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Open-Label Trial Extension Supports Continued Long-Term Treatment With Lecanemab in Patients with Early AD
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Study results demonstrated that lecanemab provided sustained benefits over 36 months, such as improved biomarker profiles and slowed cognitive decline compared with placebo.
Patients with Alzheimer disease (AD) who were treated with lecanemab (Leqembi; Eisai, Co, Ltd) continued to show benefits of treatment through 36 months, said Christopher van Dyck, MD, professor of psychiatry, neurology, and neuroscience at Yale School of Medicine, and the director of the Alzheimer's Disease Research Unit, Yale Alzheimer's Disease Research Center, and Division of Aging and Geriatric Psychiatry, during a perspectives session at the 2024 Alzheimer’s Association International Conference, which was held in Philadelphia, Pennsylvania, from July 28 to August 1. During the session, van Dyck presented clinical data from the Clarity AD study, which shows long-term safety and efficacy results as well as biomarker data after long-term lecanemab treatment.
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The Clarity AD study (NCT03887455) is a global, placebo-controlled, double-blind, parallel-group, randomized study that consisted of a randomized phase (18 months) and an open-label expansion phase. The enrolled 1795 patients had early AD with confirmed amyloid pathology, and Mini-Mental State Examination (MMSE) scores between 22 and 30 at baseline and at screening. In the randomized phase, participants were randomly assigned to receive either biweekly doses of intravenous (IV) lecanemab (10 mg/kg) or biweekly doses of IV placebo. In the extension phase, all patients, regardless of the treatment they received in the prior phase received 10/kg of IV lecanemab biweekly.
The primary outcomes in the study are changes in Clinical Dementia Rating (CDR) from baseline at 18 months (randomization phase) and the number of participants with adverse vents (AEs) and change from Core Study Baseline in CDR-SB (extension phase). Key secondary outcome measures in the randomization phase include changes in amyloid positron emission tomography (PET), Alzheimer Disease Assessment Scale Cognitive Subscale (ADAS-Cog14), Alzheimer Disease Composite Score (ADCOMS), and Alzheimer Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL) from baseline to 18 months, and additional outcome measures in the extension phase include changes in ADAS-Cog14 and ADCS MCI-ADL from baseline.
Additionally, patients in the open-label extension either received an early initiation of lecanemab or a delayed initiation. van Dyck noted during the session that the delayed start group did not catch up to the early start group, emphasizing an importance of early treatment initiation.
“And that, of course, raises the question, well, do the delayed start participants actually benefit? And I think that they do, although we're reluctant to use historical controls in research when it comes to an open label extension, we don't have a placebo-control group, and I think we'd actually be irresponsible not to—at least—look at historical controls,” explained van Dyck during the session.
After 18 months, van Dyck noted that the treatment effect between lecanemab and an AD neuroimaging initiative (ADNI) cohort—an observational cohort that represents the exact population of those enrolled in Clarity AD—was observed through 36 months. The delayed start cohort demonstrated benefit in the open-label extension phase relative to the ADNI cohort, and matched ADNI participants also showed a similar degree of decline compared to their placebo counterparts.
Additionally, early-stage patients who had either no or low tau or low amyloid, also demonstrated stability or improvement after early-initiation treatment with lecanemab. Further, amyloid pathway biomarkers had improved at 3 months in newly treated participants, and it maintained or improved in those who received continuous treatment. The therapy also showed a slowed rate of increase in plasma pTau217 and CSF MTBR-tau243, which is an indication of the drug’s effect on amyloid and tau pathology cascade.
After 6 months, amyloid-related imaging abnormalities (ARIA) were low and similar to those of placebo. van Dyck also expressed that ARIA was not found to be associated with an accelerated, long-term progression.
“And then finally, a question that's asked very frequently is, is ARIA associated with a worse clinical outcome? And the answer is still no,” said van Dyck during the presentation. “In the core study, we're looking at the placebo group, the lecanemab group, that has now been split into those who experience ARIA at any point during the study or without ARIA throughout the study. And you can see that those with ARIA are not progressing faster…they're progressing numerically slower.”
There were no new safety events or profiles observed during the study, according to van Dyck. Infusion-related reactions were the most common reported adverse event (AE), with 369 of 1616 patients (22.8%) experiencing it during the first 12 months, 26 of 1286 (2.0%) in 12 to 24 months, and 11 of 872 (1.3%) in 24 to 26 months. Other common AEs included cough (>12 months: n = 31, 1.9%; 12 to <24 months: n = 27, 2.1%; and 24 to <36 months: n = 18, 2.1%), headache (n = 131, 8.1%; n = 49, 3.8%; and n = 17, 1.9%), diarrhea (n = 58, 3.6%; n = 30, 2.3%; and n = 12, 1.4%), nausea and vomiting (n = 62, 3.8%; n = 28, 2.2%; and n = 12, 1.4%), and rash (n = 49, 3.0%; n = 33, 2.6%; and n = 14, 1.6%).
"...with additional exposure, some AEs are going to, of course, go up in the percentage of people who have them, such as [serious] AEs, deaths…but when you normalize to person months, there's no increase at all. ARIA-edema tweaks up slightly from 12.6% of people affected to 14.7% with longer-term exposure, but the normalized rate, of course, goes down because it tends not to occur late,” concluded van Dyck. “There were no new clinically significant AEs identified with long-term treatment.”
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