FDA Approves New Alzheimer’s Disease Treatment

Lecanemab, a therapy that targets amyloid proteins thought to cause Alzheimer’s disease, has been granted accelerated approval by the Food and Drug Administration (FDA).

“Lecanemab, to be marketed as Leqembi, will be the second drug on the market but is the first one that is proven to clinically slow the progression of Alzheimer’s disease,” says Dr. Lawrence S. Honig, a neurologist at NewYork-Presbyterian/Columbia University Irving Medical Center. “This is a major step forward.” It is not yet certain exactly how and when the drug will become available for patients, based on this approval.

The FDA grants accelerated approval when a drug has a demonstrated effect on biomarkers of a disease or condition, but when there might not be certainty that a drug is clinically efficacious, adds Dr. Honig. In the case of lecanemab, a New England Journal of Medicine study showed that it clearly slowed cognitive decline, such as memory loss, in a large clinical trial of individuals in the early stages of the disease. Some study participants did experience side effects from the treatment, including brain swelling or brain bleeding. With the recently demonstrated clinical efficacy, the manufacturer of the drug has submitted a supplemental application to the FDA for regular, “traditional” approval.

“Lecanemab slowed cognitive decline for people with early Alzheimer’s disease by 27%,” says Dr. Honig. “The treatment targets the beta-amyloid protein in the brain of people with early-stage Alzheimer’s and showed dramatic evidence of removal of these amyloid proteins, in addition to clinically proving to slow the progression of the disease.”

Alzheimer’s disease affects approximately six million people in the U.S. and about 30 million worldwide. The disease is associated with abnormal accumulations of beta-amyloid, which form plaques in the brain tissue, and memory and thinking abilities are affected. The study on lecanemab, based on a Phase 3 clinical trial, found that the drug removed amyloid plaques. In clinical trials, Phase 3 is the last testing phase that is finalized before a drug, such as lecanemab, is submitted for regulatory approval and released in the market.

In the clinical trial, there were 1,795 participants between 50 to 90 years of age who were in the early stages of Alzheimer’s disease. They were experiencing mild cognitive impairment or mild dementia due to the disease, and based on cerebrospinal fluid or nuclear medicine imaging, had evidence of amyloid in their brains. To determine the progression of Alzheimer’s disease in participants, a variety of scales were used. One of them captured a person’s cognition and function, such as memory, problem-solving, and day-to-day activities, through interviews with patients and their caregivers.

From March 2019 to March 2021, 898 participants received lecanemab intravenously every two weeks and 897 received a placebo at over 200 sites in North America, which included NewYork-Presbyterian/Columbia, and in Europe and Asia. The treatment markedly reduced brain amyloid levels, as determined by PET imaging. The treatment also resulted in a 26% to 37% less rate of decline in various measures of cognition and function and ability to do activities of daily living, compared with those who received placebo. However, there were also adverse risks associated with the treatment although less than 3% of treated individuals experienced adverse brain symptoms.

Dr. Honig spoke with Health Matters about how lecanemab works, its risks, and on the FDA’s accelerated approval of the drug.

How does lecanemab work? What promise does the therapy hold?
Dr. Honig: Lecanemab is a monoclonal antibody that binds amyloid and was designed to remove amyloid from the brain. It has long been suggested that removing the protein might slow the progression of Alzheimer’s disease.

The results showed that after 18 months of treatment, the mean amyloid level in most treated persons was below the threshold for amyloid positivity, showing that a radiologist would not even know they had Alzheimer’s disease. Does lecanemab reverse problems linked to Alzheimer’s disease, its signs, and its symptoms? It does not. Does it slow them down? It does, by a variety of measures; one by reducing amyloid levels. And this is the first medication clinically proven to do so.

What about aducanumab, the drug that was approved by the FDA in 2021?
Aducanumab, a similar treatment, is on the market. The FDA approved it under an accelerated approval pathway in 2021 based on it also demonstrating amyloid removal in the brain. But aducanumab did not have clear evidence of clinical efficacy in Alzheimer’s disease, such as proven slowing of the progression of cognitive decline.

The FDA may grant accelerated approval when there is a lack of certainty that a drug is clinically efficacious, but there is a demonstrated effect on biomarkers (such as brain amyloid), and there is reason to believe that biomarker change might be an indication of potential clinical efficacy.

How many participants in the clinical trial experienced the associated risks, such as brain swelling or brain bleeding, and what is there to know about these risks?
The main risks of amyloid-lowering medications often include brain bleeding or brain swelling.

In terms of brain swelling: 12.6% of participants who were on lecanemab experienced it. There were 2.8% that had what we call symptomatic brain swelling, which means that they had swelling of the brain that caused clinical signs or symptoms. If the swelling was symptomatic or very extensive or severe, the treatment was put on hold. If the swelling was minor, then dosing continued, with monitoring.

Brain bleeding occurred in 17.3% of participants who were on the treatment. But certain bleeding events in the brain, called “micro-bleeds”, are rather common in Alzheimer’s disease. And in this study, 14% of people on the treatment had micro-bleeds. It is rare that patients have symptoms from a micro-bleed; it is noticed by the doctors or radiologists looking at the scans.

Now that the results of the phase-three clinical trial were released and lecanemab was granted accelerated approval, what are the next steps for the therapy?
It will be on the market this year and we also expect that there will be a submission for regular approval. We look forward to further developments with this drug and others, to slow down and ultimately attempt to halt the progression of Alzheimer’s disease.

Lawrence S. Honig, M.D., Ph.D., is a neurologist at NewYork-Presbyterian/Columbia University Irving Medical Center and professor of neurology at the Columbia University Vagelos College of Physicians and Surgeons, specifically in its Department of Neurology, the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, and the Gertrude H. Sergievsky Center. Dr. Honig’s clinical specializations focus on Alzheimer’s disease, Lewy body dementia, frontotemporal dementia, progressive supranuclear palsy, Creutzfeldt-Jakob disease, immune-mediated encephalitis, and other disorders of nervous system aging and degeneration.

Dr. Honig was an investigator for this CLARITY study carried out at NewYork-Presbyterian/Columbia, and has been an investigator and received research funding from Eisai for other drug studies. He also has consulted for Eisai, the pharmaceutical company developing lecanemab, as well as for Biogen, Cortexyme, Genentech, Medscape, Prevail, and Roche pharmaceutical companies.