How they work on the brain and what side effects call them into question

Very little by little, Alzheimer’s drug approval This is starting to become a recurring news story. Over the last five years, this “sensitive” advertising has become a result of its emotional association with its brutal initial symptom, which is go forgetting about everythinggenerate everything from hope to skepticism. Also disappointment.

Now this disease is associated with old age and in 2% of cases with genetic heredity., became one again good news around the world because the FDA (which is like our ANMAT) has approved in the United States what is considered the most “significant” new drug against Alzheimer’s disease.

Clarion spoke to two neurologists who specialize in this brain problem to understand the “real” extent of it. Fine To donanemab. How does it work on delay “several months” The development of early Alzheimer’s disease and what changes for people diagnosed in Argentina.

Kisunla, the brand under which it will be sold in the coming months, is produced by Eli Lilly and is on display “partially stop” or “slow down” the decline of cognitive functions when it first begins to manifest in the brain. These same studies also found that treatment includes associated risks.

Kisunla very similar to Lekembifrom pharmaceutical company Eisai and Biogen, another drug approved by the FDA last year.

Both are intravenous injections. Both have the same goal: to attack a protein involved in Alzheimer’s disease. Both can slow the progression of dementia for several months. While Lekembi is given every two weeks, Kisunla is a monthly shot.

They both have serious side effects. Worst: brain hemorrhage.

But the new drug was approved in the last hours. has a difference from what is no longer a treatment eternalOnce the protein that forms the sticky coating is “cleaned,” beta amyloid“waste” substance in the brains of people with Alzheimer’s disease, Your application may be suspended.

“Once you eliminate white“You can stop,” said Anne White, Lilly’s co-executive vice president and head of its neuroscience division. White assured that such a “rest” after the desired effect “can reduce the costs and risks of treatment.”

How long does it take to finish target What does this indicate?

The lab reported that 17% of patients treated with donanemab for 18 months in a clinical trial were able to stop taking the drug at six months. 47% stopped using it after one year, and 69% stopped using the injection two years after starting treatment.

The key point is that cognitive decline continued to slow even after the doses were stopped. John Sims, one of the lab’s medical directors, said “It is still being assessed how long this effect will last.”.

Kisunly’s list price is $32,000. in the United States, the equivalent of one year’s worth of injections. Lekembi Cost Today 26,000 US dollars per year, but again, unlike the new competing drug, its use cannot be stopped once the beta-amyloid plaques are removed.

There is scientific and clinical consensus that both Kisunla and Lekembi are ““significant step” in advancing research and effective treatment of Alzheimer’s disease. But in the global expert community Nobody assures that we are close to a final solution.

In fact, in January of this year, Biogen gave up ownership of another monoclonal antibodyaducanumab (sold under the name Aduhelm) after criticism for its approval based on weak evidence: it can also cause brain bleeding.

Alzheimer’s disease is a degenerative disease of the nervous system. It is the number one cause of dementia in the brain and the leading cause of dementia in at least 65% of people over 65.

“Beta-amyloid protein accumulates outside the neurons, which is a poorly processed, poorly recycled protein that forms plaques. Apparently, although this residue outalso affects work inside neurons and ultimately triggers destruction of the neuroskeletonwhich is made up of the TAU protein,” he explains. Clarion Alejandro Andersson, neurologist and director of the Buenos Aires Institute of Neurology (INBA).

It is this skeleton that allows neurons to take on their amazing star-shaped form. But there is much more to them than shiny extensions.

«It acts as a train track.. It carries substances from one end of the neuron to the other. It’s like the circulatory system. Without it, the neuron depolymerizes and he dies,” Andersson continues.

That is why we strive to go to the source of the problem: to remove harmful plaques and, as the expert says, “look what’s happening”. He says this because the central hypothesis of therapeutic research is clear and at the same time vague: “If we take what breaksdisease Certainly it stops.” That’s not all.

Treatment developments point to antibodies against beta-amyloid.

“At first we thought about a vaccine, but it is difficult to have such a volume of antibodies and they are all the same to make it. It all ended with the decision (generalized in the studies) to make monoclonal antibodies– the doctor sums up.

Andersson spent five years as principal investigator on a clinical trial of Roche’s monoclonal antibody, gantenerumab, which was tested in Alzheimer’s patients and healthy people but was abandoned because it did not produce the expected results.

“He donanemab (which was approved on Tuesday) It is very similar (to the drug they were studying) because it is also a monoclonal antibody against beta-amyloid. These products are marketed by the pharmaceutical industry. they are slowing down progression of the disease. But they do not stop it completely. At the moment, it is known that this slow effect is effective at about 30%,” he notes.

How does the difference in this percentage between monoclonal antibodies produced against the same target depend on unwanted plaques in neurons?

“It’s because some of them, like lecanemab (Lekembi), target the more soluble beta-amyloid, whereas donanemab (Kisunla) targets the more ‘glued-together’, more insoluble amyloid. That’s why the effectiveness of this new drug is approaching 35%“.

But the progression of Alzheimer’s disease will also depend, he says, “on the evolutionary stage of the patient.”

There are currently studies underway in people with mild disease, and other studies in patients who (using biomarkers that detect prodromal Alzheimer’s disease, progressive cognitive decline) They are known to develop the disease, but they have no symptoms. Today.

Where the drug acts to “cleanse” these beta-amyloid plaques, it leaves slight swellingTherefore, those receiving it should be closely monitored to rule out the presence of cerebral hemorrhages.

“The only way to be 97% sure that someone has this deterioration and not something else is to do a lumbar puncture, which looks at the amount of beta-amyloid and the affected TAU protein. There is also a neurocognitive test and an MRI, which are less accurate for diagnosis. Very soon, a more convenient method will be launched than a puncture, which evaluates a set of blood proteins that, through a blood test, will tell you whether you are developing Alzheimer’s disease,” the neurologist notes.

Research into finding an earlier method of diagnosis should be added to efforts to find more effective treatments for the dementia, Andersson said.

“We need something less experimental and more supportive. The point is I find it difficult to achieve widespread adoption of monoclonal antibody therapy.I see these new treatments as something that needs to be further explored and, at some point, achieved. something more practical and economical“Today it costs thousands of dollars, and it doesn’t stop the disease, it slows it down.”

Is the verb “slow down” really that different from “slow down”? In the brain, where there is no place for synonyms, because this is the realm of words, yes.

“A patient who receives a monoclonal antibody that slow down Alzheimer’s in 30% or another one in which it happens in 35%… it doesn’t notice it. He feels that the disease continues to progress. You do not notice this slow evolution. You will feel worse and worse, your memory and concentration will work worse and worse. Today, the level of discovery about this disease is still relative.” he warns.

From the 90s to the present day in Argentina, every person diagnosed with Alzheimer’s disease receives anticholinesterase drugs, which promotes the accumulation of the neurotransmitter acetylcholine near nerve endings.

The four drugs approved for treatment are donepezil, rivastigmine and galantamine, three acetylcholinesterase inhibitors and memantine, which modulates glutamate (which increases the frequency of unwanted depolarizations).“The ideal duration of treatment is unknown,” Andersson concludes.

This means they have no rest or “stop” time as the new drug suggests.

“There is no drug here that slows down this disease because it is very expensive. I would say that it costs an Argentine $60,000 a year to get these monoclonal antibodies. They are not approved by ANMAT. So far, the research results are contradictory.“warns Maximo Zimerman, neurologist, medical director of the ALCLA clinic and the Cites-INECO center.

“However, the drugs available in the country slightly improve cognitive functions, and stimulation through neurorehabilitation improves the patient’s functionality in everyday life,” he continues.

Another stage of treatment, the expert notes, is beyond the brain and body. In addition to physical exercises that “reactivate” brain functions, it is important environmental containment: “Social interaction and emotional well-being are essential to slow the progression of Alzheimer’s disease.”