The European Medicines Agency (EMA) approved on Thursday, November 14, 2024, a long-awaited treatment for certain patients aimed at slowing cognitive decline in people with Alzheimer's disease, after initially blocking its approval in July. We spoke with Dr. Jean-Charles Lambert, INSERM Research Director on Alzheimer's disease at the Pasteur Institute in Lille.
Who is this new treatment intended for?
The treatment, marketed under the name Leqembi, is now recommended by the European Medicines Agency for patients who have not yet reached an advanced stage of the disease. After reviewing its initial opinion, the EMA recommended granting marketing authorization for Leqembi (also known as Lecanemab) for the treatment of mild cognitive impairment (memory and thinking difficulties) or mild dementia due to early-stage Alzheimer's disease, but only for certain patient groups.
In July, the EMA had ruled against the marketing of Leqembi in the EU, considering that the observed effect of the treatment did not outweigh the risk of serious side effects, including potential bleeding in the brain.
"The European Medicines Agency has reversed its decision because it considers that if this treatment is not given to the population most at risk of developing serious side effects (i.e., individuals carrying the e4/e4 genotype), there is a potential benefit that outweighs the risk of these side effects. Nevertheless, this benefit is very limited and still contested. It is, however, a positive signal for patients." commented Dr. Jean-Charles Lambert, INSERM Research Director on Alzheimer's disease at the Pasteur Institute of Lille.
For further : “Alzheimer’s Symptoms: Better Understanding This Disease”
The beginnings of immunotherapies to treat the disease: between hopes and controversies
Leqembi is a monoclonal antibody(1)which acts through passive immunization(2)designed to target amyloid plaques in the brain.
"Research on Alzheimer's disease really began in the 1980s." explains Dr. Lambert. "The disease is characterized by two main types of lesions: extracellular amyloid deposits and intraneuronal neurofibrillary tangles. It was during this decade that the main components of these lesions were identified: amyloid peptides and tau protein, respectively. A large part of the therapeutic approaches developed up to the mid-2010s therefore sought to control the production and level of amyloid peptides in brain tissue. This is where the concept of immunotherapy emerged, with the idea of promoting the degradation of amyloid peptides by the immune system. A clinical trial was quickly launched with this active immunization approach, but it was very quickly stopped following a death and severe encephalitis. However, autopsies later confirmed that the vaccinated patients showed a drastic reduction in the amount of amyloid plaques in their brains." The concept worked, but the approach wasn't correct. So, therapies based on passive immunization were developed, involving the creation of antibodies targeting amyloid peptides. This took time, and obviously, caution was necessary before moving on to a clinical trial..
In 2022, the first positive results from a clinical trial involving immunotherapy against amyloid peptides were published. This initial result was followed by two further positive trials, sparking a great wave of hope and intense, and entirely understandable, lobbying by patient associations to have these treatments approved for the market. This was achieved in the USA, the UK, China, and Japan. " comments Jean-Charles Lambert. »
According to Dr. Jean-Charles Lambert, These treatments quickly became controversial for several reasons:
- A slower decline in treated patients was statistically significant but without any real clinical impact. Moreover, the symptomatic treatments already available (but no longer reimbursed in France) perform just as well on average;
- Significant, even fatal, side effects have been reported, with 18 deaths currently attributed to these treatments.
- A prohibitive cost which makes it incompatible with our social security systems and therefore raises a question of accessibility and ethics;
- An important support structure is needed due to the side effects and therefore a significant indirect cost;
- The need to administer this treatment as early as possible underscores the importance of the cost-benefit/risk ratio. Indeed, the pathophysiological process of Alzheimer's disease unfolds over decades, and it is considered crucial to halt this process as early as possible. It is likely for all these reasons that the European Medicines Agency has so far refused to authorize these treatments pending further information and monitoring.
Treatments with limited effectiveness?
Why don't these treatments seem to work so well? "In fact, the first reason is quite simple. The amyloid cascade hypothesis"(3) was developed from monogenic forms(4) of Alzheimer's disease. However, these early-onset forms (around age 45 on average) represent less than 1% of cases. Most patients with AD are over 75 years old and are defined as sporadic, resulting from the interaction of environmental and genetic factors.Was it naive to think that one could extrapolate mechanisms applicable to all forms of Alzheimer's disease from rare and specific cases? Without a doubt, according to Dr. Lambert: "If immunotherapy is to be effective, it should work for monogenic forms. This is therefore something to follow in order to be able to say that the amyloid cascade hypothesis is valid for monogenic forms of the disease."
Let's take advantage of Dr. Lambert's area of expertise, genetics, to illustrate this point. “Even for common forms of Alzheimer’s disease, the genetic component of the pathology is very significant (estimated at 60% to 80% in twin studies), but in this case, we are talking about risk factors. Currently, 76 risk factors are known. It can therefore be assumed that these amyloid peptides play a role in common forms of the disease. Moreover, numerous biological and clinical data seem to indicate this. However, the metabolism of a protein often serves to control its physiological functions, and the physiological functions of APP in the brain are poorly understood. It is possible that a dysregulation of the function of the amyloid precursor protein (APP) could be involved in the disease, rather than the toxicity of the amyloid peptides themselves. Genetics also tells us that there are many other potential pathophysiological processes that do not directly involve APP and amyloid peptides, but that it is the convergence of these processes in the wrong place that would lead to the development of the disease.”
According to Dr. Lambert, it is very likely that immunotherapy will only be one therapeutic tool among others, effective for a limited number of patients depending on the pathophysiological processes involved.
Alzheimer's disease: accelerating research
Basic research is more crucial than ever for understanding the brain and the diseases that affect it. While research on Alzheimer's disease is recent compared to other diseases such as cancer, it is directly impacted by the evolution of clinical criteria for diagnosing the condition, criteria which are increasingly biological in nature. This also raises important questions regarding the early diagnosis of asymptomatic individuals. "The final message, however, is optimistic; research is indeed progressing, and even if what is being offered remains largely insufficient, there is real hope."It is nevertheless high time that our political authorities grasped the magnitude of what awaits us, with more than 2 million patients expected by 2050 in France alone. Currently, the number of new Alzheimer's patients diagnosed each year is practically equal to the number of people diagnosed with cancer. Yet, research efforts in France and Europe are ten times less significant for this neurodegenerative disease and its related syndromes. concludes Jean-Charles Lambert.
(1) Monoclonal antibodies are antibodies obtained in the laboratory from cultured cells.
(2) The principle of passive immunotherapy is to strengthen the already present immune response by using laboratory-made substances to act like certain parts of the immune system and thus attack specific cells.
(3) The amyloid cascade hypothesis is the theory, initially formulated by JA Hardy and GA Higgins in 1992, that the Alzheimer's disease is caused by the presence of amyloid plaques in the brain. It serves as the basis for the development of drugs of controversial efficacy that aim to reduce these plaques, regardless of any potential improvement in patients' cognitive state. For years, experts have highlighted other factors that contradict the amyloid hypothesis.
(4) Monogenic diseases result from a mutation that affects a single gene.
