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.”
New Blood Test Can Detect Lymphoma Cells Before a Tumor Grows Back
David Kurtz making DNA sequencing libraries in his lab.
When David M. Kurtz was doing his clinical fellowship at Stanford University Medical Center in 2009, specializing in lymphoma treatments, he found himself grappling with a question no one could answer. A typical regimen for these blood cancers prescribed six cycles of chemotherapy, but no one knew why. "The number seemed to be drawn out of a hat," Kurtz says. Some patients felt much better after just two doses, but had to endure the toxic effects of the entire course. For some elderly patients, the side effects of chemo are so harsh, they alone can kill. Others appeared to be cancer-free on the CT scans after the requisite six but then succumbed to it months later.
"Anecdotally, one patient decided to stop therapy after one dose because he felt it was so toxic that he opted for hospice instead," says Kurtz, now an oncologist at the center. "Five years down the road, he was alive and well. For him, just one dose was enough." Others would return for their one-year check up and find that their tumors grew back. Kurtz felt that while CT scans and MRIs were powerful tools, they weren't perfect ones. They couldn't tell him if there were any cancer cells left, stealthily waiting to germinate again. The scans only showed the tumor once it was back.
Blood cancers claim about 68,000 people a year, with a new diagnosis made about every three minutes, according to the Leukemia Research Foundation. For patients with B-cell lymphoma, which Kurtz focuses on, the survival chances are better than for some others. About 60 percent are cured, but the remaining 40 percent will relapse—possibly because they will have a negative CT scan, but still harbor malignant cells. "You can't see this on imaging," says Michael Green, who also treats blood cancers at University of Texas MD Anderson Medical Center.
The new blood test is sensitive enough to spot one cancerous perpetrator amongst one million other DNA molecules.
Kurtz wanted a better diagnostic tool, so he started working on a blood test that could capture the circulating tumor DNA or ctDNA. For that, he needed to identify the specific mutations typical for B-cell lymphomas. Working together with another fellow PhD student Jake Chabon, Kurtz finally zeroed-in on the tumor's genetic "appearance" in 2017—a pair of specific mutations sitting in close proximity to each other—a rare and telling sign. The human genome contains about 3 billion base pairs of nucleotides—molecules that compose genes—and in case of the B-cell lymphoma cells these two mutations were only a few base pairs apart. "That was the moment when the light bulb went on," Kurtz says.
The duo formed a company named Foresight Diagnostics, focusing on taking the blood test to the clinic. But knowing the tumor's mutational signature was only half the process. The other was fishing the tumor's DNA out of patients' bloodstream that contains millions of other DNA molecules, explains Chabon, now Foresight's CEO. It would be like looking for an escaped criminal in a large crowd. Kurtz and Chabon solved the problem by taking the tumor's "mug shot" first. Doctors would take the biopsy pre-treatment and sequence the tumor, as if taking the criminal's photo. After treatments, they would match the "mug shot" to all DNA molecules derived from the patient's blood sample to see if any molecular criminals managed to escape the chemo.
Foresight isn't the only company working on blood-based tumor detection tests, which are dubbed liquid biopsies—other companies such as Natera or ArcherDx developed their own. But in a recent study, the Foresight team showed that their method is significantly more sensitive in "fishing out" the cancer molecules than existing tests. Chabon says that this test can detect circulating tumor DNA in concentrations that are nearly 100 times lower than other methods. Put another way, it's sensitive enough to spot one cancerous perpetrator amongst one million other DNA molecules.
"It increases the sensitivity of detection and really catches most patients who are going to progress," says Green, the University of Texas oncologist who wasn't involved in the study, but is familiar with the method. It would also allow monitoring patients during treatment and making better-informed decisions about which therapy regimens would be most effective. "It's a minimally invasive test," Green says, and "it gives you a very high confidence about what's going on."
Having shown that the test works well, Kurtz and Chabon are planning a new trial in which oncologists would rely on their method to decide when to stop or continue chemo. They also aim to extend their test to detect other malignancies such as lung, breast or colorectal cancers. The latest genome sequencing technologies have sequenced and catalogued over 2,500 different tumor specimens and the Foresight team is analyzing this data, says Chabon, which gives the team the opportunity to create more molecular "mug shots."
The team hopes that that their blood cancer test will become available to patients within about five years, making doctors' job easier, and not only at the biological level. "When I tell patients, "good news, your cancer is in remission', they ask me, 'does it mean I'm cured?'" Kurtz says. "Right now I can't answer this question because I don't know—but I would like to." His company's test, he hopes, will enable him to reply with certainty. He'd very much like to have the power of that foresight.
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.
The First Mass-Produced Solar Car Is Coming Soon, Sparking Excitement and Uncertainty
Reporter Michaela Haas takes Aptera's Sol car out for a test drive in San Diego, Calif.
The white two-seater car that rolls down the street in the Sorrento Valley of San Diego looks like a futuristic batmobile, with its long aerodynamic tail and curved underbelly. Called 'Sol' (Spanish for "sun"), it runs solely on solar and could be the future of green cars. Its maker, the California startup Aptera, has announced the production of Sol, the world's first mass-produced solar vehicle, by the end of this year. Aptera co-founder Chris Anthony points to the sky as he says, "On this sunny California day, there is ample fuel. You never need to charge the car."
If you live in a sunny state like California or Florida, you might never need to plug in the streamlined Sol because the solar panels recharge while driving and parked. Its 60-mile range is more than the average commuter needs. For cloudy weather, battery packs can be recharged electronically for a range of up to 1,000 miles. The ultra-aerodynamic shape made of lightweight materials such as carbon, Kevlar, and hemp makes the Sol four times more energy-efficient than a Tesla, according to Aptera. "The material is seven times stronger than steel and even survives hail or an angry ex-girlfriend," Anthony promises.
Co-founder Steve Fambro opens the Sol's white doors that fly upwards like wings and I get inside for a test drive. Two dozen square solar panels, each the size of a large square coaster, on the roof, front, and tail power the car. The white interior is spartan; monitors have replaced mirrors and the dashboard. An engineer sits in the driver's seat, hits the pedal, and the low-drag two-seater zooms from 0 to 60 in 3.5 seconds.
It feels like sitting in a race car because the two-seater is so low to the ground but the car is built to go no faster than 100 or 110 mph. The finished car will weigh less than 1,800 pounds, about half of the smallest Tesla. The average car, by comparison, weighs more than double that. "We've built it primarily for energy efficiency," Steve Fambro says, explaining why the Sol has only three wheels. It's technically an "auto-cycle," a hybrid between a motorcycle and a car, but Aptera's designers are also working to design a four-seater.
There has never been a lack of grand visions for the future of the automobile, but until these solar cars actually hit the streets, nobody knows how the promises will hold up.
Transportation is currently the biggest source of greenhouse gases. Developing an efficient solar car that does not burden the grid has been the dream of innovators for decades. Every other year, dozens of innovators race their self-built solar cars 2,000 miles through the Australian desert.
More effective solar panels are finally making the dream mass-compatible, but just like other innovative car ideas, Aptera's vision has been plagued with money problems. Anthony and Fambro were part of the original crew that founded Aptera in 2006 and worked on the first prototype around the same time Tesla built its first roadster, but Aptera went bankrupt in 2011. Anthony and Fambro left a year before the bankruptcy and went on to start other companies. Among other projects, Fambro developed the first USDA organic vertical farm in the United Arab Emirates, and Anthony built a lithium battery company, before the two decided to buy Aptera back. Without a billionaire such as Elon Musk bankrolling the risky process of establishing a whole new car production system from scratch, the huge production costs are almost insurmountable.
But Aptera's founders believe they have found solutions for the entire production process as well as the car design. Most parts of the Sol's body can be made by 3D printers and assembled like a Lego kit. If this makes you think of a toy car, Anthony assures potential buyers that the car aced stress tests and claims it's safer than any vehicle on the market, "because the interior is shaped like an egg and if there is an impact, the pressure gets distributed equally." However, Aptera has yet to release crash test safety data so outside experts cannot evaluate their claims.
Instead of building a huge production facility, Anthony and Fambro envision "micro-factories," each less than 10,000 square feet, where a small crew can assemble cars on demand wherever the orders are highest, be it in California, Canada, or China.
If a part of the Sol breaks, Aptera promises to send replacement parts to any corner of the world within 24 hours, with instructions. So a mechanic in a rural corner in Arkansas or China who never worked on a solar car before simply needs to download the instructions and replace the broken part. At least that's the idea. "The material does not rust nor fatigue," Fambro promises. "You can pass the car onto your grandchildren. When more efficient solar panels hit the market, we simply replace them."
More than 11,000 potential buyers have already signed up; the cheapest model costs around $26,000 USD and Aptera expects the first cars to ship by the end of the year.
Two other solar carmakers are vying for the pole position in the race to be the first to market: The German startup Sono has also announced it will also produce its first solar car by the end of this year. The price tag for the basic model is also around $26,000, but its concept is very different. From the outside, the Sion looks like a conservative minivan for a family; only a closer look reveals that the dark exterior is made of solar panels. Sono, too, nearly went bankrupt a few years ago and was saved through a crowdfunding campaign by enthusiastic fans.
Meanwhile, Norwegian company Lightyear wants to produce a sleek solar-powered luxury sedan by the end of the year, but its price of around $180,000 makes it unaffordable for most buyers.
There has never been a lack of grand visions for the future of the automobile, but until these solar cars actually hit the streets, nobody knows how the promises will hold up. How often will the cars need to be repaired? What happens when snow and ice cover the solar panels? Also, you can't park the car in a garage if you need the sun to charge it.
Critics, including students at the Solar Car team at the University of Michigan, say that mounting solar panels on a moving vehicle will never yield the most efficient results compared to static panels. Also, they are quick to point out that no company has managed to overcome the production hurdles yet. Others in the field also wonder how well the solar panels will actually work.
"It's important to realize that the solar mileage claims by these companies are likely the theoretical best case scenario but in the real world, solar range will be significantly less when you factor in shading, parking in garages, and geographies with lower solar irradiance," says Evan Stumpges, the team coordinator for the American Solar Challenge, a competition in which enthusiasts build and race solar-powered cars. "The encouraging thing is that I have seen videos of real working prototypes for each of these vehicles which is a key accomplishment. That said, I believe the biggest hurdle these companies have yet to face is successfully ramping up to volume production and understanding what their profitability point will be for selling the vehicles once production has stabilized."
Professor Daniel M. Kammen, the founding director of the Renewable and Appropriate Energy Laboratory at the University of California, Berkeley, and one of the world's foremost experts on renewable energy, believes that the technical challenges have been solved, and that solar cars have real advantages over electric vehicles.
"This is the right time to be bullish. Cutting out the charging is a natural solution for long rides," he says. "These vehicles are essentially solar panels and batteries on wheels. These are now record low-cost and can be built from sustainable materials." Apart from Aptera's no-charge technology, he appreciates the move toward no-conflict materials. "Not only is the time ripe but the youth movement is pushing toward conflict-free material and reducing resource waste....A low-cost solar fleet could be really interesting in relieving burden on the grid, or you could easily imagine a city buying a bunch of them and connecting them with mass transit." While he has followed all three new solar companies with interest, he has already ordered an Aptera car for himself, "because it's American and it looks the most different."
After taking a spin in the Sol, it is startling to switch back into a regular four-seater. Rolling out of Aptera's parking lot onto the freeway next to all the oversized gas guzzlers that need to stop every couple of hundreds of miles to fill up, one can't help but think: We've just taken a trip into the future.