U.S. Food and Drug Administration (FDA)-Approved Indications

Leqembi is indicated for the treatment of Alzheimer’s disease. Treatment with Leqembi 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.

Lecanemab-irmb is an intravenous infusion available as Leqembi (Eisai Inc.). Lecanemab-irmb is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble (protofibril) and insoluble forms of amyloid beta (Aβ). In Alzheimer's disease (AD), it is believed that abnormal accumulation of proteins, such as amyloid beta which form plaques in the extracellular spaces between the neurons of the brain, and tau, which are twisted fibers that form neurofibrillary tangles inside the neurons (intracellular), leads to loss of synapses and neurons resulting in gross atrophy of the affected areas of the brain, manifesting into progressive memory and cognitive decline (Huang, 2021). Amyloid plaques typically appear earlier in the disease process, whereas tau tangles tend to appear later in the disease. "The Amyloid Theory largely states that if you were able to prevent the accumulation of beta amyloid, or clear existing amyloid, the progress of the cognitive and memory problems associated with Alzheimer’s would be slowed or prevented" (Terry, 2021). Lecanemab is believed to reduce the number of amyloid plaques present in the brain, potentially slowing neurodegeneration and disease progression.

Although there are no labeled contraindications, there are warnings and precautions which include amyloid related imaging abnormalities (ARIA) and infusion-related reactions. Monoclonal antibodies directed against aggregated forms of beta amyloid can cause ARIA, characterized as ARIA with edema (ARIA-E), which can be observed on magnetic resonance imaging (MRI) as brain edema or sulcal effusions, and ARIA with hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis. ARIA-H can occur spontaneously in patients with AD. 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 is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, rarely can occur. 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. Healthcare providers will need to obtain a recent (within one year) brain MRI prior to initiating treatment with Leqembi. An MRI will also need obtained prior to the 5th, 7th, and 14th infusions (Eisai, 2023b).

The most common adverse reactions (at approximately 10% and higher incidence compared to placebo) included in clinical trials were infusion-related reactions, headache, and ARIA-edema.

In January 2023, the FDA, under the Accelerated Approval Pathway, approved Leqembi for treatment of AD. Leqembi treatment is to be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied. The accelerated approval is based on reduction in amyloid beta plaques observed in patients treated with lecanemab (NCT01767311). Per the FDA, continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial.

Swanson et al (2021) conducted an 18-month, multicenter, double-blind, placebo-controlled Bayesian design, dose finding study (Study 201; ClinicalTrials.gov number NCT01767311) employing response adaptive randomization across placebo and 5 lecanemab arms to assess safety and efficacy in subjects with early AD. Participants were comprised of 2 subgroups: mild cognitive impairment due to AD or mild AD dementia. All subjects were confirmed to be amyloid positive via amyloid positron emission tomography (PET) or cerebrospinal fluid (CSF) Aβ

_1–42

. Key inclusion criteria included objective impairment in episodic memory (on Wechsler Memory Scale-IV Logical Memory II [WMS-IV LMII]), Mini Mental State Examination (MMSE) score equal to or greater than 22 at screening and baseline (amended to MMSE 22–28 in EU, except Italy), and naïve to or on stable dose (12 weeks) of approved AD medications. Subjects were enrolled who had a Clinical Dementia Rating (CDR) global score of 0.5 or 1.0 and a Memory Box score of 0.5 or greater. The study had a 79-week double-blind, placebo-controlled period, followed by 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. To maintain the blind, all subjects received biweekly infusions of either placebo or lecanemab. The study aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves 90% or more of the maximum treatment effect. The primary endpoint was change from baseline at 12 months on the Alzheimer’s Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of 25% or more clinical reduction in decline versus placebo. Key secondary endpoints were change from baseline at 18 months in brain amyloid by PET Standard Uptake Value ratio (SUVr) in an optional sub-study of consenting participants, ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14), CSF biomarkers (optional sub-study), and total hippocampal volume using volumetric MRI. In the study, 856 subjects were randomized to receive one of 5 doses (161 of which were randomized to the recommended dosing regimen of 10 mg/kg every two weeks) of lecanemab or placebo (n=247). Of the total number of subjects 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 two weeks dose arm. ApoE ε4 carriers who had been receiving lecanemab 10 mg/kg every two weeks for 6 months or less were discontinued from study drug. As a result, in the lecanemab 10 mg/kg every two weeks arm, 30.3% of patients were ApoE ε4 carriers and 69.7% were ApoE ε4 non-carriers. The authors found that at 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (−0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. The authors state that intravenous administration of lecanemab 10 mg/kg every 2 weeks was well-tolerated with 9.9% incidence of ARIA-E at 10 mg/kg biweekly. The authors concluded that Study 201 did not meet the 12-month primary endpoint; however, the prespecified 18-month Bayesian and frquentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. The authors note that a phase 3 study (Clarity AD) in early AD is underway.

Swanson and colleagues (2021) acknowledged limitations in Study 201. "Most notably, a small number of symptomatic ARIA-E cases at 10 mg/kg biweekly prompted one Regulatory Authority to request that subsequent ApoE4+ subjects (approximately 70% of the overall study population) not be randomized to the 10 mg/kg biweekly dose. An additional component to the request required that all ApoE4+ subjects on 10 mg/kg biweekly who were on study but who had not yet reached 6 months of treatment be immediately discontinued (N = 25 subjects). Implementation of these actions led to early (initiated between 300 and 350 randomized participants) and significant changes to the study design that resulted in a marked imbalance in the number of ApoE4+ subjects on 10 mg/kg biweekly (30% ApoE4+ subjects). The Bayesian algorithm identified 10 mg/kg biweekly as the ED90 dose despite this imposed design limitation. The constraints in this analysis were specifically associated with the ED90 dose and therefore could have had an impact on the ability to interpret the results. The safety and efficacy of 10 mg/kg biweekly lecanemab is currently being evaluated in an open label extension to this study, and in the phase 3 lecanemab Clarity AD study, where there are no dosing restrictions based on ApoE status in either study."

van Dyck and colleagues (2023) conducted an 18-month, multicenter, double-blind, placebo-controlled, parallel-group, phase 3 trial evaluating lecanemab in persons with early AD. The study (Clarity AD; NCT03887455) includes persons 50 to 90 years of age with mild cognitive impairment or mild dementia due to AD with evidence of amyloid on PET or by CSF testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment). A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The authors found that the mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; p<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; p<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; p<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; p<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and ARIA-E in 12.6%. The incidence of amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H) was 17.3%. The incidence of ARIA, including symptomatic ARIA, was numerically lower than in similar clinical trials, but differences in the drugs used and in trial design do not allow direct comparisons. ARIA-E generally occurred in the first 3 months, was mild and asymptomatic, did not lead to discontinuation of lecanemab or placebo if mild, and resolved within 4 months. The authors note that the incidences of both overall and symptomatic ARIA-E were highest among ApoE ε4 homozygotes. The authors concluded that lecanemab reduced markers of amyloid in early AD and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. The authors acknowledge study limitations which includes data for only 18 months of treatment. The authors state that longer trials are warranted to determine the efficacy and safety of lecanemab in early AD. Additional trials of lecanemab include a 5-year phase 2 long-term extension trial (NCT01767311) and a 4-year phase 3 long-term extension trial (NCT03887455) in early AD, the 4-year AHEAD 3-45 trial (NCT04468659) in preclinical AD, and the 4-year DIAN-TU (Dominantly Inherited Alzheimer Network Trials Unit) Next Generation trial (NCT05269394) in dominantly inherited AD.

On July 6, 2023, the FDA granted traditional approval for Leqembi for the treatment of Alzheimer's disease based on results from the phase 3 Clarity AD trial, which met its primary and key secondary endpoints showing statistically significant results for use of Leqembi in patients with MCI or mild dementia stage of disease. Leqembi was found to reduce clinical decline on CDR-SB by 27% at 18 months compared to placebo. Additionally, Leqembi slowed decline of activities of daily living by 37% on ADCS MCI-ADL at 18 months. "Leqembi demonstrated clinically meaningful slowing of cognitive and functional decline in a patient group generalizable to U.S. Medicare beneficiaries, which included a mix of racial and ethnic groups, patients with common comorbid conditions, concomitant medications and patients with mild cognitive impairment (MCI) due to AD or mild AD". There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied (Biogen, 2023).

The label includes an updated black box warning regarding apolipoprotein (ApoE4) genotype status. Patients treated with Leqembi who are ApoE ε4 homozygotes have a higher incidence of ARIA, including symptomatic and serious 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. The most common adverse reactions (at approximately 10% and higher incidence compared to placebo) include infusion-related reactions, amyloid related imaging abnormality-microhemorrhages, amyloid related imaging abnormalityedema/effusion, and headache (Eisai, 2023).

Appendix

Appendix A: Summary of Clinical and Cognitive Evaluation for MCI due to AD

Cognitive concern reflecting a change in cognition reported by patient or informant or clinician (i.e., historical or observed evidence of decline over time)

Objective evidence of impairment in one or more cognitive domains, typically including memory (i.e., formal or bedside testing to establish level of cognitive function in multiple domains)

Preservation of independence in functional abilities

Not demented

Appendix B: Clinical Dementia Rating (CDR) Scale

The CDR is obtained through semi-structured interviews of patients and informants with cognitive functioning rated on a 5-point scale in the following domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The score relates to the member’s level of dementia:

0 = Normal

0.5 = Very Mild Dementia

1 = Mild Dementia

2 = Moderate Dementia

3 = Severe Dementia

Source: Knight Alzheimer Disease Research Center; Morris (1993); O'Bryant et al (2008)

Appendix C: Mini-Mental Status Exam (MMSE)

The MMSE is scored on a 30-point scale, with items that assess orientation (temporal and spatial; 10 points), memory (registration and recall; 6 points), attention/concentration (5 points), language (verbal and written, 8 points), and visuospatial function (1 point). The score relates to the member’s level of dementia:

25 - 30 suggests normal cognition

20 - 24 suggests mild dementia

13 - 20 suggests moderate dementia

Less than 12 suggests severe dementia

Source: Folstein, Folstein, and McHugh (1975)

Appendix D: Montreal Cognitive Assessment (MoCA)

Per MoCA assessment, average scores for the following ranges are:

Mild Cognitive Impairment: 19 - 25

Mild Dementia: 11 - 21

Normal: 26 and above

Source: Nasreddine et al, 2019; Nasreddine, 2023

Appendix E: ARIA MRI Classification Criteria

Table 3: ARIA MRI Classification Criteria ARIA Type Radiographic Severity Mild Moderate Severe ARIA-E FLAIR hyperintensity confined to sulcus and or cortex/subcortical white matter in one location less than 5 cm FLAIR hyperintensity 5 to 10 cm in single greatest dimension, or more than 1 site of involvement, each measuring less than 10 cm FLAIR hyperintensity greater than 10 cm with associated gyral swelling and sulcal effacement. One or more separate sites of involvement may be noted. ARIA-H microhemorrhage less than or equal to 4 new incident microhemorrhages 5 to 9 new incident microhemorrhages 10 or more new incident microhemorrhages ARIA-H superficial siderosis 1 focal area of superficial siderosis 2 focal areas of superficial siderosis greater than 2 focal areas of superficial siderosis

Source: Eisai, 2023b

Note

: Requires Precertification:

Precertification of lecanemab-irmb (Leqembi) is required of all Aetna participating providers and members in applicable plan designs. For precertification of

lecanemab-irmb (Leqembi)

,

call (866) 752-7021 (commercial), or fax (888) 267-3

277. For Statement of Medical Necessity (SMN) precertification forms, see

Specialty Pharmacy Precertification

.

For Medicare Part B plans, call (866) 503-0857, or fax (844) 268-7263.

Note

: Site of Care Utilization Management Policy applies. For information on site of service for

lecanemab-irmb (Leqembi)

, see

Utilization Management Policy on Site of Care for Specialty Drug Infusions

.

Exclusions

Coverage will not be provided for members with

any

of the following conditions:

Suspected neurodegenerative etiology of cognitive impairment other than Alzheimer’s disease (AD), including but not limited to frontotemporal lobar degeneration (FTLD) or Lewy body disease (i.e., meeting consensus criteria for possible or probable dementia with Lewy bodies);

History of transient ischemic attacks (TIA), stroke, or seizures within the past 12 months;

Bleeding disorder that is not under adequate control (including a platelet count less than 50,000 or international normalized ratio [INR] greater than 1.5);

Leqembi will not be used in combination with any other amyloid beta-directed antibodies (e.g., aducanumab).

Prescriber Specialties

This medication must be prescribed by or in consultation with a geriatrician, neurologist, psychiatrist, or neuropsychiatrist.

Criteria for Initial Approval

Aetna considers lecanemab-irmb (Leqembi) medically necessary for treatment of Alzheimer’s Disease (AD) [except as outlined in Section I for exclusions] when

all

of the following criteria are met:

Member must meet one of the following criteria:

Member is 50 years of age or older;

or

If less than 50 years of age, member has a genetic mutation in amyloid precursor protein (

APP

), presenilin-1 (

PSEN1

), or presenilin-2 (

PSEN2

), or other clinical documentation to support early onset AD;

and

Member must have mild cognitive impairment due to AD or mild AD dementia;

and

Member must have objective evidence of cognitive impairment at baseline (see

Appendix A

);

and

Member must have one of the following scores at baseline on

any

of the following assessment tools:

Clinical Dementia Rating-Global Score (CDR-GS) of 0.5 or 1 (see

Appendix B

);

or

Mini-Mental Status Examination (MMSE) score of 21 - 30 (see

Appendix C

);

or

Montreal Cognitive Assessment (MoCA) score of greater than or equal to 16 (see

Appendix D

);

and

Member must meet one of the following criteria:

Have a positron emission tomography (PET) scan confirming the presence of amyloid pathology;

or

Have results from a lumbar puncture confirming the presence of elevated phosphorylated tau (P-tau) protein and/or elevated total tau (T-tau) protein, and reduced beta amyloid-42 (AB42) OR a low AB42/AB40 ratio as determined by the lab assay detected in cerebrospinal fluid (CSF);

and

Member must have a recent brain magnetic resonance imaging (MRI) within one year prior to initiating treatment to evaluate for pre-existing Amyloid Related Imaging Abnormalities (ARIA);

and

Member meets

one

of the following regarding apolipoprotein E ε4 (ApoE ε4) status:

Genotype testing for ApoE ε4 status has been performed prior to initiation of treatment to inform member of the risk of developing ARIA;

or

Genotype testing has not been performed and the prescriber has informed the member that it cannot be determined if they are ApoE ε4 homozygous and may be at higher risk for ARIA;

and

If there is concurrent use of antithrombotic medications (aspirin, other antiplatelets, or anticoagulants), the member has been on a stable dose for at least 4 weeks prior to initiation of the requested medication;

and

Member and/or provider must currently be participating in a provider-enrolled patient registry that collects information on treatments for Alzheimer’s disease (e.g., Alzheimer’s Network for Treatment and Diagnostics (ALZ-NET)).

Aetna considers all other indications as experimental and investigational.

Continuation of Therapy

Aetna considers continuation of lecanemab-irmb (Leqembi) therapy medically necessary for treatment of Alzheimer’s Disease (AD) [except as outlined in Section I for exclusions] when the criteria outlined below are met.

Continuation of therapy for 12 months (first reauthorization after the initial 6-month approval period) when

all

of the following criteria are met:

Member has met all initial authorization criteria at the time of initial approval;

and

Member has been evaluated for evidence of amyloid-related imaging abnormalities (ARIA) on MRI prior to the 5th dose, 7th dose, and 14th dose (see

Appendix E

)

For members with radiographic evidence of amyloid related imaging abnormalities-edema (ARIA-E):

Dosing may continue based on clinical judgement, if applicable, for members that meet the following criteria:

Member has mild ARIA-E on MRI and is asymptomatic or has mild clinical symptoms;

or

Dosing should be suspended until MRI demonstrates radiographic resolution and symptoms resolve for members that meet

any

of the following criteria:

Member has mild ARIA-E on MRI and has moderate or severe clinical symptoms;

or

Member has moderate ARIA-E on MRI and is asymptomatic or has mild, moderate, or severe clinical symptoms;

or

Member has severe ARIA-E on MRI and is asymptomatic or has mild, moderate, or severe clinical symptoms;

or

For members with radiographic evidence of amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H):

Dosing may continue for members that meet the following criteria:

Member has mild ARIA-H on MRI and is asymptomatic;

or

Dosing should be suspended until MRI demonstrates radiographic stabilization and symptoms resolve for members that meet

any

of the following criteria:

Member has mild ARIA-H on MRI and is symptomatic;

or

Member has moderate ARIA-H on MRI and is asymptomatic or symptomatic;

or

Member has severe ARIA-H on MRI and is asymptomatic or symptomatic;

and

Member and/or provider continues to participate in a provider-enrolled patient registry that collects information on treatments for Alzheimer’s disease (e.g., Alzheimer’s Network for Treatment and Diagnostics (ALZ-NET)).

Continuation of therapy for 12 months (reauthorizations beyond initial 18 months of therapy) when

all

of the following criteria are met:

Member has met all initial authorization criteria at the time of initial approval;

and

Member has a positive clinical response as evidenced by stabilization or slowing of disease progression as documented by

any

of the following

(Note:

repeat assessment tool(s) must be the same tool that was submitted upon initial request):

CDR-Global Score (i.e., score of 0.5 or 1);

or

MMSE (i.e., decline of 3 points or less per year);

or

MoCA (i.e., score of greater than or equal to 16);

and Note

: Continuation requests for members with assessment scores outside of the provided ranges (i.e. mild dementia) or who have progressed greater than the provided rate of decline may be reviewed on a case-by-case basis.

Member and/or provider continues to participate in a provider-enrolled patient registry that collects information on treatments for Alzheimer’s disease (e.g., Alzheimer’s Network for Treatment and Diagnostics (ALZ-NET)).

Related CMS Coverage Guidance

This Clinical Policy Bulletin (CPB) supplements but does not replace, modify, or supersede existing Medicare Regulations or applicable National Coverage Determinations (NCDs) or Local Coverage Determinations (LCDs). The supplemental medical necessity criteria in this CPB further define those indications for services that are proven safe and effective where those indications are not fully established in applicable NCDs and LCDs. These supplemental medical necessity criteria are based upon evidence-based guidelines and clinical studies in the peer-reviewed published medical literature. The background section of this CPB includes an explanation of the rationale that supports adoption of the medical necessity criteria and a summary of evidence that was considered during the development of the CPB; the reference section includes a list of the sources of such evidence. While there is a possible risk of reduced or delayed care with any coverage criteria, Aetna believes that the benefits of these criteria – ensuring patients receive services that are appropriate, safe, and effective – substantially outweigh any clinical harms.

Code of Federal Regulations (CFR):

42 CFR 417; 42 CFR 422; 42 CFR 423.

Internet-Only Manual (IOM) Citations:

CMS IOM Publication 100-02, Medicare Benefit Policy Manual; CMS IOM Publication 100-03 Medicare National Coverage Determination Manual.

Medicare Coverage Determinations:

Centers for Medicare & Medicaid Services (CMS), Medicare Coverage Database [Internet]. Baltimore, MD: CMS; updated periodically. Available at:

Medicare Coverage Center

. Accessed November 7, 2023.