Regulatory, clinical, and post-marketing challenges of lecanemab for Alzheimer’s disease: insights from real-world data

INTRODUCTION: In recent years, lecanemab received regulatory approval from several regulatory agencies. The safety profile, particularly the risk of amyloid-related imaging abnormalities (ARIA), necessitates post-marketing surveillance. From a public health perspective, generating robust real-world evidence (RWE) is essential. OBJECTIVES: This study aims to inform policy and clinical decision-makers by analyzing prescribing information, literature evidence, and the FDA Adverse Events Reporting System (FAERS) pharmacovigilance reports. METHODS: This study employed a mixed-method approach. First, prescribing information for lecanemab was collected and compared across four regulatory agencies. Second, a systematic literature review was conducted in MEDLINE and Embase to identify RWE studies reporting adverse events (AEs), symptoms, or management strategies in patients treated with lecanemab. Finally, post-marketing safety data from the FAERS database were analyzed. RESULTS: Four regulatory agencies have approved lecanemab through different pathways, each requiring confirmation of amyloid pathology and careful assessment of ARIA risk, particularly in Apolipoprotein E (ApoE) ε4 homozygotes. Notable differences exist across agencies regarding indications, contraindications, monitoring protocols, and criteria for treatment suspension, resumption, or discontinuation. All authorities mandate post-marketing programs to ensure ongoing monitoring of safety and effectiveness. A bibliographic search identified 26 studies. Nine cohort studies included between 19 and 407 participants and reported follow-up periods ranging from 6 to 14 months; in a few studies, lecanemab was administered to individuals with moderate or severe AD. As expected, infusion-related reactions (IRRs) and ARIA were the most frequent adverse events, predominantly occurring within the first seven infusions. Some studies reported preliminary efficacy outcomes, although attrition bias may have affected these findings. Seventeen case reports described nineteen individuals aged 57–82, with most AEs arising between the 3rd and 7th infusion and primarily consisting of ARIA; serious events such as stroke, seizures, and two fatalities were also noted. In most cases, lecanemab was paused or permanently discontinued. Analysis of the FAERS database identified 1,286 reports revealing 2,627 AEs, of which 30% were classified as serious, including forty-six deaths. The most reported AEs were headache, ARIA-E, ARIA-H, and chills. ARIA-E and ARIA-H have similar demographics, onset timing, and severity profiles. CONCLUSION: This study highlights the complexity of lecanemab’s safety profile and the variability in regulatory prescribing recommendations. While ARIA, especially in ApoE ε4 homozygotes, remains the most frequent adverse event, its severity ranges from mild to, in rare cases, severe or fatal. These findings underscore the need for robust post-marketing surveillance and harmonized recommendations to ensure safe and effective clinical use.