Over the last couple of years, after decades of clinical trial failures, the Food and Drug Administration (FDA) has approved three new Alzheimer’s drugs: Aduhelm (aducanumab) approved in June 2021 and currently being sunsetted (any patient currently taking the drug can continue infusions until November 2024, at which point the drug will become unavailable); Leqembi (lecanemab-irmb) approved in January 2023, and in July, 2024, Kisunla (donanemab-azbt). In fact, Adulhelm, Leqembi, and Kisunla are the first new drugs approved for Alzheimer’s in nearly 20 years.
While advocates of these drugs, such as the Alzheimer’s Association, have celebrated their approval, a look under the hood reveals that not only might these drugs be less than revolutionary — they could actually be dangerous.
Before these three drugs hit the market, doctors had been using the same drugs (such as cholinesterase inhibitors or memantine) and lifestyle adjustments to treat Alzheimer’s, with modest benefits at best. None of the drugs could stop, slow, or reverse the seemingly inevitable progression of Alzheimer’s disease, only temporarily reduce the condition’s symptoms by regulating the concentration of certain neurotransmitters that undamaged neurons use to communicate. It’s unclear if this reduction in symptoms lasts more than six months or improves quality of life in meaningful ways, such as extending the time during which a person can live independently.
The reason many scientists are touting these new drugs as breakthroughs is because data from their clinical trials suggest that they reduce the number of beta-amyloid plaques in the brain. These plaques are common, but they accumulate in high amounts in the brains of people with Alzheimer’s disease, especially in the hippocampus, an area of the brain responsible for encoding short-term memories.
The thinking goes that if the drugs can actually remove plaques, they might be able to slow or reverse the disease. Science has focused almost exclusively on plaque for years. [Note: In 2022, investigators found that some early data on beta amyloid plaques in Alzheimer’s disease had been fraudulent, but because many studies have been completed since that early work, many scientists still believe these plaques are an important, driving feature of the disease.]
Alzheimer’s Drugs Receive Accelerated Approval
Both Adulhelm and Leqembi received accelerated approval from the FDA, though Leqembi was later granted full approval in July 2023. Accelerated approval allows the FDA to approve a drug that meets an unmet need, based on a surrogate endpoint, which is a marker or a sign that the drug improved the disease, rather than proving an actual clinical benefit.
The accelerated approvals for Aduhelm and Leqembi were based on the fact that the clinical trials showed that patients who took the two drugs—which work in similar ways—had fewer beta-amyloid plaques in their brain after 18 months than patients who didn’t. Because the drug reduces the plaques, it’s expected that it will also improve patients’ symptoms. However, both of the trials didn’t initially prove that patients’ symptoms improved.
Eli Lilly also applied for accelerated approval for Kisunla, but that application was rejected in January 2023 when the FDA noted concern over the fact that only a limited number of patients had been on the drug for at least a year.
Did Aduhelm Work?
According to Biogen, the U.S-based pharmaceutical company behind Aduhlem, the drug was discontinued due to a “reprioritization [of] resources,” and had nothing to do with its safety or efficacy.
But the question remains: Did it ever really work?
The trial data for Aduhelm was “a little questionable” says Dung Trinh, M.D., founder of the Healthy Brain Clinic, and who has given his patients Leqembi as a part of clinical trials. One trial suggested it slowed patients’ memory decline, but another showed no difference compared with a placebo. Prior to the drug’s approval, an independent FDA advisory committee, a group made up of experts and consumer representatives who review clinical trial data and vote on whether to recommend that the FDA approves the medicine, unanimously voted against Aduhelm’s approval.
The FDA is not bound to the advisory committee’s opinion, and it went ahead and approved Aduhelm anyway. The approval gave Biogen another nine years to continue collecting data to prove that the drug not only reduces amyloid plaques, but actually slows memory decline in Alzheimer’s patients.
MedShadow’s founder, Suzanne Robotti, wrote about how unusual this move was back in 2021, explaining, “In my experience sitting on an FDA advisory committee for the past four years, seldom has an entire panel voted against the approval of a drug. That is an unusual occurrence and should send a very strong message to the FDA and to the medical community that this drug is not ready to be used on patients.”
She wasn’t the only one with suspicions about the approval.
Later, Medicare refused to pay for the drug, suggesting more evidence of the benefits was needed along with details about the risks. The controversy led scientists to conduct a study on how the FDA treats advice from its advisory boards, which found that the FDA was far more likely to follow advisory board recommendations that approved a drug than when they suggested rejecting it.
After the drug was approved, advocates called for an investigation. A congressional committee published a report of its investigation at the end of 2022, saying that it found serious irregularities in the Aduhelm’s approval, including excessive collaboration between the drug’s manufacturer, Biogen, and the FDA. For example, the FDA helped Biogen develop a presentation about the drug to be given to the independent advisory committee. The FDA met with Biogen 55 times or more, and many of the meetings were not documented.
As Robotti noted in 2021, the approval hinged on two studies, one of which suggested the drug slightly slowed memory decline, and another that didn’t.
Does Leqembi Work?
Google anything about Leqembi, and you’ll almost certainly find the statistic that it slows memory decline by 27%. This finding in the clinical trial was statistically significant. Over the course of 18 months, those who were given Leqembi seemed to retain more of their cognitive abilities than their counterparts who were given a placebo.
“This medication obviously is not a slam dunk,” says Dr. Trinh. “But heck, I’ll take 27% over nothing.” Many families of people with Alzheimer’s disease may feel similarly. They’ll take whatever improvement they can get.
However, other experts point out that this measure—27% slower decline—can make the benefit sound more powerful than it really is. It’s what’s called a relative value as opposed to an absolute value. In the study, researchers used a cognitive test on which patients can score 0-18. The lower the score, the better the patient’s current cognitive function. At the end of the trial, patients who took a placebo scored an average of 4.86 points, while patients who received Leqembi scored 4.41.
Representatives of PharmedOut, an organization that researches the influence of pharmaceutical marketing on the practice of medicine at Georgetown University, pointed out in a letter to the FDA that the difference between a score of 4.86 and 4.41 was not considered “clinically significant.”
“A minimal clinically meaningful difference is considered to be between 1.0 and 2.5 points, and the difference in this trial was 0.45. Moreover, there was no actual improvement, but only a slight difference in the extent of worsening, one that neither patients nor family would notice,” they write. Other experts have echoed the concerns.
Does Kisunla Work?
In the clinical trial that Eli Lilly submitted to the FDA (which included 1736 participants with early symptomatic Alzheimer’s disease), individuals who were prescribed Kisunla performed better on cognitive assessments than their counterparts who had received placebos. Over the 18-month study period, Kisunla seemed to slow cognitive decline by about 4.4 to 7.5 months. Additionally, an estimated 47% of participants receiving Kisunla had no change in disease progression at one year compared with 29% of participants receiving placebo.
As with any other Alzheimer’s treatment, the drug did not stop or reverse cognitive decline.
The drug was most effective for people whose brains had a low or moderate amount of tau proteins – a tangled protein that builds up inside of neurons as Alzheimer’s disease progresses – at the start of the study. However, the FDA approved Kisunla for use in people in the earlier stages of Alzheimer’s disease, regardless of their tau protein level, likely because there aren’t sufficient resources to offer patients a scan for tau to predict how well they might respond before prescribing Kisunla.
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What Are the Side Effects of Aduhelm, Kisunla and Leqembi?
All three of these drugs work through a similar mechanism, clearing amyloid plaques out of the brain. Doing so has caused some common and predictable side effects over the 18-month-long trials, including brain bleeds and swelling.
“It’s kind of like pulling a scab off a wound quickly,” says Trinh. “When you pull a scab off of a wound, what are you going to see below that? Blood. Inflammation and bleeding. These are the side effects of this medication.”
Both the bleeds and the swelling were more frequent with Aduhelm than with Leqembi. In the Aduhelm trials, 35.2% of patients had brain swelling and 19.1% had bleeding, while in the Lequembi trials 12.6% of patients had brain swelling and 17.3% had bleeding. About a quarter of patients with bleeding or swelling in each trial said they experienced headaches, nausea, dizziness or other symptoms from the two symptoms. In its Phase 3 trial, 36.8% of people who received Kisunla experienced brain swelling or bleeding.
One person in the Aduhelm trial, three in the Leqembi trial, and three in the Kisunla trial died due to bleeding and swelling. The PharmedOut team points out that these deaths may be underappreciated.
“This suggests a rate of one to two deaths per 1,000 patients – and that’s in the healthier-than-normal clinical trial population. The death rate is likely to be far higher in a general population,” writes the PharmedOut team.
Additionally, PharmedOut cites a meta-analysis of several trials on drugs that aim to remove beta-amyloid from the brain, which found that many of those drugs may actually shrink the brain over time, especially in patients who experienced bleeding or swelling. It’s not clear whether this finding applies specifically to the newly approved drugs.
Even more unsettling, according to an article published by the New York Times on October 23, 2024, Eisai, the Japanese pharmaceutical company that developed Leqembi along with Biogen, recruited participants for early clinical trials who had genetic profiles making them both susceptible to Alzheimer’s and at higher risk for brain bleeds — but did not inform participants of this genetic information. By withholding that information, Eisai put participants in harm’s way, and did not give them adequate information about their particular risks.
Eli Lilly, the maker of Kisunla, employed a similar tactic in their clinical trial, choosing to hide genetic profiles from 289 volunteers that signaled their vulnerability to brain injuries. According to the Times, “dozens [of participants] experienced what Lilly classified as ‘severe’ brain bleeding.”
A new 2024 analysis (that, at the time of publishing, has not been peer-reviewed) takes the side effect conversation one step further, suggesting an association between people taking Aduhelm and Leqembi and a higher mortality rate than those in the same age range who did not receive the medications.
Additionally, it’s important to note that anticoagulants (blood thinners), which are prescribed to millions of adults in the U.S., increased the risk of bleeding in patients who took the Alzheimer’s drugs.
Ongoing Research on Alzheimer’s Drugs
Leqembi and Kisunla may be approved by the FDA, but the Centers for Medicare and Medicaid Services (CMS) says it’ll only pay for the drug—or any other beta-amyloid-lowering drug approved in the future—for patients whose doctors agree to share their patients’ data on its efficacy and side effects through an online portal.
CMS says the registry will help answer the following questions:
- Does the drug meaningfully improve health outcomes (i.e., slow the decline of cognition and function) for patients in broad community practice?
- Do benefits and harms, such as brain hemorrhage and swelling, associated with the use of the drug, depend on the disease’s characteristics, treating clinicians, and setting?
- How do the benefits and harms change over time?
Habits that Help Prevent Alzheimer’s
Dr. Trinh likens the Leqembi to the original cell phone. He believes that it’s a first step to developing more effective drugs for Alzheimer’s disease. The first cell phone, he says, “didn’t work well. And it was bulky.” “These new meds are like that. Because if you think about it, every cell phone that came after the first cell phone got better.”
While we’re waiting for those better treatments, there are some lifestyle changes you can make today to help prevent the diseases. Some may even help slow memory decline if you or a loved one has already been diagnosed. To learn more, read MedShadow’s Avoiding Alzheimer’s: Lifestyle Modifications You Can Make Today.
