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Treatment with the investigational anti-amyloid agent lecanemab led to modestly less decline on cognitive and functional measures in the phase III trial of early Alzheimer's disease, but was associated with adverse events.

From a baseline score of about 3.2 on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), mean worsening at 18 months was 1.21 with lecanemab and 1.66 with placebo, a difference of -0.45 (95% CI -0.67 to -0.23, P<0.001), according to Christopher van Dyck, MD, of Yale School of Medicine in New Haven, Connecticut, and co-authors.

All key secondary endpoints were met, the researchers reported in the .

A total of 26.4% of lecanemab-treated participants had infusion-related reactions. Amyloid-related imaging abnormalities (ARIA) with edema or effusions (ARIA-E) occurred in 12.6% of people who received lecanemab. ARIA-H -- combined cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis -- occurred in 17.3%.

Results were consistent in sensitivity analyses and across a broad range of subgroups, van Dyck stated at the (CTAD) annual conference in San Francisco, where the trial results were presented.

CLARITY AD evaluated 1,795 people with early Alzheimer's disease and evidence of amyloid on PET or in cerebrospinal fluid. Overall, 898 people were assigned to lecanemab and 897 to placebo from March 2019 through March 2021. Lecanemab was given intravenously at 10 mg/kg of body weight every 2 weeks for 18 months.

Baseline ages ranged from 50 to 90 (mean 71). Slightly more than half of participants were female and about three-quarters were white. Nearly 69% carried an APOE4 allele: about 53% had one APOE4 allele and 16% had two.

About 62% of participants had mild cognitive impairment and 38% had mild dementia due to Alzheimer's. All had objective impairment in episodic memory.

The primary efficacy endpoint was the change from baseline to 18 months in the CDR-SB, a scale that ranges from 0-18 with higher scores indicating worse impairment. "The CDR is a global rating scale," van Dyck said. "It involves an interview with a participant and an informant, and it generates scores in six different domains -- some cognitive, some functional."

CDR-SB scores of 0.5-6 indicate early Alzheimer's disease. At baseline, mean CDR-SB scores were 3.17 in the lecanemab group and 3.22 in the placebo group.

Key secondary endpoints included changes from baseline at 18 months in amyloid burden and in the following scores:

• Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14), which ranges from 0-90, with higher scores indicating worse impairment
• Alzheimer's Disease Composite Score (ADCOMS), which ranges from 0-1.97, with higher scores meaning worse impairment
• Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), which ranges from 0-53, with lower scores indicating worse impairment

Mean differences in 18-month scores all favored lecanemab: ADAS-Cog14 (-1.44), ADCOMS (-0.05), and ADCS-MCI-ADL (2.0; all P<0.001).

A substudy of 698 participants showed a greater reduction in amyloid burden with lecanemab than with placebo at 18 months. Adjusted mean change from baseline was -55.48 centiloids with lecanemab versus an increase of 3.64 centiloids with placebo, a difference of -59.12 centiloids (P<0.001).

ARIA-E generally emerged in the first 3 months, was mild and asymptomatic, didn't lead to discontinuation of treatment if mild, and resolved in 4 months. ARIA-E and ARIA-H occurred most frequently in people with two APOE4 alleles. No deaths in the phase III trial occurred with ARIA.

Study limitations included a short duration and a 17.2% dropout rate, van Dyck and colleagues noted. The trial was conducted during the COVID-19 pandemic and encountered problems with missed doses, delayed assessments, and intercurrent illness. "Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease," the researchers wrote.

In recent weeks, two deaths have been reported involving participants who developed ARIA in a lecanemab open-label extension study -- one with atrial fibrillation who was taking the blood thinner apixaban (Eliquis), the other who received tissue plasminogen activator (tPA) for acute stroke.

It's not clear what caused these deaths, observed Marwan Sabbagh, MD, of the Barrow Neurological Institute in Phoenix, who presented CLARITY AD safety data at CTAD. "I understand that people want to say that there's some causality," Sabbagh said. "These things continue to be explored."

In a , drugmaker Eisai said the two cases had significant comorbidities and risk factors including anticoagulation, and the company's assessment was that the deaths can't be attributed to lecanemab.

Nonetheless, if lecanemab is approved, the cases may influence how the drug is prescribed. "The new death attributed to the combination of lecanemab and tPA will require modification of the informed consent, so patients are aware of the risk," said Sam Gandy, MD, PhD, of the Mount Sinai Alzheimer's Disease Research Center in New York City, who wasn't involved with the study. "It will be up to the FDA to decide whether this impacts the decision on approval of the drug."

The FDA is reviewing lecanemab under the program and plans to decide by . Besides long-term extension studies, ongoing lecanemab investigations include the trial in preclinical Alzheimer's disease.

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