Who should-and Can-Get Lecanemab, the New Alzheimer Disease Drug

 From JAMA.

Here is the link.

Here are some excerpts.

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Aducanumab. Crezenumab. Donanemab. Gantenerumab. Lecanemab. Solanezumab.

Those multisyllable drug names may not trip off the tongue of even the most articulate, but they’re all treatments developed to slow down a disease that eventually robs people of the simplest of words.

With varying degrees of success, these monoclonal antibodies, or mAbs for short, bind to and remove a protein from the brain called amyloid-β, a hallmark of Alzheimer disease (AD). Researchers have focused on amyloid-β for 3 decades, ever since 2 UK scientists proposed that deposition of the protein in the brain was “the central event in the aetiology of Alzheimer’s disease”—what has come to be known as the amyloid cascade hypothesis. Although these mAbs clear amyloid-β, for the most part they have failed to slow the progression of cognitive decline in people with AD.

In July, however, lecanemab (marketed as Leqembi) became the first anti–amyloid-β mAb ever to receive traditional approval from the US Food and Drug Administration (FDA). Earlier this year, the FDA had granted lecanemab accelerated approval. That regulatory pathway is reserved for drugs to treat serious conditions for which there is an unmet medical need. Such drugs must affect a surrogate end point—in this case brain amyloid levels—that is “reasonably likely” to benefit patients clinically.

Lecanemab earned traditional approval—winning it broader Medicare coverage—because a confirmatory study required as a condition of accelerated approval verified its clinical benefit, according to the FDA.

Less than 2 weeks after lecanemab’s traditional approval, researchers reported in JAMA that donanemab significantly slowed clinical progression in patients with early Alzheimer disease after nearly 18 months of follow-up, and manufacturer Eli Lilly announced it had filed for traditional approval of the drug and expected a decision from the FDA by year’s end.

Medicare is expected to pay for the bulk of treatment with anti–amyloid-β mAbs in the US. For drugs in that class that receive accelerated approval, the agency will cover costs only for beneficiaries in randomized trials. Traditional approval means Medicare will pay for treatment outside clinical trials as long as clinicians submit information about their patients to a registry designed to collect information about real-world use.

Still, lecanemab treatment is expensive, with an annual wholesale acquisition cost of $26 500 for average-weight patients for the drug alone; for some patients, drug co-pays could amount to roughly $14.50 per day. It’s also cumbersome, requiring every-other-week infusions plus multiple magnetic resonance imaging (MRI) scans, and carries the risk of a life-threatening event. And it’s far from a cure, with some skeptics questioning whether patients and their families will notice any treatment benefit. All these factors could limit its uptake.

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Mayo Clinic neurologist David Knopman, MD, was one of 3 members of the FDA advisory committee that reviewed aducanumab who resigned after the agency approved it. (He had recused himself from that particular meeting because he had served as site principal investigator for a trial of the drug.)

Knopman and his colleagues are preparing to administer lecanemab, but he’s not sure how much patients stand to gain from it.

In a phase 3 trial, “it delayed progression at 18 months by about 5 months,” Knopman noted in an interview. “Is that clinically meaningful? I don’t know. What really counts is where you are at 36 months. Is it still a 5-month delay? That’s trivial.” On the other hand, he said, if the difference between treated patients and untreated patients continues to increase as time passes, “it’s a win.”

Questions about long-term clinical benefit aren’t the only ones that make him anxious, Knopman said. Post hoc subgroup analyses of clinical trial data, reported in a supplement, found that lecanemab didn’t seem to benefit much patients younger than 65 years or women, he explained.

Women are twice as likely as men to develop Alzheimer disease, and the authors of a recent Viewpoint in JAMA Neurology expressed disappointment that phase 3 trials of lecanemab and aducanemab did not expand sex-disaggregated analyses in the main reporting of results. The supplement for the lecanemab trial publication “revealed noteworthy sex differences,” the Viewpoint authors wrote. Although the trial found that, overall, lecanemab delayed progression by 27%, the difference between the treated and placebo groups was 43% in men and only 12% in women. Similar discrepancies were seen in the aducanumab trials, the Viewpoint authors pointed out.