Long‐term safety and efficacy of lecanemab in early Alzheimer's disease: Results from the clarity AD open‐label extension study

Abstract

INTRODUCTION

In Clarity AD, lecanemab reduced markers of amyloid in early symptomatic Alzheimer's disease and slowed cognitive and functional decline at 18 months. Herein, we report 36‐month data from the ongoing open‐label extension (OLE).

METHODS

Clarity AD is an 18‐month, randomized study (Core), with an OLE where participants received open‐label lecanemab. Clinical and health‐related quality‐of‐life (HRQoL) outcomes were evaluated overall and by examining “delayed‐start” and “early‐start” cohorts. Low pathology (i.e., low baseline amyloid or tau) subgroups were analyzed.

RESULTS

ARIA rates were low after 6 months and not associated with long‐term progression. Across clinical and HRQoL endpoints, lecanemab‐treated participants continued to benefit through 36 months. Separation between early and delayed start was maintained between 18 and 36 months. The low pathology subgroup showed stability or improvement over 18–36 months.

DISCUSSION

Benefit continued to accrue with ongoing lecanemab treatment through 36 months. Results in the low pathology subgroup support early initiation of lecanemab treatment.

Highlights

• This research evaluated the long‐term efficacy, safety, and HRQoL results from an ongoing extension of the phase 3 Clarity AD, which included open‐label lecanemab treatment for up to 36 months.

• Overall, the results show participants continue to accrue a lecanemab treatment benefit up to 36 months and highlight the importance of continued long‐term lecanemab treatment.

• Results presented in our paper demonstrate that lecanemab continued suppression of amyloid plaque levels and significantly slowed clinical decline on multiple measures of cognition, function, and quality of life in early AD at 18 months and continued for 36 months to date.

• No new safety signals were observed with continued lecanemab treatment. After the first 6 months, ARIA rates were low and similar to ARIA rates on placebo, with no association between ARIA occurrence and accelerated long‐term clinical progression.

• Taken together with existing data, these results provide a clear rationale and a demonstration of the disease modification effects of long‐term lecanemab therapy.

1. INTRODUCTION

Alzheimer's disease (AD) is the most common form of dementia and is defined by neuropathologic changes, including aggregated amyloid‐beta (Aβ) plaques and neurofibrillary tau tangles. ¹ , ² , ³ , ⁴ Cognitive impairment results from neuropathologic changes due to synapse and neuronal loss, neurotransmitter deficiencies, inflammation of the neurons, and astrogliosis. ² Aβ peptides exist in a dynamic continuum of conformational states from monomeric Aβ to soluble progressively larger Aβ assemblies that include a range of low molecular weight oligomers to higher molecular weight protofibrils, and finally to insoluble fibrils (plaques). ⁵ Various lines of evidence support the “amyloid cascade hypothesis” that Aβ plays a central role in the pathogenesis of AD. ⁶ Recently, phase 3 studies have demonstrated that anti‐amyloid disease‐modifying therapies can slow progression of the disease. ⁷ , ⁸

Lecanemab is a novel humanized immunoglobulin G1 mAb developed against Aβ protofibrils, based on the discovery of “Arctic” mutation in Swedish subjects with familial AD who were found to have an increased propensity for aggregation of Aβ to form protofibrils. ⁹ , ¹⁰ Aβ peptides exist in many different conformational states, including monomeric Aβ peptide, soluble Aβ aggregates of increasing size ranging from small dimers and trimers to larger oligomers and protofibrils, and insoluble fibrils. Aβ protofibrils have been implicated in altering synaptic function and mediating neurotoxicity, leading to cognitive decline and, ultimately, the dementia observed as AD progresses clinically. ¹¹ , ¹² Lecanemab was designed to selectively target these large soluble protofibrils relative to monomers (greater than 1000‐fold over Aβ monomers), while it also interacts with the insoluble fibrils that are a major component of brain amyloid. ⁵ , ⁶ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ In two randomized controlled trials, lecanemab has demonstrated a consistent slowing of decline in clinical (global, cognitive, functional, and quality of life) outcomes, and reduction in brain amyloid in early AD and is generally well‐tolerated, with 9%–12% incidence (< 3% symptomatic) of amyloid‐related imaging abnormalities‐edema (ARIA‐E). ⁷ , ¹⁹ , ²⁰ , ²¹ These results form the basis of the lecanemab regulatory approvals across the globe.

Herein, we present the long‐term safety, efficacy, and health‐related quality of life (HRQoL) results from an open‐label extension (OLE) of the phase 3 Clarity AD, which included lecanemab treatment for up to 36 months (data cutoff data =  March 31 2024) following the 18‐month, randomized, placebo‐controlled core phase of the study. We also detail new evidence of lecanemab efficacy in individuals with lower baseline pathology considered to represent an early pathologic stage of disease (defined as either low baseline amyloid or tau), as well as new safety analyses, including demonstrating the lack of impact of ARIA‐E occurrences on clinical progression.

2. METHODS

2.1. Trial design and oversight

The overall design of Clarity AD has been previously published. ⁷ Briefly, Clarity AD was an 18‐month global, multicenter, double‐blind, placebo‐controlled, parallel‐group study with an OLE in individuals with early AD. Eligible participants were randomized to placebo or lecanemab 10 mg/kg IV biweekly according to a fixed 1:1 schedule.

The OLE evaluated the long‐term safety and tolerability of lecanemab in participants with early AD and whether the long‐term clinical effects of lecanemab, as measured by the efficacy assessments at the end of the Core Study, were maintained over time in the OLE. Any subject who completed the Core study and met OLE eligibility criteria could receive lecanemab in the OLE. Data presented include participants who received intravenous and subcutaneous lecanemab during the OLE. Clarity AD OLE substudies evaluating subcutaneous formulations and maintenance dosing regimens will be published elsewhere.

The study was conducted in accordance with International Conference on Harmonisation guidelines and ethical principles of the Declaration of Helsinki. The trial was approved by the institutional review board or independent ethics committee at each center, and all participants provided written informed consent.

The trial protocol and statistical analysis plan can be found in the Supplementary Materials.

2.2. Eligibility criteria

Clarity AD OLE participants must have completed the Core Clarity AD study and therefore, have met the Core study eligibility criteria. Clarity AD included participants aged 50 to 90 years, with either mild cognitive impairment due to AD or mild AD dementia based on National Institute of Aging–Alzheimer's Association (NIA‐AA) criteria. ²² , ²³ Amyloid pathology was confirmed by positron emission tomography (PET) or cerebrospinal fluid (CSF) measurement of t‐tau/Aβ(1‐42). All participants were required to have objective impairment in episodic memory as indicated by ≥1 standard deviation below the age‐adjusted mean in the Wechsler Memory Scale IV‐Logical Memory (subscale) II. Individuals were excluded if they developed significant medical conditions that would interfere with study conduct. Additional entry criteria are summarized in prior publications. ⁷ , ¹⁹

RESEARCH IN CONTEXT

1. Systematic review: The authors reviewed the literature utilizing PubMed and recent meeting abstracts. Relevant citations on research on anti‐amyloid therapy in Alzheimer's disease (AD) are cited. Various lines of evidence support the “amyloid cascade hypothesis” that amyloid‐beta (Aβ) plays a central role in the pathogenesis of AD. Recently, phase 3 studies have demonstrated that anti‐amyloid disease‐modifying therapies can slow progression of the disease.

2. Interpretation: Our findings demonstrate the benefits and safety of continued long‐term lecanemab treatment through 36 months. Patients at a lower pathologic stage generally showed stability or improvement over 18–36 months, supporting early initiation of treatment with lecanemab. No new safety signals were observed with low amyloid‐related imaging abnormalities (ARIA) rates similar to ARIA rates on placebo after 6 months. Taken together with existing data, our results support disease‐modification effects of long‐term lecanemab therapy.

3. Future directions: Further research may include the evaluation of lecanemab in related populations and the evaluation of lecanemab in new formulations that may improve patient care.

2.3. Endpoints

The primary endpoints were the incidence of adverse events and changes in vital signs, electrocardiograms, laboratory safety tests, suicidality assessments, anti‐drug antibodies, and magnetic resonance imaging (MRI) safety parameters and change from Core Study baseline in Clinical Dementia Rating–Sum of Boxes (CDR‐SB). Additional endpoints included change from Core Study baseline in amyloid PET using Centiloids (with either florbetaben, florbetapir, or flutemetamol tracers), Alzheimer's Disease Assessment Scale‐Cognitive Subscale 14 (ADAS‐Cog14), ²⁴ Alzheimer's Disease COMposite Score (ADCOMS), ²⁵ and Alzheimer's Disease Cooperative Study‐Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS‐MCI‐ADL). ²⁶

For the current analyses, efficacy was compared to an Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, with data obtained from the ADNI database (adni.loni.usc.edu). Briefly, a matched observational cohort from ADNI was created a priori during the design of Clarity AD to aid in decision‐making for the protocol design. The observational cohort criteria were: (1) baseline diagnosis of mild cognitive impairment (MCI) with global CDR = 0.5 and CDR memory ≥0.5 or baseline diagnosis of “AD” with global CDR = 0.5 or 1.0 and CDR memory ≥0.5; (2) proportion of MCI (60%) and mild AD (40%); (3) baseline MMSE ≥22; (4) at least 1 of 2 criteria for amyloid positivity; (4a) baseline amyloid PET standardized uptake value ratio (SUVR) florbetapir ≥1.11 or amyloid PET SUVR Pittsburgh compound B (PIB) ≥1.47 or (4b) baseline CSF total tau/amyloid beta (Aβ) > 0.222. Using this ADNI cohort, the rate of decline at 18 months and variability in the data were estimated for power calculations in Clarity AD. This same ADNI cohort was applied to Clarity AD enrollment criteria, matching expected patient characteristics, during the recruitment of the study. As can be seen from Table SA, baseline demographic and clinical characteristics match between Clarity AD core and the pre‐specified matched ADNI cohort. Additional descriptive information on the ADNI observational cohort can be found in Appendix SA.

Safety evaluations included monitoring of adverse events, vital signs, physical examinations, clinical laboratory parameters, and 12‐lead electrocardiograms. ARIA occurrence was monitored throughout the study by central reading of MRI performed for safety monitoring. Safety results include data only from participants receiving intravenous lecanemab.

Biomarker assessments included plasma biomarkers (Aβ 42/40 ratio, p‐tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL), CSF biomarkers, tau PET, and volumetric MRI. These results will be published separately.

HRQoL assessments included in this analysis European Quality of Life–5 Dimensions (EQ‐5D‐5L), Quality of Life in AD (Qol‐AD), and Zarit Burden Interview (ZBI) as described in Cohen et al. 2023. ²⁷ Briefly, the effects of lecanemab 10 mg/kg biweekly compared to placebo on HRQoL in subjects with early AD up to 36 months of treatment as measured by the EQ‐5D‐5L and Qol‐AD. In addition, the effects of lecanemab compared to placebo on study partner burden were evaluated by the ZBI. EQ‐5D‐5L measures 5 dimensions of health (mobility, self‐care, usual activities, pain or discomfort, and anxiety or depression) with 5 levels of severity in each dimension (no problems, slight problems, moderate problems, severe problems, and unable to perform or extreme problems). The overall current health is scored as Health Today by a visual analog scale (VAS; 0 [worst imaginable health state] to 100 [best imaginable health state]). Qol‐AD is a 13‐item questionnaire designed to provide an assessment of Qol of patients with AD, with each of the 13 items assessed on a scale of 1–4 (poor, fair, good, or excellent). In addition to direct reporting from the patient, the Qol‐AD scales provide the opportunity for separate reporting by the study care partner as a proxy for the patient. ZBI is a 22‐item instrument completed solely by the care partner, which is used in dementia caregiving research to assess the stresses experienced by study partners of patients with dementia. The total score range is 0–88 (0–21: no to mild burden; 21–40: mild to moderate burden; 41–60: moderate to severe burden; 61–88: severe burden).

2.4. Statistical analysis

The statistical analysis for the overall Clarity AD Core study was previously published. ⁷ For the OLE, there were no formal statistical hypothesis testing; all analyses were descriptive. Efficacy analyses were performed in the modified intention‐to‐treat population, which was defined as the group of randomly assigned participants who received at least one dose of lecanemab or placebo and who had a baseline assessment and at least one post‐dose primary efficacy (CDR‐SB) measurement. For the efficacy analyses broken down by Core drug assignment, individuals who were randomized to lecanemab in the Core were considered “early start” participants relative to those who were randomized to placebo in the Core (i.e., “delayed start” participants) since they started lecanemab 18 months earlier than those who started on placebo. Adjusted mean change from Core baseline was derived using the same mixed model for repeated measures (MMRM) as used in the Core, ⁷ which includes the baseline value as a covariate, with treatment group, visit, stratification variables (i.e., clinical subgroup, use of medication for symptoms of AD at baseline [yes or no], apolipoprotein E (ApoE) ε4 carrier status [carriers or noncarriers], and geographic region [North America, Europe, and Asia–Pacific]), baseline value–by‐visit interaction, and treatment group–by–visit interaction as fixed effects. Efficacy was compared to an ADNI cohort.

Efficacy was also assessed in the subgroup of participants with lower pathology—considered to represent an early pathologic stage of disease—as defined as having either low or no tau (cutoffs for MK tau PET: No/Low SUVR < 1.06; Intermediate SUVR 1.06–2.91; High SUVR > 2.91) or having a baseline amyloid of < 60 Centiloids (CL). The amyloid PET < 60 CL was chosen to best identify the low tau subgroup in the full cohort. Efficacy assessments were also summarized as the percentage of participants who had “no decline” or had “improvement” from the Core baseline at each time point.

A post‐hoc analysis of CDR‐SB time to worsening was conducted in which progression was defined as CDR‐SB Score progressing from MCI (0.5–4) to mild AD dementia (4.5–9) or mild dementia to moderate dementia (9.5–15.1) based on dementia staging on CDR‐SB. ²⁸ Since controlled‐based imputation was used for missing data in this analysis (especially for less frequent ADNI assessments), CDR‐SB (which has a greater range) was used rather than global CDR for disease staging. For the amyloid PET and HRQoL endpoints, the MMRM analysis was also performed.

Safety analyses were performed for the lecanemab‐treated period in the safety analysis set. Subjects who received lecanemab in the Core and subjects who received placebo in the Core and lecanemab in the OLE were included. Adverse events were reported descriptively by preferred term and coded according to the Medical Dictionary for Regulatory Activities version 25. As a detailed paper on Clarity AD OLE safety was recently published, ¹⁹ this paper focuses on data for exposure adjusted rates (EAR) of adverse events, assessing longer term ARIA risk, and whether ARIA is associated with AD progression.

ARIA‐E and isolated ARIA‐hemosiderin/hemorrhage (ARIA‐H) cases were evaluated by baseline microhemorrhages (presence or absence) and age‐related white matter change at baseline (score ranging from 0–3, with 0 = no lesions (including symmetrical, well‐defined caps or bands), 1 = focal lesions, 2 = beginning confluence of lesions, and 3 = diffuse involvement of entire region, with or without involvement of U‐fibers. Results of the subgroup analyses are summarized descriptively.

3. RESULTS

3.1. Participants

This study was conducted in sites across North America, Europe, and Asia. Data presented from the Core include 1795 participants from Clarity AD double blind, 897 randomized to placebo, and 898 randomized to lecanemab. A CONSORT diagram for the Clarity AD Core study has been previously published (van Dyck 2023), but a CONSORT diagram for the single‐arm Clarity AD OLE is provided in Figure S1. Data from the Core+OLE include 1616 participants with at least one dose of lecanemab, 898 participants randomized to lecanemab in the core, and 718 participants who received a placebo in Core and then converted to lecanemab in OLE. Enrollment for subjects who participated in the OLE started in March 2019 and ended in March 2024 (cutoff date for this 36‐month analysis).

Of the 1616 lecanemab‐treated participants, 1286 had exposure of greater than or equal to 12 months, 872 participants had exposure greater than or equal to 24 months, and 464 participants had exposure of greater than or equal to 36 months in this data cutoff (as of March 31 2024). Baseline characteristics were generally similar across treatment groups (Table 1). The Core+OLE population had a mean age of 71.4 years, was 52.3% female, and 76.2% Caucasian. Overall, 69.2% of participants were ApoE ε4 carriers (53.8% heterozygotes; 15.5% homozygotes).

TABLE 1.

Characteristics of participants at baseline

	ADNI	Early start	Delayed start	Core+OLE
Parameter	(N = 436)	Lecanemab 10 mg/kg biweekly (N = 859)	Placebo and then Lecanemab 10 mg/kg biweekly (N = 875)	Lecanemab 10 mg/kg biweekly (N = 1616)
Age, mean (standard deviation), years	73.8 (7.38)	71.4 (7.9)	71.0 (7.8)	71.4 (7.8)
Female, n(%)	183 (42.0)	443 (51.6)	464 (53.0)	845 (52.3)
Male, n(%)	253 (58.0)	416 (48.4)	411 (47.0)	771 (47.7)
Race, n(%)
Caucasian	418 (97.5)	655 (76.3)	677 (77.4)	1232 (76.2)
Black	9 (2.1)	20 (2.3)	24 (2.7)	40 (2.5)
Asian	6 (1.4)	147 (17.1)	148 (16.9)	282 (17.5)
Other	3 (0.7)	37 (4.3)	26 (3.0)	62 (3.8)
Ethnicity, n(%)
Hispanic	9 (2.1)	107 (12.5)	108 (12.3)	191 (11.8)
Mild dementia due to Alzheimer's disease	169 (38.8)	331 (38.5)	331 (37.8)	608 (37.6)
Mild cognitive impairment	267 (61.2)	528 (61.5)	544 (62.2)	1008 (62.4)
ApoE e4 status
Noncarrier	131 (30.0)	267 (31.1)	275 (31.4)	497 (30.8)
Carrier	305 (70.0)	592 (68.9)	600 (68.6)	1119 (69.2)
Heterozygous	215 (49.3)	456 (53.1)	468 (53.5)	869 (53.8)
Homozygous	90 (20.6)	136 (15.8)	132 (15.1)	250 (15.5)

Abbreviations: ADNI, Alzheimer's Disease Neuroimaging Initiative; ApoE e4 = apolipoprotein E – e4; OLE, open‐label extension;

Note: Core placebo subjects started lecanemab on OLE baseline. Age is re‐calculated at date of informed consent of the OLE.

3.2. Safety

A detailed update on Clarity AD Core+OLE safety results was published recently (Honig 2024). A summary of the incidence and EAR of adverse events, including ARIA, is shown in Table 2. Approximate Core+OLE exposure was 3480 subject‐years, with a mean of 2.2 years, and > 450 individuals with at least 3 years. The overall incidence of adverse events was similar between treatment groups (placebo: 81.9% [EAR: 59.6 per 100 subject‐years]; lecanemab: 88.9% [EAR:67.8 per 100 subject‐years]). The overall rate of adverse events over the Core+OLE was 91.6%, with an EAR of 42.5 per 100 subject‐years.

TABLE 2.

Summary of TEAE and ARIA (exposure adjusted)

	Placebo N = 897			Lecanemab N = 898			Lecanemab (double‐blind + OLE) N = 1616
Parameter	n	%	Exposure adjusted *	n	%	Exposure adjusted *	n	%	Exposure adjusted *
Adverse event (AE)	735	81.9%	59.6	798	88.9%	67.8	1480	91.6%	42.5
Serious adverse event (SAE)	101	11.3%	8.2	126	14.0%	10.7	332	20.5%	9.5
Death a	8	0.9%	0.7	7	0.8%	0.6	24	1.5%	0.7
Deaths with concurrent ARIA or ICH, irrespective of ARIA being the cause of death	1	0.1%	0.1	0	0%	0	3	0.2%	0.1
AEs leading to study drug withdrawal	28	3.1%	2.3	64	7.1%	5.4	160	9.9%	4.6
ARIA‐E	15	1.7%	1.2	113	12.6%	9.6	238	14.7%	6.8
ARIA‐H	80	8.9%	6.5	152	16.9%	12.9	385	23.8%	11.1
Isolated ARIA‐H	69	7.7%	5.6	78	8.7%	6.6	211	13.1%	6.1
ICH a	2	0.2%	0.2	6	0.7%	0.5	11	0.7%	0.3

n, %, exposure‐adjusted rate (per subject‐year) are presented. OLE is based on IV datasets (as of 31 March, 2024).

Abbreviations: ARIA‐E, amyloid‐related imaging abnormalities—edema; ARIA‐H, ARIA with hemosiderin deposits; ICH, intracerebral hemorrhage; OLE, open‐label extension; TEAE, treatment‐emergent adverse event.

^a Includes all post‐treatment events.

^*Exposure adjusted rate (per 100 subjects per year). Total exposure is 1232.99 subject‐years for Placebo, 1177.92 subject‐years for lecanemab, and 3480.74 subject‐years for lecanemab (double blind core +OLE).

There have been 24 deaths during the Core+OLE (8 in Core placebo; 7 in Core lecanemab; and 9 in OLE), with an EAR in the Core+OLE (0.7 per 100 subject‐years) similar to that of placebo (0.7 per 100 subject‐years) and lecanemab (0.6 per 100 subject‐years) in the Core study. A total of three of the deaths in Core+OLE occurred concurrently with ARIA or intracerebral hemorrhage (ICH) (irrespective of ARIA being the cause of death; EAR 0.1 per 100 subject‐years). As expected, rates for adverse events, including ARIA‐E and ARIA‐H, in the Core+OLE increased with longer duration of treatment (Table 2). However, the EAR did not increase relative to placebo. In fact, the EAR for ARIA‐E and ARIA‐H decreased somewhat relative to lecanemab treatment in the Core.

Overall, no new clinically significant safety events emerged over time with long‐term treatment (Table S1). The long‐term ARIA‐E risk for Core lecanemab participants over the course of the Core+OLE is depicted graphically in Figure 1. After 6 months, a few cases of ARIA‐E (28/1616 [1.7%]) were identified by scheduled MRI.

FIGURE 1.

Long‐term safety for core lecanemab patients: ARIA‐E. ARIA‐E, amyloid‐related imaging abnormalities–edema

An evaluation of the long‐term association of incident ARIA (ARIA‐E or ARIA‐H) with clinical progression is shown in Figure 2. Based on the time to worsening analysis of CDR‐SB by 3.0 points in the Core or OLE, progression in participants with ARIA‐E is comparable to those who did not experience ARIA‐E. Most patients who had ARIA had CDR‐SB assessments after the event. Sensitivity analyses showed no impact on CDR‐SB from ARIA using MMRM with incident ARIA as a covariate, and no accelerated long‐term progression for subjects with ARIA versus without ARIA, irrespective of threshold (Data on File, Eisai Inc.).

FIGURE 2.

Evaluation of the long‐term association of ARIA with progression via time to worsening (CDR‐SB by 3.0 points). ARIA, amyloid‐related imaging abnormalities; CDR–SB, Clinical Dementia Rating–Sum of Boxes

Subgroup analyses of baseline microhemorrhage number and age‐related white matter change at baseline were conducted to assess if their presence was a potential risk factor for ARIA‐E and ARIA‐H (Table S2). Microhemorrhage at baseline is a risk factor for both ARIA‐E and isolated ARIA‐H events in lecanemab‐treated subjects and placebo‐treated subjects during the Core phase. For lecanemab‐treated patients, ARIA‐E increased from 10.9% in the absence of baseline microhemorrhages to 21.4% in the presence of baseline microhemorrhages (1.2% and 3.8% for placebo with absence and presence of baseline microhemorrhages, respectively; this was driven by increased rate with baseline microhemorrhages in APOE4 homozygotes; rates were similar for those with or without microhemorrhage within the other genotypes). Similarly, isolated ARIA‐H increased from 7.3% in the absence of baseline microhemorrhages to 16.4% in the presence of baseline microhemorrhages; rates of isolated ARIA‐H were similar to placebo (5.4% and 18.2% for placebo with absence and presence of baseline microhemorrhages, respectively). The analysis of age‐related white matter change at baseline showed that ARIA‐E increased with the extent of white matter lesions in the brain in lecanemab‐treated patients (ARIA‐E with no lesions: 11.3%; with focal lesions: 12.2%; beginning confluence of lesions: 19.3%). Increased ARIA‐H was observed with increasing white matter lesions in both placebo and lecanemab.

3.3. Efficacy

Results for the efficacy analyses through 36 months are shown in Figure 3. Lecanemab‐treated patients continue to accrue benefit through 36 months for CDR‐SB. The delayed start group does not catch up in CDR‐SB results to the early start group, reflecting the importance of early treatment initiation (Figure 3A). When data from a matched ADNI observational cohort are added to the graph (which represents the exact population of those in the Clarity AD study), the ADNI participants show a similar degree of decline to the placebo group out to 18 months (Figure 3B). The treatment effect between lecanemab and the ADNI cohort continues to expand from 18 through 36 months. The delayed start group also shows benefit in OLE relative to the ADNI cohort.

FIGURE 3.

Efficacy endpoint results for (A) CDR‐SB; B. CDR‐SB with ADNI data line added; (C) Amyloid PET; (D) ADAS‐Cog14; and (E) ADCS MCI‐ADL. Amyloid PET was collected annually after 18 months, so there is no 36 month data point. ADAS‐Cog14, 14‐item Alzheimer's Disease Assessment Scale–Cognitive Subscale; ADCOMS, Alzheimer's Disease Composite Score; ADCS‐ADL‐MCI, Alzheimer‘s Disease Cooperative Study—Activities of Daily Living Scale—mild cognitive impairment; BL, baseline; CI, confidence interval; PET, positron emission tomography; SD, standard deviation; and SE, standard error

For the amyloid PET analysis (Figure 3C), approximately 70% of subjects were amyloid negative (< 30 CL) at the OLE baseline. Early‐start subjects maintain their reduced amyloid levels by 30 months, and delayed start subjects showed a similar reduction compared to early‐start subjects once they started treatment in the OLE phase.

ADAS‐Cog14 and ADCS MCI‐ADL had similar results as CDR‐SB (Figure 3D, E).

In a subgroup analysis of no/low tau and low amyloid participants, subjects with no/low tau and low amyloid continued to benefit through 36 months (Figure 4). Of note, the no/low tau subgroup represents 41% of the tau PET population, and the low amyloid subgroup (< 60 Centiloids) represents 27% of the overall study population. A majority of participants in this subgroup improved or maintained CDR‐SB out to 36 months, with 59% having no decline and 51% having improvement at 36 months in the no/low tau PET subgroup, and 46% had no decline and 33% had improvement at 36 months in the low amyloid group. Similar results were observed for ADAS‐Cog14 (63% and 61% in no/low tau PET and 46% and 43% for low amyloid) and ADCS MCI‐ADL (63% and 59% in no/low tau PET and 51% and 48% for low amyloid).

FIGURE 4.

CDR‐SB results and response rates (No Decline and Improvement) in participants with no/low tau PET or low amyloid PET (< 60 CL). CDR–SB, Clinical Dementia Rating–Sum of Boxes; CL, Centiloids; PET, positron emission tomography

Results for CDR‐SB time to worsening analysis, where the shift from MCI to dementia or from mild AD to moderate/severe AD was analyzed, are shown in Figure 5. Results show that lecanemab meaningfully delayed progression to the next AD stage through 36 months (hazard ratio = 0.704 (95% confidence interval: 0.59, 0.84). This outcome represented a 30% reduction in the time to worsening for individuals starting on lecanemab versus those starting on placebo.

FIGURE 5.

CDR‐SB time to worsening analysis. Progression was defined as CDR‐SB score progressing from MCI (0.5–4) to mild AD dementia (4.5–9) or mild dementia to moderate dementia (9.5–15.1) based on dementia staging on CDR‐SB (O'Bryant et al., Arch Neurol. 2008). Given less frequent assessment, “Since controlled‐based imputation was used for missing data in this analysis, CDR‐SB (which has a greater range) was used rather than global CDR for disease staging.”. AD, Alzheimer's disease; CDR–SB, Clinical Dementia Rating–Sum of Boxes

3.4. Quality of life

HRQoL data out to 36 months for EQ‐5D‐5L (health today by subject) and Qol‐AD (total score rated by subject as well as by proxy) and ZBI (total score) demonstrated that lecanemab‐treated participants continued to benefit out to 3 years (Figure 6). At month 36, adjusted mean change from baseline (standard error) in EQ‐5D‐5L health today scores were −4.129 (0.655) and −5.560 (0.661) for the early‐start lecanemab group and delayed start group, respectively. Mean change from baseline in Qol‐AD total score by subject at 36 months similarly showed less decline for the early‐start group [−0.944 (0.220)] than for the delayed start group [−1.776 (0.222)]. Qol‐AD rated by proxy was consistent with Qol‐AD rated by the subject. The ZBI total score adjusted mean change from baseline at 36 months resulted in less increase of care partner burden for the early‐start group [6.252 (0.488)] versus the delayed start group [7.887 (0.488)] at 36 months.

FIGURE 6.

Health‐related quality of life results through 36 months for (A) EQ‐5D‐5L health today (by patient); (B) Qol‐AD total score (by subject); (C) Qol‐AD total score (by proxy); and (D) Zarit's Burden Interview total score. Qol‐AD, Quality of Life in AD

4. DISCUSSION

In this report, we present the long‐term efficacy, safety, and HRQoL results from an ongoing extension of the phase 3 Clarity AD, which included open‐label lecanemab treatment for up to 36 months. Overall, the results show participants continue to accrue a lecanemab treatment benefit up to 36 months and highlight the importance of continued long‐term lecanemab treatment. Results presented in our paper demonstrate that lecanemab continued suppression of amyloid plaque levels and significantly slowed clinical decline on multiple measures of cognition, function, and quality of life in early AD at 18 months and continued for 36 months to date. Results were also consistent across key randomization strata, as well as for other factors that affect AD, consistent with the primary 18‐month analysis. ⁷ Patients at a lower pathologic stage (no/low tau or low amyloid) show stability or improvement over 18–36 months, supporting early initiation of lecanemab treatment in symptomatic AD and representing the first time lower baseline amyloid levels have been linked to better treatment outcomes.

Lecanemab was associated with ARIA and infusion reactions, tending to occur early in treatment, but no new safety signals were observed with long‐term treatment. ARIA‐E and concurrent ARIA‐H occurred most within the first 6 months of treatment, and generally occurred at rates comparable to placebo after the first 6 months. Importantly, ARIA was not associated with accelerated long‐term clinical progression, and the evidence showed that people who experienced ARIA did as well (or better) than those who did not experience ARIA. These results help to address two key concerns related to ARIA. First, the potential for unblinding–where the participant or care partner may become aware of treatment allocation, which could introduce bias favoring the active treatment group. Second, whether or not ARIA impacts long‐term outcomes. In addition, impact related to these concerns is not expected, as ARIA‐E occurs early in treatment and generally resolves; it can occur in the placebo group, and most patients with ARIA had cognitive assessments after the ARIA event. Taken together with previously outlined measures to minimize potential for bias, ⁷ these findings provide reassurance to allay these concerns.

Results from OLE were generally consistent with results of the overall core phase of Clarity AD. ⁷ , ¹⁹ Efficacy results show a continued benefit for lecanemab‐treated participants through 36 months. For those patients who were randomized to placebo in the Core, benefits were observed after starting lecanemab therapy in the OLE in comparison to the ADNI observational cohort. These benefits recapitulate those originally observed in the core; however, the subjects previously treated with placebo do not catch up to those initially treated with lecanemab, confirming a disease‐modifying effect and suggesting that starting the therapy as early as possible in early AD may be beneficial.

Safety results for lecanemab were consistent with previously published results. ⁷ , ¹⁹ As expected, the cumulative adverse event rate increased somewhat as the treatment duration increased. However, the EAR (or the rate of the adverse event over a standardized time) does not increase relative to placebo. The EAR for some events, such as ARIA‐E and ARIA‐H, decreases somewhat relative to the lecanemab rate limited to the Core period. As longer exposure in a randomized trial also means longer observation time for adverse events, exposure adjustment is helpful to better characterize the safety profile of different interventions when the treatment duration in the arms differs strongly. Of note, ARIA‐E and concurrent ARIA‐H generally appear in the first 6 months of treatment, and then observations are reduced to placebo levels after the 6 months.

Of note, ARIA‐E frequency appears to vary among Aβ antibodies; direct head‐to‐head comparisons are not available. A recent study suggested that Aβ antibody–cerebral amyloid angiopathy (CAA) interactions may relate to the ARIA‐E frequency observed in patients treated with Aβ‐based immunotherapies, and marked differences in Aβ antibody binding to CAA fibrils were observed. ¹² For example, lecanemab showed a low binding to CAA fibrils, consistent with its relatively low ARIA‐E frequency of 12.6% (vs. 1.7% for placebo), while aducanumab, bapineuzumab, and gantenerumab all showed higher binding to CAA fibrils and substantially higher ARIA‐E frequencies (25%–35%). An ARIA‐E frequency of 24% (vs. 1.9% for placebo) was reported for donanemab (700 mg for the first 3 doses and 1400 mg thereafter), and its binding to CAA fibrils correlated with the amount of pyroglutamate‐modified Aβ present.

Taken together with other available lecanemab data, these data help support the rationale for early initiation of treatment and continued therapy. Mechanistically, the extensive evidence for a dual lecanemab mechanism supports the rationale for continued dosing. Soluble and diffusible aggregated Aβ species, often called protofibrils, are abundant in AD brain and can cause synaptic dysfunction, microglial activation, tau phosphorylation and neuritic dystrophy, and impaired memory and learning. Antibodies against these species from typical AD patients prevent neuronal dysfunction. Lecanemab preferentially binds to soluble aggregated and diffusible species that continue to be present and produced after clearance of amyloid plaques.

In addition, discontinuation of treatment is associated with reaccumulation of biomarkers and reversion to the placebo rate of clinical decline. ²⁹ Long‐term therapy continues to improve biomarkers further and avoid the reaccumulation of biomarkers when anti‐amyloid treatment is stopped. ²⁹ , ³⁰ Overall, patients at a lower pathologic stage (no/low tau or low amyloid) show stability or improvement over 18–36 months, supporting early initiation of treatment with lecanemab. Amyloid pathway biomarkers improved at 3 months in newly treated participants and maintained/improved with continuous treatment. Lecanemab slows the rate of increase in plasma pTau217 & CSF MTBR‐tau243 in Clarity AD, a clear demonstration of drug effect on amyloid and tau pathology cascade. Modeling of extensive dose‐ranging, placebo‐controlled, and OLE data indicate that maintenance treatment after initial 18 months of biweekly dosing can sustain efficacy and biomarker benefit of lecanemab. ³¹ Simulations showed that discontinued lecanemab treatment may result in rapid re‐accumulation of amyloid protofibrils and rebound of tau pathology measured by tau PET. ³²

These results demonstrate the benefits of long‐term therapy.

Limitations of this paper include that the OLE phase of Clarity AD was an open‐label, single‐arm study with no control arm randomization in the OLE since efficacy was demonstrated at 18 months. In addition, historical controls are used for some analyses, which have limitations including that because baseline characteristics—although attempted to match age, disease severity, comorbidities, and so on—may not match the current trial population, which can introduce prognostic confounders; data collection may have differed; and a bias from the historical control's unblinded nature is also possible. However, the control group was preselected prior to Clarity AD and was used to power the study. In addition, the historical control data overlap with the Clarity AD placebo group data over 18 months, supporting the comparability of the historical control. Results from these analyses should be viewed as only hypothesis‐generating. The low amyloid/low tau and ARIA subgroup analyses were not pre‐specified; thus, the results are considered exploratory.

In summary, OLE results support the benefits and safety of continued long‐term lecanemab treatment. Lecanemab‐treated participants continued to accrue benefit through 36 months across a broad range of individuals. Patients at a lower pathologic stage (no/low tau or low amyloid) generally showed stability or improvement over 18–36 months, supporting early initiation of treatment with lecanemab. No new safety signals were observed with continued lecanemab treatment. After the first 6 months, ARIA rates were low and similar to ARIA rates on placebo, with no association between ARIA occurrence and accelerated long‐term clinical progression. Taken together with existing data, these results provide a clear rationale and a demonstration of the disease modification effects of long‐term lecanemab therapy.

CONFLICT OF INTEREST STATEMENT

C.V.D. has been an advisor/Consultant for Roche Pharmaceuticals, Eisai, Inc, Ono Pharmaceuticals, Cerevel, Bristol Myers Squibb, and UCB. CVD and Yale University have received grant support from Eli Lilly, Janssen Pharmaceuticals, Biogen Idec, Eisai, Inc, Roche Pharmaceuticals, Genentech, Inc, Cerevel Therapeutics, and UCB. R.S. has received consulting fees from Abbvie, AC Immune, Acumen, Alector, Alnylam, Biohaven, Bristol‐Myers Squibb, Cytox, Genentech, Ionis, Janssen, Merck, NervGen, Neuraly, Neurocentria, Oligomerix, Prothena, Roche, Shionogi, and Vaxxinity. K.J. has been a consultant for Novartis and Merck. S.D., M.K., D.L., M.G., S.H., M.I., and L.K. are employees of Eisai.

CONSENT STATMENT

All human subjects provided informed consent.

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Supporting Information

van Dyck CH, Sperling R, Johnson K, et al. Long‐term safety and efficacy of lecanemab in early Alzheimer's disease: Results from the clarity AD open‐label extension study. Alzheimer's Dement. 2025;21:e70905. 10.1002/alz.70905