Reacción a "EMA revises earlier decision and decides to approve lecanemab for Alzheimer's disease"

After 20 years without major advances in the treatment of Alzheimer's disease (AD), some hope seems to be emerging. The use of monoclonal antibodies against the amyloid peptide is a first, small step towards effective treatments for the disease.
First, the caveats. This treatment has been shown to have some efficacy provided it is administered to individuals in the early stages of the disease or with a diagnosis of mild cognitive impairment, a clinical form that in many cases is a stage prior to Alzheimer's disease itself, and who, moreover, do not carry any copies of the E4 allele in the APOE gene or, at most, are heterozygous for this allele, i.e. carry a single copy. In other words, it is a treatment that offers its maximum benefit in very early cases of the disease and in a subgroup of those with the disease. Given the high frequency of carriers of 2 copies of the E4 allele in this condition, it is clear that this is not a disruptive treatment. However, it is a much needed, long awaited and welcome development.

It is now 25 years since experimental models of AD began to be treated with antibodies directed against the amyloid peptide, the main component of a type of lesions seen in the brains of patients. In these models, the results were spectacular. The lesions disappeared over time and the treated animals performed better on memory tests. However, these results did not immediately translate to humans. It has taken intensive laboratory work to obtain formulations that are sufficiently effective to gain approval from regulatory agencies in several countries around the world, including Europe, albeit with the conditions outlined above.
However, a few months ago (July 2024), the European Medicines Agency refused to approve the use of this same antibody for the treatment of AD. Why is its use allowed now? Simply because at the time it was intended for use in all patients in the early stages of the disease and it was seen that this treatment harmed rather than benefited the patients as a whole, as a significant increase in the occurrence of oedema or cerebral haemorrhages was observed in the group using the antibody. That is, the benefit observed in terms of AD progression was less than the risk of severe symptoms associated with the treatment, not the disease.

In a subsequent analysis, the pharmaceutical companies behind the treatment (Eisai and Biogen), saw that the treatment was more effective in a subgroup of patients (those with one or no copies of the E4 allele in the APOE gene). This new way of looking at the data has now allowed the treatment to be approved subject to the conditions outlined above: patients in the early stages or with a diagnosis of mild cognitive impairment and carrying a maximum of one copy of the E4 allele. That said, the effectiveness of the treatment, contrary to what might be thought, does not lie in stopping or reversing the disease. The effect achieved is to slow the progression of the disease for at least the 18 months that the clinical trials studied for the approval of the use of lequembi as a treatment for AD have lasted.

This treatment, on the other hand, requires intensive follow-up and has an administration that implies the need for the patient to be close to a centre that can carry out this follow-up before, during and after treatment. This also opens up a discussion about how to ensure access for all those patients who could benefit from it. Not everywhere, patients can have access to tests as simple as APOE genotyping to see if they are candidates for treatment. From this point, I repeat, the simplest to consider from a technical point of view, we can clearly see how it is necessary to establish mechanisms that allow the treatment to reach all those patients who can benefit from it without the postcode being a limiting factor in this decision.

In summary, we are at a hopeful moment in that there is already a treatment that allows a certain slowing down of the progression of a disease as complex as AD, and which reinforces the opinion that many researchers have defended for a long time: that the amyloid peptide is a good candidate for the development of therapies. Although the results are unspectacular, given that the process is not reversed but slowed down, it is an important step in that direction. Let us hope that progress continues to be made in this direction without this implying the abandonment of other research based on alternative hypotheses to that of the amyloid cascade, which may also contribute to improving the therapeutic arsenal available to us in the hopefully nearer rather than more distant future. The complexity of the disease, reflecting pathological processes that begin decades before the first symptoms manifest themselves, will most likely only be resolved with equally complex treatments involving several of the molecules that are related to the disease.