Jennifer Rose V. Molano, MD, reviewing van Dyck CH et al. N Engl J Med 2023 Jan 5 Reish NJ et al. N Engl J Med 2023 Jan 4 Sabbagh M and van Dyck CH. N Engl J Med 2023 Jan 4

Patients with early Alzheimer disease taking an anti-amyloid monoclonal antibody showed improvements in cognitive, functional, and biomarker outcomes compared with placebo; monitoring for potential adverse effects is needed.

In this phase 3, industry-sponsored, multicenter, double-blind trial, researchers studied if lecanemab, a humanized immunoglobulin G1 monoclonal antibody targeting soluble amyloid-beta protofibrils, was safe and effective in treating early Alzheimer disease (AD). Participants met criteria for mild cognitive impairment (MCI) or mild dementia due to AD and had evidence of amyloid deposition on cerebrospinal fluid (CSF) or amyloid positron emission tomography (PET) imaging.

The 1795 participants (mean age, 71; about half female; about 75% white) were randomized 1:1 to 10 mg/kg of lecanemab or placebo every 2 weeks for 18 months. Approximately 80% of participants completed the study. The primary outcome was a change in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, which assesses cognition and function as observed by patients and caregivers. Secondary outcomes included change in amyloid burden on PET imaging and additional cognitive and functional assessments.

The mean CDR-SB score at baseline was 3.2. Significantly less cognitive and functional decline was seen with lecanemab versus placebo (adjusted mean difference, –0.45; 95% confidence interval, –0.67 to –0.23; P<0.001). The amyloid burden was significantly lower with the lecanemab group than with placebo. Other secondary outcomes were also significantly better with lecanemab. Adverse effects included infusion-related reactions, amyloid-related imaging abnormalities (ARIA), headache, and falls. Serious adverse effects were seen in 14% of lecanemab recipients versus 11% of placebo recipients. Most cases of ARIA were asymptomatic (78%), occurred during the first 3 months of treatment, and resolved within 4 months. Death occurred in 0.7% of the lecanemab group (vs. 0.8% of the placebo group), which was not attributed to treatment.

A subsequent correspondence presented a patient who had received at least three doses of lecanemab in the trial, developed multiple cerebral hemorrhages after receiving intravenous tissue plasminogen activator for acute ischemic stroke, and subsequently died, with autopsy results showing multifocal intracerebral hemorrhages, cerebral amyloid angiopathy, AD changes, and vasculitis. In response, study authors noted that the patient was homozygous for apolipoprotein-E ℇ4, which, in addition to systolic blood pressure >200 mm Hg, may have contributed to the patient’s clinical progression. They also noted that vasculitis has not been reported previously with lecanemab.

Comment

A clear benefit from targeting amyloid to treat AD has been elusive. The results of this study showed promising results on outcomes in early AD, although consideration of safety issues in those homozygous for apolipoprotein-E ℇ4 is needed. Close monitoring for potential adverse effects is needed. The FDA recently approved lecanemab for mild cognitive impairment or mild dementia due to AD. An ongoing open-label study will provide additional data on whether lecanemab is a viable treatment option for AD.