FDA Approves Second Anti-Amyloid for Alzheimer’s Disease

The US Food and Drug Administration (FDA) has approved the anti-amyloid beta protofibril antibody lecanemab (Leqembi, Eisai) for the treatment of Alzheimer’s disease (AD).

Like its controversial cousin aducanumab (Aduhelm, Biogen/Eisai), lecanemab was approved under the FDA’s accelerated approval pathway, which can be used to fast-track a drug that provides a meaningful therapeutic benefit over existing treatments for a serious or life-threatening illness. .

Unlike aducanumab, however, there was no formal FDA advisory committee meeting on lecanemab prior to approval.

“Alzheimer’s disease is immeasurably incapacitating the lives of those who suffer from it and has devastating effects on their loved ones,” Billy Dunn, MD, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said in a press release.

“This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease,” Dunn added.

Modest Benefit, Adverse Events

The FDA noted,[T]He labeled states that treatment with Leqembi should be initiated in patients with mild cognitive impairment or mild dementia stage of the disease, the population in which treatment was studied in clinical trials.

The agency approved the treatment on the basis of findings from the CLARITY AD trial, which showed modest cognitive benefit for patients with early AD — but at a cost of increased risk for amyloid-related edema and effusions.

As reported by Medscape Medical News, the trial enrolled 1795 adults with mild cognitive impairment or early AD in whom amyloid pathology in the brain had been confirmed. Treatment consisted of lecanemab 10 mg/kg biweekly or matching placebo.

After 18 months of treatment, lecanemab slowed cognitive decline by 27% compared with placebo, as measured by the Clinical Dementia Rating–Sum of Boxes (CDR-SB). This was an absolute difference of 0.45 points (change from baseline, 1.21 for lecanemap vs 1.66 with placebo; P <.001).

While the results are “welcome news,” a 0.45-point difference on the CDR-SB might not be clinically meaningful, authors of a recent editorial in The Lancet cautioned.

Amyloid-related imaging abnormalities that manifest as edema or microhemorrhages also occurred in 1 in 5 patients taking lecanemab.

In addition, a newly published case report in The New England Journal of Medicine describes a patient with AD who was taking lecanemab and who died after experiencing numerous intracerebral hemorrhages during treatment with tissue plasminogen activator (tPA) for acute ischemic stroke.

“The findings raise the possibility of cerebral hemorrhages and necrotizing vasculopathy associated with tPA infusion in a patient with cerebrovascular amyloid who had received lecanemab,” the authors write.

Alzheimer’s Association Reaction

Still, in anticipation of accelerated approval of lecanemab and the anti-amyloid drug donanemab (Eli Lilly), which the FDA has also fast-tracked, the Alzheimer’s Association filed a formal request last month with the Centers for Medicare & Medicaid Services (CMS) asking that it provide full and unrestricted coverage for FDA-approved AD treatments.

As reported by Medscape Medical Newsin a letter addressed to CMS administrator Chiquita Brooks-LaSure, the association asked the agency to remove the requirements for “coverage with evidence development” in its national coverage determination for FDA-approved anti-amyloid monoclonal antibodies.

“Each day matters when it comes to slowing the progression of this disease,” Joanne Pike, DrPH, president and CEO for the Alzheimer’s Association, noted in a news release at the time.

“The current CMS policy to severely limit access to these treatments eliminates people’s options, is resulting in continued irreversible disease progression, and contributes to greater health inequities. That’s not acceptable,” Pike added.

After news of today’s approval was released, Pike noted in a new release, “The Alzheimer’s Association welcomes and celebrates this action by the FDA. We now have a second approved treatment that changes the course of Alzheimer’s disease in a meaningful way for people in the early stages of the disease.”

Maria C. Carrillo, PhD, chief science officer at the Alzheimer’s Association, called today’s approval “a milestone achievement.”

“The progress we’ve seen in not only this class of treatments but also in the diversification of treatment types and targets over the past few years is exciting and provides real hope to those affected by this devastating disease,” Carrillo said.

Critical Issues

Commenting for medical News, Alvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School, Boston, Massachusetts, and chief medical officer at Linus Health, said FDA approval of lecanemab and its adoption in the clinic represent a “very exciting development and prospect; but arguably some critical issues need to be considered.

He noted that the healthcare system “is not currently prepared to cope with the challenges and demands of lecanemab,” as well as future pharmacologic agents.

“First, we need better workflows to identify suitable patients who can most benefit from this treatment,” said Pascual-Leone. He added that beyond identification of cognitive difficulties, amyloid status will need to be determined.

“Presently, this requires expensive and invasive tests,” such as positron-emission tomography scans or lumbar punctures for cerebrospinal fluid analysis. However, these are not fully covered by insurance companies and would be challenging to fully scale, he noted.

“In addition to screening, health systems will need to resolve the logistics challenges around the administration of lecanemab with twice-monthly infusions and the need for careful longitudinal evaluations for potential side effects,” said Pascual-Leone.

“While lecanemab may represent the first disease-modifying therapy widely available for early AD, the likely more promising approach is the addition of other therapies to lecanemab as part of a multi-intervention strategy combining pharmacologic and nonpharmacologic interventions,” he added.

Pascual-Leone has served as a paid member on scientific advisory boards for Neuroelectrics, Magstim Inc, TetraNeuron, Skin2Neuron, MedRhythms, and Radiant Hearts and is a co-founder of TI Solutions and Linus Health.

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