Lecanemab for Alzheimer's shows cognitive benefit despite serious risks

Lecanemab for Alzheimer's shows cognitive benefit despite serious risks

Medical authorities and researchers are urging a balanced evaluation of lecanemab, a monoclonal antibody designed to slow the progression of early Alzheimer's disease. While the drug has demonstrated a statistically significant ability to reduce cognitive decline, it is accompanied by serious safety risks, high costs, and a resource-heavy administration process.

Lecanemab works by targeting and removing amyloid-beta plaques, which are proteins that build up in the brain and serve as a hallmark of Alzheimer's pathology. By binding to toxic protofibrils of amyloid-β, the medication promotes the clearance of these plaques from the brain.

A systematic review and meta-analysis of randomized controlled trials focusing on a 10 mg/kg biweekly dosage found significant positive effects on cognitive outcomes. The analysis reported consistent reductions in ADAS-cog14, CDR-SB, and ADCOMS scores. Additionally, phase III data indicated a 27% reduction in cognitive decline over 18 months.

Serious Safety Concerns

Despite these cognitive gains, the drug carries risks of serious adverse effects, specifically amyloid-related imaging abnormalities, known as ARIA. These abnormalities manifest as ARIA-E (brain swelling/edema) and ARIA-H (small brain bleeds or hemorrhage).

The meta-analysis revealed a statistically significant increased risk for both ARIA-E and ARIA-H. While most people with ARIA do not experience symptoms, some may encounter:

• Headache, dizziness, and nausea
• Confusion that worsens
• Vision problems and seizures
• Problems walking

In rare instances, larger areas of brain bleeding can occur, which may be fatal. Certain factors can increase these risks. Patients with the ApoE4 gene may be more susceptible to ARIA, and those taking antithrombotic medications, such as aspirin, may face a higher risk of larger brain bleeds.

Other side effects include infusion-related reactions—as well as serious allergic reactions.

Clinical Administration and Access

Treatment is resource-intensive. Eligibility requires confirmation of amyloid in the brain via a lumbar puncture with cerebrospinal fluid analysis or a PET scan. Once treatment begins, patients require regular intravenous doses and frequent monitoring through MRI scans to check for ARIA.

The financial burden is substantial. In Canada, where the drug was recently approved, the cost is approximately $35 000 to $40 000 per year per patient. The medication is not currently publicly funded, and most provinces and territories have not yet decided if they will cover it through health insurance.

"The interpretation of benefits from lecanemab may be influenced by the limited availability of therapies for and the personal and societal burdens of Alzheimer disease. Clinical benefits are modest at best, with uncertain impacts on quality of life, independence, and caregiver burden,"

Dr. Sharon Straus, geriatrician at Unity Health Toronto and professor, University of Toronto, via CMAJ

The Importance of Early Diagnosis

The potential for benefit is highest when patients are diagnosed and treated in the earliest stages, such as mild cognitive impairment (MCI) or mild dementia. Early signs can include repeating questions, forgetting appointments, or difficulty with problem-solving. These symptoms are often confused with normal aging, though early AD is distinct in that symptoms are consistent and worsen over time.

According to the Alzheimer's Association, one in three people with MCI due to AD will develop dementia due to AD within five years. Diagnosis involves cognitive exams to test memory and thinking, neurological exams for reflexes and speech, and laboratory tests to rule out other conditions.

The FDA granted accelerated approval for lecanemab in January 2023, though it noted the decision was based on phase II results. Because previous clinical trials did not fully include older, less educated, or more diverse populations, efficacy and safety outcomes may differ for those groups.

Medical professionals now recommend a shared decision-making approach. Because of the uncertain clinical benefit and the financial and safety implications, the decision to start lecanemab must be individualized. Some patients may accept the risks and costs for a small potential delay in disease progression, while others may choose to defer treatment until more evidence is available.