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Aducanumab (Aduhelm) for Alzheimer Disease
08.01.93

Policy

EXPERIMENTAL/INVESTIGATIONAL

The use of aducanumab (Aduhelm) is considered experimental/investigational and, therefore, not covered  for all indications, including treatment of Alzheimer disease because the safety and effectiveness of this service cannot be established by review of the available published peer-reviewed literature.


Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, aducanumab (Aduhelm) is not eligible for payment under the medical benefits of the Company’s commercial products because the service is considered experimental/investigational and, therefore, not covered.

Services that are experimental/investigational are a benefit contract exclusion for all products of the Company. Therefore, they are not eligible for reimbursement consideration.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

In June 2021, aducanumab (Aduhelm; Biogen) was approved by the FDA for treatment of Alzheimer disease (AD). This indication was approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with aducanumab. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).

In July 2021, the FDA amended the approved label to emphasize the disease stages studied in the clinical trials. The amended label states, "Treatment with aducanumab should be initiated in patients with MCI 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 FDA, under the accelerated approval regulations (21 CFR 601.41), requires that Biogen conduct a radomized controlled trial to evaluate the efficacy of aducanumab-avwa 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 August 2029 and final report submission to the FDA by February 2030.​

Description

ALZHEIMER DISEASE


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 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 AD are progressive and occur along a continuum, and accumulation of amyloid beta may begin 20 years or more before symptoms arise. 


ADUCANUMAB (ADUHELM)


Aducanumab (Aduhelm) is a human IgG1 anti-amyloid beta 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 (FDA) approved Aduhelm (aducanumab) for the treatment of AD. It was approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with aducanumab. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory 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 AD was confirmed by presence of amyloid pathology measured by [18F]-florbetapir positron emission tomography (PET) imaging. The pivotal trials ensured enrollment of individuals at an earlier stage of their disease; mild cognitive impairment (MCI) due to AD or mild AD 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 AD (81.6%), while 18.4% of participants had mild AD 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.


The phase 3 studies randomized individuals 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 were missing for up to 45% of individuals randomized in the 2 trials. Approximately, 60% of individuals had the opportunity to complete week 78 of the trial before the trials were terminated for futility. 


Study 302 (N=1638 randomized individuals) met the primary endpoint in individuals 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. Results in the low-dose aducanumab group were not statistically significant compared with placebo (absolute difference ‐0.26, relative difference ‐15%, p=.0901). The prespecified multiplicity adjustment protocol prioritized testing the low dose on the primary endpoint before testing secondary endpoints for the high dose. Therefore, the p values reported in Table 5 should be considered nominal and no statistically valid conclusions can be made for any of the secondary endpoints for either of treatment arms. 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=1647 randomized individuals) did not meet its primary endpoint 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.


Results of pre-specified exploratory responder analysis were reported. Two thresholds for defining a responder were used: change from baseline in CDR-SB at week 78 was ≤ 0.5 or ≤ 1.5. Explanation for choosing these thresholds was not provided or whether thresholds represent important clinical meaningful change. All participants with missing data at week 78 were classified as non-responders. In study 302, proportions of responders for placebo versus high dose at week 78 was 18.8% and 25.7% respectively (using CDRSB cutoff ≤ 0.5) and 32.2% and 39.1% respectively (using CDRSB cutoff ≤ 1.5). In study 301, proportions of responders for placebo versus high dose at week 78 was 25.7% and 20.2% respectively (using CDRSB cutoff ≤ 0.5) and 39.9% and 36.8% respectively (using CDRSB cutoff ≤ 1.5). These results should be considered exploratory and are not statistically robust and the statistical significance of the results in 302 is not robust to minor recategorization.


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 individuals (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 amyloid beta 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 amyloid beta 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 amyloid beta 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 review reported no patient-level 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.


Change from baseline in markers of downstream AD tau pathophysiology and neurodegeneration were reported for a small subset of individuals collected from a voluntary non-directly randomized sample (n=45 in study 302 and n=33 in study 301). While the prescribing label reports a statistically 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 individuals on aducanumab experienced ARIA, whose clinical effects can range from asymptomatic to severe. Although the majority of individuals 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 individuals 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 individuals (refer to the prescribing label for classification of severity of ARIA). Resolution occurred in 68% of ARIA-edema individuals by 12 weeks, 91% by 20 weeks, and 98% overall after detection. Ten percent of all individuals who received aducanumab 10 mg/kg had more than 1 episode of ARIA-edema.


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 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 AD population.


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 statistically significant change in CDR-SB score in the high-dose arm. Observed magnitude of effect (0.39 points in CDR-SB) is of uncertain clinical benefit. 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. Aducanumab was approved on the basis of statistically significant dose dependent changes in amyloid beta plaques. However, no correlation between reduction in amyloid plaque and change in CDR-SB score was observed in the 10 mg/kg dosed subgroup. 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.


Amyloid beta has not been established as a valid surrogate outcome measure to evaluate clinical benefit in individuals with MCI or mild dementia due to AD. To establish surrogacy, the relationship between treatment, a surrogate and health outcome(s) have to be established. In this case, to establish PET amyloid levels as a surrogate outcome the following would be required: (1) preceding clinical trials demonstrate that the anti-amyloid treatment mitigates cognitive decline; (2) the treatment effect on mitigation of cognitive decline from previous trials is mediated by reduction of amyloid beta levels; (3) the current anti-amyloid treatment has an effect on amyloid beta levels; and (4) amyloid beta levels are associated with cognitive decline. Current evidence demonstrates that aducanumab results in a dose-dependent reduction in amyloid beta while the remaining relationships are not supported by the existing evidence.


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 were missing for up to 45% of individuals at week 78 in the trials. The average follow-up for ApoE ε4 carriers exposed to a full dose of 10 mg/kg was only 50 weeks rather than 78 weeks. Cognitive decline in MCI due to AD and mild 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. 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 individuals 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 a real world setting, particularly when it involves individuals older than the trial participants. Thus, ARIA may pose greater risks to individuals who may be older, have more comorbidities, and are less carefully monitored outside of clinical trials.


Out of 3,285 individuals enrolled, less than 1% were Black or African American and 3.2% were Hispanic or Latino. Additionally, the average age was 70 years old although trials allowed for enrolment up to 85 years of age. Given that older African Americans and Latinos are disproportionately more likely to have Alzheimer disease than White Americans and more than one-third of Alzheimer individuals in the US are over the age of 85, there is limited generalizability of these results to the broader US population.


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, individuals 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 the impact of differential functional unblinding in the 2 studies.​



SUMMARY


The evidence for aducanumab (aduhelm) includes 02 randomized controlled trials (RCTs) and 01 dose-finding and proof of concept phase I trial. These clinical investigations were for individuals with early AD (mild cognitive impairment [MCI] or mild dementia due to AD). Outcomes of interest to establish safety and effectiveness include​ 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 AD. The majority of patients had a diagnosis of MCI due to AD (81.6%) and approximately two-thirds were apolipoprotein E ε4 carriers. The primary clinical outcome was change in mean score on the Clinical Dementia Rating Scale – Sum of Boxes (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 01 to 02 points reported as the minimal clinically important difference in published literature. Approval by the FDA was based on the reduction in amyloid beta 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 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. Pooled safety data showed that about 35% of patients on aducanumab experienced amyloid-related imaging abnormalities (ARIA) as well as 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 AD. There is no consistent evidence of a clinically meaningful improvement in the net health outcome and there are concerns with the radiological findings.


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Coding

CPT Procedure Code Number(s)
N/A

ICD - 10 Procedure Code Number(s)
N/A

ICD - 10 Diagnosis Code Number(s)
N/A

HCPCS Level II Code Number(s)
J0172 Injection, aducanumab-avwa, 2 mg​

Revenue Code Number(s)


Coding and Billing Requirements


Policy History

7/1/2022
7/1/2022
08.01.93
Medical Policy Bulletin
Commercial
No