ARCHIVED

Medical Policy

Policy Num:      05.001.046
Policy Name:    Monoclonal Antibodies for Treatment of Alzheimer Disease
Policy ID:          [05.001.046]  [Ac / B / M- / P-]  [5.01.38]

Last Review:     March 27, 2026
Next Review:     January 15, 2027
 

Related Policies: None

Monoclonal Antibodies for Treatment of Alzheimer Disease

Summary

Description

Alzheimer disease (AD) is a neurodegenerative disorder leading to progressive, irreversible destruction of neurons and loss of cognitive function and memory. Over time, patients progress to severe dementia, loss of independence, and death. Extracellular deposits of amyloid beta, referred to as amyloid plaques, are considered a hallmark of the disease. Beta-amyloid monomers lead to formation of beta oligomers and fibrils, are deposited as plaques, and then interact with tau fibrils, leading to formation of neuro-fibrillatory tangles. These pathophysiological changes and clinical manifestations of AD are progressive and occur along a continuum, and accumulation of amyloid beta may begin 20 years or more before symptoms arise. Two monoclonal antibodies (aducanumab and lecanemab) have been approved by the U.S. Food and Drug Administration under accelerated approval based on the reduction in amyloid beta plaques. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial. Aducanumab (Aduhelm®), which received accelerated approval as a treatment for Alzheimer's disease from the U.S. Food and Drug Administration (FDA) in 2021, has been discontinued by its manufacturer (Biogen).

Summary of Evidence

For individuals with early AD (MCI or mild dementia due to AD) who receive lecanemab, the evidence includes includes a single dose-finding RCT. Relevant outcomes are disease-specific survival, change in disease status, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. In study 201, participants were randomized to placebo or one of 5 lecanemab dosing regimens, including the FDA approved dosing regimen of 10 mg/kg biweekly. The primary endpoint was change from baseline on a weighted composite score consisting of selected items from the CDR-SB, Mini-Mental State Examination (MMSE), and Alzheimer’s Disease Assessment Scale – Cognitive 13-Item Scale (ADAS-Cog 13) 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%. Approval by the FDA was based on the reduction in amyloid beta plaques. Change from baseline in brain amyloid plaque was assessed in a subset of patients at week 79. Treatment with lecanemab 10 mg/kg every two weeks reduced amyloid beta plaque levels in the brain, producing reductions in positron emission tomography standard uptake value ratio compared to placebo. The magnitude of the reduction was time- and dose-dependent. However, there are no satisfactory data clearly establishing that individual changes in amyloid correlate with or predict long term cognitive and functional changes. In the absence of clinical data convincingly demonstrating a clinical effect, it cannot be concluded that the observed reduction in amyloid will translate into a clinical benefit to patients. Cognitive decline in early AD generally occurs over years, and thus the follow-up duration may not be sufficient to conclude whether a drug is effective for this disease or whether the safety profile might change with longer follow-up. Safety data showed that about 12% of patients on lecanemab experienced ARIA. A confirmatory, prospective, and adequately powered trial is necessary to assess the net health benefit of lecanemab in patients with early AD. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to assess whether treatment with monoclonal antibodies improves the net health outcome in patients with early Alzheimer disease (mild cognitive impairment or mild dementia due to Alzheimer disease).

Policy Statements

The use of lecanemab is considered investigational for all indications including treatment of Alzheimer disease.

Policy Guidelines

The product label of lecanemab recommends that a baseline brain MRI within 1 year must be done prior to initiating treatment due to the risk of ARIA. Subsequently, MRI should be repeated prior to the fifth, seventh, and fourteenth infusions. Follow recommendations for dosing interruptions in patients with ARIA as specified in the US FDA approved prescribing label.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Alzheimer Disease

Alzheimer disease (AD) is a fatal neurodegenerative disease that causes progressive loss in memory, language, and thinking, with the eventual loss of ability to perform social and functional activities in daily life. Survival after a diagnosis of dementia due to AD generally ranges between 4 and 8 years; however, life expectancy can be influenced by other factors, such as comorbid medical conditions. It is estimated that 6.2 million Americans aged 65 and older are currently living with AD dementia, and the number is projected to reach over 12 million by 2050.^1,

Pathophysiology

The pathologic hallmarks of AD are extracellular deposits of amyloid beta, referred to as amyloid plaques, and intracellular aggregates of hyperphosphorylated tau in the form of neurofibrillary tangles. There are different forms of amyloid such as plaques, oligomers, and monomers, and the roles of these different forms and how specifically they are pathophysiologically associated with AD is not well understood. Generally referred to as the “amyloid hypothesis”, it is believed that aggregation of amyloid beta oligomers in the brain leads to amyloid plaques and it is thought to be the primary driver of the disease process. Amyloid aggregation is thought to precede accumulation of tau pathology and neurodegeneration. These changes in the brain result in widespread neurodegeneration and cell death, and ultimately cause the clinical signs and symptoms of dementia.^2,3,

Salient known risk factors for AD are older age, genetics, and family history. Of these, increasing age has the largest known impact on risk of developing AD. While several genes have been found to increase the risk of AD, the ε4 allele of the apolipoprotein E (ApoE) gene is the strongest known genetic risk factor.^4,5, Having a single copy of the gene is associated with a 2- to 3-fold increase in developing AD while 2 copies of the gene may increase risk of AD by as much as 15 times.^6, Approximately two-thirds of pathology-confirmed AD cases are ε4 positive (homozygous or heterozygous), compared with about 15% to 20% of the general population.^5, Autosomal dominant genetic mutations are estimated to account for less than 1% of AD cases.^7,

The pathophysiological changes and clinical manifestations of AD are progressive and occur along a continuum, and accumulation of amyloid beta may begin 20 years or more before symptoms arise.^8, The National Institute on Aging-Alzheimer’s Association (NIA-AA) have created a “numeric clinical staging scheme” (Table 1) that avoids traditional syndromal labels and is applicable for only those in the Alzheimer continuum. This staging scheme reflects the sequential evolution of AD from an initial stage characterized by the appearance of abnormal AD biomarkers in asymptomatic individuals. As biomarker abnormalities progress, the earliest subtle symptoms become detectable. Further progression of biomarker abnormalities is accompanied by progressive worsening of cognitive symptoms, culminating in dementia. This numeric cognitive staging scheme is not designed to be used in a clinical setting but to be used for interventional trials.

Clinical criteria for diagnosing AD are informed by the NIA-AA 2011 guidelines.^10,11, Mild cognitive impairment (MCI) lies between the cognitive changes of normal aging and dementia. Mild cognitive impairment is a syndrome in which persons experience memory loss (amnestic MCI) or loss of thinking skills other than memory loss (non-amnestic MCI), to a greater extent than expected for age, but without impairment of day-to-day functioning.^10, Individuals with MCI are at increased risk of developing dementia (whether from AD or another etiology), but many do not progress to dementia, and some get better. Dementia is a syndrome involving cognitive and behavioral impairment in an otherwise alert patient, due to a number of neurological diseases, alone or combined. It is not a specific cause or disease process itself. The impairment must involve a minimum of 2 domains (memory, reasoning, visuospatial abilities, language or personality behaviors), impact daily functioning, represent a decline from previous levels of functioning, not be explainable by delirium (a temporary state of mental confusion and fluctuating consciousness from various causes) or a major psychiatric disorder, and be objectively documented by a “bedside” mental status exam (e.g., the mini-mental status exam) or neuropsychological testing.^11, These guidelines describe core clinical criteria for “all-cause” dementia and “probable AD” dementia. Briefly, “probable AD” dementia must first meet the criteria for “all-cause” dementia. Additionally, there must be: (a) insidious onset; (b) documented worsening of cognition; (c) exclusion of major concomitant cerebrovascular disease (as most individuals with AD have some level of this as well); and (d) exclusion of alternative diagnoses (e.g., dementia with Lewy bodies, behavioral variant frontotemporal dementia, progressive aphasia, or other neurological disease associated with dementia). A clinical diagnosis of “possible AD” dementia would meet the criteria for “probable AD” with the exception of having an “atypical course” (e.g., sudden rather than insidious onset) or an “etiologically mixed presentation.”

Many tests are available in the market to detect the underlying core pathology such as certain biomarkers in the cerebrospinal fluid (CSF) (eg, decreased amyloid beta and increased CSF tau protein levels) and on imaging (e.g., amyloid on positron emission tomography [PET] scans). Approved amyloid PET tracers in the US include [¹⁸F]-florbetapir, [¹⁸F]-flutemetamol, and [¹⁸F]-florbetaben. In addition, there are several CSF tests for amyloid beta confirmation that are currently in development in the US. Cerebrospinal fluid tests and amyloid PET tracers are routinely used in the enrollment of participants in contemporary AD studies.^12,

Current Treatment

Treatment goals for patients with AD are often directed to maintain quality of life, treat cognitive symptoms, and manage behavioral and psychological symptoms of dementia. Treatment remains largely supportive, including creation and implementation of individualized dementia care plans, caregiver education and support, care navigation, care coordination, and referral to community-based organizations for services (eg, adult day care, caregiver training).^13, Non-pharmacologic treatments include physical activity^14,15, as well as behavioral strategies to ameliorate neuropsychiatric symptoms (eg, agitation, delusions, disinhibition), and problem behaviors (eg, resistance to care, hoarding, obsessive-compulsive behaviors).^16, Currently, FDA-approved drugs for AD include cholinesterase inhibitors, donepezil, rivastigmine, and galantamine, and the N‐methyl‐D‐aspartate antagonist, memantine. Cholinesterase inhibitors are indicated in mild, moderate, and severe AD, while memantine is approved for moderate-to-severe AD. These drugs, either alone or in combination, focus on managing cognitive and functional symptoms of the disease and have not been shown to alter disease trajectory. The evidence for efficacy is limited and these agents are associated with significant side effects.^16,17,

Table 1. National Institute on Aging-Alzheimer’s Association Numerical Clinical Staging for Individuals in the Alzheimer Continuum^a

Adapted from Table 6, Jack et al (2018)^18,
CSF: cerebrospinal fluid; FDG: fluorodeoxyglucose; MCI: mild cognitive impairment; MRI: magnetic resonance imaging; PET: positron emission tomography.
^aApplicable only to individuals in the Alzheimer continuum that fall into 1 of the 4 biomarker groups: 1) A+T+N+ 2) A+T-N- 3) A+T+N- 4) A+T-N+ where A: Aggregated amyloid beta or associated pathologic state (CSF amyloid beta₄₂, or amyloid beta₄₂/amyloid beta₄₀ ratio or Amyloid PET), T: Aggregated tau (neurofibrillary tangles) or associated pathologic state (CSF phosphorylated tau or Tau PET) and N: Neurodegeneration or neuronal injury (anatomic MRI, FDG PET or CSF total tau)
For stages 1 to 6: Cognitive test performance may be compared to normative data of the investigator's choice, with or without adjustment (choice of the investigators) for age, sex, education, etc.
For stages 2 to 6: Although cognition is the core feature, neurobehavioral changes—for example, changes in mood, anxiety, or motivation—may coexist.
For stages 3 to 6: Cognitive impairment may be characterized by presentations that are not primarily amnestic.

Regulatory Status

Aducanumab (Aduhelm®), which received accelerated approval as a treatment for Alzheimer's disease from the U.S. Food and Drug Administration (FDA) in 2021, has been discontinued by its manufacturer (Biogen).

In April 2022, FDA amended the approved label to emphasize that physicians confirm that amyloid beta pathology is present before starting treatment.

In January 2023, lecanemab (Leqembi; Eisai) was approved by the FDA for treatment of AD. This indication was approved under accelerated approval based on the reduction in amyloid beta plaques observed in patients treated with lecanemab. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).

The FDA, under the accelerated approval regulations (21 CFR 601.41), requires that Eisai conduct a RCT to evaluate the efficacy of lecanemab compared to an appropriate control for the treatment of AD. The trial should be of sufficient duration to observe changes on an acceptable endpoint in the patient population enrolled in the trial. The expected date of trial completion is September 2022 and final report submission to the FDA by March 2023.

Rationale

This evidence review was created in June 2021 with searches of the PubMed database. The most recent literature update was performed through February 1. 2023.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Population Reference No. 1

Early Alzheimer Disease

Clinical Context and Therapy Purpose

The purpose of monoclonal antibody such as lecanemab is to provide a treatment option that is an alternative to or an improvement on existing therapies for individuals with early Alzheimer disease (AD; mild cognitive impairment [MCI] or mild dementia due to AD).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with early AD.

Interventions

The therapy being considered is monoclonal antibody which include lecanemab. The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of AD. Lecanemab-irmb is a immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta.

Comparators

The following practice is currently being used to treat early AD. Currently approved AD treatments include the cholinesterase inhibitors, donepezil, rivastigmine, and galantamine, and the N-methyl-D-aspartate antagonist, memantine. None of these agents addresses the underlying pathology of the disease. Their effects are reversible and lessen over time due to the continued progression of the disease process.

Outcomes

The general outcomes of interest are disease-specific survival, change in disease status, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. Follow-up at 2 to 5 years is of interest to monitor outcomes. See Table 2 for the description and relevance of specific outcome measures considered in this review.

As per the U.S. Food and Drug Administration (FDA) 2018 draft guidance for developing drugs for treatment of early AD, treatment for mild to moderate AD dementia (corresponding to stages 4 and 5) would be considered substantially effective if there is improvement on a core symptom (eg, a measure of cognition) and a global clinical measure (eg, a clinician’s judgement of change) or a functional measure (eg, activities of daily living).^9, For studies including prodromal patients with MCI (corresponding to Stage 3 in the FDA 2018 draft guidance), the FDA requires only a statistically significant change on a prespecified composite measure that includes cognition and daily function combined, as a demonstration of substantial effectiveness. In the 2013 draft guidance, the agency specifically recommended the Clinical Dementia Rating Sum of Boxes (CDR-SB) as a composite measure that had shown validity and reliability for this purpose. No quantified minimum differences were specified, but the rationale was that such a composite measure serves as an indicator of change in both the core or cognitive outcome.^19, Meeting minimal clinically important difference (MCID) thresholds, however, are not requisites for the FDA to conclude a trial shows substantial effectiveness or to authorize marketing approval.^20,

Table 2. Health Outcome Measures That May Be Relevant to Early Alzheimer Disease

AD: Alzheimer disease; MCI: mild cognitive impairment; MCID: minimally clinical important difference. 

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Population Reference No. 1 

Lecanemab

The clinical development program of lecanemab includes 3 studies that are summarized in Table 9.

Table 9. Summary of the Clinical Development Program for Lecanemab

AD: Alzheimer disease; DB: double-blind; MCI: mild cognitive impairment;NCT: national clinical trial;; OLE: open label extension; RCT: randomized controlled trial.

Randomized Controlled Trials

Lecanemab was approved by the FDA on January 6, 2023 under the accelerated approval pathway based on reduction in amyloid plaque. It is proposed that reduction in amyloid plaque is reasonably likely to predict clinical benefit. Subsequent to the accelerated approval, the manufacturer submitted a supplemental Biologics License Application (sBLA) to the U.S. FDA supporting the conversion of the accelerated approval of lecanemab to a traditional approval. This submission included the results of the Clarity study, a randomized, double-blind, placebo-controlled phase III trial. Results of the Clarity trial have been published.^50, The sBLA has been granted priority review and FDA is expected to make a decision by July 6, 2023. The FDA is also currently planning to hold an advisory committee to discuss this application but has not yet publicly announced the date of the meeting. At this time, the results of the phase III Clarity trial have not been included in this review as the additional data is being reviewed by the FDA. This review will be updated if lecanemab receives a traditional approval by the FDA.

Current evidence for lecanemab includes a single dose-finding double-blind, placebo-controlled trial (study 201). Trial characteristics and results are summarized in Tables 10 to 12. The trial included an 18-month placebo-controlled treatment period, and a safety follow-up period of 3 months after the final dose. For the placebo-controlled period, patients were randomized to placebo or one of 5 lecanemab dosing regimens, including the FDA approved dosing regimen of 10 mg/kg biweekly. The primary endpoint was change from baseline on a weighted composite score called Alzheimer’s Disease Composite Score (ADCOMS) consisting of selected items from the CDR-SB, MMSE, and Alzheimer’s Disease Assessment Scale – Cognitive 13-Item Scale (ADAS-Cog 13) 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%. Change from baseline in brain amyloid plaque as measured by ¹⁸F-florbetapir PET and quantified by a composite SUVR was assessed in a subset of patients at week 79 and serves as the endpoint to support accelerated approval. Treatment with lecanemab 10 mg/kg every 2 weeks reduced amyloid beta plaque levels in the brain, producing reductions in PET SUVR compared to placebo at both weeks 53 and 79 (p<.001). The magnitude of the reduction was time- and dose-dependent. During an off-treatment period (range from 9 to 59 months; mean of 24 months), SUVR and centiloid values began to increase with a mean rate of increase of 2.6 centiloids/year. However, treatment difference relative to placebo at the end of the double-blind, placebo-controlled period was maintained.^46,51, While lecanemab showed statistically significant dose dependent changes from baseline in amyloid beta plaques, there are no satisfactory data clearly establishing that individual changes in amyloid correlate with or predict long term cognitive and functional changes as measured by ADCOMS, CDR-SB or ADAS-Cog13.

Safety

Data with limited follow-up are available to analyze safety. In study 1, ARIA was observed in about 12% (20/161) of individuals treated with lecanemab 10 mg/kg biweekly compared to 5% (13/245) in the placebo arm. Respective incidences of ARIA-E were 10% (16/161) versus 1% (2/245) and ARIA-H was 6% (10/161) versus 5% (12/245). Symptomatic ARIA occurred in 3% (5/161) of individuals treated with lecanemab. Clinical symptoms associated with ARIA resolved in 80% of patients during the period of observation. The incidence of ARIA was higher in ApoE ε4 homozygotes than in heterozygotes and noncarriers among individuals treated with lecanemab. Of the 5 individuals treated with lecanemab who had symptomatic ARIA, 4 were ApoE ε4 homozygotes, 2 of whom experienced severe symptoms. While the recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers, as per the label, consider testing for ApoE ε4 status to inform the risk of developing ARIA when deciding to initiate treatment with lecanemab.^46,

Table 10. Summary of Key Study Characteristics

ApoE ε4: apolipoprotein E ε4; ADCOMS: Alzheimer’s Disease Composite Score; CDR: Clinical Dementia Rating; CSF: cerebrospinal fluid; MCI: mild cognitive impairment; MMSE: Mini-Mental State Examination; NIA-AA: National Institute on Aging-Alzheimer’s Association; PET: positron emission tomography; RCT: randomized controlled trial; WMS-IV LMII: Wechsler-Memory Scale-IV Logical Memory II
^a Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease^10,11,
b Change from baseline in brain amyloid plaque as measured by 18F-florbetapir PET and quantified by a composite standard uptake value ratio (SUVR) was assessed in a subset of patients at week 53 and week 79 and serves as the endpoint to support accelerated approval.
^c Randomization stratified by clinical subgroups (MCI due to Alzheimer’s disease and mild Alzheimer’s disease dementia), ApoE ε4 carrier status (carrier or non-carrier), and ongoing treatment with concurrent medications for treatment of Alzheimer’s disease

Table 11. Summary of Pivotal Trial Results for Clinical Outcomes

ADAS-Cog13: Alzheimer’s Disease Assessment Scale-Cognitive 13-Item Scale; ADCS-ADL-MCI: Alzheimer’s Disease Cooperative Study-Activities of Daily Living-Mild Cognitive Impairment; CDR-SB: Clinical Dementia Rating Sum of Box; CI: confidence interval; LS: least square; MMSE: Mini-Mental State Examination; NA: not applicable; SE: standard error.
Results presented above are based on ITT analysis which was defined as all randomized subjects who received at least one dose of study treatment and excluding data collected after March 20, 2019.

Table 12. Summary of Pivotal Trial Results for Biomarker Outcomes

NA: not applicable; PET: positron emission tomography; p-Tau; phosphorylated tau; SUVR: standard uptake value ratio
Results as reported in the prescribing label. N is the number of patients with baseline value.
^a P-values were not statistically controlled for multiple comparisons.
^b As per the label, plasma Aβ42/40 and plasma p-tau181 results should be interpreted with caution due to uncertainties in bioanalysis 

The purpose of Tables 13 and 14 is to display notable limitations in the evidence. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement. Key limitations in study relevance include use of physiologic measures such as amyloid beta and tau proteins and insufficient duration of follow-up to assess clinical benefits and harms. Key design and conduct limitations of phase 3 studies include the potential for partial unblinding due to adverse events, high loss to follow up or missing data, and generalizability to broader clinical populations and real world settings.

Table 13. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 14. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Lecanemab

For individuals with early AD (MCI or mild dementia due to AD) who receive lecanemab, the evidence includes a single dose-finding RCT (study 201). In this placebo-controlled trial, participants were randomized to placebo or one of 5 lecanemab dosing regimens, including the FDA approved dosing regimen of 10 mg/kg biweekly. The primary endpoint was change from baseline on a weighted composite score consisting of selected items from the CDR-SB, MMSE, and ADAS-Cog 14 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%. Approval by the FDA was based on the reduction in amyloid beta plaques. Change from baseline in brain amyloid plaque was assessed in a subset of patients at week 79. Treatment with lecanemab 10 mg/kg every 2 weeks reduced amyloid beta plaque levels in the brain, producing reductions in PET SUVR compared to placebo. The magnitude of the reduction was time- and dose-dependent. However, there are no satisfactory data clearly establishing that individual changes in amyloid correlate with or predict long term cognitive and functional changes. In the absence of clinical data convincingly demonstrating a clinical effect, it cannot be concluded that the observed reduction in amyloid will translate into a clinical benefit to patients. Cognitive decline in early AD generally occurs over years, and thus the follow-up duration may not be sufficient to conclude whether a drug is effective for this disease or whether the safety profile might change with longer follow-up. Safety data showed that about 12% of patients on lecanemab experienced ARIA. A confirmatory, prospective, and adequately powered trial is necessary to assess the net health benefit of lecanemab in patients with early AD.

For individuals with early AD (MCI or mild dementia due to AD) who receive lecanemab, the evidence includes includes a single dose-finding RCT. Relevant outcomes are disease-specific survival, change in disease status, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. In study 201, participants were randomized to placebo or one of 5 lecanemab dosing regimens, including the FDA approved dosing regimen of 10 mg/kg biweekly. The primary endpoint was change from baseline on a weighted composite score consisting of selected items from the CDR-SB, Mini-Mental State Examination (MMSE), and Alzheimer’s Disease Assessment Scale – Cognitive 13-Item Scale (ADAS-Cog 13) 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%. Approval by the FDA was based on the reduction in amyloid beta plaques. Change from baseline in brain amyloid plaque was assessed in a subset of patients at week 79. Treatment with lecanemab 10 mg/kg every two weeks reduced amyloid beta plaque levels in the brain, producing reductions in positron emission tomography standard uptake value ratio compared to placebo. The magnitude of the reduction was time- and dose-dependent. However, there are no satisfactory data clearly establishing that individual changes in amyloid correlate with or predict long term cognitive and functional changes. In the absence of clinical data convincingly demonstrating a clinical effect, it cannot be concluded that the observed reduction in amyloid will translate into a clinical benefit to patients. Cognitive decline in early AD generally occurs over years, and thus the follow-up duration may not be sufficient to conclude whether a drug is effective for this disease or whether the safety profile might change with longer follow-up. Safety data showed that about 12% of patients on lecanemab experienced ARIA. A confirmatory, prospective, and adequately powered trial is necessary to assess the net health benefit of lecanemab in patients with early AD. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

Institute for Clinical and Economic Review

The Institute for Clinical and Economic Review published a report assessing the effectiveness and value of lecanemab for Alzheimer disease on April 17, 2023. The report concluded, “the net health benefits of lecanemab in participants with early AD [Alzheimer Disease] may be small or even substantial, but there remains a possibility of net harm from ARIA [amyloid-related imaging abnormalities], we rate treatment with lecanemab in MCI [mild cognitive impairment] due to AD or mild AD as promising but inconclusive (P/I)." ^53,

U.S. Preventive Services Task Force Recommendations

Not applicable

Medicare National Coverage

The Centers for Medicare & Medicaid Services (CMS) covers US Food and Drug Administration (FDA) approved monoclonal antibodies directed against amyloid for the treatment of AD when furnished in accordance with Coverage Criteria under coverage with evidence development (CED) for patients who have: a clinical diagnosis of MCI due to AD or mild AD dementia, both with confirmed presence of amyloid beta pathology consistent with AD.

Detailed CMS coverage criteria can be accessed here.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 15.

Table 15. Summary of Key Trials

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

References

1. 2021 Alzheimer's disease facts and figures. Alzheimers Dement. Mar 2021; 17(3): 327-406. PMID 33756057
2. Alzheimer's Association. 2021 Alzheimers disease facts and figures. Published 2021. Available at https://www.alz.org/media/Documents/alzheimers-facts-and-figures.pdf. Accessed April 6, 2023.
3. Roberts RO, Aakre JA, Kremers WK, et al. Prevalence and Outcomes of Amyloid Positivity Among Persons Without Dementia in a Longitudinal, Population-Based Setting. JAMA Neurol. Aug 01 2018; 75(8): 970-979. PMID 29710225
4. Elias-Sonnenschein LS, Viechtbauer W, Ramakers IH, et al. Predictive value of APOE-ε4 allele for progression from MCI to AD-type dementia: a meta-analysis. J Neurol Neurosurg Psychiatry. Oct 2011; 82(10): 1149-56. PMID 21493755
5. Mattsson N, Groot C, Jansen WJ, et al. Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease. Alzheimers Dement. Jul 2018; 14(7): 913-924. PMID 29601787
6. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. Oct 1997; 278(16): 1349-56. PMID 9343467
7. Bekris LM, Yu CE, Bird TD, et al. Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol. Dec 2010; 23(4): 213-27. PMID 21045163
8. Vermunt L, Sikkes SAM, van den Hout A, et al. Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype. Alzheimers Dement. Jul 2019; 15(7): 888-898. PMID 31164314
9. US Food and Drug Administration. Early Alzheimers disease: developing drugs for treatment guidance for industry. Draft Guidance. Published online Feb 29, 2018. Available at https://www.fda.gov/media/110903/download. Accessed on May 19, 2022
10. Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. May 2011; 7(3): 270-9. PMID 21514249
11. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. May 2011; 7(3): 263-9. PMID 21514250
12. Combined FDA and Applicant PCNS Drugs Advisory Committee Briefing Document: Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee Meeting- November 6, 2020. Available at https://www.fda.gov/media/143502/download Accessed April 6, 2023.
13. Reuben DB, Tan ZS, Romero T, et al. Patient and Caregiver Benefit From a Comprehensive Dementia Care Program: 1-Year Results From the UCLA Alzheimer's and Dementia Care Program. J Am Geriatr Soc. Nov 2019; 67(11): 2267-2273. PMID 31355423
14. Gronek P, Balko S, Gronek J, et al. Physical Activity and Alzheimer's Disease: A Narrative Review. Aging Dis. Dec 2019; 10(6): 1282-1292. PMID 31788339
15. Du Z, Li Y, Li J, et al. Physical activity can improve cognition in patients with Alzheimer's disease: a systematic review and meta-analysis of randomized controlled trials. Clin Interv Aging. 2018; 13: 1593-1603. PMID 30233156
16. Gitlin LN, Kales HC, Lyketsos CG. Nonpharmacologic management of behavioral symptoms in dementia. JAMA. Nov 21 2012; 308(19): 2020-9. PMID 23168825
17. Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, et al. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ. Aug 06 2005; 331(7512): 321-7. PMID 16081444
18. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. Apr 2018; 14(4): 535-562. PMID 29653606
19. US Food and Drug Administration. Draft guidance for industry on Alzheimers disease: developing drugs for the treatment of early stage disease. Published online March 28, 2013. Available at https://isctm.org/public_access/FDAGuidance_AD_Developing_Drugs_Early_Stage_Treatment.pdf. Accessed on April 6, 2023.
20. Liu KY, Schneider LS, Howard R. The need to show minimum clinically important differences in Alzheimer's disease trials. Lancet Psychiatry. Nov 2021; 8(11): 1013-1016. PMID 34087114
21. Cedarbaum JM, Jaros M, Hernandez C, et al. Rationale for use of the Clinical Dementia Rating Sum of Boxes as a primary outcome measure for Alzheimer's disease clinical trials. Alzheimers Dement. Feb 2013; 9(1 Suppl): S45-55. PMID 22658286
22. Andrews JS, Desai U, Kirson NY, et al. Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer's disease clinical trials. Alzheimers Dement (N Y). 2019; 5: 354-363. PMID 31417957
23. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. Nov 1975; 12(3): 189-98. PMID 1202204
24. Chapman KR, Bing-Canar H, Alosco ML, et al. Mini Mental State Examination and Logical Memory scores for entry into Alzheimer's disease trials. Alzheimers Res Ther. Feb 22 2016; 8: 9. PMID 26899835
25. Franco-Marina F, García-González JJ, Wagner-Echeagaray F, et al. The Mini-mental State Examination revisited: ceiling and floor effects after score adjustment for educational level in an aging Mexican population. Int Psychogeriatr. Feb 2010; 22(1): 72-81. PMID 19735592
26. Galasko D, Abramson I, Corey-Bloom J, et al. Repeated exposure to the Mini-Mental State Examination and the Information-Memory-Concentration Test results in a practice effect in Alzheimer's disease. Neurology. Aug 1993; 43(8): 1559-63. PMID 8351011
27. Spencer RJ, Wendell CR, Giggey PP, et al. Psychometric limitations of the mini-mental state examination among nondemented older adults: an evaluation of neurocognitive and magnetic resonance imaging correlates. Exp Aging Res. 2013; 39(4): 382-97. PMID 23875837
28. Mohs RC, Knopman D, Petersen RC, et al. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that broaden its scope. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997; 11 Suppl 2: S13-21. PMID 9236948
29. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. Nov 1984; 141(11): 1356-64. PMID 6496779
30. Schrag A, Schott JM. What is the clinically relevant change on the ADAS-Cog?. J Neurol Neurosurg Psychiatry. Feb 2012; 83(2): 171-3. PMID 22019547
31. McDougall F, Edgar C, Mertes M, et al. Psychometric Properties of the Clinical Dementia Rating - Sum of Boxes and Other Cognitive and Functional Outcomes in a Prodromal Alzheimer's Disease Population. J Prev Alzheimers Dis. 2021; 8(2): 151-160. PMID 33569561
32. Vellas B, Bateman R, Blennow K, et al. Endpoints for Pre-Dementia AD Trials: A Report from the EU/US/CTAD Task Force. J Prev Alzheimers Dis. Jun 2015; 2(2): 128-135. PMID 26247004
33. Bullock R, Touchon J, Bergman H, et al. Rivastigmine and donepezil treatment in moderate to moderately-severe Alzheimer's disease over a 2-year period. Curr Med Res Opin. Aug 2005; 21(8): 1317-27. PMID 16083542
34. Tariot PN, Solomon PR, Morris JC, et al. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology. Jun 27 2000; 54(12): 2269-76. PMID 10881251
35. Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. Jan 23 2014; 370(4): 311-21. PMID 24450890
36. Cummings J. The Neuropsychiatric Inventory: Development and Applications. J Geriatr Psychiatry Neurol. Mar 2020; 33(2): 73-84. PMID 32013737
37. Howard R, Phillips P, Johnson T, et al. Determining the minimum clinically important differences for outcomes in the DOMINO trial. Int J Geriatr Psychiatry. Aug 2011; 26(8): 812-7. PMID 20848576
38. Wang J, Logovinsky V, Hendrix SB, et al. ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials. J Neurol Neurosurg Psychiatry. Sep 2016; 87(9): 993-9. PMID 27010616
39. Tahami Monfared AA, Houghton K, Zhang Q, et al. Staging Disease Severity Using the Alzheimer's Disease Composite Score (ADCOMS): A Retrospective Data Analysis. Neurol Ther. Mar 2022; 11(1): 413-434. PMID 35099758
40. FDA Pre-Recorded Presentation Slides for the November 6, 2020: Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee. Available at https://www.fda.gov/media/143504/download. Accessed on April 6, 2023.
41. Center for Drug Evaluation and Research. Statistical Review. Application Number: 761178orig1s000. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000StatR_Redacted.pdf. Accessed April 6, 2023.
42. Prescribing Label for LEQEMBI (lecanemab-irmb) injection, for intravenous use. Available at https://www.leqembi.com/-/media/Files/Leqembi/Prescribing-Information.pdf?hash=3d7bf1a2-5db2-4990-8388-81086f415676. Accessed on April 6, 2023.
43. Biogen Presentation for the November 6, 2020: Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee. Available at https://www.fda.gov/media/143577/download. Accessed on April 6, 2023.
44. Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther. Apr 17 2021; 13(1): 80. PMID 33865446
45. McDade E, Cummings JL, Dhadda S, et al. Lecanemab in patients with early Alzheimer's disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study. Alzheimers Res Ther. Dec 21 2022; 14(1): 191. PMID 36544184
46. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med. Jan 05 2023; 388(1): 9-21. PMID 36449413
47. Summary Review for Leqembi (lecanemab) Application Number: 761269Orig1s000. Center for Drug Evaluation and Research. Available at https://www.accessdata.fda.gov/drugsatfda_docs/summary_review/2023/761269Orig1s000SumR.pdf. Accessed on April 6, 2023.
48. Lecanemab for Early Alzheimers Disease Final Evidence Report April 17, 2023. Available at https://icer.org/wp-content/uploads/2023/04/ICER_Alzheimers-Disease_Final-Report_For-Publication_04172023.pdf. Accessed on April 17, 2023.

Codes

Policy History