Lecanemab Clearance of Amyloid Beta Occurs Early and Correlates With Decreased Rates of Clinical Decline and Changes in Blood Biomarkers
In the phase 2 Study 201 (NCT01767311), lecanemab (Eisai, Woodcliffe Lake, NJ and Biogen, Cambridge, MA), treatment reduced amyloid beta (Aβ) plaque in the brains of people with mild cognitive impairment (MCI) due to Alzheimer disease (AD) or mild AD. At the highest dose tested, there was a 64% likelihood that the highest dose slowed cognitive decline relative to placebo by at least 25% after 12 months of treatment, which rose to a 76% likelihood after 18 months. Although this was less than the prespecified 80% likelihood target and thus, did not achieve the primary endpoint at 12 months, it was considered a strong signal and provided valuable information for the design of ongoing phase 3 trials.
Additional analyses of Study 201 show reduction in Aβ plaque with lecanemab vs placebo continued throughout the 18-month double-blind period. During a prespecified treatment gap (mean 24 months), those treated with lecanemab had small increases in Aβ plaque, that again cleared with lecanemab treatment in the open-label period. During the off-treatment period, clinical improvement vs placebo initially persisted, although clinical progression continued at a similar rate as with placebo. After reinitiating or initiating lecanemab in the open-label period, Aβ plaque levels dropped significantly within 3 months for both those who had lecanemab or placebo in the double-blind period. These patterns suggest a disease-modifying effect of lecanemab.
Reductions in Aβ plaque correlated with slowing of cognitive decline and decreases corresponding changes in potential blood biomarkers for AD, the Aβ42/40 ratio and phosphorylated tau-181 (Ptau-181) levels.
Michael Irizarry, MD, vice president, deputy chief clinical officer, Neurology Business Group, Eisai, said ". . .lecanemab showed robust clearance of brain amyloid, corresponding biomarker changes, and slowing of clinical decline across several clinical endpoints. Sensitivity analyses supported that the lecanemab clinical efficacy results across statistical models are consistent and reliable, and further enhances our confidence in the clinical potential of this investigational therapy."
A confirmatory phase 3 trial, Clarity AD study (NCT03887455) is fully enrolled with 1,795 participants. The phase 3 AHEAD 3-45 study (NCT04468659) will evaluate lecanemab in people with preclinical AD. Notably, AHEAD 3-45 is the first clinical trial to use the blood biomarker Aβ42/40 as a test for eligibility to move on to amyloid PET imaging. The AHEAD 3-45 study will have 2 arms with different treatment doses based on the individual participant's Aβ plaque levels.
The adverse event of amyloid-related imaging abnormalities-edema (ARIA-E), which is more common in people who carry the apolipoprotein E ε4 allele (ApoE4), occurred in 14.3% (7/49) of ApoE4 carriers in the double-blind period. Many ApoE carriers were not given the highest dose of lecanemab in the double-blind period to mitigate risk of ARIA-E, and instead received the second highest dose. In the open-label period, however, all participants were given the highest dose of lecanemab, and rates of ARIA-E in ApoE4 carriers newly treated with lecanemab were consistent at 12.9% (4/31).
Dr. Irizarry noted, “ARIA-E is an important adverse event of amyloid-lowering therapies that is critical to monitor and manage during treatment. Rates and timing of ARIA-E may differ for each of the amyloid antibodies approved or in development, and we need to understand appropriate monitoring and management for ARIA-E across the therapeutic agents. It is essential to educate physicians, patients, and care partners about this potential risk as these therapies become available.”
In Study 201, Aβ plaques in the brain were measured with amyloid-positron emission tomography (PET) using standardized uptake value ratio (SUVr) units. Clinical change was measured with the Alzheimer's Disease Composite Score (ADCOMS) at 12 and 18 months and, as select key secondary endpoints at 18 months, the Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14).