Alzheimer’s drug FDA approval spurs optimism—and some caution

Until recently, decades of research on Alzheimer’s had failed to produce a single drug that could reverse the disease, much less cure it. Now, in just a year and a half, the Food and Drug Administration has approved two that may slow the cognitive decline destroying the lives of millions of people.

But both decisions are highly controversial. The approvals were not based on the drugs’ impact on disease progression, but on their ability to remove abnormal clumps—plaques—of a toxic form of a protein called beta amyloid that aggregates in the brains of Alzheimer’s patients, which were thought to be the underlying cause of the disease. Also, the drugs are expensive, can cause adverse side effects, and may have modest benefits, at best, in preserving brain function as the disease progresses. Some experts argue that the treatment benefits don’t clearly outweigh the risks.

For years, eliminating plaques has been the primary focus of dementia research and drug development. But the approvals have reignited a debate in the field over whether this is the best way to attack the complex disease. Many scientists note that the result so far is just two drugs with limited efficacy, and they have called for far more funding to probe alternative theories.

The drug the FDA approved last week, known as lecanemab, is the first to show evidence of slowing cognitive decline in clinical trials. The other drug, known as aducanumab, was shown to remove plaque, but was not proven to arrest the loss of cognitive ability. But lecanemab’s promise has been clouded by the death of three patients who were taking the drug in an extension of the study.

Lecanemab’s accelerated approval was based on the results of a phase 3 clinical trial—called CLARITY—which found that the drug removed beta amyloid plaques in the brains of patients with early stage Alzheimer’s. The study was funded by pharmaceutical giants Biogen and Eisai, which developed the drug, and revealed that there was 27 percent less cognitive decline among patients who received lecanemab compared to those on the placebo.

But Matthew Schrag, a neurologist at Vanderbilt University Medical Center in Nashville, Tennessee, thinks that the benefits demonstrated by the clinical trial are modest at best. After the clinical trial the researchers used an 18-point clinical dementia rating scale to assess a patient’s memory, problem solving skills, orientation, among other aspects of cognitive and functional performance; the higher the score, the worse the dementia. Those on lecanemab scored 1.21 whereas those taking the placebo averaged 1.66, which shows that those taking the drug experienced 27 percent less cognitive decline.

“The question is whether the average patient in a clinic would notice that benefit,” Schrag says. “I don’t think they would.” More importantly, it’s the drug’s safety that concerns him. “I think we’re just beginning to see the tip of the iceberg with the risks.” But Schrag and others believe that beta amyloid proteins are only a small piece of a complicated puzzle and are not convinced they are central to delaying or arresting disease progression.

The FDA did not respond to National Geographic’s email requesting comment on the drug’s approval and the death of three patients who took the medication.

Targeting amyloid plaque

In the United States, an estimated 6.5 million people 65 years and older currently live with Alzheimer’s. By 2050, the Alzheimer’s Association expects that number to reach 12.7 million.

Alzheimer’s disease still has no proven cure, although there are treatments to help manage some of its symptoms. Patients and their families are desperate for treatments that will slow the disease’s progression and prolong the period during which an individual’s cognitive impairment is still mild and they can go about their daily activities independently, says neurobiologist Joshua Grill at the University of California, Irvine.

In the last few decades, drug development has focused on the removal of plaque but the hypothesis that beta amyloids are key to Alzheimer’s disease and its treatment is the subject of enormous debate.

“We have 20 years of clinical trials targeting this, and every single trial without fail has been a failure, except for one or maybe two,” Schrag says. “And those produced a barely detectable result.”

Both lecanemab and aducanumab (marketed as Aduhelm), which the FDA approved in 2021, are monoclonal antibodies—laboratory manufactured proteins—designed to target and remove the beta amyloid plaques that are believed to trigger the disease. While aducanumab binds more strongly to insoluble forms of beta amyloid, lecanemab targets a soluble version called a protofibril, which is thought to be more toxic to neurons.

Many experts say that aducanumab, which is also administered to patients via an intravenous infusion and developed by Biogen and Eisai, only slowed cognitive decline marginally and shouldn’t have been greenlit. It also caused adverse side effects like brain swelling and bleeding in some patients.

Lecanemab, on the other hand, shows some evidence of slowing disease progression, and it’s possible the benefits may increase if patients continue using it beyond 18 months, the length of the CLARITY trial, says clinical neurologist David Knopman at the Mayo Clinic in Rochester, Minnesota. “However, that data simply isn’t available at this point.” But like aducanumab, lecanemab comes with similar serious risks.

Brain swelling, hemorrhage, and deaths

In the CLARITY trial, neurologist Christopher van Dyck at Yale University and his colleagues reported brain swelling in nearly 13 percent of the patients who received lecanemab and hemorrhage in about 17 percent; by contrast, only 2 and 9 percent, respectively, of the placebo group experienced those side effects. Of the patients who took the drug and experienced brain swelling and hemorrhage, roughly 3 percent developed symptoms like headache, dizziness, and confusion. The others exhibited no symptoms, despite the swelling and bleeding. 

That could suggest that taking lecanemab is largely safe, Schrag says, “but we don’t know that.” It’s possible that the drug could change the physiology of the disease at a later point, he says, which could be a problem.

But the deaths of three patients in a follow-up study assessing the drug’s tolerability after the clinical trial have raised questions. It’s not been revealed whether these patients were in the placebo group or received lecanemab during the 18-months period, but they opted to use the drug after the double-blind clinical trial ended.

The first two deaths reported by STAT on October 28 and Science on November 27 revealed that the two patients had cerebral amyloid angiopathy—a condition frequently seen in Alzheimer’s patients, in which amyloid replaces smooth muscle cells in blood vessel walls. If you take away the amyloid, you could break up the structural integrity of the vessel and cause a hemorrhage, says neurobiologist George Perry at the University of Texas at San Antonio. That process could be worsened if individuals are also using anticoagulants, which the deceased patients were.

While Perry argues that the removal of amyloid by lecanemab may have caused the deaths, Libby Holman, senior director of product communications for Eisai, wrote in an email to National Geographic, that the company’s assessment was that the deaths could not be attributed to lecanemab. Instead, it said they were associated with risk factors like heart-related comorbidities and use of blood thinners, which could have caused the hemorrhages.

On December 21, Science reported the death of a third patient, a 79-year-old Florida woman, who had no other obvious health problems and wasn’t using blood thinners prior to being hospitalized for a seizure. Schrag who examined her medical reports at Science’s request noted extensive brain swelling and small areas of bleeding, which he attributed to lecanemab use and her death.

In a Jan 11 email to National Geographic, Christopher Vancheri, associate director of corporate communications and advocacy for Eisai, wrote that the company has been working to learn more about this third case, and so far, the investigator has not been given access to the patient’s hospital records. Vancheri stated that “the reports of deaths in the lecanemab treated patients is similar to the placebo group and does not suggest an increase in deaths overall or from any individual cause.”

But Perry argues that the treatment is too risky. “If it was me deciding for my family—irrespective of cost—I wouldn’t advise giving it,” he says.

The FDA label for lecanemab includes warnings for brain swelling and microhemorrhages and urges caution when prescribing the drug to people on blood thinners. But the advice is buried deep in the label, Schrag says. “My advice to other clinicians would be to be incredibly cautious.”

Future research

In their study, van Dyck and his colleagues noted the need for longer trials to determine lecanemab’s safety and efficacy.

Meanwhile, as part of the National Institutes of Health and Eisai-funded AHEAD study, scientists are now testing if the drug can slow or stop changes in the brain of people who haven’t been diagnosed with Alzheimer’s but are at an increased risk of developing the disease. That risk is determined based on whether study subjects have family members with a dementia diagnosis, elevated levels of brain amyloid, or Alzheimer’s–associated gene variants.

“We now understand that Alzheimer’s disease begins in the brain years before a person begins to exhibit memory problems or other cognitive problems,” Grill says. Despite the lack of symptoms, their brain scans can show elevated amyloid levels. He and his colleagues are testing whether lecanemab can remove the plaques from brains of people in this pre-clinical disease stage to prevent the onset of memory problems. Participants will receive intravenous injections of the drug every two weeks for 96 weeks and then switch to every four weeks until week 216.

Other experimental drugs like Eli Lilly’s donanemab are also in the pipeline. The company is testing whether this anti-amyloid antibody can help treat early symptomatic Alzheimer’s disease patients.

There is also much discussion about other proteins and factors that might be involved in triggering the disease. One protein in the brain, called tau, has been linked to cognitive loss and dementia, and some scientists are developing treatments that target tau. Others are exploring treatments like suppressing oxidative stress; a cellular state in which toxic molecules called reactive oxygen species overwhelm the antioxidants in the cell and damage neurons, contributing to Alzheimer’s.

Van Dyck says it’s possible that future treatment of this progressively debilitating disease may involve using a combination of medications aimed at multiple targets, not just beta amyloid.

For now, some see lecanemab’s approval as a positive development. “For so long we’ve had absolutely nothing in the space that modifies the disease,” says Jim McAleer, CEO of Alzheimer’s Orange County, a nonprofit that provides care and support services to thousands affected by the disease. “To have something that finally does that I think is a tremendous boost to people, even if this particular drug is not the end-all, be-all for a person with Alzheimer’s disease.”