Results from Eisai’s large global Phase 3 confirmatory Clarity AD clinical study of lecanemab, an investigational anti-amyloid beta (Aβ) protofibril antibody for the treatment of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) and mild AD (collectively known as early AD) with confirmed presence of amyloid pathology in the brain, were presented at the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference, in San Francisco, California. Simultaneously, the results were published in the New England Journal of Medicine – read the full article here.
You can also read an interesting editorial in The Lancet: Lecanemab for Alzheimer’s disease: tempering hype and hope – ScienceDirect
Design of Clarity AD Study1
Eisai’s Clarity AD was a global confirmatory Phase 3 placebo-controlled, double-blind, parallel-group, randomised study in 1,795 people with early AD (lecanemab group: 898 placebo group: 897) at 235 sites in North America, Europe, and Asia. The participants were randomised 1:1 to receive either placebo or lecanemab 10-mg/kg IV biweekly, and the randomisation was stratified according to clinical subgroup (MCI due to AD or mild AD), presence or absence of concomitant approved AD symptomatic medication at baseline (e.g., acetylcholinesterase inhibitors, memantine, or both), ApoE4 status and geographical region.
The primary endpoint was change from baseline at 18 months in the CDR-SB (Clinical Dementia Rating Sum of Boxes), the global cognitive and functional scale, and key secondary endpoints were the change from baseline at 18 months in amyloid Positron Emission Tomography (PET) using centiloids, AD Assessment Scale – Cognitive Subscale 14 (ADAS-Cog14), AD Composite Score (ADCOMS) and AD Cooperative Study-Activities of Daily Living (ADCS MCI-ADL). In addition, longitudinal changes in brain tau pathology as measured by tau PET (n=257) and cerebrospinal fluid (CSF) biomarkers of AD pathology (n=281) were evaluated in optional sub-studies.
Efficacy results of Clarity AD2
Mean change of CDR-SB from baseline at 18 months as the primary endpoint was 1.21 and 1.66 for lecanemab (n=859) and placebo (n=875) groups, respectively. Lecanemab treatment resulted in highly statistically significant results, reducing clinical decline on the global cognitive and functional scale, compared with placebo at 18 months by -0.45 (95% Confidence Interval (CI): -0.67, -0.23; P=0.00005), representing a 27% slowing of decline. Starting as early as six months (difference: -0.17 [95% CI: -0.29, -0.05]; P<0.01), and increasing in absolute difference over time across all time points every 3 months, the treatment showed highly statistically significant changes in CDR-SB from baseline compared to placebo (all P-values are less than 0.01).
All key secondary endpoints also showed highly statistically significant results compared with placebo (P<0.001). In the amyloid PET sub-study, treatment with lecanemab showed statistically significant reduction in amyloid plaque burden at all timepoints starting at 3 months. Mean change in centiloids at 18 months was -55.5 and 3.6 for lecanemab (n=354) and placebo (n=344) groups, respectively (mean difference: -59.1 [95%CI: -62.6, -55.6]; P<0.00001). Lecanemab slowed decline of cognitive function by 26% on ADAS-Cog14 at 18 months (lecanemab (n=854), placebo (n=872); mean difference: -1.44 [95%CI: -2.27, -0.61]; P=0.00065). In the ADCOMS assessment, lecanemab slowed disease progression by 24% at 18 months (lecanemab (n=857), placebo (n=875); mean difference: -0.050 [95% CI: -0.074, -0.027; P=0.00002]). Lecanemab slowed decline of activities of daily living by 37% on ADCS MCI-ADL at 18 months (lecanemab (n=783), placebo (n=796); mean difference: 2.016 [95%CI: 1.208, 2.823]; P<0.00001).
Safety Results of Clarity AD3
The most common adverse events (>10%) in the lecanemab group were infusion reactions (lecanemab (n=898): 26.4%; placebo (n=897): 7.4%), ARIA-H (combined cerebral microhaemorrhages, cerebral macrohaemorrhages, and superficial siderosis; lecanemab (n=898): 17.3%; placebo (n=897): 9.0%), ARIA-E (edema/effusion; lecanemab (n=898): 12.6%; placebo 9n=897): 1.7%), headache (lecanemab (n=898): 11.1%; placebo (n=897): 8.1%), and fall (lecanemab (n=898): 10.4%; placebo (n=897): 9.6%). Infusion reactions were largely mild-to-moderate (grade 1-2: 96%) and occurred on the first dose (75%).
During the study period, deaths occurred in 0.7% and 0.8% of participants in the lecanemab and placebo groups, respectively and no deaths were related to lecanemab or occurred with amyloid-related imaging abnormalities (ARIA) in 18-month double-blind study period. Serious adverse events were experienced by 14.0% of participants in the lecanemab group and 11.3% of participants in the placebo group. Treatment-emergent adverse events occurred in 88.9% and 81.9% of participants in the lecanemab and placebo groups, respectively. Treatment-emergent adverse events leading to drug withdrawal occurred in 6.9% and 2.9% of participants in the lecanemab and placebo groups, respectively.
Overall, lecanemab’s ARIA incidence profile was within expectations based on the Phase 2b results.
Eisai serves as the lead of lecanemab development and regulatory submissions globally with both Eisai and Biogen co-commercialising and co-promoting the product and Eisai having final decision-making authority.
- Irizarry M. Clarity AD: Clinical Trial Background and Study Design Overview. Presented at: 15th Annual Clinical Trials on Alzheimer’s Disease (CTAD) Conference, November 29 – December 2, 2022, San Francisco, California, USA.
- van Dyck C. Lecanemab for the Treatment of Early Alzheimer’s Disease: Topline Efficacy Results from Clarity AD. Presented at: 15th Annual Clinical Trials on Alzheimer’s Disease (CTAD) Conference, November 29 – December 2, 2022, San Francisco, California, USA.
- Sabbagh M. Safety Profile of Lecanemab in Early Alzheimer’s Disease. Presented at: 15th Annual Clinical Trials on Alzheimer’s Disease (CTAD) Conference, November 29 – December 2, 2022, San Francisco, California, USA.