A scientific rebellion to get Europe to approve a controversial Alzheimer’s drug

The first drug to have shown any effect against Alzheimer’s in several decades, lecanemab, is dividing the scientific and medical community. The United States, China, Japan, Israel, South Korea and the United Arab Emirates have already approved the medical use of this monoclonal antibody. The United Kingdom has just given it the green light, although its public health system will not supply it, because it considers that its effects are too modest for its cost, of about €24,000 per year per patient. Going against the trend, in July the European Medicines Agency (EMA) issued a negative opinion and recommended not granting a marketing authorization, considering that lecanemab’s benefits (it reduces the progression of the disease by 27%) do not outweight the risks, which include brain haemorrhages and the death of two patients.

Alzheimer’s is the leading cause of dementia, affecting around 50 million people worldwide. Population aging could multiply these figures before the middle of the century. Patient associations have welcomed the arrival of this drug with great hope, but the truth is that the vast majority will not be able to benefit from it, as it only works in very early cases, before the disease has progressed. Donanemab, a second similar antibody that reduces the progression of Alzheimer’s by 35%, has also been approved in the United States, but is still under evaluation in Europe.

In an unusual move, four prestigious international researchers who have been studying this disease for decades have sent an open letter to EL PAÍS to ask Europe to reconsider its decision and approve this class of drugs. The EMA’s decision “denies patients and their doctors access to a treatment that can change their lives,” write Bart de Strooper, co-founder of the UK Dementia Research Institute, Henrik Zetterberg, from the University of Gothenburg (Sweden), Christian Haass, from Ludwig Maximilians University in Munich (Germany), and John Hardy, from University College (United Kingdom).

These researchers point out the paradox that lecanemab was born in Europe, when the Swedish scientist Lars Lannfelt founded a company in the 1990s to develop a monoclonal antibody against the beta-amyloid protein, which accumulates in the brains of patients. Lannfelt’s business was subsequently acquired by the Japanese company Eisai, which ultimately developed the drug together with the American company Biogen under the trade name Leqembi.

Europe’s rejection of the drug is “strangling” research in this field within the European Union, which is positioned “as a follower, rather than a leader,” the signatories add.

This situation “is due to the nihilism that exists regarding dementia,” De Strooper added by email. “A drug with the efficacy and side effects of lecanemab would be accepted in other fields of medicine where, as in this case, there is no alternative available.” A few weeks ago, Hardy warned that in Europe there will be different Alzheimer’s treatments for the rich, those who can travel to the United States or another country, and the rest of the population.

The pressure from manufacturers to get their product approved is enormous. Biogen was the main proponent of an earlier monoclonal antibody, aducanumab. The US Food and Drug Administration (FDA) approved it against the advice of several of its experts, who resigned in protest. The compound ended up being a multi-million dollar commercial failure.

Conflicts of interest are at the heart of the controversy. Unlike the FDA, the EMA bans scientists who have commercial ties with pharmaceutical companies from its review panels. This is precisely what De Strooper, Zetterberg and the other signatories are complaining about: they have not been allowed to participate in the evaluation process of lecanemab because they are regular consultants for various companies, including Eisai. Both scientists explain to EL PAÍS that they earn around €300 an hour for these consultancies, and that these are one-off collaborations that do not condition their opinion as “leaders” of Alzheimer’s research. The researchers want the patients to be the ones to decide whether to take the drug after weighing the risks.

Based on the data published so far, there is no way of knowing whether lecanemab has an appreciable cognitive effect. The 27% reduction in disease progression could translate into five months gained over a year and a half, but it is not known whether these benefits continue if the drug is taken for a longer period. Leqembi’s two makers have just presented data on patient follow-up for three years at the International Alzheimer’s Association Congress in Philadelphia. The results, which have not yet been reviewed by independent experts, show that cognitive improvement is maintained if treatment is continued and that it would already be right on the threshold of clinical relevance.

In the original study, which looked at about 1,700 patients, brain scans of 12% showed abnormalities associated with the amyloid protein that can lead to brain swelling and bleeding. Two patients died from using the drug. The companies say the side effects go away on their own in most cases and are more likely to occur in the first few months of treatment. No other complications have been detected so far, an Eisai spokesman said.

In the United States, lecanemab costs $26,500 a year, or about €24,000. The DFA approved the drug in January 2023, but its rollout to patients has been slow due to questions about its efficacy, cost and side effects, Reuters reports. Last summer, a study estimated that implementing Leqembi in Europe would cost €133 billion, half of all pharmaceutical spending in the EU. But that amount could be much lower because many people would be excluded due to contraindications, such as taking blood thinners or having the APOE4 genetic profile.

These new drugs require a genetic test, a spinal tap to determine the amount of amyloid in the brain and several scans to rule out side effects. They would also have to be administered as a preventive measure for the rest of the patient’s life. The current dose is two intravenous injections that must be administered in the hospital. The great hope is that early diagnosis will be made, especially with blood tests for tau protein, which are not yet common in many hospitals.

Raquel Sánchez del Valle, coordinator of the behavior and dementia group of the Spanish Neurology Society, acknowledges that within her organisation there are mixed opinions about the new drug. This neurologist at the Hospital Clínic in Barcelona says that in several European scientific societies there is “concern that patients cannot access these drugs.” The ideal user of lecanemab would be a person who is still independent enough to live on their own, but is beginning to have mild memory lapses, such as forgetting appointments or repeating phrases several times, she explains.

Juan Fortea is a neurologist at Sant Pau Hospital in Barcelona, one of the 12 who participated in the lecanemab clinical trial in Spain. The doctor stresses that this drug is not a cure, and that “no one should trust any personal success story.” “We cannot expect miracles from this drug, such as the resurrection of neurons that have already died when the disease is advanced. What it does do is make the decline slower,” he explains. Although it is still “an unknown” whether the benefits shown by the 18-month trial will accumulate over time, Fortea “neither understands nor agrees with the EMA’s decision,” because “it is not justified.” The neurologist believes that this type of drug ushers “a new era in the treatment of Alzheimer’s.” “Europe cannot go against the world. With these drugs the cost of treatment and care will increase a lot, but it is the same as we have already seen in oncology,” he believes.

Miguel Medina, deputy scientific director of the Biomedical Research Network on Neurodegenerative Diseases, is more skeptical. “The EMA is always more conservative than the FDA, and in this case the situation has been complicated by the history of aducanumab [the previous failed drug] and conflicts of interest, which is a very delicate issue in itself, because there are researchers who are closely tied to companies,” he warns. “It is true that doctors and clinical researchers are more in favor of approving the drug, especially because it gives them something to offer patients. But there are also adverse effects that would affect people around 65 years old who may still have a good few years of life left. It may be necessary to accept experts who collaborate with pharmaceutical companies, although I prefer to be strict with conflicts of interest. The agencies have to be very careful,” he adds.

All the pressure is now on the EMA. Its Committee for Medicinal Products for Human Use has a chair, one member from each EU country and up to five additional experts proposed by each country. The body did not recommend approving lecanemab in July. The pharmaceutical company Eisai has appealed the decision, and the committee is expected to meet again to make a final decision before the end of the year.

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