How Leqembi became the biggest news in Alzheimer’s disease in 40 years, and what comes next
Betsy Groves, 73, with her granddaughter. Groves learned in 2021 that she has Alzheimer's disease. She hopes to take Leqembi, a drug approved by the FDA last week.
A few months ago, Betsy Groves traveled less than a mile from her home in Cambridge, Mass. to give a talk to a bunch of scientists. The scientists, who worked for the pharmaceutical companies Biogen and Eisai, wanted to know how she lived her life, how she thought about her future, and what it was like when a doctor’s appointment in 2021 gave her the worst possible news. Groves, 73, has Alzheimer’s disease. She caught it early, through a lumbar puncture that showed evidence of amyloid, an Alzheimer’s hallmark, in her cerebrospinal fluid. As a way of dealing with her diagnosis, she joined the Alzheimer’s Association’s National Early-Stage Advisory Board, which helped her shift into seeing her diagnosis as something she could use to help others.
After her talk, Groves stayed for lunch with the scientists, who were eager to put a face to their work. Biogen and Eisai were about to release the first drug to successfully combat Alzheimer’s in 40 years of experimental disaster. Their drug, which is known by the scientific name lecanemab and the marketing name Leqembi, was granted accelerated approval by the U.S. Food and Drug Administration last Friday, Jan. 6, after a study in 1,800 people showed that it reduced cognitive decline by 27 percent over 18 months.
It is no exaggeration to say that this result is a huge deal. The field of Alzheimer’s drug development has been absolutely littered with failures. Almost everything researchers have tried has tanked in clinical trials. “Most of the things that we've done have proven not to be effective, and it's not because we haven’t been taking a ton of shots at goal,” says Anton Porsteinsson, director of the University of Rochester Alzheimer's Disease Care, Research, and Education Program, who worked on the lecanemab trial. “I think it's fair to say you don't survive in this field unless you're an eternal optimist.”
As far back as 1984, a cure looked like it was within reach: Scientists discovered that the sticky plaques that develop in the brains of those who have Alzheimer’s are made up of a protein fragment called beta-amyloid. Buildup of beta-amyloid seemed to be sufficient to disrupt communication between, and eventually kill, memory cells. If that was true, then the cure should be straightforward: Stop the buildup of beta-amyloid; stop the Alzheimer’s disease.
It wasn’t so simple. Over the next 38 years, hundreds of drugs designed either to interfere with the production of abnormal amyloid or to clear it from the brain flamed out in trials. It got so bad that neuroscience drug divisions at major pharmaceutical companies (AstraZeneca, Pfizer, Bristol-Myers, GSK, Amgen) closed one by one, leaving the field to smaller, scrappier companies, like Cambridge-based Biogen and Tokyo-based Eisai. Some scientists began to dismiss the amyloid hypothesis altogether: If this protein fragment was so important to the disease, why didn’t ridding the brain of it do anything for patients? There was another abnormal protein that showed up in the brains of Alzheimer’s patients, called tau. Some researchers defected to the tau camp, or came to believe the proteins caused damage in combination.
The situation came to a head in 2021, when the FDA granted provisional approval to a drug called aducanumab, marketed as Aduhelm, against the advice of its own advisory council. The approval was based on proof that Aduhelm reduced beta-amyloid in the brain, even though one research trial showed it had no effect on people’s symptoms or daily life. Aduhelm could also cause serious side effects, like brain swelling and amyloid related imaging abnormalities (known as ARIA, these are basically micro-bleeds that appear on MRI scans). Without a clear benefit to memory loss that would make these risks worth it, Medicare refused to pay for Aduhelm among the general population. Two congressional committees launched an investigation into the drug’s approval, citing corporate greed, lapses in protocol, and an unjustifiably high price. (Aduhelm was also produced by the pharmaceutical company Biogen.)
To be clear, Leqembi is not the cure Alzheimer’s researchers hope for. While the drug is the first to show clear signs of a clinical benefit, the scientific establishment is split on how much of a difference Leqembi will make in the real world.
So far, Leqembi is like Aduhelm in that it has been given accelerated approval only for its ability to remove amyloid from the brain. Both are monoclonal antibodies that direct the immune system to attack and clear dysfunctional beta-amyloid. The difference is that, while that’s all Aduhelm was ever shown to do, Leqembi’s makers have already asked the FDA to give it full approval – a decision that would increase the likelihood that Medicare will cover it – based on data that show it also improves Alzheimer’s sufferer’s lives. Leqembi targets a different type of amyloid, a soluble version called “protofibrils,” and that appears to change the effect. “It can give individuals and their families three, six months longer to be participating in daily life and living independently,” says Claire Sexton, PhD, senior director of scientific programs & outreach for the Alzheimer's Association. “These types of changes matter for individuals and for their families.”
To be clear, Leqembi is not the cure Alzheimer’s researchers hope for. It does not halt or reverse the disease, and people do not get better. While the drug is the first to show clear signs of a clinical benefit, the scientific establishment is split on how much of a difference Leqembi will make in the real world. It has “a rather small effect,” wrote NIH Alzheimer’s researcher Madhav Thambisetty, MD, PhD, in an email to Leaps.org. “It is unclear how meaningful this difference will be to patients, and it is unlikely that this level of difference will be obvious to a patient (or their caregivers).” Another issue is cost: Leqembi will become available to patients later this month, but Eisai is setting the price at $26,500 per year, meaning that very few patients will be able to afford it unless Medicare chooses to reimburse them for it.
The same side effects that plagued Aduhelm are common in Leqembi treatment as well. In many patients, amyloid doesn’t just accumulate around neurons, it also forms deposits in the walls of blood vessels. Blood vessels that are shot through with amyloid are more brittle. If you infuse a drug that targets amyloid, brittle blood vessels in the brain can develop leakage that results in swelling or bleeds. Most of these come with no symptoms, and are only seen during testing, which is why they are called “imaging abnormalities.” But in situations where patients have multiple diseases or are prescribed incompatible drugs, they can be serious enough to cause death. The three deaths reported from Leqembi treatment (so far) are enough to make Thambisetty wonder “how well the drug may be tolerated in real world clinical practice where patients are likely to be sicker and have multiple other medical conditions in contrast to carefully selected patients in clinical trials.”
Porsteinsson believes that earlier detection of Alzheimer’s disease will be the next great advance in treatment, a more important step forward than Leqembi’s approval.
Still, there are reasons to be excited. A successful Alzheimer’s drug can pave the way for combination studies, in which patients try a known effective drug alongside newer, more experimental ones; or preventative studies, which take place years before symptoms occur. It also represents enormous strides in researchers’ understanding of the disease. For example, drug dosages have increased massively—in some cases quadrupling—from the early days of Alzheimer’s research. And patient selection for studies has changed drastically as well. Doctors now know that you’ve got to catch the disease early, through PET-scans or CSF tests for amyloid, if you want any chance of changing its course.
Porsteinsson believes that earlier detection of Alzheimer’s disease will be the next great advance in treatment, a more important step forward than Leqembi’s approval. His lab already uses blood tests for different types of amyloid, for different types of tau, and for measures of neuroinflammation, neural damage, and synaptic health, but commercially available versions from companies like C2N, Quest, and Fuji Rebio are likely to hit the market in the next couple of years. “[They are] going to transform the diagnosis of Alzheimer's disease,” Porsteinsson says. “If someone is experiencing memory problems, their physicians will be able to order a blood test that will tell us if this is the result of changes in your brain due to Alzheimer's disease. It will ultimately make it much easier to identify people at a very early stage of the disease, where they are most likely to benefit from treatment.”
Learn more about new blood tests to detect Alzheimer's
Early detection can help patients for more philosophical reasons as well. Betsy Groves credits finding her Alzheimer’s early with giving her the space to understand and process the changes that were happening to her before they got so bad that she couldn’t. She has been able to update her legal documents and, through her role on the Advisory Group, help the Alzheimer’s Association with developing its programs and support services for people in the early stages of the disease. She still drives, and because she and her husband love to travel, they are hoping to get out of grey, rainy Cambridge and off to Texas or Arizona this spring.
Because her Alzheimer’s disease involves amyloid deposits (a “substantial portion” do not, says Claire Sexton, which is an additional complication for research), and has not yet reached an advanced stage, Groves may be a good candidate to try Leqembi. She says she’d welcome the opportunity to take it. If she can get access, Groves hopes the drug will give her more days to be fully functioning with her husband, daughters, and three grandchildren. Mostly, she avoids thinking about what the latter stages of Alzheimer’s might be like, but she knows the time will come when it will be her reality. “So whatever lecanemab can do to extend my more productive ways of engaging with relationships in the world,” she says. “I'll take that in a minute.”
Blood Donated from Recovered Coronavirus Patients May Soon Yield a Stopgap Treatment
Antibodies from the blood of recovered patients is being tested as a stopgap treatment.
In October 1918, Lieutenant L.W. McGuire of the United States Navy sent a report to the American Journal of Public Health detailing a promising therapy that had already saved the lives of a number of officers suffering from pneumonia complications due to the Spanish influenza outbreak.
"These antibodies then become essentially drugs."
McGuire described how transfusions of blood from recovered patients – an idea which had first been trialed during a polio epidemic in 1916 – had led to rapid recovery in a series of severe pneumonia cases at a Naval Hospital in Massachusetts. "It is believed the serum has a decided influence in shortening the course of the disease, and lowering the mortality," he wrote.
Now more than a century on, this treatment – long forgotten in the western world - is once again coming to the fore during the current COVID-19 pandemic. With fatalities continuing to rise, and no vaccine expected for many months, experts are urging medical centers across the U.S. and Europe to initiate collaborations between critical care and transfusion services to offer this as an emergency treatment for those who need it most.
As of March 20, there are more than 90,000 individuals globally who have recovered from the disease. Some scientists believe that the blood of many of these people contains high levels of neutralizing antibodies that can kill the virus.
"These antibodies then become essentially drugs," said Arturo Casadevall, professor of Molecular Microbiology & Immunology at John Hopkins Bloomberg School of Public Health, who is currently co-ordinating a clinical trial of convalescent serum for COVID-19 involving 20 institutions across the US.
"We're talking about preparing a therapy right out of the serum of those that have recovered. It could also be used in patients who are already sick, but have not progressed to respiratory failure, to treat them before they enter intensive care units. That will provide a lot of support because there's a limited number of respirators and resources."
The first conclusive data on how the blood of recovered patients can help tackle COVID-19 is set to come out of China, where it was also used as an emergency treatment during the SARS and MERS outbreaks. On February 9, a severely ill patient in Wuhan was treated with convalescent serum and since then, hospitals across China have used the therapy on a total of 245 patients, with 91 reportedly showing an improvement in symptoms.
In China alone, more than 58,000 patients have now recovered from COVID-19. Casadevall said that last week the country shipped 90 tons of serum and plasma from these patients to Italy – the center of the pandemic in Europe – for emergency use.
Some of the first people to be treated are likely to be doctors and nurses in hospitals who are most at risk of exposure.
A current challenge, however, is that the blood donation from the recovered patients must be precisely timed in order to maximize the number of antibodies a future patient receives. Doctors in China say that obtaining the necessary blood samples at the right time is one of the major barriers to applying the treatment on a larger scale.
"It's difficult to get the donations," said Dr. Yuan Shi of Chongqing Medical University. "When patients have recovered from the disease, we would like to collect their blood two to four weeks afterwards. We try our best to call back the patients, but it's sometimes difficult to get them to come back within that time period."
Because of such hurdles, Japan's largest drugmaker, Takeda Pharmaceuticals, is now working to turn neutralizing antibodies from recovered COVID-19 patients into a standardized drug product. They hope to launch a clinical trial for this in the next few months.
In the U.S., Casadevall hopes blood transfusions from recovered patients can become clinically available as a therapy within the next four weeks, once regulatory approval has been received. Some of the first people to be treated are likely to be doctors and nurses in hospitals who are most at risk of exposure, to provide a protective boost in their immunity.
"A lot of healthcare workers in the U.S. have already been asked to quarantine, and you can imagine what effect that's going to have on the healthcare system," he said. "It can't take large numbers of people staying home; there's not the capacity."
But not all medical experts are convinced it's the way to go, especially when it comes to the most severe cases of COVID-19. "There's no knowing whether that treatment would be useful or not," warned Dr. Andrew Freedman, head of Cardiff University's School of Medicine in the U.K.
"There are going to be better things available in a few months, but we are facing, 'What do you do now?'"
However, Casadevall says that the treatment is not envisioned as a panacea to treating coronavirus, but simply a temporary measure which could give doctors some options until stronger options such as vaccines or new drugs are available.
"This is a stopgap option," he said. "There are going to be better things available in a few months, but we are facing, 'What do you do now?' The only thing we can offer severely ill people at the moment is respiratory support and oxygen, and we don't have anything to prevent those exposed from going on and getting ill."
Social distancing is a critical part of the strategy to defeat the novel coronavirus.
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.