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An experimental drug against Alzheimer's confirms positive effects, but may be behind the death of two patients

2022-11-30T23:28:06.539Z


The results of a trial with more than 1,700 people confirm that lecanemab reduces cognitive decline by 27%


A sense of uncertainty continues to surround lecanemab, the most promising Alzheimer's drug to be developed in recent decades.

The complete results of a clinical trial with more than 1,700 patients from various countries, including Spain, show that this drug reduces the mental deterioration caused by Alzheimer's by 27%.

This drug would be the first in 20 years that has shown some effect, albeit timid, on a devastating disease that affects 50 million people and their families worldwide.

The full results of this trial were presented this morning in San Francisco (USA) during an international conference focused on this disease.

The data has also been published in the

New England Journal of Medicine

, one of the world's most prestigious medical journals.

One day before the presentation, it was learned that two of the patients who participated in the trial had died of brain hemorrhages.

Both deaths are being analyzed by medical teams to determine if they were caused by the drug.

In one of the cases, advanced by journalists from the magazine

Science

,

the patient's doctors say that if she had not taken lecanemab, the woman would still be alive.

These two deaths may be related to an interaction between anticoagulant drugs and lecanemab itself, a monoclonal antibody that has been designed to target and destroy concentrations of amyloid protein in the brain, which are a classic marker of the disease.

Eisai, the Japanese pharmaceutical company that has developed lecanemab together with the American Biogen, has explained to EL PAÍS that they cannot say anything about the specific cases of people involved in the trial, as privacy policies prevent it.

The study, reviewed by independent experts and subjected to the control of a panel of medical specialists, ensures that during the 18 months that the clinical trial lasted there were no more deaths in the group that took the drug than in the one that received placebo.

None of the deaths—six in the treated, seven in the untreated—was related to lecanemab, the paper says.

People who received the treatment did have a higher rate of adverse effects, including small brain bleeds, although most are usually not serious.

The frequency of major bleeding in the brain is very low in both groups, although it is six times higher in the lecanemab group;

0.6% vs. 0.1%.

7% of the treated patients had adverse effects that required discontinuation of treatment, while in the placebo group the percentage was 3%.

The trial included people aged 50 to 90 who had mild memory loss due to Alzheimer's, but no severe symptoms or significant disability.

Cognitive impairment was measured with a test widely used in this disease that includes the perception of the patient and their doctors and caregivers about mental and physical abilities.

This test has a score from 0 — when there is no trace of Alzheimer's — to 18. After a year and a half, the deterioration of people who took lecanemab was 0.45 points less than that of those who took placebo.

The dozens of doctors from around the world who sign the study acknowledge that this improvement is "modest".

Juan Fortea, a neurologist at Hospital Sant Pau in Barcelona who has participated in the trial, explains that the presentation "has been very encouraging and the results, very solid within modesty."

"The data on safety [and adverse effects] are quite reassuring," he added.

The big question is whether this result, which is statistically significant, also has a perceptible clinical effect.

For now, the improvement is so timid that neither patients nor caregivers will probably be able to notice it.

David Pérez, head of neurology at Hospital 12 de Octubre in Madrid, explains: “Normally, it is considered that in Alzheimer's the patient needs a point of difference to notice something.

In early Alzheimer's, such as these cases, the difference should be even greater, 1.6 points”, adds the doctor, who did not participate in the trial.

The key is whether the positive effect increases over time or stagnates, as is now the case with the drugs available for this disease, which alleviate the symptoms but are unable to cure it.

If the reduction in mental deterioration accumulates four years or more, tangible effects would be achieved for doctors, caregivers and patients.

In this case, the drug would have made history by being able to modify the course of this disease, something that no one has achieved since the German neurologist Alois Alzheimer discovered it in 1906 in a 50-year-old woman who suffered from paranoia, insomnia, mood swings flashes, memory loss, and confusion.

In the opinion of Pérez, spokesman for the Spanish Society of Neurology, this trial must be kept running for about four years to resolve doubts.

This would also bring up rare and dangerous side effects, such as lethal bleeding.

If lecanemab were approved for all people with mild symptoms of Alzheimer's, it would present unaffordable material challenges for health systems such as the Spanish one, since it requires intravenous administration every two weeks, warns the doctor.

The companies responsible for this drug have confirmed that they will continue with the trial, but they will not wait to get it approved by the medical authorities.

Eisai and Biogen have already submitted a fast-track application that the US Federal Medicines Agency (FDA) will analyze in January 2023. An Eisai spokesperson has confirmed to this newspaper that they will also submit a full application —with a longer and more extensive analysis. exhaustive—before the FDA and its European counterparts —the EMA— and Japan.

The trial results also make interesting scientific reading.

116 years after its discovery, the cause of this disease is still unknown.

It is known that the deposits of harmful molecules begin to appear about 20 years before the first symptoms.

By the time Alzheimer's is diagnosed, it's too late to prevent it.

The amyloid proteins that accumulate in the brain have been one of the main suspects, but a direct relationship between these aggregates and the unstoppable course of this chronic disease has never been demonstrated.

Lecanemab is a monoclonal antibody directed against amyloid protofibrils, one of the configurations that this protein takes in the brain.

The trial has shown that the drug reduces levels of this molecule in the brain and has also shown less cognitive decline.

This would prove that amyloid is at least one of the culprits, although probably not the only one and perhaps not even the most important one.

Other hypotheses are based on the Tau protein, on inflammatory processes caused by the immune system itself or even on viral infections.

Until now, billions of euros have been spent on developing drugs against amyloid, but none had achieved results.

The most recent was the promising gantenerumab, another antibody that eliminates amyloid protein developed by the pharmaceutical company Roche whose negative results have also been presented in San Francisco.

In mid-2023, Lilly plans to unveil the results of its trial with donanemab, another molecule similar to the previous ones that is also directed against amyloid.

There is also a huge economic derivative.

Monoclonal antibodies are among the most expensive drugs in the world.

Aducanumab—a lecanemab-like antibody that was developed by Biogen against Alzheimer's—cost $56,000 per patient.

Clinical trials of that drug did not show clear benefits, but against all odds it was approved by the FDA.

Several experts who had participated in the evaluation and did not agree with the conclusion resigned from their posts.

The drug has been a medical and financial flop for Biogen.

Since the preliminary results of lecanemab were known, this company and its associate Eisai have not stopped going up on the stock market and Biogen has been able to recover a good part of its losses.

If the drug is finally approved, both pharmaceutical companies know that it will bring enormous benefits.

If that happens, there are many doubts as to which patients will be given lecanemab, for how long and at what price, since its cost has not yet been set.

Eva Carro, principal investigator at the Center for Networked Biomedical Research on Neurodegenerative Diseases, is highly skeptical of the published results.

“The study has shown no clinical benefit,” she recalls.

"In addition, this drug must be given every two weeks by intravenous injection at prices of tens of thousands of euros, it is unfeasible," she settles.

Miguel Medina, deputy scientific director of the same center, highlights that the new study represents "a milestone", although only modest effects have been observed.

“Given the precedent of aducanumab, which was approved without significant effectiveness, I think the FDA will approve this new drug,” he says.

“The key will be in which patients it is approved for and which ones could not take it due to dangerous side effects.

Precisely patients with the APOE-ε4 mutation, which increases the risk of Alzheimer's, seem to be the ones who may suffer the most complications.

I believe that with these results a new path is opened.

It is probably not this drug that will end up being used, but perhaps other future ones that are more effective and with less risk”, he concludes.

Mariló Almagro, president of the Spanish Alzheimer's Confederation, believes that the results "are good news."

“We believe that the way is to continue investigating to have an early diagnosis, since these drugs, the sooner they are administered, the better.

In addition, we must continue researching this type of medication so that this percentage of effectiveness increases.


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Source: elparis

All news articles on 2022-11-30

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