FDA Review of Alzheimer’s Drug Clouded by Questions of Cost and Benefit

The Food and Drug Administration appears poised to grant full approval to a new Alzheimer’s drug that has modestly slowed cognitive decline in clinical trials – despite persistent questions about its safety and what its hefty price tag could mean for Medicare. 

An FDA advisory panel will meet Friday to review the evidence for Leqembi (lecanemab), an antibody intended to treat patients with early Alzheimer’s by busting up amyloid plaques, the sticky substance thought to cause the disease. The agency granted accelerated approval to the drug in January, but Medicare has so far limited coverage to people enrolled in clinical trials of the $26,500-a-year drug, given concerns about its efficacy and side effects, which can include brain swelling. 

FDA released a largely positive staff analysis of the drug ahead of Friday’s meeting suggesting that the agency is ready to grant full approval by July 6. That would make the drugs more widely available to Medicare patients – as long as they and their doctors participate in registries to collect data on Leqembi’s real-world performance. Such restrictions are highly unusual after full approval. They reflect the controversial nature of an emerging class of Alzheimer’s drugs whose promise is tempered by worry that a large-scale rollout would bust Medicare’s budget without meaningfully improving patient’s lives.

“With these drugs we’re seeing for the first time Medicare's coverage decision straying from FDA's,” said Juliette Cubanski, a deputy director of the program on Medicare policy at KFF, a health policy research group. She suspects that’s because “the evidence for exactly how effective these drugs are is not perhaps where it is with other medications.”

Advocates for the roughly 6.7 million people with Alzheimer’s in the U.S. argue the drugs should be covered without strings attached given the lack of other treatments for the disease. 

“These treatments, while not a cure, are a huge step forward for people living with early-stage Alzheimer’s,” said Rebecca Edelmayer, senior director of scientific engagement at the Alzheimer’s Association. People who’d qualify for the new drugs “don’t have time to wait for a registry or search for a doctor who participates in one,” she said. 

Leqembi’s performance in clinical trials represents a significant improvement over the first amyloid-targeting antibody treatment, a drug called Aduhelm that was controversially approved in 2021 without clear evidence that it helped patients. Many observers are keeping a close eye on Leqembi’s approval process, especially since similar drugs are coming down the regulatory pike.

Meanwhile, the Centers for Medicare and Medicaid Services is already drawing fire for the requirements it plans to impose on Leqembi upon FDA approval, a rule that will apply to future amyloid-targeting antibodies. Representatives Anna Eshoo (D-Calif.) and Nanette Barragán (D-Calif.) blasted CMS for releasing few details on how the patient registries would actually work. And former FDA commissioner Scott Gottlieb recently argued the restrictions should be dropped, tweeting that the scientific rationale was flawed.

Yet other lawmakers are balking at the potential cost. Sen. Bernie Sanders (D-Vermont) called on the Health and Human Services Department to do everything in its power to ensure that the government gets a better price. 

“Alzheimer’s is a horrible disease. We must do everything possible to find a cure for the millions of people who suffer from it,” he wrote to HHS Secretary Xavier Becerra. “But we cannot allow pharmaceutical companies to bankrupt Medicare and our federal government in the process.”

Drugs of uncertain promise

The shadow of Aduhelm’s controversial history looms large over Leqembi’s imminent ascent to full FDA approval.

In 2021, the FDA fast-tracked Aduhelm, made by pharmaceutical company Biogen, despite overwhelming opposition from an FDA advisory panel. The FDA based their decision on evidence that the drug cleared amyloid plaque from the brain, but the independent advisory committee concluded there wasn’t enough evidence the drugs actually slowed the progression of Alzheimer’s. Weeks after approval, the FDA narrowed who can get the drug, which initially cost $56,000 per year. 

“It was a total failure of regulatory science,” said Jason Karlawish, co-director of the University of Pennsylvania’s Penn Memory Center. Aduhelm is now widely considered a flop, in part because CMS balked at the FDA’s decision making and only agreed to cover the medication for patients enrolled in clinical trials. It was an unusual public split between the nation’s top drug regulator and the agency that runs Medicare.

Leqembi’s efficacy is backed by more clinical evidence. In addition to data showing that it also clears amyloid by about 70 percent, the drug slowed cognitive decline (as measured by a suite of cognitive tests) by 27 percent in a large clinical trial over 18 months.

While that’s significant, some experts question whether those effects are large enough to make a noticeable difference for patients. 

“The looming question becomes, is this [improvement] something doctors will be able to see in an exam room, or something patients or loved ones will see,” said Reshma Ramachandran, a physician and assistant professor at Yale Medical School. “It’s unclear what it would actually mean in the real world.”

Side effects raise concern

That unclear benefit runs up against serious risks of brain bleeds and swelling. Two patients receiving Leqembi died during or after clinical trials from complications many experts link to the drug. Approximately 20 percent of participants in one trial experienced amyloid-related imaging abnormalities — a form of brain swelling or bleeding. Seventeen percent experienced brain bleeds, though none were life-threatening. The FDA currently requires patients taking the drug get three brain scans during the first 14 weeks of treatment to check for swelling or bleeding.

“These are significant safety concerns, and there’s not really clear evidence of the types of patients most at risk,” said Ramachandran. “No clinician wants to be in a position of prescribing something that could potentially harm or kill our patients.” 

Ramachandran hopes Friday’s advisory meeting will focus on such safety issues, and flesh out uncertainty around the benefits and risks of these drugs. But she and other experts worry that the burden of weighing that uncertainty is shifting from FDA to insurers, providers and patients. 

“People who suffer from Alzheimer's may say three [extra] months is worth a fortune to me,” said Arthur Caplan, a bioethicist at New York University. “Whereas a lot of independent observers, economists and others who are asking ‘is this worth it?’ are going to say, ‘well no, not really,’” he said, given the enormous expense of the drugs and the marginal benefit seen in trials. 

Over time, data from the CMS-required patient registry — details of which haven’t yet been announced — could further clarify the real-world impact of these drugs. But simply gathering those data will be expensive. “We’re starting to confront the fact that [these drugs] particularly with price increases as they are, could break the budget,” said Caplan.

Expensive drugs

Neither the FDA nor CMS is supposed to take financial cost into account when deciding how to regulate and cover drugs. But the eye-popping price tags of Leqembi and Aduhelm, coupled with the enormous demand for Alzheimer’s treatment, has many observers worried.

“The reality is that these drugs are costly, and high demand will translate to a high price tag for Medicare, which will in turn translate to higher premiums for Medicare beneficiaries,” said Cubanski.

Exactly how many of the 6.7 million Americans suffering from Alzheimer’s would qualify for Lequembi upon its approval is hard to predict, she said. Potential patients would face substantial out-of-pocket costs, and be able to travel to a clinic for infusions and brain scans.

 Still, if just 5 percent of Alzheimer’s patients — roughly 300,000 people — take Lequembi, and Medicare pays full price, it’d add $8.9 billion a year in spending. Medicare Part B spent about $40 billion on all drugs in 2021. Spending on Lequembi would be equivalent to spending on the program's top three drugs.

On the lower end, Eisai predicts only about 100,000 Medicare beneficiaries would take the drug in the first year. “But we're still talking roughly $3 billion a year on one drug,” said Cubanski. 

That cost would push up premiums. When Aduhelm was approved in 2021, “just the anticipation of increased spending was enough to trigger a pretty significant premium increase,” said Cubanski.

In the long term, FDA is likely to approve more Alzheimer’s drugs. Eli Lilly’s amyloid-targeting antibody treatment, which slowed cognitive decline by 35 percent according to a company press release, could be approved later this year. More competition could push down prices, said Cubanski, or they might all come to market at roughly the same price. Either way, this new era of Alzheimer’s treatments will likely cost taxpayers billions of dollars.

“From the perspective of patients with Alzheimer's and their loved ones, that may not be a bad thing. It is the price that we pay for innovative new drugs,” said Cubanski. “But we can't deny that we are paying a price.”