Early Alzheimer’s disease cognitive decline slowed by lecanemab

8th December 2022

An RCT has found that the cognitive decline in early Alzheimer’s disease and amyloid burden can be significantly reduced with lecanemab

The cognitive decline present in patients with early Alzheimer’s disease (AD) as well as the amyloid burden are significantly reduced compared to placebo, in those treated with lecanemab according to the results of a randomised, double-blind, phase 3 trial by US researchers.

There are an estimated 55 million across the world living with dementia of whom, approximately 60 to 70% have the most common form, Alzheimer’s disease. Currently available treatments such as cholinesterase inhibitors and memantine, do not alter disease progression but can help with some symptoms. Current thinking the pathophysiology of Alzheimer’s disease is based on the amyloid β-protein (Aβ peptides) theory which purports that in the early stages, there is an imbalance between production and clearance of Aβ peptides and which is a very early, often initiating factor in Alzheimer’s disease (AD). This leads to a build-up of Aβ peptides, and one therapeutic approach gaining interest is the use of monoclonal antibodies directed against amyloid-β (Aβ). In a 2021 systematic review of such antibodies directed against Aβ, there were clinical improvements but with small effect sizes.

In the current study, researchers examined the value of one such monoclonal antibody, lecanemab. Although in a phase 2b proof of concept trial in patients with early Alzheimer’s disease, the drug did not change clinical progression of the disease, it did demonstrate a reduction in brain amyloid accompanied by a consistent reduction of clinical decline in several endpoints. The current study was designed to evaluate the efficacy of lecanemab in patients with early Alzheimer’s disease, i.e., either mild cognitive impairment or mild dementia due to AD and with evidence of amyloid protein as assessed by either PET scan or CSF fluid measurement. Participants were randomised 1:1 to either intravenous lecanemab (10 mg/kg every two weeks) or placebo. The primary endpoint was the change from baseline after 18 months in the Clinical Dementia Rating Sum of Boxes (CDR-SB) which ranges from 0 to 18 and for which higher scores indicate greater cognitive impairment. There were several secondary endpoints, one of which was the change in amyloid burden on PET scanning whereas others assessed changes in cognition.

Early Alzheimer’s disease and change in cognition

A total of 1734 participants with a mean age of 71.2 years (52.3% women) were included and randomised to lecanemab (859) or placebo. The mean baseline CDR-SB score was approximately 3.2 in both groups.

The adjusted mean change from baseline in CDR-SB score was less with lecanemab (1.21) compared to placebo (1.66), i.e., there was less decline in cognition and the mean difference of -0.45 (95% CI -0.67 to -0.23) was statistically significant (p < 0.001).

In a subgroup of 698 participants, the mean amyloid level reduced by -55.48 centiloids in the lecanemab group and by 3.64 in the placebo group (mean difference = -59.12, 95% CI -62.64 to -55.60, p < 0.001).

There were also significant and positive changes favouring lecanemab in the cognition-related outcomes.

The overall incidence of adverse effects was similar between the two groups although lecanemab use resulted in a higher incidence of infusion-related reactions compared to placebo (26.4% vs 7.4%).

The authors concluded that the use of lecanemab reduced markers of amyloid in early Alzheimer’s disease and gave rise to moderately less decline on measures of cognition compared to placebo. They called for longer trials to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.

Citation
van Dyck CH et al. Lecanemab in Early Alzheimer’s Disease. N Eng J Med 2022 DOI: 10.1056/NEJMoa2212948

Lecanemab promising therapy for early Alzheimer’s disease

6th October 2022

Lecanemab use in patients with early Alzheimer’s disease appears to be a promising therapy according to early findings of a phase 3 trial

Lecanemab use in patients with mild cognitive impairment due to Alzheimer’s disease (AD) and mild AD (collectively known as early AD) demonstrated an improvement in cognitive function compared to placebo after 18 months of treatment according to a press release by the joint manufacturers Eisai Co., Ltd and Biogen Inc.

Alzheimer’s disease is a progressive neurodegenerative disease that slowly impairs cognition and function and is the most common form of dementia. The discoveries of amyloid β (Aβ) and tau, the main components of plaques and tangles respectively, has provided detailed information about the molecular pathogenetic events of the disease. Given the build-up of soluble Aβ aggregates, it is possible that a reduction of such aggregates could represent an effective treatment approach in the early stages of AD. Lecanemab is a humanised IgG1 monoclonal antibody that binds to soluble Aβ aggregates and in a phase 1 dose ranging study in patients with mild to moderate AD, the drug (known as BAN 2401) was well-tolerated across all doses. Based on these findings, a randomised, double-blind, placebo-controlled, phase 2 trial was undertaken in 854 subjects with early Alzheimer’s disease and observed a reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints.

Clarity AD was a phase 3 trial to evaluate the efficacy of lecanemab in patients with early Alzheimer’s disease. Participants were administered lecanemab at a dosage of 10 mg/kg bi-weekly and randomised 1:1 to either placebo or lecanemab. The primary endpoint was the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) after 18 months of treatment. The CDR-SB is a numeric scale used to quantify the various severity of symptoms of dementia and is an appropriate item for evaluating the effectiveness of therapeutic drugs targeting the early stages of AD. Based on interviews of people living with AD and family/caregivers, qualified healthcare professionals assess cognitive and functional performance in six areas: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The total score of the six areas is the score of CDR-SB. Key secondary endpoints for the trial were the change from baseline at 18 months compared with placebo of treatment in amyloid levels in the brain measured by amyloid positron emission tomography (PET), the AD Assessment Scale-cognitive sub-scale14 (ADAS-cog14), AD Composite Score (ADCOMS) and the AD Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL).

Lecanemab and treatment outcome

Clarity AD included 1,795 people with early AD and according to the press release, lecanemab met the primary endpoint and reduced clinical decline on the CDR-SB, compared with placebo at 18 months by 27%, which represents a treatment difference in the score change of -0.45 (p=0.00005) in the analysis of Intent-to-treat (ITT) population. Starting as early as six months, across all time points, the treatment showed highly statistically significant changes in CDR-SB from baseline compared to placebo (all p-values are less than 0.01). All key secondary endpoints were also met with highly statistically significant results compared with placebo (p<0.01).

The incidence of amyloid-related imaging abnormalities-oedema/effusion (ARIA-E), an adverse event associated with anti-amyloid antibodies, was 12.5% in the lecanemab group and 1.7% in the placebo group. The ARIA-H (ARIA cerebral micro-haemorrhages, cerebral macro-haemorrhages, and superficial siderosis) rate was 17.0% in the lecanemab group and 8.7% in the placebo group. The total incidence of ARIA (ARIA-E and/or ARIA-H) was 21.3% in the lecanemab group and 9.3% in the placebo group. Overall, lecanemab’s ARIA incidence profile was within expectations.

Commenting on these early findings, Dr Susan Kohlhaas, director of research at Alzheimer’s Research UK, said: “this is a historic moment for dementia research, as this is the first phase 3 trial of an Alzheimer’s drug in a generation to successfully slow cognitive decline. These results show that lecanemab slows the progression of memory and thinking problems in people with early Alzheimer’s, demonstrating a major breakthrough in dementia research. This is the first drug that’s been shown to not only remove the build-up of a protein called amyloid in the brain, but to have a small but statistically significant impact on cognitive decline in people with early-stage disease.’

In July 2022, it was announced that the U.S. Food and Drug Administration (FDA) has accepted the Biologics License Application (BLA) under the accelerated approval pathway for lecanemab.