The therapeutic revolution for Alzheimer's comes from the hand of new biological drugs

• Neurology "With the new drug for Alzheimer's, the rules of the game in this disease change"

• Health Alzheimer's: "You have to make a pit stop to win the brain health race"

After one setback after another in pharmacological research in Alzheimer's, a drug has finally obtained clear results of clinical efficacy.

Biogen and Eisai announced in late September that their monoclonal antibody lecanemab has passed all primary and secondary endpoints

trial .

This immunotherapeutic treatment, designed to clear brain deposits of beta-amyloid, aspires to become the first

therapy for Alzheimer's, after the controversial precedent of aducanumab.

The succession of failed clinical trials with immunotherapies against beta-amyloid had raised many doubts about the validity of research against this target to find effective treatments.

The pharmaceutical industry and governments have buried millions of dollars in dozens of projects that have never reached the market.

Some companies, like Pfizer, have thrown in the towel and eliminated Alzheimer's from their R&D departments.

Against this background, the commotion that has arisen with the publication of the first results of phase III of lecanemab was to be expected.

The

study , which included

with early-stage Alzheimer's, indicates that the drug is capable of modifying the course of the disease by demonstrating a 27% reduction in the progression of clinical deterioration at 18 months compared to placebo on the CDR-SB clinical assessment scale for dementia.

The results of the trial are "very encouraging", agree

, coordinator of the Behavior and Dementia Group of the Spanish Society of Neurology (SEN) and director of the Memory Unit of Hospital Sant Pau, and

, deputy director of Trials Clinics of the Ace Alzheimer Center Barcelona.

Both know the drug closely because their centers have participated in the phase III study.

A paradigm shift in Alzheimer's: early detection and early treatment

Fortea describes the companies' announcement as a "paradigm shift" and "revolutionary": "Alzheimer's seemed invincible, we have been continuously failing for twenty years. The fact of being able to modify the course of the disease is

, which fills us with hope".

"With the low investment in Alzheimer's trials compared to other pathologies, we are showing that we can be successful: that we are

", observes Morató.

"Lecanemab is the first monoclonal antibody aimed at removing amyloid protein accumulated in the brain with clear clinical benefits. It is great news for the world of Alzheimer's, and its approval will have a high impact on research and health systems. But In

addition, it reveals the

, since it will allow people to be treated in the early stages of the disease".

Still, the drug's efficacy is "modest," in Fortea's words.

He warns that this percentage of 27% slowdown is an average, there will be patients in whom the effect is greater and in others it is smaller.

"Unfortunately, families

. But just as there are now patients who deteriorate in a few years and others take much longer without us knowing why, what this drug will do is slow down the decline."

clinical trial

appears in a corporate press release.

The SEN expert warns that given the social and economic importance of Alzheimer's, companies are obliged to publish results as they become known to

for shareholders.

The full results are expected to be released in conjunction with the 15th Congress on Clinical Trials in Alzheimer's (CTAD), which takes place in San Francisco from November 29 to December 2.

Extending the results may shed light on the effect of lecanemab in different

, such as patients with mild cognitive impairment or dementia, or between carriers or not of the ApoE 4 genotype. As well as on the frequency of adverse effects in risk groups , such as ApoE 4 carriers, and the correlation of clinical changes with Alzheimer's biomarkers, Morató points out.

"The long-term effect of these drugs on the course of the disease remains to be evaluated," she warns.

Beta-amyloid, reduction of one of the symptoms

The information that is known about this monoclonal antibody suggests once again a slowing of the cognitive deterioration

in the brain.

"This effect should no longer be considered surprising, because it is consistent with the results and the size of the effect observed in other monoclonal antibody trials, such as the

or the

," explains Morató.

"We are seeing converging data showing that a significant reduction in amyloid-beta plaque in the brain can delay clinical deterioration in the early stage of this dementia."

On the other hand, the expert from the Ace Alzheimer Center adds that it will be interesting to know the results that emerge from the

trial in secondary prevention with lecanemab in a presymptomatic population with the presence of accumulation of this amyloid protein in the brain.

This will be the marketing of new drugs in 2023

Lecanemab could reach the market in

.

The FDA granted priority review status in July and a decision is expected in January.

In addition, it is expected that the application for traditional approval will be submitted to the FDA at the end of March, and in parallel, and the dossier will be sent to the European and Japanese agencies.

It is not the only

anti-amyloid antibody in advanced stages of development.

The FDA has also accepted the expedited review of donanemab (Eli Lilly), a decision on which could be made in February.

While the phase III results of gantenerumab, from Roche, are expected at the end of the year.

"What is expected, based on the set of data we have, is that donanemab and gantenerumab show

of the same order as lecanemab, between 20% and 40% slowing of progression", understands the expert from the Society Spanish of Neurology.

Therefore, large differences in the effect they may have are not expected.

However, regarding the route of administration, gantenerumab has the advantage of the

compared to the intravenous formulation of lecanemab and donanemab.

"The costs associated with

administration have nothing to do with subcutaneous administration, since it implies that the treatment has to be applied in a day hospital, and that increases the logistical problems," warns Fortea.

"But intense work is already being done on subcutaneous formulations, and it is foreseeable that by the time these drugs reach Spain, they will have bioequivalence trials, which are much faster and easier to carry out than efficacy trials."

The injectable route of the new drugs for Alzheimer's is just one more sign that the treatment of the disease will become more complex.

In the short term, Morató sees it plausible to have different anti-amyloid biologicals that, depending on the results of clinical trials, could be applied

of the disease.

"In addition to starting treatments in increasingly early stages, we will see a change in direction towards

", announces Morató.

"Molecules are already being developed for populations with a specific genetic profile, such as ApoE 4/4 patients or those with elevated pro-inflammatory cytokines."

Aducanumab, the drug that was 'approved' in the US, but was rejected in Europe

What is clear is that if it is confirmed that lecanemab has achieved all the

objectives , its

than the one that aducanumab, also from Biogen and Eisai, had to overcome.

The companies had prematurely halted two phase III trials, anticipating they would fail.

But a subsequent reanalysis found a positive clinical effect in one of the studies (a statistically significant slowdown in clinical deterioration, estimated between 25% and 30%) that

.

Even so, the US FDA agency gave the drug the green light for the accelerated route, basing its decision on the effect on beta-amyloid, although the European EMA rejected it.

The contradictory data on efficacy and "the high presence of

(acronym in English for abnormalities associated with imaging, including brain edema and hemorrhage) raised doubts about its benefit-risk balance", recalls Morató.

However, when the FDA made the controversial decision to approve the drug in June last year, it was taking "a broad view" of the role these drugs may play, interprets the journal

.

The agency noted that aducanumab was the first treatment to act against the

, and considered it "reasonably likely" that its effect on beta-amyloid corresponds to a slowing of clinical deterioration.

Despite many voices against the decision, new data emerged over the following months showing a trend toward a

of cognitive decline as beta-amyloid was cleared and levels of other biomarkers of disease progression fell. of Alzheimer's, such as the accumulation of tau.

Later that year, the agency granted gantenerumab, lecanemab, and donanemab

designation .

Like aducanumab, all three had shown their action against beta-amyloid in early trials.

can be learned from the aducanumab experience

, from how to conduct clinical trials and analyze them at multiple levels," Fortea reflects.

The neurologist is "convinced" that if the company could go back, it would not have stopped phase III trials prematurely.

"Given the results of lecanemab, perhaps they would have been unequivocally positive. We will never know, but it is a perfectly plausible hypothesis."

In the United States, the commercial trajectory of the drug has been much shorter than expected and has set a

for other monoclonal antibodies that can be approved through the accelerated route.

Morató explains that in the United States there are six million Americans with Alzheimer's, and the average annual cost of these biological drugs has been estimated at about 56,000 dollars per year, to which must be added those associated with the intravenous route, clinical follow-up and neuroimaging.

Since April of this year, the federal Medicare health coverage program decided to stop financing monoclonal antibodies for Alzheimer's if they have obtained regulatory approval through the accelerated route and not the traditional one.

In this sense, Medicare only covers treatment with aducanumab for participants in clinical trials or other studies supported by the Government.

A new drug, new demands for the health system

The possible arrival of lecanemab at the clinic will have a high economic cost for health systems such as the Spanish one, beyond the price of the drug and the high prevalence of the disease:

alone it is estimated that there are around one million patients with Alzheimer's .

To the pharmaceutical bill must be added the costs associated with the

of dementia, the administration of intravenous drugs and the monitoring of treatments.

"A new way of treating Alzheimer's opens up with radical changes, of such depth that they

as a whole in check," warns the spokesman for the Spanish Society of Neurology (SEN).

Precisely because of their enormous socioeconomic impact, Fortea affirms that these new drugs are the subject of great scrutiny: "Alzheimer

in which a small improvement has been achieved. We are facing a structural epidemic of the 21st century, and any This change brings with it an increase in costs and such important implications that it is necessary to monitor all processes and to do so with total transparency".

Among the many challenges of the availability of these biologicals, the expert from the Ace Alzheimer Center Barcelona highlights the identification of patients in the early stages of dementia and the monitoring and detection by neuroimaging of their characteristic

, such as edema and hemorrhage brain and other abnormalities known by the acronym ARIA (

).

Since they are drugs for the initial phases of dementia, they require a greater effort in detection.

Fortea explains that the tools to advance diagnoses even before the onset of symptoms exist, but until now limited use has been made of them.

"We have good neuropsychological tests and also good

, and we have been asking for their general use for years, but so far very few patients have benefited."

The development and possible arrival of disease-modifying therapies is driving the field of diagnostics.

According to

, also from the SEN, work is being done on ultra-sensitive techniques for the detection of blood biomarkers, digital cognitive tests and the increasingly complete characterization of genetic risk.

techniques

, "allows us to think of a much more precise diagnosis in symptomatic subjects, and even a risk stratification in presymptomatic phases, especially useful in populations considered to be at risk, such as individuals with a high burden of family history or diabetes.

The availability of more accessible diagnostic tools, such as digital ones or plasma biomarkers, can "help contain what we hope will be a wave of new patients," warns Fortea,

Consequently, it is foreseeable that diagnoses will increase.

"Some of the

surrounding dementia is going to go away," she realizes.

"If a treatment is available that can slow down the disease, patients and their families will have a much more proactive attitude and will not look the other way at the first signs of dementia."

Although studies are currently being carried out for the administration of these monoclonal antibodies subcutaneously, lecanemab, as it is being developed in clinical trials, is an intravenous drug that is administered

.

Specialists point out that it requires a day hospital, a Hospital Pharmacy service to prepare it and a nursing team to administer it and keep the patient under observation.

As long as the health system is not prepared, Fortea understands that the message that must be transmitted to patients and their families is that "today lecanemab is a

".

Adapting the infrastructures, he understands, will be a job that will have to be undertaken

.

"It will not be the same in my hospital, where we have been working on biomarkers for many years, than in another with no experience and having to start from scratch. We must begin to analyze the starting point of each one and take advantage of the time until the drug. It doesn't make sense to think that it will be available in two years and when the time comes you won't be able to give it because you're not prepared".

The follow-up of patients by

is an added difficulty.

"Anyone who receives this drug has to undergo three annual MRIs. We know how difficult it is to get an MRI and the waiting lists there are. Probably more means will have to be put in and MRIs are not something that is done in two months" Fortea warns.

While monoclonal antibodies do or do not reach Europe, Fortea applauds the work of the Alzheimer's Association of the United States, which has been periodically updating its recommendations for the use of aducanumab, the first of these biologics available.

Surely his work will serve as a guide for those to come.

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