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.”
Dr. Steffanie Strathdee, an infectious disease epidemiologist, saved her husband Tom from a superbug infection by mobilizing scientists around the world to help him access experimental phage therapy.
[Editor's Note: This is the fifth episode in our Moonshot series, which explores cutting-edge scientific developments that stand to fundamentally transform our world.]
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.
The latest tools, like whole genome sequencing, are allowing food outbreaks to be identified and stopped more quickly.
With the pandemic at the forefront of everyone's minds, many people have wondered if food could be a source of coronavirus transmission. Luckily, that "seems unlikely," according to the CDC, but foodborne illnesses do still sicken a whopping 48 million people per year.
Whole genome sequencing is like "going from an eight-bit image—maybe like what you would see in Minecraft—to a high definition image."
In normal times, when there isn't a historic global health crisis infecting millions and affecting the lives of billions, foodborne outbreaks are real and frightening, potentially deadly, and can cause widespread fear of particular foods. Think of Romaine lettuce spreading E. coli last year— an outbreak that infected more than 500 people and killed eight—or peanut butter spreading salmonella in 2008, which infected 167 people.
The technologies available to detect and prevent the next foodborne disease outbreak have improved greatly over the past 30-plus years, particularly during the past decade, and better, more nimble technologies are being developed, according to experts in government, academia, and private industry. The key to advancing detection of harmful foodborne pathogens, they say, is increasing speed and portability of detection, and the precision of that detection.
Getting to Rapid Results
Researchers at Purdue University have recently developed a lateral flow assay that, with the help of a laser, can detect toxins and pathogenic E. coli. Lateral flow assays are cheap and easy to use; a good example is a home pregnancy test. You place a liquid or liquefied sample on a piece of paper designed to detect a single substance and soon after you get the results in the form of a colored line: yes or no.
"They're a great portable tool for us for food contaminant detection," says Carmen Gondhalekar, a fifth-year biomedical engineering graduate student at Purdue. "But one of the areas where paper-based lateral flow assays could use improvement is in multiplexing capability and their sensitivity."
J. Paul Robinson, a professor in Purdue's Colleges of Veterinary Medicine and Engineering, and Gondhalekar's advisor, agrees. "One of the fundamental problems that we have in detection is that it is hard to identify pathogens in complex samples," he says.
When it comes to foodborne disease outbreaks, you don't always know what substance you're looking for, so an assay made to detect only a single substance isn't always effective. The goal of the project at Purdue is to make assays that can detect multiple substances at once.
These assays would be more complex than a pregnancy test. As detailed in Gondhalekar's recent paper, a laser pulse helps create a spectral signal from the sample on the assay paper, and the spectral signal is then used to determine if any unique wavelengths associated with one of several toxins or pathogens are present in the sample. Though the handheld technology has yet to be built, the idea is that the results would be given on the spot. So someone in the field trying to track the source of a Salmonella infection could, for instance, put a suspected lettuce sample on the assay and see if it has the pathogen on it.
"What our technology is designed to do is to give you a rapid assessment of the sample," says Robinson. "The goal here is speed."
Seeing the Pathogen in "High-Def"
"One in six Americans will get a foodborne illness every year," according to Dr. Heather Carleton, a microbiologist at the Centers for Disease Control and Prevention's Enteric Diseases Laboratory Branch. But not every foodborne outbreak makes the news. In 2017 alone, the CDC monitored between 18 and 37 foodborne poison clusters per week and investigated 200 multi-state clusters. Hardboiled eggs, ground beef, chopped salad kits, raw oysters, frozen tuna, and pre-cut melon are just a taste of the foods that were investigated last year for different strains of listeria, salmonella, and E. coli.
At the heart of the CDC investigations is PulseNet, a national network of laboratories that uses DNA fingerprinting to detect outbreaks at local and regional levels. This is how it works: When a patient gets sick—with symptoms like vomiting and fever, for instance—they will go to a hospital or clinic for treatment. Since we're talking about foodborne illnesses, a clinician will likely take a stool sample from the patient and send it off to a laboratory to see if there is a foodborne pathogen, like salmonella, E. Coli, or another one. If it does contain a potentially harmful pathogen, then a bacterial isolate of that identified sample is sent to a regional public health lab so that whole genome sequencing can be performed.
Whole genome sequencing can differentiate "virtually all" strains of foodborne pathogens, no matter the species, according to the FDA.
Whole genome sequencing is a method for reading the entire genome of a bacterial isolate (or from any organism, for that matter). Instead of working with a couple dozen data points, now you're working with millions of base pairs. Carleton likes to describe it as "going from an eight-bit image—maybe like what you would see in Minecraft—to a high definition image," she says. "It's really an evolution of how we detect foodborne illnesses and identify outbreaks."
If the bacterial isolate matches another in the CDC's database, this means there could be a potential outbreak and an investigation may be started, with the goal of tracking the pathogen to its source.
Whole genome sequencing has been a relatively recent shift in foodborne disease detection. For more than 20 years, the standard technique for analyzing pathogens in foodborne disease outbreaks was pulsed-field gel electrophoresis. This method creates a DNA fingerprint for each sample in the form of a pattern of about 15-30 "bands," with each band representing a piece of DNA. Researchers like Carleton can use this fingerprint to see if two samples are from the same bacteria. The problem is that 15-30 bands are not enough to differentiate all isolates. Some isolates whose bands look very similar may actually come from different sources and some whose bands look different may be from the same source. But if you can see the entire DNA fingerprint, then you don't have that issue. That's where whole genome sequencing comes in.
Although the PulseNet team had piloted whole genome sequencing as early as 2013, it wasn't until July of last year that the transition to using whole genome sequencing for all pathogens was complete. Though whole genome sequencing requires far more computing power to generate, analyze, and compare those millions of data points, the payoff is huge.
Stopping Outbreaks Sooner
The U.S. Food and Drug Administration (FDA) acquired their first whole genome sequencers in 2008, according to Dr. Eric Brown, the Director of the Division of Microbiology in the FDA's Office of Regulatory Science. Since then, through their GenomeTrakr program, a network of more than 60 domestic and international labs, the FDA has sequenced and publicly shared more than 400,000 isolates. "The impact of what whole genome sequencing could do to resolve a foodborne outbreak event was no less impactful than when NASA turned on the Hubble Telescope for the first time," says Brown.
Whole genome sequencing has helped identify strains of Salmonella that prior methods were unable to differentiate. In fact, whole genome sequencing can differentiate "virtually all" strains of foodborne pathogens, no matter the species, according to the FDA. This means it takes fewer clinical cases—fewer sick people—to detect and end an outbreak.
And perhaps the largest benefit of whole genome sequencing is that these detailed sequences—the millions of base pairs—can imply geographic location. The genomic information of bacterial strains can be different depending on the area of the country, helping these public health agencies eventually track the source of outbreaks—a restaurant, a farm, a food-processing center.
Coming Soon: "Lab in a Backpack"
Now that whole genome sequencing has become the go-to technology of choice for analyzing foodborne pathogens, the next step is making the process nimbler and more portable. Putting "the lab in a backpack," as Brown says.
The CDC's Carleton agrees. "Right now, the sequencer we use is a fairly big box that weighs about 60 pounds," she says. "We can't take it into the field."
A company called Oxford Nanopore Technologies is developing handheld sequencers. Their devices are meant to "enable the sequencing of anything by anyone anywhere," according to Dan Turner, the VP of Applications at Oxford Nanopore.
"The sooner that we can see linkages…the sooner the FDA gets in action to mitigate the problem and put in some kind of preventative control."
"Right now, sequencing is very much something that is done by people in white coats in laboratories that are set up for that purpose," says Turner. Oxford Nanopore would like to create a new, democratized paradigm.
The FDA is currently testing these types of portable sequencers. "We're very excited about it. We've done some pilots, to be able to do that sequencing in the field. To actually do it at a pond, at a river, at a canal. To do it on site right there," says Brown. "This, of course, is huge because it means we can have real-time sequencing capability to stay in step with an actual laboratory investigation in the field."
"The timeliness of this information is critical," says Marc Allard, a senior biomedical research officer and Brown's colleague at the FDA. "The sooner that we can see linkages…the sooner the FDA gets in action to mitigate the problem and put in some kind of preventative control."
At the moment, the world is rightly focused on COVID-19. But as the danger of one virus subsides, it's only a matter of time before another pathogen strikes. Hopefully, with new and advancing technology like whole genome sequencing, we can stop the next deadly outbreak before it really gets going.