FDA Grants Traditional Approval to Lecanemab as Therapy for Early-Stage Alzheimer Disease

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Key Takeaways

Lecanemab received traditional FDA approval, supported by phase 3 Clarity AD trial results, showing a 27% reduction in Alzheimer's disease progression.
The drug targets amyloid-ß protofibrils and is the second early Alzheimer's treatment approved in 20 years, following aducanumab.
CMS plans to cover lecanemab, requiring Medicare Part B enrollment, diagnosis of early Alzheimer's, and participation in a registry.
Safety concerns include amyloid-related imaging abnormalities, with higher rates of ARIA-E and ARIA-H in treated patients compared to placebo.
Despite approval, a petition challenges lecanemab's efficacy, safety, and cost, highlighting the need for further research and alternative approaches.

The decision was based on findings from the phase 3 confirmatory Clarity AD study, in which treatment with the agent resulted in significant reductions in amyloid-ß in the brain.

According to an announcement, the FDA has granted traditional approval to Eisai’s Alzheimer disease (AD) medication lecanemab (Leqembi), a major step in enabling broader access and coverage of the therapy to the aging population. It originally received FDA approval under the accelerated approval pathway in January.¹

The decision was expected after a recent meeting between the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee in which the panel voted unanimously in favor of the agent. The committee was asked to vote on whether the results of the phase 3 Clarity AD trial (NCT03887455), the confirmatory study, verified the clinical benefit of lecanemab for the treatment of AD.² Lecanemab is only the second early AD treatment that has received FDA approval in the past 20 years following the contentious approval of aducanumab (Aduhelm; Eisai/Biogen) in 2021, which remains under conditional approval.

"Today’s action is the first verification that a drug targeting the underlying disease process of Alzheimer’s disease has shown clinical benefit in this devastating disease," Teresa Buracchio, acting director of the Office of Neuroscience, Center for Drug Evaluation and Research, FDA, said in a statement.¹ "This confirmatory study verified that it is a safe and effective treatment for patients with Alzheimer’s disease."

Lecanemab comes with a boxed warning and is contraindicated for patients with serious hypersensitivity to lecanemab-irmb or to any of its inactive ingredients. The prescribing information states that testing for apolipoprotein e4 status should be performed before starting treatment with lecanemab to inform the risk of developing amyloid-related imaging abnormalities (ARIA).

"This is really exciting. I have been doing research in Alzheimer disease for over 40 years, and I remember back in 1980, when we didn’t really know anything about AD, and I remember in 1984 when the ß-amyloid discovery was made. It’s taken us about 40 years to get here, but I feel we’re right on time" Howard Fillit, MD, the cofounder and chief science officer of the Alzheimer's Drug Discovery Foundation, told NeurologyLive^®.

"We had to learn how to do better clinical trials to answer the question about if amyloid slows down the disease. I think we have proof of concept now, and the key breakthrough was the PET amyloid scan. Imagine trying to develop a statin if you didn’t have blood cholesterol—having these biomarkers is critical to drug development, and I'm proud to say the ADDF was a funder of this scan back in the early 2000s," Fillit added.

He noted that the therapy's slowing in rate of decline, while promising, is not enough. "We need to get to 100%, and even prevention," he said, pointing to the slew of ongoing clinical trials in AD that are exploring nonamylid and nontau approaches—targets such as neuroinflammation and metabolic disturbances. "We're just starting to see these new pathways being tested," Fillit said.

Formerly known as BAN2401, lecanemab is a humanized monoclonal antibody that eliminates toxic amyloid-ß protofibrils. Published in the New England Journal of Medicine, Clarity AD included 1795 patients with evidence of amyloid on PET or cerebrospinal fluid who were followed for an 18-month treatment period. At the conclusion of the analysis, lecanemab met its primary end point of change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, with treated patients demonstrating a statistically significant 27% reduction.³

Do you agree with the FDA's decision to grant traditional approval?

Days prior to the AdComm meeting, the Centers for Medicare & Medicaid Services (CMS) announced plans to provide coverage to therapies like lecanemab that are designed to slow the progression of AD that have received traditional approval. The announcement came months after the agency doubled down on its April 2022 decision to restrict the coverage of FDA-approved antiamyloid therapies to treat the neurodegenerative disease.⁴

"It is exciting to see the first full FDA approval of a disease-modifying drug that targets the underpinning of Alzheimer disease pathology," Anton P. Porsteinsson, MD, the William B. and Sheila Konar Professor of Psychiatry, Neurology, Neuroscience, and Medicine, and the director of the Alzheimer's Disease Care, Research and Education Program at the University of Rochester School of Medicine and Dentistry, told NeurologyLive. "Now, we have to focus on understanding insurance coverage and what the CMS registry requirements entail as well as build up infrastructure that can deliver these medications safely and competently to appropriate and interested patients."

Under CMS’ current coverage policy, if the FDA grants traditional approval to other drugs in this class, they would be eligible for broader coverage. To get Medicare coverage, individuals will need to be enrolled in Medicare Part B, have a diagnosis of mild cognitive impairment or early dementia caused by AD, and have a qualified physician participating in a registry with an appropriate clinical team and follow-up care. According to CMS, clinicians participating in the registry need to complete a short data submission.

The CMS-facilitated registry is open for clinicians to access here. Additional background information is available for providers here, and for patients here, and on medicare.gov.

MEDcast: Recent Advances and Emerging Therapies in the Management of Alzheimer's Disease

In this episode of MEDcast, Marc Agronin, MD; Stephen Scheinthal, DO, DFACN, DFAPA, CS; and Marwan Sabbagh, MD, delve into the recent advances in the treatment of Alzheimer’s dementia, including treatments that are on the cusp of FDA approval and others that are coming down the pipeline.

In Clarity AD, lecanemab also met secondary end points of change in amyloid PET centiloids (difference in least squares [LS], –50.12; P <.0001) and Alzheimer’s Disease Assessment Scale-Cognitive 14 (LS difference, –1.442; P = .00005) relative to placebo over the 18-month period. Additionally, it outperformed placebo on the Alzheimer's Disease Composite Scale (ADCOMS; LS difference, –0.00; P = .00002), and Alzheimer’s Disease Cooperative Study-Activities of Daily Living (LS difference, 2.016; P <.00001). Specifically, it slowed disease progression on ADCOMS by 24% and disease progression on ADCS MCI-ADL by 37% at the same time point.³

Lecanemab’s safety profile shown in Clarity AD was similar to that previously observed, with amyloid-related imaging abnormalities-edema (ARIA-E) occurring in 12.5% of treated patients. Symptomatic ARIA-E occurred at a rate of 2.8% in the lecanemab group and 0.0% in the placebo group. Furthermore, ARIA cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis (ARIA-H) occurred at a rate of 17.3% in lecanemab-treated individuals and 9.0% for those on placebo. Symptomatic ARIA-H was found in 1.4% of the lecanemab group and 0.2% of the placebo group.

Following the positive FDA AdComm meeting, a petition against the approval of lecanemab was started by Alberto Espay, MD, PhD, a movement disorder expert, with nearly 500 signatures to date. The petition doc claimed that lecanemab does not improve patient status, may be harmful, and is too expensive, considering its price is $26,000 a year. It references donepezil, an FDA-approved therapy for mild, moderate, and severe AD, which has shown an absolute difference of 2.3 points vs placebo on ADAS-Cog over a 24-week period vs lecanemab, which only showed a 1.4-point difference.⁵

“This treatment, while not a cure, can give people in the early stages of Alzheimer’s more time to maintain their independence and do the things they love,” Joanne Pike, DrPH, the president and CEO of the Alzheimer’s Association, said in a statement.⁶ “This gives people more months of recognizing their spouse, children, and grandchildren. This also means more time for a person to drive safely, accurately, and promptly take care of family finances, and participate fully in hobbies and interests. People living with this fatal disease deserve the opportunity to discuss and choose, with their doctor and family, whether an FDA-approved treatment is right for them."

“Access to FDA-approved therapies—including Medicare and insurance coverage—is a number-one priority of the Alzheimer’s Association,” Pike added.