The Second Drug Approved for Alzheimer’s Is Not Much Better Than Aduhelm, Experts Say

When Leqembi (lecanemab) received FDA approval last week as the second-ever drug to reduce cognitive decline in people with Alzheimer’s disease, it was met with optimism from those seeking more treatment options. But many Alzheimer’s researchers were frustrated by the news.

There is currently no cure for Alzheimer’s, and existing treatments can only temporarily improve symptoms. Leqembi is likely to reach more patients than the controversial Aduhelm (aducanumab-avwa), but researchers disagree about how much the latest drug improves upon its predecessor.

The FDA approved Leqembi under an accelerated approval pathway based on early-phase testing results because it fills an “unmet clinical need.” The treatment is an intravenously infused antibody that aims to address the underlying mechanisms of Alzheimer’s, not just treat the symptoms.

“By slowing progression of the disease when taken in the early stages of Alzheimer’s, individuals will have more time to participate in daily life and live independently,” Maria Carrillo, PhD, chief science officer at the Alzheimer’s Association, told Verywell in an email. “This could mean more months of recognizing their spouse, children, and grandchildren.”

Leqembi is made by Eisai and Biogen, the same company behind Aduhelm. The 2021 approval of Aduhelm was welcomed by the Alzheimer’s Association, which partially funded the development of both drugs. But others criticized the FDA for approving the drug despite warnings from an independent panel of experts that the data was insufficient to show it worked in patients.

Leqembi slowed patients’ cognitive decline over a year-and-a-half-long trial, according to phase 3 clinical trial data from the drugmakers.

The effects are modest, however, and may not even be noticeable to a patient or their loved ones, said Matthew Schrag, MD, PhD, assistant professor of neurology at Vanderbilt School of Medicine.

Leqembi appears safer than Aduhelm, though it also poses significant health risks, including the risk of brain bleeding and swelling. It comes at a price of $26,500 per year—slightly cheaper than Aduhelm, which costs $28,200 annually.

“This is a very, very small change in memory function in a single clinical trial. And it’s so small that most patients probably would not be aware of the difference in their trajectory,” Schrag said. “You have to ask whether that difference that incredibly slight improvement is worse than negative consequences of the drug.”

Leqembi Only Offers Modest Benefit for Alzheimer’s Patients

After conducting a phase 3 study of 1,800 patients, drugmakers Biogen and Eisai reported that the drug led to a 27% decrease in the rate of progression for patients treated with Leqembi, compared to those receiving a placebo.

Schrag said this figure is a “really deceptive number.” He said that while he is convinced that there is an effect, it is below the minimal clinically important difference.

This figure, he said, represents a relative difference between those who took the drug and those who got a placebo. When looking only at the absolute difference, the treatment really only improved patients’ condition by about 2.5%.

“It’s like going to your boss and asking for a pay raise and negotiating with them, and they finally say, ‘okay, we’ll give you a pay raise,’ but then they give you $5,” Schrag said. “Is it technically a raise? Yes. Is it measurable? Yes. Is it the effect you’re looking for? No.”

Although the drugmakers said they expect to see a continued slowing of disease progression for at least three years, the clinical trial data indicates the effect of the drug may wane after the first year of treatment.

If the drug doesn’t continue to slow disease progression, it may not be treating the underlying mechanism at all, but rather alleviating some of the symptoms, Madhav Thambisetty, MD, PhD, a neurologist a senior investigator in the Clinical & Translational Neuroscience Section at the National Institute on Aging, National Institutes of Health, told Verywell.

“It brings hope that what we’re seeing is a small clinical benefit, but really longer-term studies are needed to see if this benefit actually holds up,” Thambisetty said. “Showing that these benefits potentially increase over time would be one big step towards proving that these are truly disease-modifying treatments. And we really don’t have that data as of now.”

The drug comes with a fair amount of logistical complications as well. Patients need multiple scans before they can start taking the drug, and then several more to monitor their condition once they start the injections. They must travel to an infusion center or hospital every two weeks.

How Does Leqembi Compare to Aduhelm?

Both Aduhelm and Leqembi are monoclonal antibodies that target beta-amyloid, a protein that can clump together, forming plaques that disrupt the function of brain cells. Leqembi works by targeting a particularly toxic form of beta-amyloid called protofibrils.

Both drugs received FDA approval based on two trials—one showing the drugs had a neutral effect on patients and the other indicating a slight decline in patients’ memory loss.

“It might be interesting to ask the question, does lecanemab meet a critical unmet need? Certainly, Alzheimer’s disease is, but this is a drug that’s being developed by the same company that got accelerated approval for aducanumab and it’s almost a clone of aducanumab,” Schrag said. “I’m not sure what it adds to this problem.”

The two drugs have never gone head-to-head in a clinical trial, so it’s not clear which is more effective. But the mechanisms of action aren’t all that different, Thambisetty said. The main differentiation is in safety—Leqembi is slightly less likely to cause serious side effects than Aduhelm.

In the phase 3 trial, 21.3% of people in the Leqembi group experienced amyloid-related imaging abnormalities (ARIA), compared with 9.3% of those in the placebo group. ARIA is a type of adverse event that can manifest as brain swelling or brain bleeding. Most participants with ARIA were asymptomatic.

By comparison, about 40% of patients who took Aduhelm experienced ARIA.

People on blood thinners or anticoagulants for other medical conditions might be at greater risk of significant bleeding from Leqembi, Thambisetty said. The clinical trial indicated, too, that people with certain genetic risk factors could have a higher chance of developing brain bleeding.

“While the prescribing label does not restrict use of this drug in patients with this particular gene, it appears as if physicians will have to make that decision on a case-by-case basis whether or not to get genetic testing to better inform their clinical decision-making,” Thambisetty said.

Schrag said most groups of patients don’t stand to benefit from taking Leqembi. It was less effective in women, in those with genetic risk factors, and even in patients who underwent the trial in European sites.

Researchers caution that some safety concerns haven’t yet been fully explored. Thambisetty said that the phase 2 trial data indicated that Leqembi, like other anti-amyloid drugs, may accelerate brain shrinkage. The drugmakers said they would assess the risk in longer-term follow-ups.

Additionally, three people who received Leqembi died during the extension portion of the study, Science and STAT reported. Neurologists contacted by those publications said they believe Leqembi caused those deaths.

The trial results published in the New England Journal of Medicine noted six deaths in the Leqembi group and seven in the placebo group, though none of the “deaths were considered by the investigators to be related to lecanemab or occurred with ARIA.”

A Sky-High Price Tag

Leqembi is priced at $26,500 per year. The Centers for Medicare and Medicaid Services (CMS) said it won’t cover the cost of Leqembi until it receives full FDA approval. When Aduhelm was approved, the CMS set the precedent that it must review full clinical data for all future therapies that attack amyloid in the brain before agreeing to cover them. Only those enrolled in continuing clinical trials can be reimbursed for their treatment.

Whether Medicare and Medicaid will cover the treatment matters not only for beneficiaries of those systems, but also for other insured individuals, as private insurers often follow CMS’s lead.

Carrillo said patients deserve to have conversations with their providers about whether they may benefit from Leqembi without the cost barrier.

“Because of these unprecedented and unnecessary CMS and coverage obstacles, people are losing the opportunity to discuss with their health care providers and their families if this treatment is right for them,” Carrillo said. “They’re losing days, weeks, months — memories, skills, and independence. They’re losing time. And it is unacceptable.”

The CMS said it would consider changing the policy when the results from the phase 3 studies are submitted to FDA. Eisai provided that data to the FDA last week, on the same day it received accelerated approval.

Eisai is continuing to test Leqembi as a preventive treatment in pre-symptomatic individuals who have amyloid buildup.

Researchers Warn Against Banking on the Amyloid Hypothesis

Scientists have been developing products to attack beta-amyloid for some 20 years. The amyloid hypothesis claims that beta-amyloid is the major driver of Alzheimer’s disease and that clearing out the plaques could help prevent Alzheimer’s disease and improve cognition.

Earlier Alzheimer’s drugs address disease symptoms, such as delaying memory loss by a few months. But many clinical trials of anti-amyloid treatments over the years have failed to show any improvement in memory. Schrag said that remains true of Leqembi and Aduhelm. These drugs, he said, may not even continue to benefit patients after a year of treatment.

In fact, some of the key data underpinning the amyloid theory may have been fabricated, according to an investigation by Schrag that was reported by Science.

“I think the data is absolutely conclusive that the amyloid hypothesis is wrong,” Schrag said. “[Beta amyloid] should not be discounted as one of many processes that contribute to a very complex disease, but it’s not the central driver. It appears to be, if anything, a very small component of the underlying disease process. And I think it’s time for the field to move past this idea.”

With a pathway to approval established and now reaffirmed, drugmakers are likely to double down on developing anti-amyloid therapies.

But there are other potential mechanisms that could be driving Alzheimer’s disease. Emerging evidence suggests that clumps of proteins in neurons, called tau tangles, could underpin Alzheimer’s. Researchers are also studying how brain inflammation, metabolic abnormalities in the brain, and blood vessel problems factor in.

“We need to have a big rethink of this disease,” Schrag said “We need to have investment in these alternative pathways. We need to develop a much more intellectually diverse field and not punish people for not working on the leading hypothesis.”