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New Alzheimer’s drugs showing success slowing disease progression, especially when treated early

New monoclonal antibody therapies targeting beta-amyloid deposition in the brain have shown success in slowing the progression of Alzheimer’s disease, though the risk of serious side effects necessitates careful evaluation and discussion before initiating treatment..

In January 2023, the Food and Drug Administration (FDA) gave accelerated approval to lecanemab, which goes by the brand name Leqembi, for patients with mild cognitive impairment or mild dementia stage of Alzheimer’s disease. Centers for Medicare & Medicaid Services concomitantly made a declaration of coverage, meaning Medicare covers the drug.

The FDA approved another anti-amyloid monoclonal antibody treatment option, donanemab, in July 2024 for adults with early symptomatic Alzheimer’s disease, including those with mild cognitive impairment or mild dementia. Donanemab, which is sold under the brand name Kisunla, is also covered by Medicare.

“The amyloid hypothesis has been around for years, really decades now, as the prevailing idea as to the underlying cause of Alzheimer’s disease. And very simply, it states that it’s the deposition of beta amyloid in the brain that is the key trigger to a long and complex cascade of events, ultimately leading to what we clinically know as Alzheimer’s disease,” said Gregory E. Cooper, M.D., Ph.D., a behavioral neurologist at Norton Neuroscience Institute and director of the Memory Center.

Lecanemab has a high affinity for soluble beta amyloid and beta-amyloid protofibrils. The goal of the drug is to clear these proteins and protein aggregates from the brain before they can cause damage.

“One school of thought states that it’s the protofibrils, just as the amyloid is starting to stick together, really before you have amyloid plaque formation, that is the toxic form of beta amyloid,” Dr. Cooper said.

Dr. Cooper presented recently on the topic at a continuing medical education opportunity, “Clinical Updates in Alzheimer’s Disease — Treatment for Alzheimer’s Disease: Focus on Anti-amyloid.”

An 18-month, double-blind, placebo-controlled trial, with infusions every two weeks of lecanemab showed that the drug was highly effective at removing amyloid. The drug did not stop or reverse memory loss but did slow the pace of the disease, compared to the placebo, by an average of 27%.

Amyloid-related imaging abnormalities

The most common serious side effect in the clinical trial was amyloid-related imaging abnormalities (ARIA), which affected 21.3% of patients receiving lecanemab. ARIA can present as edema (ARIA-E) or hemorrhage (ARIA-H).

Only 3% of patients with amyloid-related imaging abnormalities side effects were symptomatic. The most common side effects included headache, nausea, confusion, dizziness, gait impairment and vision changes. ARIA-H typically resulted in micro-hemorrhages and five of the almost 900 participants in the trial developed a larger hemorrhage.

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This means providers should expect rare but serious side effects from ARIA-H, affecting fewer than 1% of patients, including seizures, general encephalopathy, stupor and focal deficits that will mimic a stroke, according to Dr. Cooper. Because of a potential heightened risk of intracerebral hemorrhage with lecanemab, reported in two patients in the trial, experts are recommending against patients on anticoagulents taking the medication.

Genetic testing is recommended in patients considering lecanemab. Patients with two copies of the APOE-E4 allele have triple the incidence of ARIA, including serious and severe ARIA, compared to people who are heterozygous for the allele or noncarriers.

If a patient on the drug has develops ARIA, and it is mild or asymptomatic, treatment with lecanemab continues. If the symptoms are moderate or severe, treatment stops and monthly MRIs are monitored. Providers should consider treatment when the imaging stabilizes or resolves.

Based on results from a recent clinical trial, lecanemab may soon be available by subcutaneous injection, rather than infusion, which will be easier on the patient.

Like lecanemab, donanemab targets amyloid. In a randomized clinical trial, patients who had Alzheimer’s — confirmed both by an amyloid PET scan and tau PET scan — received intravenous infusions of the drug. When their amyloid levels became negative, the treatment was stopped.

Slowing disease progression and cognitive decline

“It does seem clear from the study that the progression of the disease is slowed and that benefit continues to accrue, even after stopping treatment,” Dr. Cooper said.

Disease progression in the low-to-medium tau group was 36%, compared to the placebo group. For people who were clinically and pathologically the mildest, the benefits were the greatest, with disease progression slowing 60%, according to the study.

“If we catch people very early in the process, we’re starting to see a bigger and bigger impact of treatment,” Dr. Cooper said.

The ARIA rate for donanemab was about twice that of lecanemab. On donanemab almost 37% of all treated patients had amyloid-related imaging abnormalities, combining ARIA-E and ARIA-H, and symptomatic patients accounted for 6.1%. On lecanemab, only 21.3% of patients had amyloid-related imaging abnormalities, and serious side effects were seen in less than 1%  of the patients.

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