After decades of clinical trial failures, two new Alzheimer’s drug approvals by the Food and Drug Administration (FDA) have thrilled many healthcare providers and advocacy groups. Others warn that the two new drugs, Aduhelm (aducanumab) and Leqembi (lecanemab-irmb), may not be the medical miracles they seem to be.
Doctors have been using the same drugs and lifestyle adjustments to treat Alzheimer’s for years with modest benefits at best. None of these drugs can stop, slow, or reverse the seemingly inevitable progression of Alzheimer’s disease. They may temporarily reduce the condition’s symptoms. To learn about the efficacy of older Alzheimer’s drugs and their side effects, read MedShadow’s Need to Know—Alzheimer’s Medications.
The reason that many scientists have touted the two new drugs, Aduhelm and Leqembi, as breakthroughs is because data from their clinical trials suggested that they reduce the number of beta-amyloid plaques in the brain. These plaques are not rare, 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. [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 the early work, many scientists still believe these plaques are an important, driving feature of the disease.]
The thinking goes that if the drugs can actually remove plaques, they might be able to slow or reverse the disease. No study has ever proven that plaque causes or increases Alzheimer’s disease, yet science has focused almost exclusively on plaque for years.
Adulhelm and Leqembi are the first new drugs approved for Alzheimer’s in nearly 20 years.
Alzheimer’s Drugs Receive Accelerated Approval
Both drugs 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.
Does Aduhelm Work?
The trial data for Aduhelm was “a little questionable” says Dung Trinh, MD, founder of the Healthy Brain Clinic. 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, Aduhelm’s manufacturer, 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. She wasn’t the only one with suspicions about the approval.
Later, Medicare refused to pay for the drug. 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 when those recommendations were to approve a drug than when they suggested rejecting it. Congress also investigated, and found serious irregularities in the Aduhelm’s approval specifically, 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 wrote in 2021, “Eventually, Aduhelm may be proven effective at slowing the progression of Alzheimer’s,” but right now, we just don’t know. Robotti said the approval hinged on two studies, one of which suggested the drug slightly slowed memory decline and another which didn’t.
“There’ve been so many controversies that it just flopped and died.” Despite the fact that it’s still on the market, Trinh says, it’s not being used very much. “Really, Aduhelm died last year, because it was controversial. It was very expensive. And it’s very controversial. The data was iffy.”
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 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.
What Are the Side Effects of Aduhelm and Leqembi?
Both 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 Leqembi 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.
One person in the Aduhelm trial and three in the Leqembi trial died due to the 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.
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 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 real-world data on its efficacy and side effects for their patients 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
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.
