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Alzheimer’s disease“/>If the amyloid plaques have already caused irreversible damage to the brain, removing them will no longer be of any use. (Archive image) © picture alliance / dpa
For the first time, a therapy against Alzheimer’s is about to be approved in the EU. However, it only makes sense for a small proportion of patients. The treatment is also complex and risky.
Amsterdam – In Germany alone, around a million people are affected by Alzheimer’s. The European Medicines Agency (EMA) has now given the EU the green light for the first time for an Alzheimer’s therapy that targets underlying disease processes. It recommends approval of the antibody lecanemab for the treatment of mild cognitive impairment (memory and thinking problems) or mild dementia in the early stages of Alzheimer’s disease.
Why is the decision so special?
Current Alzheimer’s therapies only treat symptoms of the disease, not causal processes in the brain. This is different with Lecanemab: The antibody is directed against amyloid deposits in the brain and is intended to slow down the progression of the disease. However, this active ingredient is not about healing or improvement; such a remedy is still not in sight.
The main measure of effectiveness was change in cognitive and functional symptoms at 18 months, measured using a dementia rating scale. The scale ranges from 0 to 18, with higher scores indicating greater impairment. Patients treated with lecanemab had a slightly smaller increase in the value after 18 months on average (1.22 versus 1.75). This indicates slower cognitive decline, the EMA said.
Current Alzheimer’s therapies only treat symptoms of the disease, not causal processes in the brain. (Archive image) © Daniel Naupold/dpa
Why can’t all Alzheimer’s patients get Lecanemab?
If the amyloid plaques have already caused irreversible damage to the brain, removing them will no longer be of any use. According to Johannes Levin from the German Center for Neurodegenerative Diseases (DZNE), the first three years are considered the early Alzheimer’s phase. This currently probably affects at least 250,000 people in Germany. In this early phase, a sufferer can still cope very well on their own, but increasingly notices that their memory is failing.
However, there is another limitation to the EMA recommendation: the drug should only be used for Alzheimer’s patients who have only one or no copy of ApoE4, a specific form of the gene for the protein apolipoprotein E. They are therefore less likely to experience certain serious side effects – swelling and bleeding in the brain – than people with two ApoE4 copies.
Depending on the region, people with only one or no copy of ApoE4 make up between two thirds and 80 percent of Alzheimer’s patients, explained Gabor Petzold, director of clinical research at the DZNE. In Germany it is around 80 percent.
There are also other restrictive requirements – according to experts, overall, only a small fraction of Alzheimer’s sufferers are eligible for antibody therapy.
Are we starting straight away with such treatments?
No. It should be borne in mind that there are still a few steps to be taken before it can be used in Germany, said Petzold: Approval by the EU Commission is still pending, and the manufacturer has also been obliged, for example, to develop detailed handouts and training courses for doctors, among others to create an observation register.
It will still be a few months before the drug can actually be used. In patients, Alzheimer’s disease must first be confirmed through biomarker tests, followed by a genetic test. The therapy is only an option for those affected with a preliminary stage or a very early stage of the disease.
In the next few days, however, we can expect a large number of inquiries from those affected and relatives to family doctors, Alzheimer’s centers and memory care consultations, said Petzold. Levin fears an influx of tens of thousands of people for even the slightest forgetfulness. The diagnostic centers would hardly be able to handle such a flood of clarifications, he said.
The neurologist Özgür Onur from the University Hospital of Cologne also assumes that he can only treat relatively few patients with the new therapy each year, as the frequent doses represent a major challenge. “I assume that we can treat 50 to 100 patients per year in Cologne. And we are a big center.”
Didn’t the EMA actually already reject Lecanemab?
Yes. In July, the EU Medicines Agency decided that the risk of serious side effects from the antibody was higher than the expected positive effect. The Eisai company then requested a second examination.
The EMA’s Committee for Medicinal Products for Human Use (CHMP) has now concluded that in the limited population examined in the re-examination, the benefits of lecanemab in slowing the progression of disease symptoms are greater than the risks. In the first review, no subgroup analyzes were taken into account, but all patients.
The EU Commission responsible for approval usually follows the authority’s vote. The manufacturers of Lecanemab are the pharmaceutical companies Eisai (Japan) and Biogen (USA).
Why the reference to a subgroup?
According to the EMA, edema in the brain occurred in 8.9 percent of patients treated with lecanemab with only one or no ApoE4 copy, and an average of 12.6 percent for all patients. Microbleeds occurred in 12.9 percent of patients with only one or no ApoE4 copy, compared to 16.9 percent of the broader population. In patients with only one or no copy of ApoE4 who were treated with placebo (a dummy treatment), the rates of swelling were 1.3 percent and bleeding was 6.8 percent, according to the EMA.
Playing memory is said to counteract brain deterioration. © Sven Hoppe/dpa
How dangerous are such edema and microbleeds?
The swellings and microbleeds recorded in the brain mostly remained without symptoms and were usually only noticed through imaging procedures such as magnetic resonance imaging (MRI). However, particularly if it occurs repeatedly, there is a risk of reduced brain performance or coordination difficulties. Microbleeds are also considered a risk factor for larger, potentially life-threatening cerebral hemorrhages.
The EMA therefore emphasizes in its statement that there must be measures to minimize risks. Before starting treatment and before the 5th, 7th and 14th lecanemab doses, patients must have MRI scans, and additional scans for warning signs such as headaches, visual disturbances and dizziness. The treatment itself is also complex: Lecanemab is administered as an intravenous infusion every two weeks.
Is lecanemab the only causative agent?
No. The antibody aducanumab, developed by the US biotech company Biogen, was not recommended for approval by the EMA at the end of 2021: the supposed clinical effect of the drug is questionable. Another application for approval was submitted by the US pharmaceutical company Eli Lilly for the active ingredient donanemab. This process is still ongoing.
The US Food and Drug Administration (FDA) approved aducanumab for Alzheimer’s therapy in 2021, but Biogen stopped production again at the beginning of the year. Lecanemab came onto the market in the USA at the beginning of 2023. Donanemab was approved by the FDA on July 2 this year. All three antibodies have a similar mechanism of action.
Are there any concerns?
Experts recently expressed criticism of the FDA decisions in the specialist journal “The BMJ”. The drugs showed only an imperceptible slowing of dementia, but showed serious undesirable side effects, including death, it is said. The financial connections of members of the FDA advisory committee to pharmaceutical companies are also questionable.
There is also criticism in “The BMJ” of the manufacturers’ statements that the progression of Alzheimer’s disease is significantly slowed – compared to placebo therapy by up to 35 percent, depending on the subgroup. “This is a misleading statement,” University of Cincinnati neurologist Alberto Espay was quoted as saying specifically about the donanemab data. “This is a relative difference that turns a very small absolute difference into a number that seems impressive.”
It is questionable how relevant the measurable slight delay in the progression of the disease actually is to everyday life. “As soon as the full picture of Alzheimer’s disease is present, the statistically described effects are usually no longer noticeable for the patient and those around him,” said Walter Schulz-Schaeffer from the Saarland University Hospital in Homburg. “This must be counteracted by the side effects of the medication.”
