of the virus appear, we note a decrease in the activity of monoclonal antibodies, which forces us to constantly adapt in our clinical decisions”, points out Oriol Manuel, assistant doctor in the Infectious Diseases Department. of the Vaud University Hospital Center (CHUV). Proof of the fragility of these treatments: “The monoclonal antibody developed by Regeneron was approved by Swissmedic (Swiss Institute for Therapeutic Products) the same day that we stopped using it in the clinic, it had then become totally ineffective against the Omicron variant”, recalls the specialist.
An antiviral as a ray of hope
Lilly’s monoclonal antibody inaccessible, what do doctors now rely on to care for patients at risk of developing serious forms of Covid-19? Fortunately, the bad news did not follow, Swissmedic authorized this June 15, for a limited period (nearly 5 months after the European Medicines Agency (EMA) the use of Paxlovid, the oral antiviral developed by Pfizer, whose clinical studies have shown very good efficacy against hospitalizations. “This drug seems to be more resistant to the antigenic changes of SARS-CoV-2, including those that occur in the Omicron family, rejoices Alexandra Calmy. From now on, we use Paxlovid on the front line to protect the most fragile patients from serious forms, which means that we are not completely helpless. It is a ray of hope.”
“The fact that Paxlovid has been authorized reassures us, supports Oriol Manuel. For the time being, this treatment is still limited to patients at very high risk of serious complications from Covid-19, but data from other countries show us that it could also possibly be used in more patients. .” Its limitation? Possible interactions with certain medications for heart disease or immunosuppressants. “This requires having an in-depth discussion on the benefits and risks of such a treatment, explains the doctor. But it will still make it much easier to care for patients at risk.”
In the remaining therapeutic arsenal there is still in particular the antiviral Remdesivir which is administered intravenously, but whose manufacturer Gilead is currently testing oral forms in the early phases of clinical trials. Or Evusheld, a combination of monoclonal antibodies used in prevention in people at high risk of complications, and perhaps soon in early treatment of Covid-19.
Faced with developments in antiviral drugs against Covid-19, what will monoclonal antibodies still be used for? “They can be useful in very immunosuppressed patients, explains Oriol Manuel. The antiviral reduces the viral load in the body and avoids immediate complications, but recurrences are not excluded when patients do not have enough antibodies allowing them to fight against an infection. These antibodies could give them some immunity.” “Given the race against variants, we absolutely must have treatments with different mechanisms of action, otherwise we’re playing the lottery,” says Alexandra Calmy.
The example of bebtelovimab also underlines more broadly the question of the independence of Europe concerning treatments against Covid-19. “Europe will perhaps understand that it lacked audacity and risk-taking in the development of treatment against Covid-19, analyzes Antoine Flahault. There is no ambitious R&D program in this area.” And the epidemiologist recalls that the best strategy to deal with the rebound in infections and avoid an increase in mortality is to test and treat.
“Prevention is also very important, especially in nursing homes, where the mask should once again be worn by healthcare staff and visitors, says the Geneva epidemiologist. Vaccination would also prevent an increase in mortality with a welcome fourth dose to boost the immunity of those whose booster dose dates back a long time.