Highlights

See Patient counseling information and medication guide available in the DAILYMED drug label information.

Boxed warning

WARNING: Amyloid-related imaging abnormalities

Monoclonal antibodies directed against aggregated forms of beta amyloid, including lecanemab, can cause amyloid-related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E) and ARIA with hemosiderin deposition (ARIA-H). Incidence and timing of ARIA vary among treatments. ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events can occur. ARIA can be fatal. Serious intracerebral hemorrhages > 1 cm, some of which have been fatal, have been observed in patients treated with this class of medications. Because ARIA-E can cause focal neurologic deficits that can mimic an ischemic stroke, treating clinicians should consider whether such symptoms could be due to ARIA-E before giving thrombolytic therapy to a patient being treated with lecanemab.

ApoE ε4 homozygotes. Patients who are apolipoprotein E ε4 (ApoE ε4) homozygotes (approximately 15% of patients with Alzheimer disease) treated with this class of medications, including lecanemab, have a higher incidence of ARIA, including symptomatic, serious, and severe radiographic ARIA, compared to heterozygotes and noncarriers. Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Prescribers should inform patients that if genotype testing is not performed, they can still be treated with lecanemab; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA.

Consider the benefit of lecanemab for the treatment of Alzheimer disease and the potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with lecanemab.

Indications and usage

Lecanemab is indicated for the treatment of Alzheimer disease. Treatment with lecanemab should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials.

Dosage and administration

Patient selection

Confirm the presence of amyloid beta pathology prior to initiating treatment.

Recommended dosage

Initiate lecanemab as an intravenous infusion using the starting dosage (see Table 1). After 18 months, the starting dosage may be continued or a transition to a maintenance dosage regimen may be considered, which can be administered by either intravenous infusion or subcutaneous injection (see Table 1). If transitioning from starting dosage to a maintenance dosage regimen, administer the first maintenance dose 2 weeks after the last starting dose.

Table 1. Starting and Maintenance Dosage Regimens

For intravenous infusion, use lecanemab vials. Lecanemab vials must be diluted before administration.

For subcutaneous administration, use lecanemab IQLIK autoinjector.

Switching between maintenance dosage regimens

During maintenance dosage regimen, patients may switch the route of administration (intravenous or subcutaneous lecanemab). This transition should be initiated at 1 week following the last maintenance dose of either the intravenous or subcutaneous dosing regimen. Thereafter, follow the dosing schedule for the newly assigned maintenance dosage regimen.

Monitoring and dosing interruption for amyloid-related imaging abnormalities

Lecanemab can cause amyloid-related imaging abnormalities -edema (ARIA-E) and -hemosiderin deposition (ARIA-H).

Monitoring for ARIA. Obtain a recent baseline brain MRI prior to initiating treatment with lecanemab. Obtain an MRI prior to the 3rd, 5th, 7th, and 14th infusions. In general, the MRI should be performed within approximately 1 week before the scheduled infusion of lecanemab and reviewed prior to proceeding with the infusion. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including an MRI if indicated.

Recommendations for dosing interruptions in patients with ARIA.

ARIA-E. The recommendations for dosing interruptions for patients with ARIA-E are provided in Table 2.

Table 2. Dosing Recommendations for Patients with ARIA-E

ARIA-H. The recommendations for dosing interruptions for patients with ARIA-H are provided in Table 3.

Table 3. Dosing Recommendations for Patients with ARIA-H Clinical Symptom Severity ARIA-H Severity on MRI1

In patients who develop intracerebral hemorrhage greater than 1 cm in diameter during treatment with lecanemab, suspend dosing until MRI demonstrates radiographic stabilization and symptoms, if present, resolve. Use clinical judgment in considering whether to continue treatment after radiographic stabilization and resolution of symptoms or permanently discontinue lecanemab.

Preparation and administration of lecanemab for intravenous infusion

Dilution.

Administration.

Preparation and administration of lecanemab autoinjector for subcutaneous injection

Instruct patients and caregivers on the proper subcutaneous administration of lecanemab. Direct patients and caregivers to follow the directions provided in the Instructions for Use for additional details on administration. Periodically reassess the ability of the patient or caregiver to safely and adequately administer lecanemab IQLIK (subcutaneous autoinjector).

Missed dose

Intravenous infusion. If a starting dosage or maintenance dosage infusion is missed, administer the next dose as soon as possible.

Subcutaneous injection. If a scheduled dose of the subcutaneous maintenance dosing regimen is missed, administer lecanemab IQLIK as soon as possible up to 6 days after the missed dose and administer the next dose on the regularly scheduled day. Thereafter, resume the original dosing schedule.

Dosage forms and strengths

Lecanemab-irmb is a clear to opalescent and colorless to pale yellow solution, available as:

Intravenous infusion.

Subcutaneous injection.

Contraindications

Lecanemab is contraindicated in patients with serious hypersensitivity to lecanemab-irmb or to any of the excipients of lecanemab. Reactions have included angioedema and anaphylaxis.

Warnings and precautions

Amyloid-related imaging abnormalities

Monoclonal antibodies directed against aggregated forms of beta amyloid, including lecanemab, can cause amyloid-related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and ARIA with hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with Alzheimer disease, particularly in patients with MRI findings suggestive of cerebral amyloid angiopathy, such as pretreatment microhemorrhage or superficial siderosis. ARIA-H associated with monoclonal antibodies directed against aggregated forms of beta amyloid generally occurs in association with an occurrence of ARIA-E. ARIA-H of any cause and ARIA-E can occur together.

ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, can occur. ARIA can be fatal. When present, reported symptoms associated with ARIA may include headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms associated with ARIA usually resolve over time. In addition to ARIA, intracerebral hemorrhages greater than 1 cm in diameter have occurred in patients treated with lecanemab.

Consider the benefit of lecanemab for the treatment of Alzheimer disease and the potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with lecanemab.

Incidence of ARIA. Symptomatic ARIA occurred in 3% (29/898) of patients treated with lecanemab in Study 2. Serious symptoms associated with ARIA were reported in 0.7% (6/898) of patients treated with lecanemab. Clinical symptoms associated with ARIA resolved in 79% (23/29) of patients during the period of observation. Similar findings were observed in Study 1.

Including asymptomatic radiographic events, ARIA was observed in 21% (191/898) of patients treated with lecanemab, compared to 9% (84/897) of patients on placebo in Study 2.

In Study 2, ARIA-E was observed in 13% (113/898) of patients treated with lecanemab, compared to 2% (15/897) of patients on placebo. ARIA-H was observed in 17% (152/898) of patients treated with lecanemab, compared to 9% (80/897) of patients on placebo. There was no increase in isolated ARIA-H (ie, ARIA-H in patients who did not also experience ARIA-E) for lecanemab compared to placebo.

Incidence of intracerebral hemorrhage. Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.7% (6/898) of patients in Study 2 after treatment with lecanemab, compared to 0.1% (1/897) on placebo. Fatal events of intracerebral hemorrhage in patients taking lecanemab have been observed.

Risk factors for ARIA and intracerebral hemorrhage.

ApoE ε4 carrier status. The risk of ARIA, including symptomatic and serious ARIA, is increased in apolipoprotein E ε4 (ApoE ε4) homozygotes.

Approximately 15% of patients with Alzheimer disease are ApoE ε4 homozygotes. In Study 2, 16% (141/898) of patients in the lecanemab arm were ApoE ε4 homozygotes, 53% (479/898) were heterozygotes, and 31% (278/898) were noncarriers. The incidence of ARIA was higher in ApoE ε4 homozygotes (45% on lecanemab vs. 22% on placebo) than in heterozygotes (19% on lecanemab vs 9% on placebo) and noncarriers (13% on lecanemab vs 4% on placebo). Among patients treated with lecanemab, symptomatic ARIA-E occurred in 9% of ApoE ε4 homozygotes compared to 2% of heterozygotes and 1% noncarriers. Serious events of ARIA occurred in 3% of ApoE ε4 homozygotes, and approximately 1% of heterozygotes and noncarriers. The recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers. Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Prescribers should inform patients that if genotype testing is not performed, they can still be treated with lecanemab; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA. An FDA-authorized test for the detection of ApoE ε4 alleles to identify patients at risk of ARIA if treated with lecanemab is not currently available. Currently available tests used to identify ApoE ε4 alleles may vary in accuracy and design.

Radiographic findings of cerebral amyloid angiopathy (CAA). Neuroimaging findings that may indicate CAA include evidence of prior intracerebral hemorrhage, cerebral microhemorrhage, and cortical superficial siderosis. CAA has an increased risk for intracerebral hemorrhage. The presence of an ApoE ε4 allele is also associated with cerebral amyloid angiopathy.

The baseline presence of at least two microhemorrhages or the presence of at least one area of superficial siderosis on MRI, which may be suggestive of CAA, has been identified as a risk factor for ARIA. Patients were excluded from enrollment in Study 2 for the presence of more than four microhemorrhages and additional findings suggestive of cerebral amyloid angiopathy (prior cerebral hemorrhage greater than 1 cm in greatest diameter, superficial siderosis, vasogenic edema) or other lesions (aneurysm, vascular malformation) that could potentially increase the risk of intracerebral hemorrhage.

Concomitant antithrombotic or thrombolytic medication. In Study 2, baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed if the patient was on a stable dose. The majority of exposures to antithrombotic medications were to aspirin. Antithrombotic medications did not increase the risk of ARIA with lecanemab. The incidence of intracerebral hemorrhage was 0.9% (3/328 patients) in patients taking lecanemab with a concomitant antithrombotic medication at the time of the event, compared to 0.6% (3/545 patients) in those who did not receive an antithrombotic. Patients taking lecanemab with an anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of intracerebral hemorrhage of 2.5% (2/79 patients), compared to none in patients who received placebo.

Fatal cerebral hemorrhage has occurred in a patient taking an anti-amyloid monoclonal antibody in the setting of focal neurologic symptoms of ARIA and the use of a thrombolytic agent.

Additional caution should be exercised when considering the administration of antithrombotics or a thrombolytic agent (eg, tissue plasminogen activator) to a patient already being treated with lecanemab. Because ARIA-E can cause focal neurologic deficits that can mimic an ischemic stroke, treating clinicians should consider whether such symptoms could be due to ARIA-E before giving thrombolytic therapy in a patient being treated with lecanemab.

Caution should be exercised when considering the use of lecanemab in patients with factors that indicate an increased risk for intracerebral hemorrhage and in particular for patients who need to be on anticoagulant therapy, or patients with findings on MRI that are suggestive of cerebral amyloid angiopathy.

Radiographic severity. The radiographic severity of ARIA associated with lecanemab was classified by the criteria shown in Table 4.

Table 4. ARIA MRI Classification Criteria

In Study 2, the majority of ARIA-E radiographic events occurred early in treatment (within the first seven doses), although ARIA can occur at any time, and patients can have more than one episode. The maximum radiographic severity of ARIA-E in patients treated with lecanemab was mild in 4% (37/898) of patients, moderate in 7% (66/898) of patients, and severe in 1% (9/898) of patients. Resolution on MRI occurred in 52% of ARIA-E patients by 12 weeks, 81% by 17 weeks, and 100% overall after detection. The maximum radiographic severity of ARIA-H microhemorrhage in patients treated with lecanemab was mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of patients; superficial siderosis was mild in 4% (38/898), moderate in 1% (8/898), and severe in 0.4% (4/898). Among patients treated with lecanemab, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes 5% (7/141), compared to heterozygotes 0.4% (2/479), or noncarriers 0% (0/278). Among patients treated with lecanemab, the rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes 13.5% (19/141), compared to heterozygotes 2.1% (10/479), or noncarriers 1.1% (3/278).

Monitoring and dose management guidelines. Recommendations for dosing in patients with ARIA-E depend on clinical symptoms and radiographic severity. Recommendations for dosing in patients with ARIA-H depend on the type of ARIA-H and radiographic severity. Use clinical judgment in considering whether to continue dosing in patients with recurrent ARIA-E.

Baseline brain MRI and periodic monitoring with MRI are recommended. Enhanced clinical vigilance for ARIA is recommended during the first 14 weeks of treatment with lecanemab. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including MRI if indicated. If ARIA is observed on MRI, careful clinical evaluation should be performed before continuing treatment.

There is no experience in patients who continued dosing through symptomatic ARIA-E, or through asymptomatic but radiographically severe ARIA-E. There is limited experience in patients who continued dosing through asymptomatic but radiographically mild to moderate ARIA-E. There are limited data on dosing patients who experienced recurrent ARIA-E. Although experience is limited in these situations, dose management guidelines are provided.

Providers should encourage patients to participate in real-world data collection (eg, registries) to help further the understanding of Alzheimer disease and the impact of Alzheimer disease treatments. Providers and patients can contact Eisai at 888-274-2378 for a list of currently enrolling programs.

Hypersensitivity reactions

Hypersensitivity reactions, including angioedema, bronchospasm, and anaphylaxis, have occurred in patients who were treated with lecanemab. If lecanemab is being administered intravenously, promptly discontinue the infusion on the first observation of any signs or symptoms consistent with a hypersensitivity reaction, and initiate appropriate therapy. Lecanemab is contraindicated in patients with a history of serious hypersensitivity to lecanemab-irmb or to any of the excipients of lecanemab.

Infusion-related reactions

In Study 2, infusion-related reactions were observed in 26% (237/898) of patients treated with lecanemab, compared to 7% (66/897) of patients on placebo, and the majority (75%, 178/237) occurred with the first infusion. Infusion-related reactions were mostly mild (69%) or moderate (28%) in severity. Infusion-related reactions resulted in discontinuations in 1% (12/898) of patients treated with lecanemab. Symptoms of infusion-related reactions include fever and flu-like symptoms (chills, generalized aches, feeling shaky, and joint pain), nausea, vomiting, hypotension, hypertension, and oxygen desaturation.

After the first infusion in Study 1, 38% of patients treated with lecanemab had transient decreased lymphocyte counts to less than 0.9 x109/L, compared to 2% in patients on placebo, and 22% of patients treated with lecanemab had transient increased neutrophil counts to greater than 7.9 x109/L, compared to 1% of patients on placebo. Lymphocyte and neutrophil counts were not obtained after the first infusion in Study 2.

Infusion-related reactions can occur during the infusion or after completion of the infusion. In the event of an infusion-related reaction during the infusion, the infusion rate may be reduced, or the infusion may be discontinued, and appropriate therapy initiated as clinically indicated. Consider prophylactic treatment with antihistamines, acetaminophen, nonsteroidal anti-inflammatory drugs, or corticosteroids prior to future infusions.

Adverse reactions

The following clinically significant adverse reactions are described elsewhere in the labeling:

Clinical trials experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical trials with intravenous administration. The safety of lecanemab has been evaluated in 2090 patients who received at least one dose of lecanemab by intravenous infusion. In Studies 1 and 2 in patients with Alzheimer disease, 1059 patients received lecanemab 10 mg/kg every 2 weeks by intravenous infusion. Of these 1059 patients, 50% were female, 79% were White, 15% were Asian, 12% were of Hispanic or Latino ethnicity, and 2% were Black. The mean age at study entry was 72 years (range from 50 to 90 years).

In the combined double-blind, placebo-controlled period and long-term extension period of Studies 1 and 2, 1604 patients received lecanemab for at least 6 months, 1261 patients for at least 12 months, and 965 patients for 18 months.

In the double-blind, placebo-controlled period in Study 1, patients stopped study treatment because of an adverse reaction in 15% of patients treated with lecanemab, compared to 6% patients on placebo; in Study 2, patients stopped study treatment because of an adverse reaction in 7% of patients treated with lecanemab, compared to 3% patients on placebo. In Study 1, the most common adverse reaction leading to discontinuation of lecanemab was infusion-related reactions that led to discontinuation in 2% (4/161) of patients treated with lecanemab, compared to 1% (2/245) of patients on placebo. In Study 2, the most common adverse reaction leading to discontinuation of lecanemab was ARIA-H microhemorrhages that led to discontinuation in 2% (15/898) of patients treated with lecanemab, compared to <1% (1/897) of patients on placebo.

Table 5 shows adverse reactions that were reported in at least 5% of patients treated with lecanemab and at least 2% more frequently than in patients on placebo in Study 1.

Table 5. Adverse Reactions Reported in at Least 5% of Patients Treated with Lecanemab 10 mg/kg Every 2 Weeks and at least 2% Higher than Placebo in Study 1

Table 6 shows adverse reactions that were reported in at least 5% of patients treated with lecanemab and at least 2% more frequently than in patients on placebo in Study 2.

Table 6. Adverse Reactions Reported in at Least 5% of Patients Treated with Lecanemab 10 mg/kg Every 2 Weeks and at least 2% Higher than Placebo in Study 2

Less common adverse reactions. Atrial fibrillation occurred in 3% of patients treated with lecanemab, compared to 2% in patients on placebo. In Study 1, lymphopenia or decreased lymphocyte count was reported in 4% of patients treated with lecanemab after the first dose, compared to less than 1% of patients on placebo; lymphocytes were not measured after the first dose in Study 2.

Clinical trials with subcutaneous administration. The safety of lecanemab IQLIK for maintenance treatment was evaluated in an open-label study, which included 49 patients who received lecanemab IQLIK 360 mg by subcutaneous administration once every week. The overall safety profile in these patients was similar to what was observed in patients who received lecanemab by intravenous infusion in Study 1 and Study 2. Patients who received lecanemab IQLIK experienced localized and systemic injection-related reactions. Localized injection-related reactions included erythema, induration, swelling, heat, pain, pruritis, rash, ecchymosis, and hematoma. Systemic injection-related reactions were observed less frequently, with symptoms of headache, fever, and fatigue. Injection-related reactions in patients receiving lecanemab IQLIK were mild or moderate in severity.

Use in specific populations

Pregnancy

Risk summary. There are no adequate data on lecanemab use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No animal studies have been conducted to assess the potential reproductive or developmental toxicity of lecanemab.

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Lactation

Risk summary. There are no data on the presence of lecanemab-irmb in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Published data from other monoclonal antibodies generally indicate low passage of monoclonal antibodies into human milk and limited systemic exposure in the breastfed infant. The effects of this limited exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lecanemab and any potential adverse effects on the breastfed infant from lecanemab or from the underlying maternal condition.

Pediatric use

The safety and effectiveness of lecanemab in pediatric patients have not been established.

Geriatric use

In Studies 1 and 2, the age of patients exposed to lecanemab 10 mg/kg every 2 weeks (n=1059) ranged from 50 to 90 years, with a mean age of 72 years; 81% were 65 years and older, and 39% were 75 years and older. No overall differences in safety or effectiveness of lecanemab have been observed between patients 65 years of age and older and younger adult patients.

Clinical pharmacology

Mechanism of action

Lecanemab-irmb is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer disease. Lecanemab reduces amyloid beta plaques, as evaluated in Study 1 and Study 2.

Pharmacodynamics

Effect of lecanemab on amyloid beta pathology. The effect of lecanemab on amyloid beta plaque levels in the brain was evaluated using positron emission tomography imaging. The PET signal was quantified using both the standard uptake value ratio and Centiloid scale to estimate levels of amyloid beta plaque in composites of brain areas expected to be widely affected by Alzheimer disease pathology (frontal, parietal, lateral temporal, sensorimotor, and anterior and posterior cingulate cortices), compared to a brain region expected to be spared of such pathology (cerebellum).

Lecanemab reduced amyloid beta plaque in a dose- and time-dependent manner in the dose-ranging study (Study 1) and in a time-dependent manner in a single-dosing regimen study (Study 2) compared to placebo.

In Study 1, treatment with lecanemab 10 mg/kg every 2 weeks reduced amyloid beta plaque levels in the brain, producing reductions in PET standard uptake value ratio compared to placebo at both Weeks 53 and 79 (P<0.0001). The magnitude of the reduction was time- and dose-dependent.

During an off-treatment period in Study 1 (range from 9 to 59 months; mean of 24 months), standard uptake value ratio and Centiloid values began to increase with a mean rate of increase of 2.6 Centiloids per year; however, the treatment difference relative to placebo at the end of the double-blind, placebo-controlled period in Study 1 was maintained.

In Study 2, treatment with lecanemab 10 mg/kg every 2 weeks reduced amyloid beta plaque levels in the brain, producing reductions compared to placebo starting at Week 13 and continuing through Week 79 (P<0.0001). After Week 79 of treatment with lecanemab 10 mg/kg every 2 weeks, 67% of patients had amyloid levels less than 30 Centiloids as measured by PET. Reduction of amyloid to levels less than 30 Centiloids was inversely related to amyloid PET levels at baseline. The percentage of patients achieving amyloid levels less than 30 Centiloids after continuous treatment with lecanemab 10 mg/kg every 2 weeks is predicted to increase over time. It is predicted that, after Week 79 of treatment with lecanemab intravenous infusion of 10 mg/kg every 2 weeks, transitioning to a dosing regimen of either lecanemab intravenous infusion of 10 mg/kg every 4 weeks or a lecanemab IQLIK subcutaneous injection of 360 mg once a week will also continue the reduction in amyloid beta plaque levels. Based on exposure-response modeling, the intravenous (10 mg/kg every 4 weeks) and subcutaneous (360 mg once weekly) maintenance dosing regimens of lecanemab-irmb are predicted to have similar reduction of amyloid beta plaque levels.

An increase in plasma Aβ42/40 ratio (Table 6) and CSF Aβ[1-42] was observed with lecanemab 10 mg/kg every 2 weeks dosing compared to placebo. Exposure-response modeling predicts that, after Week 79 of treatment with lecanemab intravenous infusion of 10 mg/kg every 2 weeks, transitioning to a dosing regimen of either lecanemab intravenous infusion of 10 mg/kg every 4 weeks or a lecanemab IQLIK subcutaneous injection of 360 mg once a week will maintain increases in the plasma Aβ42/40 ratio.

Effect of lecanemab on tau pathophysiology. A reduction in plasma p-tau181 (Table 7), CSF p-tau181, and CSF t-tau was observed with lecanemab 10 mg/kg every 2 weeks compared to placebo. Exposure-response modeling predicts that, after Week 79 of treatment with lecanemab intravenous infusion of 10 mg/kg every 2 weeks, transitioning to a dosing regimen of lecanemab intravenous infusion of 10 mg/kg every 4 weeks or a lecanemab IQLIK subcutaneous injection of 360 mg once a week will maintain the reduction in plasma p-tau181.

Table7. Effect of Lecanemab on Plasma Aβ42/40 and Plasma p-tau181 in Study 1 and Study 2

A substudy was conducted in Study 2 to evaluate the effect of lecanemab on neurofibrillary tangles composed of tau protein using PET imaging (18F-MK6240 tracer). The PET signal was quantified using the standard uptake value ratio method to estimate brain levels of tau in brain regions expected to be affected by Alzheimer disease pathology (whole cortical gray matter, meta-temporal, frontal, cingulate, parietal, occipital, medial temporal, and temporal) in the study population, compared to a brain region expected to be spared of such pathology (cerebellum). The adjusted mean change from baseline in tau PET standard uptake value ratio, relative to placebo, was in favor of lecanemab in the medial temporal (P<0.01), meta temporal (P<0.05), and temporal (P<0.05) regions. No statistically significant differences were observed for the whole cortical gray matter, frontal, cingulate, parietal, or occipital regions.

Exposure-response relationships. Model-based exposure-response analyses demonstrated that higher exposures to lecanemab-irmb were associated with greater reduction in clinical decline on Clinical Dementia Rating scale Sum of Boxes (CDR-SB) and Alzheimer Disease Assessment Scale – Cognitive Subscale 14 (ADAS-Cog14). In addition, higher exposures to lecanemab-irmb were associated with a greater reduction in amyloid beta plaque. An association between a reduction in amyloid beta plaque and clinical decline on CDR-SB and ADAS-Cog14 was also observed.

Higher exposures to lecanemab-irmb were also associated with a greater increase in plasma Aβ42/40 ratio and a greater reduction in plasma p-tau181.

Pharmacokinetics

Steady-state concentrations of lecanemab-irmb were reached after 6 weeks of 10 mg/kg administered every 2 weeks, and systemic accumulation was 1.4-fold. The peak concentration (Cmax) and area under the plasma concentration versus time curve (AUC) of lecanemab-irmb increased dose proportionally in the dose range of 0.3 to 15 mg/kg following a single dose.

The estimated mean steady-state concentrations of lecanemab-irmb following 10 mg/kg biweekly intravenous infusion, 10 mg/kg monthly intravenous infusion, and 360 mg weekly subcutaneous administration by autoinjector are provided in Table 8. Using population pharmacokinetic modeling and simulation, the intravenous (10 mg/kg once every 4 weeks) and subcutaneous (360 mg once weekly) maintenance dosing regimens of lecanemab-irmb were predicted to have similar pharmacokinetic exposure.

Table 8. Estimated Systemic Exposure of Lecanemab-irmb at Steady State in Patients with Alzheimer Disease*

Absorption. The bioavailability of lecanemab-irmb following subcutaneous administration of 360 mg by autoinjector relative to a 10 mg/kg intravenous infusion in patients was approximately 53% and was not affected by the injection site (abdomen, upper thigh, or back of the upper arm).

Distribution. The mean value (95% CI) for central volume of distribution at steady state is 3.24 (3.18-3.30) L.

Elimination. Lecanemab-irmb is degraded by proteolytic enzymes in the same manner as endogenous IgGs. The clearance of lecanemab-irmb (95% CI) is 0.370 (0.353-0.384) L/day. The terminal half-life is 5 to 7 days.

Specific populations. Sex, body weight, and albumin were found to impact exposure to lecanemab-irmb. However, none of these covariates were found to be clinically significant.

Patients with renal or hepatic impairment. No clinical studies were conducted to evaluate the pharmacokinetics of lecanemab-irmb in patients with renal or hepatic impairment. Lecanemab-irmb is degraded by proteolytic enzymes and is not expected to undergo renal elimination or metabolism by hepatic enzymes.

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of lecanemab-irmb or of other lecanemab products.

Intravenous infusion. During the 18-month treatment period in Study 1, 63/154 (40.9%) of patients treated with lecanemab 10 mg/kg every 2 weeks by intravenous infusion developed anti-lecanemab-irmb antibodies. Of these patients, neutralizing anti-lecanemab-irmb antibodies were detected in 16/63 (25.4%) patients. However, the assays used to measure anti-lecanemab-irmb antibodies and neutralizing antibodies are subject to interference by serum lecanemab concentrations, possibly resulting in an underestimation of the incidence of antibody formation. Therefore, there is insufficient information to characterize the effects of anti-lecanemab-irmb antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of lecanemab.

Subcutaneous injection. After 18 months of intravenous lecanemab 10 mg/kg once every 2 weeks, patients who received 360 mg subcutaneous lecanemab IQLIK once weekly in the open-label portion of Study 2 were assessed for immunogenicity using a different assay that was drug-tolerant for anti-lecanemab-irmb antibodies and neutralizing antibodies. The anti-lecanemab-irmb antibody incidence was 2.0% (1/49) following a median treatment duration of 83 days with 360 mg subcutaneous lecanemab IQLIK. Neutralizing anti-lecanemab-irmb antibodies were not detected in this patient. Because of the limited data regarding anti-lecanemab-irmb antibodies, there is insufficient information to characterize the effects of anti-lecanemab-irmb antibodies on the pharmacokinetics, pharmacodynamics, safety, or effectiveness of subcutaneous lecanemab IQLIK.

Nonclinical toxicology

Carcinogenesis, mutagenesis, and impairment of fertility

Carcinogenesis. Carcinogenicity studies have not been conducted.

Mutagenesis. Genotoxicity studies have not been conducted.

Impairment of fertility. No studies in animals have been conducted to assess the effects of lecanemab-irmb on male or female fertility. No adverse effects on male or female reproductive organs were observed in a 39-week intravenous toxicity study in monkeys administered lecanemab-irmb weekly at doses up to 100 mg/kg. The highest dose tested was associated with plasma exposures (Cave) approximately 27 times that in humans at the recommended human dose (10 mg/kg every 2 weeks).

Clinical studies

The efficacy of lecanemab was evaluated in two double-blind, placebo-controlled, parallel-group, randomized studies (Study 1, NCT01767311; Study 2 NCT03887455) in patients with Alzheimer disease (patients with confirmed presence of amyloid pathology and mild cognitive impairment [64% of patients in Study 1; 62% of patients in Study 2] or mild dementia stage of disease [36% of patients in Study 1; 38% of patients in Study 2], consistent with Stage 3 and Stage 4 Alzheimer disease). In both studies, patients were enrolled with a Clinical Dementia Rating (CDR) global score of 0.5 or 1.0 and a Memory Box score of 0.5 or greater. All patients had a Mini-Mental State Examination (MMSE) score of ≥22 and ≤30, and had objective impairment in episodic memory as indicated by at least one standard deviation below age-adjusted mean in the Wechsler-Memory Scale-IV Logical Memory II (subscale) (WMS-IV LMII). Patients were enrolled with or without concomitant approved therapies (cholinesterase inhibitors and the N-methyl-D-aspartate antagonist memantine) for Alzheimer disease. The dosage of 10 mg/kg administered once every 2 weeks by intravenous infusion was assessed in the 18-month placebo-controlled portions of Study 1 and Study 2 and continued in the optional long-term extension in each study. Transitioning to intravenous 10 mg/kg once every 4 weeks or subcutaneous 360 mg every week after 18 months of dosing is supported by pharmacokinetic and pharmacodynamic modeling using observed data; however, there are limited data to assess the long-term clinical benefit of transitioning to the dosing regimen of intravenous 10 mg/kg once every 4 weeks or subcutaneous 360 mg every week.

Study 1

In Study 1, 856 patients were randomized to receive one of five doses (161 of which were randomized to the recommended dosing regimen of 10 mg/kg every 2 weeks) of intravenous infusion of lecanemab or placebo (n=247). Of the total number of patients randomized, 71.4% were ApoE ε4 carriers and 28.6% were ApoE ε4 non-carriers. During the study, the protocol was amended to no longer randomize ApoE ε4 carriers to the 10 mg/kg every 2 weeks dose arm. ApoE ε4 carriers who had been receiving lecanemab 10 mg/kg every 2 weeks for 6 months or less were discontinued from the study drug. As a result, in the lecanemab 10 mg/kg every 2 weeks arm, 30.3% of patients were ApoE ε4 carriers and 69.7% were ApoE ε4 non-carriers. At baseline, the mean age of randomized patients was 71 years, with a range of 50 to 90 years. Fifty percent of patients were male and 90% were White.

In Study 1, a subgroup of 315 patients was enrolled in the amyloid PET substudy; of these, 277 were evaluated at Week 79. For results from the amyloid beta PET substudy, see Figure 1 and Table 9 in the Clinical studies section of the DAILYMED drug label information. Plasma biomarkers are described in Table 7.

The primary endpoint was change from baseline on a weighted composite score consisting of selected items from the Clinical Dementia Rating scale Sum of Boxes (CDR-SB), MMSE, and Alzheimer Disease Assessment Scale – Cognitive Subscale 14 (ADAS-Cog14) at Week 53. Lecanemab had a 64% likelihood of 25% or greater slowing of progression on the primary endpoint relative to placebo at Week 53, which did not meet the prespecified success criterion of 80%.

Key secondary efficacy endpoints included the change from baseline in amyloid PET standard uptake value ratio composite at Week 79 and the change from baseline in the CDR-SB and ADAS-Cog14 at Week 79. Results for clinical assessments showed less change from baseline in CDR-SB and ADAS-Cog14 scores at Week 79 in the lecanemab group than in patients on placebo (CDR-SB: -0.40 [26%], 90% CI [-0.82, 0.03]; ADAS-Cog14: -2.31 [47%], 90% CI [-3.91, -0.72]).

After the 79-week double-blind, placebo-controlled period of Study 1, patients could enroll in an open-label extension period for up to 260 weeks, which was initiated after a gap period (range 9 to 59 months; mean 24 months) off treatment.

Study 2

In Study 2, 1795 patients were enrolled and randomized 1:1 to receive intravenous infusion of lecanemab 10 mg/kg or placebo once every 2 weeks. Of the total number of patients randomized, 69% were ApoE ε4 carriers and 31% were ApoE ε4 non-carriers. The overall median age of patients was 72 years, with a range of 50 to 90 years. Fifty-two percent were women, and 1381 (77%) were White, 303 (17%) were Asian, and 47 (3%) were Black.

The randomization was stratified according to clinical subgroup (mild cognitive impairment or mild dementia stage of the disease); the presence or absence of concomitant approved therapies for Alzheimer disease at baseline (cholinesterase inhibitors and the N-methyl-D-aspartate antagonist memantine); ApoE ε4 carrier status; and geographical region.

The primary efficacy outcome was a change from baseline at 18 months in the CDR-SB. Key secondary endpoints included change from baseline at 18 months for the following measures: amyloid Positron Emission Tomography (PET) using Centiloids, ADAS-Cog14, and Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL).

Lecanemab treatment met the primary endpoint and reduced clinical decline on the global cognitive and functional scale, CDR-SB, compared to placebo at 18 months (-0.45 [-27%], P<0.0001).

Statistically significant differences (P<0.01) between treatment groups were also seen in the results for ADAS-Cog14 and ADCS MCI-ADL at 18 months, as presented in Table 10.

Both ApoE ε4 carriers and ApoE ε4 noncarriers showed statistically significant treatment differences for the primary endpoint and all secondary endpoints. In an exploratory subgroup analysis of ApoE ε4 homozygotes, which represented 15% of the trial population, a treatment effect was not observed with lecanemab treatment on the primary endpoint, CDR-SB, compared to placebo, although treatment effects that favored lecanemab were observed for the secondary clinical endpoints, ADAS-Cog14 and ADCS MCI-ADL. Treatment effects on disease-relevant biomarkers (amyloid beta PET, plasma Aβ42/40 ratio, plasma p-tau 181) also favored lecanemab in the ApoE ε4 homozygous subgroup.

Starting at 6 months, across all time points, lecanemab treatment showed statistically significant changes in the primary and all key secondary endpoints from baseline compared to placebo; see Figure 2 and Table 10 in the Clinical studies section of the DAILYMED drug label information.

How supplied/storage and handling

How supplied

Lecanemab single-dose vials and prefilled autoinjectors contain lecanemab-irmb as a sterile, preservative-free, clear to opalescent, and colorless to pale yellow solution, available as described below.

Intravenous infusion. Each lecanemab glass vial is closed with a stopper and flip cap and is available as follows:

Subcutaneous injection. Each lecanemab IQLIK prefilled autoinjector consists of a 2.25 mL glass syringe with a fixed 29-gauge ½-inch needle with a needle guard and is available as follows:

Lecanemab subcutaneous autoinjector is not made with natural rubber latex.

Storage and handling

Intravenous infusion.

Unopened vial.

Diluted solution. For storage of the diluted infusion solution, see Dosage and Administration (2.5).

Subcutaneous injection.

Patient counseling information

Advise the patient or caregiver to read the FDA-approved patient labeling.

Amyloid-related imaging abnormalities. Inform patients that lecanemab may cause Amyloid Related Imaging Abnormalities or “ARIA.” ARIA most commonly presents as a temporary swelling in areas of the brain that usually resolves over time. Some people may also have small spots of bleeding in or on the surface of the brain. Inform patients that most people with swelling in areas of the brain do not experience symptoms; however, some people may experience symptoms such as headache, confusion, dizziness, vision changes, nausea, aphasia, weakness, or seizure. Instruct patients to notify their healthcare provider immediately if these symptoms occur. Clinical evaluation should be performed, and an MRI may be considered. Inform patients that serious symptoms of ARIA may occur and that ARIA can be fatal. Inform patients that events of intracerebral hemorrhage greater than 1 cm in diameter have been reported infrequently in patients taking lecanemab, and that the use of antithrombotic or thrombolytic medications while taking lecanemab may increase the risk of bleeding in the brain. Notify patients that their healthcare provider will perform MRI scans to monitor for ARIA.

Inform patients that although ARIA can occur in any patient treated with lecanemab, there is an increased risk in patients who are ApoE ε4 homozygotes, and that testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Inform patients that if testing is not performed, it cannot be determined if they are ApoE ε4 homozygotes and at a higher risk for ARIA.

Inform patients that some symptoms of ARIA-E can mimic ischemic stroke and that their healthcare providers may need to perform additional testing to determine how to treat those symptoms in patients taking lecanemab. Advise patients to carry information that they are being treated with lecanemab.

Patient registry. Providers should encourage patients to participate in real-world data collection (eg, registries) to help further the understanding of Alzheimer disease and the impact of Alzheimer disease treatments. Providers and patients can contact Eisai at 888-274-2378 for a list of currently enrolling programs.

Hypersensitivity reactions. Inform patients that hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients who were treated with lecanemab. Advise patients to seek immediate medical attention if they experience any symptoms of serious or severe hypersensitivity reactions.

Infusion-related reactions. For patients receiving lecanemab via intravenous infusion, advise them of the potential risk of infusion-related reactions, which can include flu-like symptoms, nausea, vomiting, and changes in blood pressure. Advise patients that most infusion-related reactions occur with the first infusion but may occur with any of the infusions during treatment. Advise patients that symptoms can occur during infusion or after they leave the infusion center and to contact their healthcare provider if infusion-related reactions occur.

Injection-related reactions. For patients receiving lecanemab via subcutaneous injection, advise them of the potential risks of injection reactions, which may present as erythema, induration, swelling, heat, rash, pain, itching, ecchymosis and hematoma at the injection site, but may also present with symptoms such as headache, fever, and fatigue. Instruct patients to contact their healthcare provider if injection-related reactions occur.

Medication guide

See the Medication guide section of the DAILYMED drug label information.

Acknowledgement

This article was excerpted from U.S. FDA Drug Labeling information available on the DailyMed website.