It’s a reversal that continues to generate ink. The European Medicines Agency finally issued a marketing authorization a few days ago for lecanemab (its commercial name Leqembi), a treatment against Alzheimer’s disease to which it had initially opposed an end of non-receipt in July. This decision delights at least some of the specialists in this formidable pathology, as much as it arouses the concern of pharmacologists, who are today launching an alert on this subject through the French Society of Therapeutic Pharmacology, as revealed by L ‘Express.
The debate is only just beginning, because European marketing authorization is only a first step before the drug reaches French patients. The High Authority for Health (HAS) will now have to decide on whether or not to reimburse this treatment, and everyone is sharpening their arguments with a view to this decision…
Head of the medical pharmacology department at the Lille University Hospital Center and professor at the University of Lille.
© / DR
Professor Dominique Deplanque*: “Pharmacologists do not recommend the use of this medication”
After an initial negative opinion in July 2024, the EMA, the European Medicines Agency, finally granted marketing authorization on November 14 for lecanemab (trade name: leqembi) in Alzheimer’s disease. This medicine is intended for the treatment of adult patients with mild cognitive impairment or early-stage dementia. This new position of the EMA was taken despite the absence of additional data, while the effectiveness of this product appears to be low, even questionable, at the cost of frequent and sometimes potentially serious adverse effects. Despite high expectations from patients, patients and caregivers, the French Society of Pharmacology and Therapeutics (SFPT) cannot, as it stands, recommend the use of this new drug.
Lecanemab was the subject of a randomized, double-blind placebo-controlled clinical trial: patients are randomly assigned to the treated group and the placebo group, and no one knows who is receiving the treatment. A total of 1,795 patients were included, and their cognitive performance was assessed on a score scale with values ranging from 0 to 18 points. The improvement observed in this test was 0.53 points. If these data appear statistically significant, we know that to obtain a clinically relevant result, that is to say perceptible by patients and those around them, we would have to reach at least one point.
The result of intense lobbying
The clinical trial also showed that a significant proportion of the patients treated presented worrying adverse events: 17.3% suffered from cerebral microhemorrhages (compared to 9% in the placebo group) and 12.6% from edema. cerebral (1.7% in the placebo group). Additional analyzes having shown that these effects appeared more often in patients with a particular genetic profile, the results were reanalyzed by excluding this subgroup of patients. However, even after this statistical reprocessing, the data show the persistence of a significant proportion of adverse effects: the risk of microhemorrhages and cerebral edema appears multiplied respectively by 6.8 and 1.9 in patients with received the medicine. Remember that the patients included in clinical trials are generally very selected and very well monitored: what will happen when this product is administered more widely?
In view of these results, we fear that the modification of the EMA’s position is above all the result of intense lobbying on the part of laboratories and patient associations, some of which are partly financed by manufacturers. This subgroup analysis also poses a methodological problem. In this scenario, it would have been necessary, strictly speaking, to conduct a new trial on the treated population to validate the results on this set of patients alone. This is not an excess of caution, but recommended practices to validate the benefit-risk balance of a product, in the interest of patients as well as for their safety.
Under these conditions, the SFPT will follow with interest the decisions that will be taken in France on this treatment. Once the European Marketing Authorization has been issued, each Member State retains the possibility of deciding whether or not to reimburse a medicine, and if necessary to negotiate the price with the laboratory. In France, it will be up to the High Authority of Health to analyze the lecanemab file, to inform the public authorities. His opinion will determine the reimbursement, then the price discussions. The pressure on this body therefore promises to be strong. Remember that this drug will also require significant mobilization of the healthcare system, since its intravenous administration requires day hospitalization, and that patients will have to benefit from monitoring by MRI. For all these reasons, the SFPT would like to warn of the significant limitations of this product.
* Professor Dominique Deplanque is head of the medical pharmacology department at the Lille University Hospital Center and professor at the University of Lille.
Neurologist and Director of the Institute of Memory and Alzheimer’s Disease at the Pitié-Salpêtrière Hospital.
/ © Laurence Dentinger / APHP / Sorbonne University
Professor Bruno Dubois*: “This drug is the way of the future, we cannot let the train pass us by”
Lecanemab is both disappointing and exciting. Disappointing because it is a medicine that we will give to our patients, if it is reimbursed in France, telling them that their condition will still continue to worsen. It’s a complicated message to get across. When we are faced with this disease, we would like to at least succeed in blocking its progression, or even going back in time. Unfortunately, no medication will give this result. When patients are ill, that is to say their brain lesions begin to give visible symptoms, it is too late to hope to regain lost cognitive functions. Even the idea of completely stopping the progression of the disease seems today an unattainable prospect, because we have the impression that when the process is underway, there is a sort of runaway which today seems difficult to control. stop.
But the very positive point with these new drugs is that the patients’ condition worsens less quickly than if they did not take treatment. We follow their worsening score, and we observe that the treated subjects arrive at a given severity score in eighteen months, while the untreated subjects arrive at the same stage in twelve months. This is a statistically significant effect. From there, if we extrapolate, we can hope that the curves continue to diverge over time, but this has not been demonstrated because we do not, by definition, have sufficient hindsight.
Incremental progress
There is therefore a disappointment in relation to the desired objective of going back, but to say that the benefit observed is not “clinically relevant” is biased. No one knows today at what level such an effect would occur: this has not yet been well defined by the scientific community. Deciding on this observed six-month delay, knowing whether it is relevant or not, remains a question of point of view only. We had the same debate with symptomatic medications used against Alzheimer’s disease, which were defunded a few years ago on equally questionable grounds: when patients stopped taking these products, families told us that their condition seemed degrade more quickly.
In any case, the statistical effect is very present, and it must be weighed against the undesirable events. These only affect 10% of patients, they are well controlled, and precautions will be taken, including regular MRIs. The prescription must certainly be supervised, monitored, limited to specialist doctors, in expert centers. A patient register will also be required, that is to say a database allowing the benefits and risks of this medication to be monitored “in real life”. Of course, this promises to be heavy and expensive for an effect that remains modest. In these conditions, why should we still take this path? As with any medicine that brings progress, we must support it.
We cannot ignore that this is the way of the future, and it would be unthinkable that our patients would not be able to benefit from it. We can’t stand on the platform watching the train go by. It is up to us to clearly define the indications, to be vigilant about the contraindications, but we will progress. As with any medication in a serious illness with no available treatment, progress is incremental: we start by gaining six months, then nine months, etc. Over time, we will better understand which patients benefit most from treatment. This six-month slowdown in the progression of symptoms is only an average, some respond better, others less well. We will be able to carry out a more detailed analysis which will also, in the future, provide food for thought to develop even more effective drugs. Finally, let us not forget that it will always be up to patients and their families, after in-depth explanations from caregivers, to accept the treatment or not. It seems important that they can have a choice.
* Bruno Dubois is professor of neurology at Sorbonne University, director of the Institute of Memory and Alzheimer’s Disease (IM2A) at the Pitié Salpêtrière hospital in Paris and winner of the Lifetime Achievement Award Alzheimer’s Disease Therapeutic Research.
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