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Continuous treatment with lecanemab (Leqembi, Eisai/Biogen) demonstrated sustained disease-modifying benefit over 4 years in patients with early-stage Alzheimer’s disease (AD) enrolled in the open-label extension of the phase 3 CLARITY AD trial.

Through 4 years, lecanemab “meaningfully” delayed progression to dementia stage of disease compared to untreated observational cohorts, said study investigator Christopher van Dyck, MD, Yale University School of Medicine, New Haven, Connecticut.

With 4 years of treatment, “there is in the vicinity of a full year’s time saved” in early-stage disease. In addition, more than half of patients in the low tau subgroup showed improvement in cognitive function over time, van Dyck added.

The results were presented on July 30 at the Alzheimer’s Association International Conference (AAIC) 2025.

Widening Benefit Over Time

The core CLARITY AD trial included 1795 adults with mild cognitive impairment or early AD and confirmed amyloid pathology in the brain. Treatment consisted of IV infusions of lecanemab 10 mg/kg biweekly (n = 898) or matching placebo (n = 897).

After 18 months of treatment, lecanemab slowed cognitive and functional decline, as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB), by 27% compared with placebo — an absolute difference of 0.45 points (P = .00005).

To provide context, a change from 0.5 to 1.0 on the CDR score domains of memory, community affairs, and home/hobbies reflects a shift from mild impairment to loss of independence.

Of the patients who completed the core 18-month study, 95% elected to continue in the open-label extension study, with 478 patients treated for 4 years.

Some of these participants transitioned to once-monthly intravenous (IV) infusions, consistent with the FDA-approved regimen, and some transitioned to subcutaneous injections, a regimen currently under review by the FDA.

Over 3 years of treatment, including both the core study and the open-label extension, lecanemab demonstrated a reduction in cognitive decline of 1.01 points on the CDR-SB compared to the expected decline observed in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, van Dyke reported. This benefit grew more pronounced after 4 years, with a reduction of 1.75 points compared to natural history.

Similarly, when benchmarked against the expected decline in the BioFINDER cohort, lecanemab showed a reduction of 1.40 points at 3 years and 2.17 points at 4 years.

Through 4 years, lecanemab reduced the relative risk of progression to next disease stage by 34% compared with ADNI; 53% of lecanemab-treated patients progressed to next disease stage vs 70% of those in the ADNI cohort.

Lecanemab also reduced the relative risk of progression to dementia stage by 56%; 19% of lecanemab-treated patients progressed to dementia vs 37% of ADNI patients. 

Earlier Treatment Better

Among participants in the tau PET substudy who had low tau levels, 69% showed improvement or no decline and 56% showed improvement from baseline on the CDR-SB after 4 years of lecanemab. 

Similar results were seen on the AD Assessment Scale-cognitive subscale-14; 51% of patients showed improvement or no decline, and 51% showed improvement. 

Likewise, on the AD Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment, 64% of patients showed improvement or no decline, and 58% showed improvement. 

These findings suggest that starting and maintaining treatment with lecanemab in early-stage AD may help slow clinical decline and may provide sustained benefits over the long term, van Dyck said. 

No new safety signals were observed in the open-label extension phase with continued lecanemab treatment over 4 years. “Most all of the adverse events actually go down in frequency over time, and none of them go up,” he said. 

Rates of amyloid-related imaging abnormalities (ARIA) decreased after the initial 12 months and remained consistent throughout four years of continuous treatment.

Rates of ARIA related to edema (ARIA-E) were 13% at less than 12 months and declined to 1% at 36-48 months. Rates of ARIA related to hemorrhage (ARIA-H) were 15% at less than 12 months and 9% at 36-48 months. 

‘Exciting’ Long-Term Data

Reached for comment, Rebecca M. Edelmayer, PhD, vice president of scientific engagement for the Alzheimer’s Association, told Medscape Medical News it’s “exciting to see that patients continue to show less decline and potentially even improvement in their clinical scores over time” and that the safety profile is “consistent over time without any new types of safety events.” 

Edelmayer also noted that the open-label extension data from CLARITY-AD are in line with other “real-world” data presented at AAIC 2025 from clinics using lecanemab that have demonstrated “fairly similar safety and efficacy patterns.” 

Also providing perspective, Howard Fillit, MD, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation, noted that the analysis didn’t have a stable control group, so the comparisons lean on historical data. But the fact that some patients improved or remained stable over time with continued lecanemab dosing is a “major advance.”

“It’s actually pretty amazing because not only has this historically been thought of as a chronic, uniformly progressive and ultimately fatal disease, but we never really thought that there would be a drug, at least I didn’t, that would actually improve patients on a disease-modifying basis as this drug seems to do,” Fillit, who wasn’t involved in the study, told Medscape Medical News.

Fillit noted that the risk-benefit profile for lecanemab in this open-label study is “fairly favorable. The rate of serious side effects is quite low, and I think this kind of study can help allay some of those fears about side effects.”

He also noted that having a subcutaneous dosing option or lecanemab (if approved) will be a “game changer” enabling at-home dosing and reducing the burden and inconvenience of having to go to a center to get an infusion of lecanemab.

The FDA is set to decide on whether or not to approve the company’s biologics license application for lecanemab subcutaneous autoinjector later this month.

The CLARITY AD study was funded by Eisai and Biogen. van Dyck has been an advisor/consultant for Eisai, Roche Pharmaceuticals, Ono Pharmaceuticals, Bristol Myers Squibb, Cerevel, and UCB.