Let’s say it right off the bat: monoclonal antibodies represent a real beacon of hope. Immunologists and infectious diseases alike are eagerly awaiting the arrival of these innovative treatments, because they could be very useful for the management of fragile patients recently infected with Covid-19 and at high risk of getting worse. But within this new family of drugs, not all products are created equal. In ongoing clinical trials, some are picking up positive signals about their effectiveness, while others are not at all. And, surprisingly, the drug that the government chose to authorize first, bamlanivimab from the company Eli Lilly, is the one that raises the most questions.
“When the Directorate General of Health asked us in January about this product, we said that we really saw no reason to rush, that it was better to wait for convincing data, or even the arrival of other monoclonal antibodies. “, says Pierre Tattevin, the president of Spilf, the French-speaking infectious pathology society. However, the public authorities rushed. A few weeks later, on February 22, it is for bamlanivimab that the National Medicines Safety Agency (ANSM) issues a temporary authorization for use, intended for people over 80 and immunocompromised people due to illnesses or treatment (chemotherapy, transplants, etc.). On Thursday February 25 at the end of the day, the Minister of Health Oliver Véran was therefore able to announce with great pomp, during a press point, the purchase by France “of thousands of doses of this treatment”, already distributed “in 83 hospitals”, and presented as “a solution to strengthen our anti-Covid arsenal”.
Has there been a poor flow of information? Was it too late to change the agenda for the press conference? Still, the same day, the experts of the ANRS-emerging infectious diseases (ANRS-MIE), who advise the government on the choice of innovative treatments, had alerted the services of Olivier Véran of an “element of concern “about this drug. And not least: the risk that it will cause new variants to emerge, as they then reported in a letter to the ministry. It was the laboratory itself which had warned the experts. “We are in a very fluid period, and when we had this new information, we indicated that it would be advisable to tighten the type of patient who can benefit from this drug, and to increase the monitoring of the patients treated, so as to do not allow variants to emerge, “reports Professor Brigitte Autran, who heads the monoclonal antibody reflection group within the ANRS-MIE.
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Concerns of infectious disease specialists
This risk was known. Immunocompromised patients are the most in need of these synthetic antibodies since they are unable to build their own defenses, but it is also in them that these products are most likely to cause the development of variants. And, in fact, a certain number of infectious disease specialists had already been alarmed for several days by the choice of the public authorities: “When we saw the text of the drug agency arrive, with a target audience that did not seem appropriate to us, we met between specialists, and we decided to suggest that this drug be prescribed only on a case-by-case basis, on a compassionate basis and after consultation between doctors for each patient “, explains Pr Karine Lacombe, head of the infectious disease department. Saint-Antoine Hospital (APH-HP) in Paris which, for its part, decided that it would probably use very little, pending the imminent arrival of other treatments.
As a result of these alerts, the Ministry of Health and the ANSM have partially rectified the situation. On Saturday February 27, two days after Oliver Véran’s announcement, the administration announced that the patients treated will have to remain in the hospital to guarantee their isolation, and to facilitate the monitoring of the evolution of viruses in their organism. “Clearly, we will find ourselves hospitalizing patients when the goal, with this treatment, was precisely to avoid aggravation and hospitalization”, quips Professor Pierre Tattevin. On the other hand, the list of potentially eligible patients is reduced only at the margin, contrary to the wishes of certain infectious diseases specialists: “This question remains to be decided”, confirms Professor Gilles Pialoux, head of the infectious disease department of the hospital. Tenon in Paris. This expert also regrets “that this drug was not tested on the target population: in one of the trials, only 10% of the patients included are over 65 years old, whereas this product is intended for the moment in particular for over 80 years “.
The ministry, meanwhile, is working hard to encourage hospitals to use the drug. “All the CHUs have been contacted to be ready to offer it, but no one is really excited, because behind us we know that we will have other more interesting drugs which will arrive quickly”, continues Professor Tattevin. These treatments, the first of which are expected in mid-March, combine two monoclonal antibodies. They have the advantage of less facilitating the emergence of variants, but also of presenting somewhat stronger evidence of efficacy than bamlanivimab.
A decision more political than scientific
Because this is the other problem with this drug: not only is it potentially dangerous, but in addition, nothing at this stage shows that it brings any benefit to patients. When the temporary authorization for use was published, a few pharmacologists looked at the data available to support the availability of the product. And what they discovered stunned them: “A temporary authorization for use issued on such a low level of evidence is probably unheard of”, denounces Professor Mathieu Molimard, head of the clinical pharmacology department at Bordeaux University Hospital. The drift even seemed so important to them that for the first time in its history, the French society of pharmacology and therapy (SFPT), which brings together and represents these experts, cracked a press release.
“It’s exactly the same as what we saw with hydroxychloroquine last year”
What is it? The data comes from a phase 2, small-scale study that is purely exploratory in nature, these experts say: “The purpose of this type of work is to obtain preliminary information in order to determine whether the product is sufficiently promising to warrant the completion of a phase 3 study “. Covering a larger number of patients, this will enable the effectiveness of the product to be evaluated. While it is not necessarily unusual to issue authorizations for temporary use on phase 2 results, they still need to be convincing. However, this is not at all the case here, according to the SFPT: “No statistically significant difference was obtained on the main endpoint or the most clinically relevant endpoint (hospitalizations), whatever the dose. . It is therefore impossible to conclude to any effect of the treatment (…) or to a clinical benefit “. Asked to understand the reasons which led it to issue the ATU under these conditions, the ANSM did not answer our questions.
“There are no drugs without risks. Here, politics have taken precedence over science. However, it is precisely in times of stress and tension as currently that we must respect the methodology, be rigorous “Otherwise, we’re going to do anything. It’s exactly the same as what we saw last year with hydroxychloroquine,” insists Professor Molimard. But under these conditions, why did this drug benefit from a temporary authorization? “The agencies are in direct connection with the cabinet, and the French need good news. In the mind of the politician, monoclonal antibodies have a place to fill the void between now and the improvement of vaccination coverage. C ‘is a way of occupying space “, analyzes a doctor.
More than 1000 euros per dose
But that does not explain the government’s desire to order this monoclonal antibody, in particular when others, benefiting from more convincing data, should arrive by mid-March, or in a fortnight. Was it about not appearing to be lagging behind other countries, like Germany and the UK, who also bought this product? France had yet been able to distinguish itself from its neighbors by not ordering remdesivir – with good reason since it did not ultimately succeed in showing any real benefit for patients either. Under these conditions, was there really an emergency? “For now, we have nothing else to offer to patients at risk of getting worse, although it is true that it is not a miracle treatment. But it was planned since long that the State buys, and there was a schedule of production and provision of drugs by the firms: we could not have at our disposal earlier the dual therapy of this producer “, explains Professor Brigitte Autran.
Will these economic and industrial considerations be enough to convince doctors to prescribe this product to their patients? Not sure. In the United States, where this drug was authorized more quickly than in France, the vast majority of practitioners shunned it. In France, the doses have already been purchased by the public authorities. The exact price and the quantities ordered remain confidential, indicate both the Ministry of Health and Eli Lilly. But across the Atlantic, for example, these products were billed a little over 1000 euros per dose. At this price, the bill will be heavy, especially for a product without demonstrated effectiveness …
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