On Friday, January 6, the U.S. Food and Drug Administration (FDA) granted accelerated approval of a new drug, Leqembi (lecanemab-irmb), for the treatment of early-stage Alzheimer’s disease.
Leqembi works by removing amyloid beta plaques, a protein that can accumulate in the brains of people with Alzheimer’s and that is believed to be a key factor in the disease.
According to the FDA, Leqembi was evaluated for the accelerated approval in a double-blind, placebo-controlled trial that included 856 people with Alzheimer’s disease. The medication, given every two weeks as an intravenous infusion, was given to subjects with mild cognitive impairment who also had imaging scans to confirm amyloid plaques in their brains.
Data submitted by Eisai — the company that makes Leqembi — to the FDA shows that patients who received Leqembi had significant reduction in their amyloid plaques between Week 1 and Week 79 of treatment compared with patients who got a placebo. Patients on placebo had no reduction in amyloid beta plaque.
In a written statement, Billy Dunn, MD, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said, “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.”
What Is Alzheimer’s Disease?
Alzheimer’s disease is an irreversible, progressive brain disorder that affects more than 6.5 million Americans. It slowly destroys memory and thinking skills and, eventually, the ability to carry out simple tasks.
While the specific causes of Alzheimer’s are not fully known, it is characterized by changes in the brain — including the accumulation of protein clumps called amyloid plaques and neurofibrillary, or tau, tangles — that result in loss of neurons and their connections. These changes affect a person’s ability to remember and think.
Accelerated Approval Process
Leqembi was approved using the FDA's accelerated approval pathway, which the FDA uses to approve drugs for serious conditions where there is an unmet medical need and a drug is shown to have an effect on a factor associated with the condition, such as amyloid plaques, that the FDA says “is reasonably likely to predict a clinical benefit to patients.”
The accelerated approval of a drug can be withdrawn if the company can’t show actual clinical benefit within a year or two of the accelerated approval. Eisai also submitted an application for full approval on the day it received the accelerated approval, using data from a study published on January 5, 2023, in The New England Journal of Medicine (NEJM).
The international, double-blind, phase 3 clinical trial followed nearly 1,800 participants for 18 months. According to the study’s authors, the drug “resulted in moderately less decline on measures of cognition and function,” particularly in study participants in the early stages of the disease with mild cognitive symptoms.
Clinical Trial Results
Anton Porsteinsson, MD, head of the University of Rochester Medical Center Alzheimer's Disease Care, Research, and Education Program (AD-CARE), who led one of the Leqembi trials at the medical center, says the NEJM study “is one of the largest clinical trials in Alzheimer's disease and was unique in that it had higher participation of historically underrepresented groups than in previous studies.” (One-quarter of participants were people of color.) Porsteinsson says the trial also included some participants with health issues other than Alzheimer’s disease, which has not been usual for Alzheimer’s medication studies.
“This created a more representative sample of the Alzheimer's population in the real world,” says Porsteinsson.
After 18 months, most of the study participants had no detectable plaques in their brain or other abnormalities commonly associated with Alzheimer’s, such as tau, says Porsteinsson, and neuroinflammation biomarkers also looked like they “moved more towards normal,” he says.
While both the participants who took the drug and the participants who got the placebo had cognitive decline over the 18 months of the study, the placebo group declined at a faster rate.
Side Effects of Leqembi
In the NEJM study, about 12.5 percent of participants showed evidence of mild to moderate localized brain swelling that resolved over several weeks when the medication was temporarily halted. There was also a higher rate of small bleeds that can be seen in some people with Alzheimer’s disease.
The FDA's prescribing information for Leqembi (PDF) includes a warning about amyloid-related imaging abnormalities (ARIA), meaning evidence of swelling or bleeding on the brain found in imagings test such as a magnetic resonance imaging (MRI) scan.
ARIA usually does not have symptoms, although serious and life-threatening events rarely may occur. Most commonly, evidence of ARIA is temporary swelling in areas of the brain that usually resolves over time and may be accompanied by small spots of bleeding in or on the surface of the brain. Some people may have symptoms such as headache, confusion, dizziness, vision changes, nausea, and seizure.
People taking Leqembi may also have infusion-related reactions, such as flu-like symptoms, nausea, vomiting, and changes in blood pressure. The most common side effects of the drug are infusion-related reactions, headache, and ARIA.
According to the drug label, Leqembi is indicated for patients with “mild cognitive impairment or mild dementia stage of disease,” which is the population studied in clinical trials. There is no safety or effectiveness data on starting treatment at earlier or later stages of the disease than were studied.
Long Term Outlook for Alzheimer’s Treatment
Dr. Porsteinsson says that since there are likely multiple factors that contribute to Alzheimer’s disease, effective treatments will likely be combination ones, which is how diseases such as heart disease, diabetes, and cancer are now often treated.
“Those of us who have been studying Alzheimer’s for a long time have become humble, and we recognize that lecanemab is a start and not a cure. It is a modest start but represents an approach to treatment that we can build upon.”
Cost and Coverage
Eisai has announced that the drug will cost $26,5000 per year. After the accelerated approval of Aduhelm, an Alzheimer’s drug similar to Leqembi, in 2021, Medicare announced that it would only cover the cost of drugs authorized under the accelerated approval process in that category — monoclonal antibodies directed against amyloid — for people enrolled in a clinical trial.
With respect to Leqembi, the Centers for Medicare and Medicaid Services, which administers Medicare, released a statement after the drug’s approval on Friday:
“Alzheimer’s disease is a devastating illness that affects millions of Americans and their families,” said CMS Administrator Chiquita Brooks-LaSure. “At CMS, we will continue to expeditiously review the data on these products as they become available and are committed to timely access to treatments, including drugs, that improve clinically meaningful outcomes.”
“If lecanemab subsequently receives traditional FDA approval, CMS would provide broader coverage using the framework we announced last year, under coverage with evidence development, on the same day. For FDA traditional approval, the drug demonstrates evidence of efficacy from a direct measure of clinical benefit.”
Response From Alzheimer’s Advocates
In a press release saluting the approval of the drug on Friday, the Alzheimer’s Association called the approval “the right decision” but said that Medicare, “by severely restricting coverage … is unprecedented and wrong.”
Joanne Pike, DrPH, Alzheimer’s Association president and chief executive officer, said in the statement, “Without access to and coverage of this treatment and others in its class, people are losing days, weeks, months — memories, skills, and independence. They’re losing time.”
“People living with this fatal disease today do not have time to wait for a miracle drug or cure,” said Pike. “While we continue efforts to discover new targets and test new treatments, people living with Alzheimer’s deserve the opportunity to discuss and make the choice with their doctor if an FDA-approved treatment that offers benefits is right for them.”