Lecanemab moderately slows decline in early AD, associated with AEs

Lecanemab reduces brain amyloid burden and offers moderate slowing of cognitive decline in early Alzheimer’s disease (AD), but is associated with adverse events (AEs), according to the results of the phase III, double-blind, placebo-controlled CLARITY AD trial, presented at the 15^th Clinical Trials on Alzheimer’s Disease (CTAD 2022) conference.

CLARITY AD enrolled 1,795 participants with mild cognitive impairment (MCI) due to AD or mild Alzheimer’s dementia with confirmed amyloid pathology (age range, 50–90 years; female, 52.3 percent; Asian, 16.9 percent), who were randomized 1:1 to receive intravenous lecanemab (10 mg/kg every 2 weeks) or placebo. The primary end point was change from baseline at 18 months in Clinical Dementia Rating–Sum of Boxes score (CDR-SB; range, 0–18, with higher scores indicating greater impairment). The mean CDR-SB score at baseline was approximately 3.2 in both groups. [N Engl J Med 2022;doi:10.1056/NEJMoa2212948]

At 18 months, the adjusted least-squares mean change from baseline was 1.21 with lecanemab vs1.66 with placebo (difference, -0.45; 95 percent confidence interval [CI], -0.67 to -0.23; p<0.001). “Lecanemab significantly slowed disease progression by 27 percent on CDR-SB at 18 months and at all time points beginning at 6 months,” commented study presenter, Prof Christopher van Dyck of Yale School of Medicine, New Haven, Connecticut, US.

Lecanemab also produced statistically significant results in the key secondary endpoints of change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale, the Alzheimer’s Disease Composite Score, and the score on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment. The results were consistent across a broad range of subgroups, including AproE4 genotype, age, sex, and race.

A substudy involving 698 participants found greater reductions in brain amyloid burden with lecanemab vs placebo (difference, −59.1 Centiloids; 95 percent CI, −62.6 to −55.6; p<0.00001). “Lecanemab significantly reduced fibrillar amyloid burden at all time points beginning at 3 months. After 18 months of treatment in the amyloid PET substudy, the average amyloid level was 23 Centiloids in the lecanemab group, which is below the amyloid positivity threshold of approximately 30 Centiloids above which participants are considered to have elevated brain amyloid,” reported van Dyck.

Treatment-emergent AEs (TEAEs) occurred in 88.9 percent of main study participants on lecanemab and 81.9 percent of those on placebo, while serious AEs occurred in 14.0 percent and 11.3 percent of participants, respectively. TEAEs led to drug withdrawal in 6.9 percent of lecanemab recipients vs 2.9 percent of placebo recipients.

The most common AEs were infusion-related reactions, which were reported in 26.4 percent of lecanemab vs 7.4 percent of placebo recipients. Most infusion-related reactions were mild-to-moderate (grade 1–2, 96 percent) and occurred with the first dose (75 percent), with most study participants (65 percent) experiencing only one infusion-related reaction.

Amyloid-related imaging abnormalities–oedema (ARIA-E) occurred in 12.6 percent of lecanemab vs 1.7 percent of placebo recipients. In the 2.8 percent of participants with symptomatic ARIA-E in the lecanemab group, the most common symptoms were headache, visual disturbance and confusion. No symptomatic ARIA-E events were reported in the placebo group.

The rate of amyloid-related imaging abnormalities with hemosiderin deposits (ARIA-H, including cerebral microhaemorrhages, cerebral macrohaemorrhages, and superficial siderosis) was 17.3 percent in the lecanemab group and 9.0 percent in the placebo group, while symptomatic ARIA-H occurred in 0.7 percent and 0.2 percent of participants, respectively.