Full Phase 3 Trial Data Support Lecanemab for Early Alzheimer’s
FDA expected to decide on approval of dementia treatment early next year
About 1.5 years of treatment with lecanemab (BAN2401) — now under regulatory review in the U.S. — was found to significantly slow the progression of dementia symptoms in people with early-onset Alzheimer’s disease.
That’s according to just-released full data from the Phase 3 Clarity AD clinical trial, which showed that lecanemab slowed symptoms of dementia by 27% compared with a placebo.
Moreover, use of the amyloid-targeting antibody, co-developed by Eisai and Biogen, resulted in significant reductions in the amounts of toxic amyloid protein clumps found in the brains of patients. It also slowed decline in other measures of disease severity.
The experimental therapy is under accelerated review by the U.S. Food and Drug Administration, with a decision on its approval expected in early January 2023.
Full results from the Clarity AD trial (NCT03887455) were presented for the first time at the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held Nov. 29–Dec. 2 in San Francisco, California, and also virtually. The data also were published in the New England Journal of Medicine, in a Biogen- and Eisai-funded study, titled “Lecanemab in Early Alzheimer’s Disease.”
Targeting amyloid-beta plaques with Lecanemab
Amyloid-beta plaques are toxic protein clumps that are a hallmark of Alzheimer’s, found in virtually all disease cases and thought to drive the neurodegenerative disorder — itself the most common cause of dementia.
Lecanemab is an antibody designed to clear these plaques, which is expected to slow disease progression.
The Clarity AD trial enrolled 1,795 people with early Alzheimer’s, defined as mild cognitive impairment due to disease or mild Alzheimer’s dementia, with confirmed amyloid buildup in the brain.
Patients were allowed to receive medications for a number of coexisting diseases, such as high blood pressure, diabetes, heart disease, kidney disease, and obesity. Also, Eisai adopted a diversity recruitment strategy, which resulted in the enrollment of 4.5% Black individuals and 22.5% Hispanic participants.
The trial recruited at 235 sites in North America, Europe, and Asia, and participants were randomly assigned to receive a 10 mg/kg dose of lecanemab or a placebo, administered intravenously (into the bloodstream) every other week.
The primary outcome, or goal, was a change in a scale known as the Clinical Dementia Rating-Sum of Boxes (CDR-SB), after 18 months of treatment. The CDR-SB, which is scored by a clinician based on interviews with patients and caregivers, assesses dementia symptoms across six domains: memory, judgment and problem solving, orientation, personal care, home and hobbies, and community affairs.
Results showed that, over the 18-month trial, patients on lecanemab experienced a mean increase in CDR-SB scores, indicating worsening dementia, of 1.21 points. In contrast, those on a placebo saw an increase of 1.66 points over the same period of time. According to a joint press release by Eisai and Biogen, this difference represented a 27% relative slowing of dementia progression, which the companies called “highly statistically significant.”
A statistically significant difference in CDR-SB between lecanemab and a placebo appeared as early as six months and increased over time at every three-month assessment.
In secondary assessments, brain scans revealed the treatment significantly and sustainably reduced the number of amyloid plaques starting at three months. After 18 months, the amount of amyloid plaques on brain PET scans dropped by 55.5 centiloids with lecanemab, but increased by 3.6 centiloids in the placebo group, also a significant difference.
Notably, the mean amount of amyloid plaques reached 23 centiloids after 18 months of treatment with lecanemab, which is considered negative for the presence of amyloid plaques.
Lecanemab also slowed disease progression in other measures of disease severity. In particular, declines in the Alzheimer’s Disease Assessment Scale-cognitive subscale14 (ADAS-cog14), a standard measure of cognitive function, were slowed by 26% after 18 months of treatment. In the Alzheimer’s Disease Composite Score (ADCOMS), lecanemab also slowed disease progression by 24%.
Finally, the treatment slowed decline in activities of daily living by 37%, as measured with the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL) scale.
Lecanemab results similar for all subgroups
The findings were consistent across all subgroups, regardless of disease stage, use of medications, being or not a carrier of the ApoE4 gene — a known Alzheimer’s risk factor — or geographic location.
Biomarkers also showed an early and sustained reversal of amyloid plaques in the blood and cerebrospinal fluid (CSF), the liquid that surrounds the brain and spinal cord. Biomarkers for tau protein, which also forms damaging clumps in Alzheimer’s, also improved with treatment, as did tau buildup in the brain.
Infusion reactions were the most common adverse event associated with lecanemab treatment. These mostly occurred in the first dose and were largely mild to moderate. Amyloid-related imaging abnormalities (ARIA) like brain bleeding and swelling also occurred more frequently with lecanemab than a placebo.
Serious adverse events were reported by 14% of lecanemab-treated patients and 11.3% of placebo group participants. Most patients in both groups reported treatment-emergent adverse events (88.9% vs. 81.9%). These side effects led to treatment withdrawal in 6.9% of those treated with lecanemab and 2.9% of those in the placebo group.
During the study period, deaths occurred in 0.7% of lecanemab-treated patients and 0.8% of the placebo group. No deaths were related to lecanemab or ARIA events.
Encouraged by Clarity AD data, the Alzheimer’s Association has released a statement calling on the Centers for Medicare and Medicaid Services (CMS) to modify its policy on lecanemab. That policy is now set to block Medicare patients with a terminal, progressive disease from accessing lecanemab, if approved.
Lecanemab also is being tested in the AHEAD 3-45 Phase 3 (NCT04468659) clinical study, which is recruiting up to 1,400 patients at more than 100 study locations, many in the U.S. The trial seeks participants ages 55–80, with preclinical Alzheimer’s disease — meaning those without symptoms but with elevated levels of amyloid in their brains.
Top-line data for AHEAD 3-45 is expected in 2027.