Description
Alzheimer disease 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 (A-β), referred to as amyloid plaques, are considered a hallmark of the disease. Beta-amyloid monomers lead to formation of beta oligomers and fibrils and are deposited as plaques and then interact with tau fibrils, leading to formation of neuro-fibrillatory tangles. These pathophysiological changes and clinical manifestations of Alzheimer disease are progressive and occur along a continuum, and accumulation of A-β may begin 20 years or more before symptoms arise. Aducanumab is a human IgG1 anti-A-β antibody targeting amyloid aggregates. The drug is administered by intravenous infusion every 4 weeks. Binding of antibody is intended to lead to clearance of amyloid from the brain. On June 7, 2021, the U.S. Food and Drug Administration approved Aduhelm (aducanumab) for the treatment of Alzheimer disease. It was approved under accelerated approval based on reduction in A-β plaques observed in patients treated with aducanumab. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial.

Background 
Alzheimer Disease
Alzheimer disease 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 Alzheimer disease 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 Alzheimer disease dementia, and the number is projected to reach over 12 million by 2050.¹

Pathophysiology
The pathologic hallmarks of Alzheimer disease are extracellular deposits of beta-amyloid (A-β), 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 Alzheimer disease is not well understood. Generally referred to as “amyloid hypothesis,” it is believed that aggregation of A-β oligomers in the brain leads to amyloid plaques and 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 Alzheimer disease are older age, genetics, and family history. Of these, increasing age has the largest known impact on risk of developing Alzheimer disease. While several genes have been found to increase the risk of Alzheimer disease, the ε4 allele of the apolipoprotein E (ApoE) gene is the strongest known genetic risk factor.^4,5 Having 1 copy of the gene is associated with a 2- to 3-fold increase in developing Alzheimer disease while 2 copies of the gene may increase risk of Alzheimer disease by as much as 15 times.⁶ Approximately two-thirds of pathology-confirmed Alzheimer disease 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 Alzheimer disease cases.⁷

The pathophysiological changes and clinical manifestations of Alzheimer disease are progressive and occur along a continuum, and accumulation of A-β may begin 20 years or more before symptoms arise.⁸ 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 Alzheimer disease from an initial stage characterized by the appearance of abnormal Alzheimer disease 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 such as those of aducanumab. The phase 3 randomized controlled trials for aducanumab were stratified to include 80% of stage 3 patients and 20% of stage 4 patients. This numeric staging scheme is very similar to the categorical system for staging Alzheimer disease outlined in the Food and Drug Administration (FDA) guidance for industry pertaining to developing drugs for treatment of early Alzheimer disease.⁹

Many tests are available in the market to detect the underlying core pathology of such use of certain biomarkers in the cerebrospinal fluid (CSF) (e.g., decreased A-β 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 A-β confirmation that are currently in development in the US. CSF tests and amyloid PET tracers are routinely used in the enrollment of participants in contemporary Alzheimer disease studies.¹⁰

Current Treatment
Current treatment goals for patients with Alzheimer disease 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 (e.g., adult day care, caregiver training, etc).¹¹ Non-pharmacologic treatments include physical activity^12,13 as well as behavioral strategies to ameliorate neuropsychiatric symptoms (e.g., agitation, delusions, disinhibition), and problem behaviors (e.g., resistance to care, hoarding, obsessive-compulsive behaviors).¹⁴ Currently FDA-approved drugs for Alzheimer 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 associated with significant side effects.^14,15

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)^16
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 Aβ or associated pathologic state (CSF Aβ₄₂, or Aβ₄₂/Aβ₄₀ 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 investigators 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.
CSF: cerebrospinal fluid; FDG: fluorodeoxyglucose; MCI: mild cognitive impairment; MRI: magnetic resonance imaging; PET: positron emission tomography.

Regulatory Status
In June 2021, aducanumab (Aduhelm; Biogen) was approved by the U.S. FDA for treatment of Alzheimer disease. This indication was approved under accelerated approval based on reduction in A-β plaques observed in patients treated with aducanumab. 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 Biogen conduct a randomized, controlled trial to evaluate the efficacy of aducanumab-avwa compared to an appropriate control for the treatment of Alzheimer disease. 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 August 2029 and final report submission to the FDA by February 2030.

Policy
The use of aducanumab is considered investigational/unproven therefore is considered NOT MEDICALLY NECESSARY for all indications including treatment of Alzheimer disease.

Policy Guidelines 
The product label recommends that a baseline brain magnetic resonance imaging (MRI) within 1 year must be done prior to initiating treatment due to the risk of amyloid-related imaging abnormalities (ARIA). Subsequently, MRI should be repeated prior to the 7th and 12th infusions. If radiographic severe ARIA-hemorrhage (ARIA-H) is observed, treatment may be continued with caution only after a clinical evaluation and a follow-up MRI demonstrates radiographic stabilization (i.e., no increase in size or number of ARIA-H).

Coding
See the Codes table for details.

Benefits Application
BlueCard/National Account Issues 
State or federal mandates (e.g., 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.

Rationale 
This evidence review was created in June 2021 with searches of the PubMed database. The most recent literature update was performed through June 16, 2021.

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 one or more intended clinical uses 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.

Early Alzheimer Disease
Clinical Context and Therapy Purpose
The purpose of aducanumab is to provide a treatment option that is an alternative to or an improvement on existing therapies for patients with early Alzheimer disease (mild cognitive impairment (MCI) or mild dementia due to Alzheimer disease).

The question addressed in this evidence review is: Does the use of aducanumab improve the net health outcome in patients with early Alzheimer disease (MIC or mild dementia due to Alzheimer disease)?

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

Populations
MCI or mild dementia due to Alzheimer disease.

Interventions
The therapy being considered is aducanumab. It is a human IgG1 anti-beta-amyloid (A-β) monoclonal antibody selective for A-β aggregates, including soluble oligomers and insoluble fibrils, but not monomers, as demonstrated in a variety of biochemical and structural analyses. Binding of aducanumab to aggregated A-β promotes the removal of amyloid from the brain, through a microglia-mediated phagocytosis mechanism.

Comparators
The following practice is currently being used to treat early Alzheimer disease. Currently approved Alzheimer disease treatments include the cholinesterase inhibitors donepezil, rivastigmine, and galantamine, and the N-methyl-D-aspartate antagonist memantine. None of these agents address 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 Alzheimer disease, treatment for mild to moderate Alzheimer disease dementia (corresponding to stages 4 and 5) would be considered substantially effective if there is improvement on a core symptom (e.g., a measure of cognition) and a global clinical measure (e.g., a clinician’s judgement of change) or a functional measure (e.g., activities of daily living).¹⁷ 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.¹⁸ 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.¹⁹

Table 2. Health Outcome Measures That May Be Relevant to Early 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
The clinical development program of aducanumab includes 4 studies that are summarized in Table 3.

Table 3. Summary of the Clinical Development Program for Aducanumab

DB: double-blind; LTE: long-term extension; RCT: randomized controlled trial. 

Randomized Controlled Trials
The evidence for aducanumab includes a dose-finding and proof of concept phase 1 trial (PRIME) and 2 phase 3 pivotal trials (ENGAGE (study 301) and EMERGE (study 302). PRIME was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging, staggered study conducted in the United States with the primary objectives of safety and tolerability. The phase 3 studies were multicenter, global, randomized, double-blind, placebo-controlled studies of identical design with the primary objective of efficacy and safety. In all 3 studies, the diagnosis of Alzheimer disease was confirmed by presence of amyloid pathology measured by [¹⁸F]-florbetapir positron emission tomography (PET) imaging. The pivotal trials ensured enrollment of patients at an earlier stage of their disease; MCI due to Alzheimer disease or mild Alzheimer disease dementia based on an entry criteria of baseline Mini-Mental State Examination (MMSE) score of 24 to 30, baseline CDR global score of 0.5 and Repeatable Battery for the Assessment of Neurological Status (RBANS) delayed memory index score ≤ 85. Per the protocol design, most participants had a diagnosis of MCI due to Alzheimer disease (81.6%), while 18.4% of participants had mild Alzheimer disease dementia. Approximately two-thirds of the study population in the phase 3 trials are apolipoprotein E (ApoE) ε4 carriers. The trial had approximately 90% power to detect a true mean difference of 0.5 in change from baseline CDR‐SB at week 78. The range for CDR-SB is 0 to 18, with higher scores indicating greater disease severity.¹⁰

The phase 3 studies randomized patients to aducanumab low dose (3 or 6 mg/kg for ApoE ε4 carriers and noncarriers, respectively), aducanumab high dose (10 mg/kg), or placebo every 4 weeks for 18 months, followed by an optional, dose-blind, long-term extension period. Although aducanumab 10 mg/kg was hypothesized to be the most efficacious dose, due to safety concerns and limited understanding of amyloid-related imaging abnormalities (ARIA), both studies included an initial titration period of up to 6 months to the maximum target dose. At the beginning of the study, ApoE ε4 carriers were initially titrated up to a maximum of 6 mg/kg in the high-dose group, which was later adjusted to 10 mg/kg. Both pivotal trials were terminated prior to their planned completion. Study endpoints were analyzed based on a prespecified statistical analysis plan. Due to the early termination and consequent administrative censoring, data was missing for up to 45% of patients randomized in the 2 trials. Approximately, 60 percent of patients had the opportunity to complete week 78 of the trial before the trials were terminated for futility.¹⁰ Trial characteristics and results are summarized in Tables 4 to 6.

Study 302 (N = 1,638 randomized patients) met the primary endpoint in patients treated with high-dose aducanumab with an absolute difference of -0.39 in favor of aducanumab on the 18-point CDR-SB scale (a relative 22% less decline in high dose aducanumab group compared to placebo, p = .0120). The reported MCID is generally considered to be 1 to 2 points on a scale from 0 to 18.²¹ Results of responder analysis describing proportion of individuals who achieved a predefined level of improvement were not reported. Results in the low-dose aducanumab group were not statistically significant compared with placebo (absolute difference ‐0.26, relative difference ‐15%, p=.0901) and therefore no statistically valid conclusions can be made for any of the secondary endpoints for either of treatment arms.

Study 301 (N = 1,647 randomized patients) did not meet its primary end point of a reduction relative to placebo in the CDR-SB score. For the high-dose arm, an absolute difference of 0.03 and a relative difference of 2% favored placebo (p = .8330). For the low-dose arm, an absolute difference of -0.18 and a relative difference of 12% favored aducanumab (p = .8330). Because of the pre-specified plans to control for type I error for multiple comparisons, no statistically valid conclusions can therefore be made for any of the secondary endpoints.¹⁰

Change in brain amyloid signal was measured by (¹⁸F)-florbetapir PET and quantified by a composite standard uptake value ratio (SUVR) in a subset of sites and patients (n = 488) at week 78. In study 302, adjusted mean change from baseline to week 78 relative to placebo showed a dose-dependent reduction in A-β by -0.179 and -0.278 in the low- and high-dose arms respectively. In study 301, adjusted mean change from baseline to week 78 relative to placebo showed a dose-dependent reduction in A-β by -0.167 and -0.232 in the low- and high-dose arms respectively. While aducanumab showed statistically significant dose dependent changes from baseline in A-β plaques, there are no satisfactory data, clearly establishing individual changes in amyloid correlate with or predict long term cognitive and functional changes as measured by CDR-SB. The FDA statistical review³⁸ reported no correlation in study 302 between reduction in amyloid plaque and long term clinical change among the high-dose cohort or full 10 mg/kg dosed subgroup. In the absence of clinical data convincingly demonstrating a clinical effect, it cannot be concluded that observed reduction in amyloid will translate into a clinical benefit to patients.

Change from baseline in markers of downstream Alzheimer disease tau pathophysiology and neurodegeneration were reported for a small subset of patients collected from a voluntary non-directly randomized sample (n = 45 in study 302 and n = 33 in study 301). While the prescribing label³⁹ reports a statistical significant lowering of both phosphorylated tau and total tau in the treatment arms, aducanumab is not known to directly target tau pathways. Therefore, it is difficult to clinically interpret the observed findings on an off-target exploratory biomarker from a small voluntary non-directly randomized sample.

Safety
Data with limited follow-up are available to analyze safety because the phase 3 trials were stopped prematurely due to futility. Pooled safety data from the 2 phase 3 clinical trials showed that about 35% (compared to 3% in the placebo arm) of patients on aducanumab experienced ARIA, whose clinical effects can range from asymptomatic to severe. Although the majority of patients were asymptomatic or had symptoms such as headache, confusion, or dizziness that resolved with temporary stoppage of the drug, 6.2% of participants receiving the high dose of aducanumab discontinued the drug due to ARIA. The incidence of ARIA-edema was higher in ApoE ε4 carriers than non-carriers (42% and 20%, respectively). The majority of ARIA-edema radiographic events occurred early in treatment (within the first 8 doses), although ARIA can occur at any time. Among patients treated with a planned dose of aducanumab 10 mg/kg who had ARIA-edema, the maximum radiographic severity was mild in 30%, moderate in 58%, and severe in 13% of patients (refer to prescribing label for classification of severity of ARIA). Resolution occurred in 68% of ARIA-edema patients by 12 weeks, 91% by 20 weeks, and 98% overall after detection. Ten percent of all patients who received aducanumab 10 mg/kg had more than 1 episode of ARIA-edema.^39,

An increase in falling adverse events was observed in the high-dose as compared to placebo across the 2 phase 3 studies (15% vs. 12%, respectively). FDA statistical review^38, reported a hazard ratio of 1.33 (p=.016) suggesting a 33% relative increase in hazard of falling for 10 mg/kg compared to placebo. A quantitative integration of benefit and risk was not done, but if the high dose increases falls it could be a significant risk for the Alzheimer disease population.

Table 4. Summary of Key Study Characteristics

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; ApoE ε4: apolipoprotein E ε4; CDR: Clinical Dementia Rating; CDR-SB: Clinical Dementia Rating Sum of Box; LTE: long-term extension; MMSE: Mini-Mental State Examination; PET: positron emission tomography; RBANS: Repeatable Battery for Assessment of Neuropsychological Status.

Table 5. 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; MMSE: Mini-Mental State Examination; NA: not applicable
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 6. Summary of Pivotal Trial Results for Biomarker Outcomes

Results summarized from Prescribing Label^39,
CSF: cerebrospinal fluid; NA: not applicable; PET: positron emission tomography; p-Tau; phosphorylated tau; t-Tau: total tau. 

The purpose of the Tables 7 and 8 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 for phase 3 studies include use of physiologic measures such as A-β 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 (more than 45% of trials participants did not contribute week 78 data for primary clinical outcome) and generalizability to broader clinical populations and real world settings. These limitations are explicated below.

Outcomes
Data supporting patient-centric clinical and humanistic outcomes related to cognition (e.g., memory, orientation, judgment/problem-solving, ability to perform cognitive tasks and everyday functioning) are not interpretable due to conflicting evidence from 2 identical phase 3 RCTs. Study 302 met the primary endpoint of statistical significant change in CDR-SB score in the high-dose arm. However, the magnitude of observed statistical significant difference are not supported by a responder analysis describing proportion of individuals who achieved a predefined level of improvement. Study 301 failed to meet the same CDR-SB endpoint. In fact, the high-dose arm’s change in CDR-SB score was numerically worse than placebo at 78 weeks.^38, Aducanumab was approved on the basis of statistically significant dose dependent changes in A-β plaques. However, no correlation between reduction in amyloid plaque and change in CDR-SB score was observed in the 10 mg/kg dosed subgroup.^38, Further, lowering of phosphorylated tau and total tau levels as supportive evidence in the biomarker framework is difficult to interpret as tau levels were an off-target biomarker and results were exploratory from a small voluntary non-directly randomized sample.

Durability and External Validity
The intended double-blind duration of the 2 RCTs was 78 weeks followed by an 18-week safety follow-up period after the final dose. Since the trial was terminated early due to futility, the available data are limited. Due to the early termination and consequent administrative censoring, data was missing for up to 45% of patients at week 78 in the trials. The average follow-up for ApoE ε4 carriers exposed to full dose of 10 mg/kg was only 50 weeks rather than 78 weeks. Cognitive decline in MCI due to Alzheimer disease and mild Alzheimer disease 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. Further, a statistically significant difference was only reported at week 78 and not any other earlier timepoints. Pooled safety data showed that about 35% of patients on aducanumab experienced ARIA as well as an increase in the risk of falling. While ARIA was detected early by frequent magnetic resonance imaging (MRI) monitoring in the clinical trials, it may be challenging to implement routine monitoring in real world settings, particularly when it involves patients older than the trial participants. Thus, ARIA may pose greater risks to patients who may be older, have more comorbidities, and are less carefully monitored outside of clinical trials.

Study Conduct
Pivotal trial protocols minimized functional blinding by mandating use of an independent rater who was blinded to patient management (including occurrence of ARIA and subsequent monitoring). However, patients and caregivers could become aware of the occurrence of ARIA due to differential management including additional MRIs and dose modification. The CDR-SB and ADCS‐ADL‐MCI rating scales require more patient and caregiver input and could therefore be susceptible to biased estimates if respondents knew they were on therapy. Further, differential rates of ARIA between study 301 and 302 could have contributed to discordant results because of impact of differential functional unblinding in the 2 studies.

Table 7. 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 8. 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: Early Alzheimer Disease
For individuals with early Alzheimer disease (MCI or mild dementia due to Alzheimer disease) who receive aducanumab, the evidence includes 2 RCTs and 1 dose-finding and proof of concept phase I trial. ENGAGE (study 301) and EMERGE (study 302) were identical randomized, double-blind, placebo-controlled studies that enrolled patients with early Alzheimer disease. The majority of patients had a diagnosis of MCI due to Alzheimer disease (81.6%) and approximately two-thirds were apolipoprotein E ε4 carriers. The primary clinical outcome was change in mean score on the CDR-SB. Both trials were terminated early following a prespecified interim analysis for futility. In study 301, there was no treatment benefit observed in either the high- or low-dose arms at week 78. In study 302, a statistically significant difference in change from baseline in CDR-SB was observed in the high-dose arm (difference vs. placebo -0.39 [95% confidence interval [CI], -0.69 to -0.09]) but not the low-dose arm at week 78. The observed change of 0.39 was well below the range of 1 to 2 points reported as the MCID in published literature. Approval by the FDA was based on the reduction in A-β plaques, which was observed in both trials and at all doses. 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 Alzheimer disease 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. Pooled safety data showed that about 35% of patients on aducanumab experienced ARIA as well an increase in the risk of falling. A confirmatory, prospective and adequately powered trial is necessary to assess the net health benefit of aducanumab in patients with early Alzheimer disease.

Summary of Evidence
For individuals with early Alzheimer disease (MCI or mild dementia due to Alzheimer disease) who receive aducanumab, the evidence includes 2 RCTs and 1 dose-finding and proof of concept phase I trial. Relevant outcomes are disease-specific survival, change in disease status, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. ENGAGE (study 301) and EMERGE (study 302) were identical randomized, double-blind, placebo-controlled studies that enrolled patients with early Alzheimer disease. The majority of patients had a diagnosis of MCI due to Alzheimer disease (81.6%) and approximately two-thirds were apolipoprotein E ε4 carriers. The primary clinical outcome was change in mean score on the CDR-SB. Both trials were terminated early following a prespecified interim analysis for futility. In study 301, there was no treatment benefit observed in either the high- or low-dose arms at week 78. In study 302, a statistically significant difference in change from baseline in CDR-SB was observed in the high-dose arm (difference vs. placebo -0.39 [95% CI, -0.69 to -0.09]) but not the low-dose arm at week 78. The observed change of 0.39 was well below the range of 1 to 2 points reported as the MCID in published literature. Approval by the FDA was based on the reduction in A-β plaques, which was observed in both trials and at all doses. 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 Alzheimer disease 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. Pooled safety data showed that about 35% of patients on aducanumab experienced ARIA as well an increase in the risk of falling. A confirmatory, prospective and adequately powered trial is necessary to assess the net health benefit of aducanumab in patients with early Alzheimer disease. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

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 U.S. professional society, an international society with U.S. 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 is assessing the effectiveness and value of aducanumab for Alzheimer disease and have released a draft report.^41, A final report is expected to be released in August 2021. The draft report concludes, “[g]iven the certainty that harms can occur in patients treated with aducanumab and uncertainty about benefits, we rate the evidence to be insufficient to determine the net health benefit of aducanumab (“I”)." The conclusion about uncertainty of benefits stems from a number of methodologic issues raised in the report that includes use of phase Ib trial to provide a “second” positive trial as supportive evidence, post-hoc analyses to explain failure of study 301, and role of functional blinding due to amyloid-related imaging abnormalities.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 9.

Table 9. Summary of Key Trials

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

References 

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39. Prescribing Label: ADUHELM (aducanumab-avwa) injection, for intravenous use Available at https://www.biogencdn.com/us/aduhelm-pi.pdf. Accessed on June 28, 2021

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Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

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