Leqembi, Is This New Drug The Turning Point In Curing Alzheimer’s?

Updated November 18, 2024 at 4:40 p.m.*

HAMBURG — Hermine Schmitt and her husband used to attend senior dance classes. They’d groove to rock ‘n’ roll or boogie and then relax with friends, chatting away. But one day, while she was enthusiastically describing one of her cakes at the table and someone asked her a question, everything vanished. Not just the recipe — she suddenly couldn’t even remember talking about a cake.

Seventeen years later, Hermine no longer recognizes her loved ones.

Countless families have endured the same heartbreak, watching those they love fade away to Alzheimer’s disease, memory by memory. But now, there’s a glimmer of hope. If Alzheimer’s is ever conquered, Nov. 14, 2024, may go down in history as a turning point.

That Thursday, for the first time, the European Medicines Agency (EMA) approved a drug that targets the cause — not just the symptoms — of the disease. The decision didn’t come easily; the EMA initially voted against approval in July.

But after further consultations and at the manufacturer’s insistence, the agency reversed its decision. Though it may take a few weeks, final approval by the European Commission is just a matter of time.

It is the first drug of its kind, 120 years after the Munich doctor Alois Alzheimer first wrote about a “peculiar disease of the cerebral cortex”. It took 40 years for U.S. scientists to first decipher the composition of the typical Alzheimer-caused deposits in the brain. And it took two decades for the Swedish professor Lars Lannfelt and his colleagues at Uppsala University to develop this drug.

Just like Post-It notes

Lecanemab, marketed under the name Leqembi, was invented by Lannfelt’s biomedical company BioArctic, and co-developed by the Japanese pharmaceutical company Eisai. It targets the fatal cascade in the brain that kills nerve cells until those affected no longer recognize their lifelong companions.

Hermine Schmitt herself was part of the Leqembi test group. But her story, as well as the hesitant approval, show that it’s too early to call this a miracle drug: the benefits of this new therapy are still limited.

“We felt very hopeful” her husband Walter Schmitt says in a comfortable, rolling Bavarian accent as he pours coffee in the tidy living room of his apartment in the east of Munich. Schmitt’s real name is different; he asked for anonymity.

By removing these plaques, the brain’s nerve cells are protected from further damage.

The Schmitts agreed to receive a monthly infusion of Aducanumab, which is based on the same principle as Leqembi: It is an antibody, in this case from the U.S. biotechnology company Biogen. Like several other preparations currently being developed, the two drugs aim to remove the tough, gritty lumps (up to a tenth of a millimeter in size) that form in the brain and accumulate between the nerve cells.

These plaques, called beta-amyloid, are characteristic of Alzheimer’s and are a major cause of memory loss. Monoclonal antibodies — distinguished by their names ending in “mab” — mimic the body’s natural antibodies. They attach themselves to specific harmful proteins or pathogens, and trigger the immune system to clear them out.

Essentially, they act like Post-it notes, sticking to the plaques and signaling the immune system: Hazardous waste — clean up immediately. By removing these plaques, the brain’s nerve cells are protected from further damage.

Five months: a lot or a little?

Leqembi cannot cure Alzheimer’s, nor can it stop it; it just delays its progression. The approximately 1,600 test subjects in the approval trial received an infusion every two weeks for 18 months, half of them with the active ingredient, the other half a placebo. In those who received the drug, the Alzheimer’s symptoms were delayed by an average of five months, almost half a year.

Half a year is how long it has been since Hermine Schmitt had to go into a care home. Her husband misses her dearly. He is 76 years old, tall and slim, and he is happy to have a visit from a journalist. His everyday life has gotten lonely: “You sit there, you have no one to talk to, no discussions with your wife, just the Süddeutsche Zeitung and the television,” he says, falls silent for a moment. The kitchen clock ticks into the silence.

For Schmitt, half a year feels like a heartbeat. But for the doctors and researchers behind the Aducanumab study that his wife was a part of, this is a significant success. Aducanumab itself ultimately failed, but Leqembi proves the principle behind it is sound.

The Institute for Stroke and Dementia Research is a modern, bright cube, where researchers and specialists in neurology, psychiatry and psychotherapy, neuropsychologists and social workers operate together to detect and prevent dementia and strokes. A place for cutting-edge research, hope and healing, writes the Bavarian state government.

Senior physician Katharina Bürger heads the memory clinic at the institute. She has been treating patients since the 1990s, including Hermine Schmitt. But she is still nervous before she has to reveal the diagnosis of Alzheimer’s to a patient.

It’s a tough thing to say: You still have a few years, maybe even a decade, in which you can live happily, with almost no symptoms. But we can’t do anything about the gradual, silent death of your brain. At least, she had to say it until now.

Antibodies against Alzheimer’s

The first antibody therapies should soon become available to patients.

At the beginning of 2023, 111 drugs were in clinical trials. Six antibody therapies alone, which, like Leqembi, target amyloid, are in the third, crucial phase of clinical trials. Bürger works in a team with Matthias Brendel and Christian Haass.

Brendel is an energetic, young doctor with a three-day beard and a full head of hair, and he is also an award-winning nuclear medicine specialist. His magic trick: making what happens in the brain when people have Alzheimer’s visible.

Haass, on the other hand, is an Alzheimer’s veteran; he has been researching the causes of dementia for decades, and at Harvard in the 1990s, he co-discovered the role of beta-amyloid as a cause of the deposits in the brain.

Blood tests for early detection of Alzheimer’s are about to be approved.

Haass speaks of Leqembi as the beginning of a new era. More antibodies are being developed. There are even vaccines that stimulate the immune system to produce the antibodies itself, against both tau and beta-amyloid proteins. And it’s not just therapies that are improving. Blood tests for early detection of Alzheimer’s are about to be approved, and in a few years they could become widely used, Brendel says.

Haass sees the development as similar to that of HIV therapies: There was never a single drug that defeated AIDS. But research progressed step by step until HIV was, de facto, defeated.

Haass’ hope is that in a few years there will be a range of drugs that will slow down the symptoms so much that those affected will live into old age without any real complications. Maybe, in the near future, no doctor will have to tell an Alzheimer’s patient the devastating news that medicine has nothing to offer for them.

Skepticism

And yet some are skeptical. The media wrote that the therapies have few advantages and many side effects. The general tone: What’s half a year anyway?

Brendel and Haass are hardly willing to talk about it; it annoys them too much. In 2012, the Süddeutsche Zeitung declared Alzheimer’s research to be a failure. Haass remembers that at the time there were voices in Bavarian politics that doubted whether it was worth continuing to fund amyloid research. In 2015, there was great hope; initial results with the antibody Solanezumab were promising, but the drug flopped in clinical trials.

“We need to be careful not to build castles in the air,” Bürger say. The antibodies are only suitable for those in a very early stage of Alzheimer’s.

Brendel has the figures ready: Elisai, the manufacturer, only expects to supply with the drug 1% of Alzheimer’s patients, especially those that have not yet been diagnosed. Other estimates go up to 6.4%, the most optimistic scenario assumes it could work on 16% of the patients. It’s still a big number: It means that 50,000 to 800,000 people in Germany alone could benefit from antibody therapy.

In studies testing antibodies, around 30% of the test subjects experienced brain hemorrhages.

But Leqembi is currently not an option for most of those affected. During the course of the conversation with the three Alzheimer’s experts, it becomes clear that the German health care system is not yet prepared for the use of the new antibody therapies. And despite all the opportunities, it can also represent a dilemma for many doctors.

This begins with the fact that people with a gene variant called ApoE4, which is associated with a particularly high risk of Alzheimer’s, must not take it. They are particularly susceptible to the brain hemorrhages caused by antibody therapies. Hermine Schmitt also has this gene variant.

She had to stop the clinical trial prematurely. In fact, brain hemorrhages are perhaps the biggest obstacle: In the studies testing antibodies, around 30% of the test subjects experienced brain hemorrhages. This is another reason why many media outlets came to a negative conclusion.Yet brain hemorrhages sound much more dramatic than they often are.

Is it worth it?

Brain hemorrhages are bleeding, probably caused by tiny blood vessels tearing when the extremely sticky beta-amyloid is transported away. In the Leqembi study, however, three-quarters of those affected did not notice anything at all. Only slightly less than one in every 100 test subjects had serious problems.

“Epileptic seizures, strokes and even death can occur,” Bürger says. “But that is very rare.”

To prevent the bleeding, patients would have to undergo repeated MRI scans. “Yet it is not that easy to detect water retention and bleedings. Many radiologists are not yet trained in this area,” Bürger says. In addition, MRI scans are expensive, and it is uncertain whether health insurance companies will cover the costs.

The next open question: How long should an antibody therapy last? The approval study shows that anyone who takes Leqembi for one and a half years gains an average of six months of memory. But if the treatment is stopped, the plaques return. So do patients have to take the drug permanently? And doesn’t that increase the risk of side effects?

Walter Schmitt says that he had a good 16 years with his wife after their first visit to the family doctor in 2006, when it became clear that she had Alzheimer’s. Even though the symptoms gradually increased, Hermine Schmitt was still herself, her soul was still there. She could still wash and dress herself. The two of them gardened, cooked together and went on trips, hiking in the mountains.

Is it worth it for a patient like this to undergo years of experimental therapy? Or does the risk of a stroke, which could have robbed the Schmitts of many fulfilling years, outweigh the risk?

Haass, Bredel and Bürger cannot give a definite answer. In the end, these are always individual decisions. But they too seem uncertain about the idea of an antibody therapy that lasts for years. “The antibody goes to the brain, our most complicated organ. With long-term treatment, it would stay there for several decades, in high concentrations. And we don’t really know yet what consequences that could have,” Haass says.

The earlier the better

When the disease is already well advanced, the therapies have little effect. All of this almost inevitably leads to the big question: If the new antibodies were used to consistently remove the plaques from the brain from a very early stage, years or even a decade before the first symptoms appear, then could the disease be delayed by years?

“We don’t know yet,” Bürger asy cautiously.”It’s a horror scenario for us if everyone over 50 suddenly stormed into clinics and demanded early detection of Alzheimer’s.”

In Germany, as everywhere else in the world, the infrastructure for this is simply lacking at the moment. Millions of people would have to undergo expensive PET scans, which makes the plaques visible. Currently, says Brendel, only 3,000 such tests are carried out in Germany every year to diagnose Alzheimer’s.

So should everyone go to the doctor and have a puncture between the lumbar vertebrae to take a sample?

Plus, patients would need regular cerebrospinal fluid tests to detect it. So should everyone go to the doctor and have a puncture between the lumbar vertebrae to take a sample?

That, says Brendel, is not so easy either: the results with the typical Alzheimer’s biomarkers are often ambiguous, especially in the early stages of the disease, and every cerebrospinal fluid puncture is complex and potentially associated with risks.

At this moment, in the meeting room of the CSD, there is a vision that Alzheimer’s could one day be treatable like HIV. But it’s clear that there is still a long way to go before that happens. Consistent early detection would be one way, Haass believes, but only in the long term, in a few years, when more therapies and simpler blood tests are available.

Today, Schmitt says he is slowly getting used to life without his wife. She has also found a friend in the care home, a patient who also has Alzheimer’s. The two of them always sit next to each other, hold hands and smile.

*Originally published November 15, 2024, this article was updated November 18, 2024 with enriched media and multiple references to Leqembi, the commercial name of the drug.