Abstract
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.
Introduction
Alzheimer's disease (AD), an irreversible, progressive neurodegenerative condition, is the leading cause of dementia globally and the leading cause of age-related disease. 1 It is becoming a more serious public health issue, with an estimated threefold rise in incidence during the following 50 years. 1 However, the specific etiology of this condition is still unknown. Pathophysiologically, AD is defined by the buildup of extracellular senile plaques consisting of amyloid-beta (Aβ) peptides and intracellular neurofibrillary tangles. The absence of widely accessible disease-modifying medication and no curative treatment makes managing patients with AD challenging. For more than two decades, it has been proposed to treat AD by eliminating amyloid. Findings from several studies show that when Aβ peptides accumulate abnormally in the brain, they serve as the pathogenic trigger of downstream events that culminate in progressive cognitive impairment. 2 As a result, Aβ peptides have emerged as a possible target for disease-modifying interventions. 2 With the first active Aβ immunotherapy, AN1792, removal of Aβ from the brain has been accomplished but safety issues have pushed researchers to transition from active to passive immunization, mostly by monoclonal antibodies (mAbs). These medications represent a significant advancement in the ongoing battle to treat AD effectively. Lecanemab, also known as BAN2401, is such an agent that targets the fundamental pathophysiology of AD. On 6 January 2023, the U.S. Food and Drug Administration (FDA) approved it for the treatment of early AD under the Accelerated Approval pathway. 3 On July 6, 2023, it was granted traditional approval making it the first Alzheimer's treatment of its kind to make this transition. 4
Lecanemab is a humanized IgG1 form of the murine antibody mAb158 that primarily targets soluble Aβ protofibrils while still being active against insoluble fibrils (Figure 1). Aβ protofibrils are large, soluble Aβ aggregates that cause neurotoxicity by interfering with the electrophysiological systems involved in memory function.
2
Lecanemab has been demonstrated to decrease pathogenic Aβ, prevent Aβ deposition, and specifically diminish Aβ protofibrils in the brain and CSF of animal models of AD.5,6 The selective target of Aβ protofibrils separates lecanemab from other anti-amyloid mAbs. Lecanemab is the most efficient second-generation mAb for immunodepletion of Aβ protofibrils, particularly soluble protofibrils and oligomers. Lecanemab binds tiny protofibrils with 100 times the affinity of aducanumab and big protofibrils with 25 times the affinity, with lower binding affinity for monomers.
7
In humans, lecanemab has been evaluated in several clinical trials. However, there is a need for a systematic review of the available evidence to evaluate the efficacy and safety of lecanemab in AD. Mechanism of action of lecanemab.
Therefore, the aim of this systematic review is to comprehensively assess the current evidence on lecanemab for the treatment of AD. To the authors' knowledge, this is the first systematic review to discuss the efficacy, safety, and tolerability of this novel medication. A systematic search of electronic databases and identification of relevant studies that evaluate the effects of lecanemab on cognitive outcomes and adverse events in individuals with AD have been conducted in this study.
Methods
A systematic review was conducted to identify clinical trials of lecanemab therapy for AD. Until July 2023, a systematic search of the National Institute of Health clinical trials registry, PubMed, and the Cochrane library was conducted using the following search terms: lecanemab, BAN2401, and Alzheimer's PRISMA flow diagram showing selection process of the studies included in this review.
Results
Initially, 107 studies were identified, and 69 studies were retained after duplicates were removed; among these, 3 clinical trials were included for final analysis because they focused on the efficacy, tolerability, and safety of lecanemab (Figure 2). There was no research discovered that was not in English.
Clinical pharmacology
Pharmacokinetic parameters of IV lecanemab 10 mg/kg, biweekly.
The parameters were calculated after the final dose of lecanemab.
AUC area under the concentration-time curve, C max maximum concentration achieved.
The study by Logovinsky et al. 7 investigated the pharmacokinetics and pharmacodynamics of lecanemab. In the single ascending dose (SAD) cohort, the mean serum concentration time profiles of BAN2401 for increasing doses were consistent with first-order elimination kinetics. The median tmax (time to reach maximum concentration) occurred approximately 1.8 to 2.2 h after the start of infusion. The mean maximum concentration (C max ) and the area under the curve (AUC) increased proportionally with BAN2401 dose from 0.3 to 15 mg/kg. The mean serum half-life of BAN2401 was estimated to be 165 h (6.9 days) and 174 h (7.3 days) for subjects receiving 10 and 15 mg/kg of BAN2401, respectively.
In the multiple ascending doses (MAD) cohorts, the levels of Cmax and AUC for both the first and final doses of BAN2401 increased in proportion to the dosage, ranging from 0.3 mg/kg monthly to 10 mg/kg biweekly. The elimination phase of the drug showed consistency with first-order kinetics, with the mean half-life of BAN2401 varying between approximately 127 h (5.3 days) after the final dose in the 10 mg/kg biweekly MAD cohort and 174 h (7.3 days) in the 15 mg/kg SAD cohort.
Furthermore, the study explored the concentration of BAN2401 in cerebrospinal fluid (CSF) compared to serum. The CSF:serum ratios ranged from 0.04 to 0.08% at 24 h after the final dose in the three lower dose MAD cohorts, showing no accumulation. However, in the 10 mg/kg biweekly MAD cohort, where there was serum accumulation of BAN2401, the CSF:serum ratio was 0.13% at 24 h after the final dose, increasing to 0.29% at 14 days after the final dose.
The pharmacodynamics of BAN2401 were also evaluated, revealing small dose-dependent increases in plasma Aβ(1-40) levels in the MAD cohorts within a few hours after both the first and final doses. However, there were no significant effects of BAN2401 on CSF Aβ(1-42), t-tau, or p-tau compared to placebo in the MAD cohorts.
Clinical trials
Description of trials and characteristics of trial participants.
SAD: Single ascending dose, MAD: Multiple ascending doses, MMSE: Mini-Mental State Examination, SD: Standard deviation.
Key characteristics of randomized clinical trials of lecanemab.
CFB: Change from baseline, ADCOMS: Alzheimer’s Disease Composite Score, TRAEs: Treatment-related adverse events, SAEs: Serious adverse events.
The first double-blind, randomized, placebo-controlled study (NCT01230853) investigated the safety and tolerability of BAN2401 in subjects with mild to moderate AD. 9 The study was divided into two parts: a SAD study and a MAD study. In the SAD study, subjects received a single infusion of BAN2401 at varying doses (0.1–15 mg/kg), while in the MAD study, subjects received multiple infusions of BAN2401 at doses of 0.3, 1, or 3 mg/kg every 4 weeks for a total of four doses or 10 mg/kg biweekly for a total of seven doses.
Each cohort consisted of eight subjects, with two randomized to placebo and six to lecanemab. The study monitored the safety and tolerability of BAN2401, including the presence of ARIA-E, ARIA-H, vital signs, electrocardiogram (ECG), laboratory data, and adverse events.
The results showed that BAN2401 was generally well-tolerated, with no severe treatment-emergent adverse events (TEAEs) reported. The most frequently observed TEAEs were mild or moderate and included dizziness (8.3 vs. 8.3% on placebo), fatigue (5.6 vs 8.3% on placebo), sinusitis (5.6 vs 0% on placebo), upper respiratory tract infection (16.7 vs. 12.5% on placebo), headache (12.5 vs. 25% on placebo), and orthostatic hypotension (12.5 vs. 0% on placebo). There was no trend of increasing incidence of TEAEs with increasing doses of BAN2401.
In the SAD study, one subject in the 0.3 mg/kg cohort and one subject in the 1 mg/kg cohort experienced asymptomatic ARIA-H detected on routine MRI scans, which were considered possibly related to the study drug. However, both subjects remained clinically stable throughout the study, and the ARIA-H had completely resolved by the end of the study. One subject in the 3 mg/kg cohort had an abnormal MRI finding associated with a brain nodule secondary to metastasis from a primary lung tumor, which was not considered related to the study.
Three participants in the MAD trial (including one on placebo) had new asymptomatic ARIA-H found on MRI scans, but all three were clinically stable throughout the research, and no new aberrant neurological or MRI abnormalities related with these ARIA-Es were discovered. Overall, the results suggest that BAN2401 was generally well-tolerated in subjects with mild to moderate AD, with no severe adverse events reported.
In another randomized, double-blind, phase 2b proof-of-concept clinical trial (NCT01767311), the efficacy and safety of lecanemab in participants with early AD was evaluated. 8 The study randomized 856 subjects, of whom 854 received treatment (lecanemab: 609; placebo: 245), at 117 sites across North America, Europe, and the Asia-Pacific region. The allocation of subjects to different doses was determined by an adaptive randomization algorithm that identified both 10 mg/kg biweekly and 10 mg/kg monthly as potential effective doses. With the exception of more male individuals in the lecanemab group compared to placebo, demographic and baseline characteristics were similar across treatment groups.
Using a Bayesian model, the study determined that the effective dosage of lecanemab was 10 mg/kg biweekly, defined as the dose achieving at least 90% of the maximum therapeutic effect. The Bayesian analyses for reducing clinical decline at 18 months compared to placebo for the 10 mg/kg biweekly dosage on ADCOMS, CDR-SB, and ADAS-Cog14 were consistent with the results obtained from the equivalent frequentist analysis for clinical measures.
Over the 18-month period, lecanemab exhibited a dose-dependent reduction in change from baseline on ADCOMS, with 30% less clinical decline compared to placebo at 10 mg/kg biweekly and 15% less decline at the intermediate dosage of 10 mg/kg monthly. In relation to placebo, lecanemab decreased clinical deterioration on CDR-SB by 26% at 10 mg/kg biweekly and 17% at 10 mg/kg monthly, but these changes did not reach nominal significance. On the ADAS-Cog14, lecanemab at 10 mg/kg biweekly reduced clinical deterioration by 47% compared to placebo over the 18 months. The intermediate dosage of 10 mg/kg monthly decreased clinical deterioration by 6% on the ADAS-Cog14. These differences from placebo were observed as early as 6 months and were sustained throughout the 18-months treatment period. The data on the moderate AD dementia and MCI subgroups within the study population were generally consistent, although limited and challenging to interpret due to the small sample size.
The rates of adverse events, major adverse events, and treatment-emergent adverse events were comparable between the placebo and lecanemab treatment groups and aligned with the expectations for the population under investigation. Infusion reactions were the most frequent treatment-emergent adverse events, occurring more frequently in the lecanemab groups, but generally responding well to preventive measures. ARIA-E occurred in approximately 10% of the overall population and 14.3% of ApoE4-positive individuals. Most cases of ARIA-E were mild-to-moderate and resolved within 4–12 weeks. Symptomatic ARIA-E occurred in 11% of ApoE4+ participants with ARIA-E, with most instances involving headache, visual abnormalities, or disorientation. The radiologic severity of symptomatic cases varied from mild to severe, with the highest incidence seen in the 10 mg/kg biweekly group. ARIA-H occurred in a higher proportion of participants in the lecanemab groups compared to the placebo group, but there were no dose-related trends in the incidence of ARIA-H on lecanemab. ARIA-H was more common in ApoE4 carriers than non-carriers, and there were no symptomatic cases in Study 201. Overall, lecanemab was well-tolerated, with a safety profile comparable to previous studies.
Another pivotal phase III clinical trial (NCT03887455) involved 5967 individuals who underwent screening, and out of them, 1795 were randomized. 11 The participants, aged between 50 and 90 years, had early AD, characterized by mild dementia or mild cognitive impairment due to AD, with evidence of amyloid presence confirmed through positron emission tomography (PET) or cerebrospinal fluid testing. Among the 1795 participants, 898 were randomly assigned to receive lecanemab (10 mg/kg of body weight every 2 weeks), while 897 received a placebo. The enrollment took place at 235 sites in North America, Europe, and Asia from March 2019 to March 2021. Ultimately, 729 participants in the lecanemab group and 757 in the placebo group completed the trial and provided data on the primary endpoint.
The primary endpoint of the study was the change in the CDR-SB score at 18 months. The adjusted mean change from baseline at 18 months in the CDR-SB score was 1.21 in the lecanemab group and 1.66 in the placebo group, showing a statistically significant difference of –0.45 (95% confidence interval [CI], –0.67 to –0.23; p<.001) in favor of lecanemab. The study also examined several secondary endpoints, including the change in amyloid burden on PET, ADAS-cog14, ADCOMS), and ADCS-MCI-ADL score, all of which demonstrated significantly better outcomes in the lecanemab group compared to the placebo group.
Efforts were made in the trial to ensure global enrollment of a diverse group of participants, particularly in the United States, where 6.1% and 28.1% of the 3638 screened participants, and 4.5% and 22.5% of randomly assigned participants were Black and Hispanic, respectively. However, the study noted an underrepresentation of Black individuals in the United States and an overrepresentation of Hispanic individuals in the country.
The study's findings were generally consistent across sensitivity analyses and key randomization strata. However, the authors advise against drawing firm conclusions based solely on the visual inspection of graphs at 3 months, as there was no predefined plan for analysis that included adjusting confidence intervals for multiple comparisons at any intermediate time point. Additionally, in an exploratory subgroup analysis involving ApoE ε4 homozygotes, consistent results were observed across key endpoints.
The most common adverse events in the lecanemab group were infusion-related reactions, ARIA-H, headache, and falls. Infusion-related reactions were mostly mild to moderate, and preventative medications were not used by over half of the participants who did not experience any reactions after the first dose. ARIA-E events with lecanemab were mostly mild to moderate, asymptomatic, and occurred early in the treatment period. Symptomatic ARIA-E occurred in a small percentage of participants, with headache, visual disturbance, and confusion being the most commonly reported symptoms. ARIA-H occurred more frequently with lecanemab than with placebo, and isolated symptomatic ARIA-H occurred in a small percentage of participants. The incidence of ARIA-E and ARIA-H tended to be higher among ApoE ε4 carriers than non-carriers, and higher among ApoE ε4 homozygotes than heterozygotes.
The incidence of deaths in both the lecanemab and placebo groups was low (0.7% vs. 0.8%, respectively), and none of the deaths were considered related to the drug. The overall incidence of adverse events was similar in both groups, but the lecanemab group had a higher rate of serious adverse events (14.0% vs. 11.3%). The most common serious adverse events reported with lecanemab were infusion-related reactions, ARIA-E, atrial fibrillation, syncope, and angina pectoris.
This trial has several limitations to consider. Firstly, it only covers 18 months of treatment, with an ongoing open-label extension study. Conducted during the COVID-19 pandemic, the trial faced challenges like missed doses, delayed assessments, and intercurrent illnesses. The dropout rate was 17.2%, and sensitivity analyses showed consistent results with the primary analysis, accounting for missed doses. Furthermore, the occurrence of ARIA may have led to participants and investigators becoming aware of the trial-group assignments. Efforts were made to minimize this bias by keeping clinical raters unaware of safety assessments and trial-group assignments.
Appropriate use recommendations
Patients receiving lecanemab should closely resemble those in the clinical trials that demonstrated its safety and efficacy. To reduce the risk of ARIA, it's advisable to exclude individuals with more than four microhemorrhages or evidence of cerebrovascular disease. Patients on anticoagulants or needing thrombolytic therapy for ischemic stroke should not be given lecanemab. The treatment is administered intravenously every other week without titration. MRI scans are recommended at baseline, before the 5th, 7th, and 14th infusions, and at 52 weeks for APOE4 carriers or those with prior ARIA. Additional MRIs are needed if symptoms of ARIA arise. Infusion reactions are common and may require preventive measures with anti-inflammatory therapies. 12
Discussion
For years, large clinical trials of anti-amyloid immunotherapies have failed to translate into clinical benefit, leading to doubts about the viability of this therapeutic strategy. However, the positive results from the lecanemab trial, 11 along with previous observations in mouse models and early human studies, indicate that targeting amyloid-β might be a promising approach for disease modification in AD. The trial's findings provide strong evidence that amyloid removal could be a worthwhile pursuit, even in the symptomatic stages of AD. Despite previous disappointments, the substantial reduction in decline observed in the lecanemab-treated group is encouraging. While other contributing causes may be targeted as well, the ability to slow the disease's progression at a symptomatic stage offers hope for patients and their families. However, it is essential to recognize that achieving clinical benefits may require reducing amyloid levels significantly and for an extended period. As such, further investigations into the optimal treatment duration and dosing are warranted.
Although the 27% slowing observed in the lecanemab-treated group over 18 months represents an improvement, important questions remain about the sustainability of this effect and the potential for cumulative clinical benefits. The trial's design did not address these questions explicitly, but some data trends indicate a gradual widening of the gap between the treatment and placebo groups over time. Therefore, longer-term follow-up studies are critical to assess the durability of lecanemab's effects and its potential to provide cumulative benefits in the management of AD.
The success of lecanemab in delaying decline is commendable, especially when coupled with findings from a Phase 2 trial of donanemab, 13 another anti-amyloid immunotherapy. These results validate the clinical benefits of amyloid-β removal, providing valuable insights into the necessary features for successful outcomes. However, the modest clinical benefits observed raise intriguing questions about the factors influencing treatment response. Potential reasons for this modesty include incomplete amyloid-β removal or the emergence of autonomous neurodegenerative processes independent of amyloid-β accumulation. To enhance the clinical benefits, targeting downstream pathways and initiating treatment in asymptomatic individuals before tauopathy acceleration may be viable strategies worth exploring. 14
It is crucial to address the therapeutic challenges of AD. While amyloid-β targeting has shown promise, its limitations highlight the complexity of late-life cognitive impairment. The heterogeneity of the disease necessitates personalized approaches and potentially combination therapies to maximize therapeutic efficacy. Additionally, safety concerns, such as the occurrence of ARIA, underscore the importance of comprehensive strategies to manage adverse events and preserve blinding in clinical trials.
As lecanemab enters the marketplace, careful consideration of its potential impact and challenges is essential. Affected individuals and their families will face difficult decisions in weighing the modest benefits against safety concerns, especially considering the treatment limitations for certain patients. Overcoming these challenges will require collaborative efforts from researchers, clinicians, and policymakers to ensure equitable access to potentially more beneficial therapies for patients worldwide.
Conclusion
Lecanemab's approval represents a significant advancement in the treatment of AD, with promising results in clinical trials. While it is a significant step forward in the treatment of AD, there are still many unanswered questions about the drug's long-term safety and effectiveness. Additionally, the high cost of the drug may limit its accessibility to those who need it. Long-term studies are needed to assess the safety and effectiveness of lecanemab beyond the clinical trial period. Identifying reliable biomarkers to monitor disease progression and response to treatment is essential for the optimal use of lecanemab. While clinical studies have demonstrated that lecanemab is more effective than placebo in lowering Aβ burden in persons with early AD, no head-to-head evaluations of lecanemab versus other AD medicines have been conducted. Combining lecanemab with other treatments may improve outcomes for patients with AD. Future research and clinical efforts should focus on improving the use of lecanemab for patients with AD by investigating its long-term safety and effectiveness, identifying reliable biomarkers, exploring combination therapy, addressing cost-effectiveness, and developing appropriate patient selection criteria.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
