Physicians and patients alike have long awaited a drug that slows or stops the progression of Alzheimer’s disease (AD). A new milestone came last week when the US Food and Drug Administration (FDA) granted full traditional approval for the anti-amyloid lecanemab (Leqembi, Eisai).

Although hailed by some AD experts as a major advance, others are less certain and have concerns about the drug’s efficacy, safety, and cost.

Ronald Petersen, MD, PhD, director of the Mayo Clinic Alzheimer’s Disease Research Center in Minnesota, told Medscape Medical News that there’s no doubt that lecanemab’s approval “is a landmark moment, because it’s the first drug with disease-modifying effects to receive traditional approval.”

Designed to slow AD progression, the monoclonal antibody is only modestly effective in slowing cognitive decline. In addition, it is only indicated for patients with early AD. These individuals will have to undergo biweekly infusions and regular monitoring for side effects, requirements that could pose a logistical challenge for the millions affected by the disease.

The FDA’s approval of the drug was based on a study published in The New England Journal of Medicine in January. The multicenter, double-blind trial included more than 1700 patients with mild cognitive impairment (MCI) who showed evidence of beta-amyloid.

Among patients in the lecanemab group, the rate of cognitive decline at 18 months, as indicated by scores on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), was 27% lower than among the patients who received placebo, and there was a 26% difference on the AD Assessment Scale–Cognitive Subscale (ADAS-Cog).

Managing Expectations

“I think one of the controversial topics out there is, what does that mean, and is it clinically meaningful?” said Petersen. “This is a drug that is going to slow down the rate of progression of the disease, not stop it.”

David Knopman, MD, a neurologist at Mayo Clinic in Rochester, Minnesota, said one of the major challenges for physicians who will be prescribing the drug is managing the expectations of patients and their families.

“Contrary to what some of the advocates of the drug might say, lecanemab therapy in the clinical trial did not bring about improvement at all ― it delayed decline,” Knopman told Medscape Medical News.

Patients who took lecanemab still got worse over time, but compared to those who took a placebo, the progression was slightly less, he added. That delay in cognitive decline might not be a result that patients or their family members can grasp, he added.

“It’s very difficult to see delay and decline, it’s impossible. I think the hype about the conceptual advance has to be separated from the therapeutic reality on the ground,” Knopman said.

Petersen suggested that the optimal way to help patients understand what to expect from the drug may be to discuss it in terms of relative preservation of function.

“I think the best way to phrase it for patients is that you’re trying to keep them at their current functional level, whatever that is, for a longer period of time,” he said.

But Rob Howard, professor of old age psychiatry at University College London in the UK, said the drug’s effect is “so tiny, so tiny as to be unnoticeable in individual patients.”

The trial is being extended for a further 4 years, but for now, its effects beyond the 18-month threshold are unclear. “If the effect magnifies beyond 18 months, that would be great,” Knopman said. “If it attenuates or stays the same, that’s kind of modest.”

Small but Serious Side Effect Risk

In the trial, the incidence of amyloid-related imaging abnormalities (ARIAs), which can be life-threatening, was higher among the patients who took lecanemab. ARIAs were detected in 1 in 5 patients taking lecanemab, but most cases were asymptomatic.

“For a small number of people who take this treatment, the adverse events are really very serious,” said Howard.

“You have to have that honest discussion with the patient. There’s a small but real chance of having severe side effects.”

The risk of ARIAs can be managed with prudent patient selection. For instance, patients receiving anticoagulation and those who carry two copies of the genotype E4 appear to be at greater risk of developing ARIAs. Careful and diligent monitoring with MRIs and frequent clinical evaluations should be conducted to mitigate the risk, said Knopman.

Currently, the infrastructure to provide all the pieces that are necessary to safely administer the drug does not exist, Knopman added. Needed are a neuroradiologist to recognize ARIA and a nuclear medicine specialist to interpret an amyloid PET scan or a neurologist to interpret a cerebrospinal fluid analysis. Also needed are a neuropsychologist to diagnose MCI and an infusion center that can handle large patient volumes, he said.

Howard Fillit, MD, the founding executive director of the Alzheimer’s Drug Discovery Foundation, said he believes the infrastructure can change to accommodate the need, as occurred for cancer treatments. “Up till now, there really hasn’t been an incentive for infusion centers that are focused on Alzheimer’s disease,” he said.

Cost a Major Issue

The drug’s cost is another major issue. The price tag is set to go beyond the $26,500 proposed annual acquisition cost of the drug. Ancillary spending ― including costs for imaging ― could add up to more than $7000 per patient.

For patients and their families, it’s a difficult trade-off. For people with mild MCI, the rate of decline is often slow, even if they’re amyloid positive, said Knopman. “There’s no ability to say, it will happen next year, or 3 years from now, or 6 years from now,” he said.

Many people will come forward for treatment who might have a stroke or get run over by a bus in 5 to 10 years’ time before they develop dementia, said Howard. “When you weigh up the really tiny benefits with those costs, and very real risks, I wouldn’t want this for my patients, and if I had a family member with Alzheimer’s disease, I wouldn’t want them to have it.”

But for patients and families struggling with AD, little else is available to address the underlying disease process. “I think this is going to be important for people,” said Petersen. “And yes, there are some side effects. Yes, it’s going to be expensive, but I think this is just the first step, and only the first step, in treating these degenerative diseases.”

“I’m very excited because I’ve seen our field go from a time when there was very little knowledge about the disease to a time now where we have tremendous knowledge about the disease,” said Fillit. “It provides a lot of hope for the patients and their loved ones.”

Not Clinically Useful?

While the drug is no panacea, there is hope that lecanemab marks a new era in AD research ― signaling better therapies to come.

Lecanemab only targets amyloid, but another research focus is tau. Several drugs aimed at this protein are in development.

“Treating one element of the disease may be helpful but probably insufficient in the long run,” said Petersen. “Ultimately, we’re going to need a combination therapy that will attack several aspects of Alzheimer’s disease and other conditions that exist with Alzheimer’s disease.”

Howard said there is a danger in skewing research toward amyloid because that will mean that the bulk of available resources would flow into a drug class that, “while scientifically interesting, is not really clinically useful.”

Clinical trial results for donanemab, an anti-amyloid manufactured by Eli Lilly, will be presented next week at the Alzheimer’s Association International Conference in Amsterdam.

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