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.”
Here's how one doctor overcame extraordinary odds to help create the birth control pill
Dr. Percy Julian had so many personal and professional obstacles throughout his life, it’s amazing he was able to accomplish anything at all. But this hidden figure not only overcame these incredible obstacles, he also laid the foundation for the creation of the birth control pill.
Julian’s first obstacle was growing up in the Jim Crow-era south in the early part of the twentieth century, where racial segregation kept many African-Americans out of schools, libraries, parks, restaurants, and more. Despite limited opportunities and education, Julian was accepted to DePauw University in Indiana, where he majored in chemistry. But in college, Julian encountered another obstacle: he wasn’t allowed to stay in DePauw’s student housing because of segregation. Julian found lodging in an off-campus boarding house that refused to serve him meals. To pay for his room, board, and food, Julian waited tables and fired furnaces while he studied chemistry full-time. Incredibly, he graduated in 1920 as valedictorian of his class.
After graduation, Julian landed a fellowship at Harvard University to study chemistry—but here, Julian ran into yet another obstacle. Harvard thought that white students would resent being taught by Julian, an African-American man, so they withdrew his teaching assistantship. Julian instead decided to complete his PhD at the University of Vienna in Austria. When he did, he became one of the first African Americans to ever receive a PhD in chemistry.
Julian received offers for professorships, fellowships, and jobs throughout the 1930s, due to his impressive qualifications—but these offers were almost always revoked when schools or potential employers found out Julian was black. In one instance, Julian was offered a job at the Institute of Paper Chemistory in Appleton, Wisconsin—but Appleton, like many cities in the United States at the time, was known as a “sundown town,” which meant that black people weren’t allowed to be there after dark. As a result, Julian lost the job.
During this time, Julian became an expert at synthesis, which is the process of turning one substance into another through a series of planned chemical reactions. Julian synthesized a plant compound called physostigmine, which would later become a treatment for an eye disease called glaucoma.
In 1936, Julian was finally able to land—and keep—a job at Glidden, and there he found a way to extract soybean protein. This was used to produce a fire-retardant foam used in fire extinguishers to smother oil and gasoline fires aboard ships and aircraft carriers, and it ended up saving the lives of thousands of soldiers during World War II.
At Glidden, Julian found a way to synthesize human sex hormones such as progesterone, estrogen, and testosterone, from plants. This was a hugely profitable discovery for his company—but it also meant that clinicians now had huge quantities of these hormones, making hormone therapy cheaper and easier to come by. His work also laid the foundation for the creation of hormonal birth control: Without the ability to synthesize these hormones, hormonal birth control would not exist.
Julian left Glidden in the 1950s and formed his own company, called Julian Laboratories, outside of Chicago, where he manufactured steroids and conducted his own research. The company turned profitable within a year, but even so Julian’s obstacles weren’t over. In 1950 and 1951, Julian’s home was firebombed and attacked with dynamite, with his family inside. Julian often had to sit out on the front porch of his home with a shotgun to protect his family from violence.
But despite years of racism and violence, Julian’s story has a happy ending. Julian’s family was eventually welcomed into the neighborhood and protected from future attacks (Julian’s daughter lives there to this day). Julian then became one of the country’s first black millionaires when he sold his company in the 1960s.
When Julian passed away at the age of 76, he had more than 130 chemical patents to his name and left behind a body of work that benefits people to this day.
Therapies for Healthy Aging with Dr. Alexandra Bause
My guest today is Dr. Alexandra Bause, a biologist who has dedicated her career to advancing health, medicine and healthier human lifespans. Dr. Bause co-founded a company called Apollo Health Ventures in 2017. Currently a venture partner at Apollo, she's immersed in the discoveries underway in Apollo’s Venture Lab while the company focuses on assembling a team of investors to support progress. Dr. Bause and Apollo Health Ventures say that biotech is at “an inflection point” and is set to become a driver of important change and economic value.
Previously, Dr. Bause worked at the Boston Consulting Group in its healthcare practice specializing in biopharma strategy, among other priorities
She did her PhD studies at Harvard Medical School focusing on molecular mechanisms that contribute to cellular aging, and she’s also a trained pharmacist
In the episode, we talk about the present and future of therapeutics that could increase people’s spans of health, the benefits of certain lifestyle practice, the best use of electronic wearables for these purposes, and much more.
Dr. Bause is at the forefront of developing interventions that target the aging process with the aim of ensuring that all of us can have healthier, more productive lifespans.
