Lecanemab 500mg/5ml solution for infusion vials

Abstract Background Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease (AD) and mild AD dementia. Methods BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer’s Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging. Results A total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (−0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly. Conclusions BAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer’s disease is underway. Trial registration Clinical Trials.gov NCT01767311 .

Abstract licence: CC BY 4.0

Abstract We report the case of a 79-year-old woman with Alzheimer’s disease who participated in a Phase III randomized controlled trial called CLARITY-AD testing the experimental drug lecanemab. She was randomized to the placebo group and subsequently enrolled in an open-label extension which guaranteed she received the active drug. After the third biweekly infusion, she suffered a seizure characterized by speech arrest and a generalized convulsion. Magnetic resonance imaging revealed she had multifocal swelling and a marked increase in the number of cerebral microhemorrhages. She was treated with an antiepileptic regimen and high-dose intravenous corticosteroids but continued to worsen and died after 5 days. Post-mortem MRI confirmed extensive microhemorrhages in the temporal, parietal and occipital lobes. The autopsy confirmed the presence of two copies of APOE4, a gene associated with a higher risk of Alzheimer’s disease, and neuropathological features of moderate severity Alzheimer’s disease and severe cerebral amyloid angiopathy with perivascular lymphocytic infiltrates, reactive macrophages and fibrinoid degeneration of vessel walls. There were deposits of β-amyloid in meningeal vessels and penetrating arterioles with numerous microaneurysms. We conclude that the patient likely died as a result of severe cerebral amyloid-related inflammation.

Abstract licence: CC BY 4.0

Background Lecanemab is the latest monoclonal antibody that targets beta-amyloid approved exclusively for treatment of Alzheimer’s disease with mild cognitive impairment or mild dementia. This article aims to provide a systematic review of the efficacy, and safety of lecanemab in slowing clinical decline in Alzheimer’s disease. Methods A comprehensive search of various databases, including the National Institute of Health clinical trials registry, PubMed, and the Cochrane library, was conducted until July 2023 using the keywords lecanemab, BAN2401, and Alzheimer's disease. Additionally, conference abstracts listed in the Cochrane database (including Embase) and drug information from the US Food and Drug Administration (FDA) label were examined. Only clinical trials published in the English language were considered. In total, 107 articles were retrieved, and after thorough evaluation, three randomized, double-blind, multicenter clinical trials involving 2729 participants were included in the analysis. Results The FDA approved lecanemab for Alzheimer's disease in January 2023 which acts as a novel disease-modifying anti-amyloid-beta (Aβ) human monoclonal antibody and is administered intravenously. Based on the clinical trials included in this review, lecanemab was found efficacious in reducing the accumulation of beta-amyloid and slowing down the cognitive decline and it was well tolerated. Lecanemab had a statistically significant change from baseline in Clinical Dementia Rating–Sum of Boxes (CDR-SB), Alzheimer’s Disease Composite Score (ADCOMS), Alzheimer’s Disease Assessment Scale (ADAScog14), Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), and reductions in brain amyloid burden. The most common treatment-emergent adverse events were headache, infusion-related reactions, and Amyloid related imaging abnormalities-edema. Conclusions Lecanemab therapy led to a substantial decrease in amyloid plaques and a noticeable slowing of clinical decline. The findings suggest a meaningful connection between the reduction in amyloid and the positive impact on patients' clinical outcomes, hinting at potential disease-modifying effects.

Abstract licence: CC BY-NC 4.0

ObjectiveWe performed a systematic review and meta-analysis of the cognitive effectiveness and safety of lecanemab on subjects with Alzheimer's disease (AD).MethodsWe screened the literature published before February 2023 in PubMed, Embase, Web of Science, and Cochrane that were searched for randomized controlled trials testing lecanemab for the treatment of cognitive decline in patients with MCI or AD. Outcomes measured were CDR Sum of Boxes (CDR-SB), Alzheimer's Disease Composite Score (ADCOMS), AD Assessment Scale–Cognitive Subscale (ADAS-Cog), Clinical Dementia Rating (CDR), amyloid PET Standardized Uptake Volume Ratio (SUVr), amyloid burden on PET, and risks for adverse events.ResultsA total of four randomized controlled trials were included, involving 3,108 AD patients (1,695 lecanemab groups and 1,413 placebo groups) to synthesize evidence. Baseline characteristics of the two groups were similar in all outcomes except that ApoE 4 status and higher MMSE score were observed in the lecanemab group. It is reported that lecanemab was beneficial to stabilize or slow down the decrease in CDR-SB (WMD: −0.45; 95% CI: −0.64, −0.25;p< 0.00001), ADCOMS (WMD: −0.05; 95% CI: −0.07, −0.03;p< 0.00001), ADAS-cog (WMD: −1.11; 95% CI: −1.64, −0.57;p< 0.0001), amyloid PET SUVr (WMD: −0.15; 95% CI: −0.48, 0.19;p= 0.38), amyloid burden on PET (WMD:−35.44; 95% CI: −65.22,−5.67;p= 0.02), adverse events (subjects with any TEAE) (OR: 0.73; 95% CI: 0.25, 2.15;p= 0.57), ARIA-E (OR:8.95; 95% CI: 5.36, 14.95;p< 0.00001), and ARIA-H (OR:2.00; 95% CI: 1.53, 2.62;p< 0.00001) in early AD patients.ConclusionOur analysis found that lecanemab showed significant positive statistical efficacy with respect to cognition, function, and behavior in patients with early AD though the actual clinical significance is yet to be establishedSystematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier: CRD42023393393.

Abstract licence: CC BY 4.0