Aducanumab-avwa (Aduhelm)

Number: 0996

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses aducanumab-avwa (Aduhelm) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of aducanumab-avwa (Aduhelm) is required of all Aetna participating providers and members in applicable plan designs. For precertification of aducanumab-avwa (Aduhelm), call (866) 752-7021 or fax (866) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification. 

Note: Site of Care Utilization Management Policy applies.  For information on site of service for aducanumab-avwa (Aduhelm), see Utilization Management Policy on Site of Care for Specialty Drug Infusions. 

1. Exclusions

   Coverage will not be provided for members with any of the following conditions:

   1. Suspected neurodegenerative etiology of cognitive impairment other than Alzheimer’s disease (AD), including but not limited to frontotemporal lobar degeneration (FTLD) or Lewy body disease (i.e., meeting consensus criteria for possible or probable dementia with Lewy bodies);
   2. Requirement for therapeutic anticoagulation (e.g., anticoagulants, antiplatelets), except for aspirin at a prophylaxis dose or less (no more than 325mg daily);
   3. History of transient ischemic attacks (TIA), stroke, or seizures within the past 12 months;
   4. Bleeding disorder that is not under adequate control (including a platelet count less than 50,000 or international normalized ratio [INR] greater than 1.5);
   5. Aduhelm will not be used in combination with any other amyloid beta-directed antibodies (e.g., donanemab-azbt, lecanemab).

2. Prescriber Specialties

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

3. Criteria for Initial Approval

   Aetna considers aducanumab-avwa (Aduhelm) medically necessary for treatment of Alzheimer's disease (AD) [except as outlined in Section I for exclusions] when all of the following criteria are met:

   1. Member must meet one of the following criteria:

      1. Member is 50 years of age or older; or
      2. If less than 50 years of age, member has a genetic mutation in amyloid precursor protein (APP), presenilin-1 (PSEN1), or presenilin-2 (PSEN2), or other clinical documentation to support early onset AD; and
         
   2. Member must have mild cognitive impairment due to AD or mild AD dementia; and
   3. Member must have objective evidence of cognitive impairment at baseline (see Appendix A); and
   4. Member must have one of the following scores at baseline on any of the following assessment tools:
      
      
      1. Clinical Dementia Rating (CDR)-Global Score of 0.5 or 1 (see Appendix B); or
      2. Mini-Mental Examination Status (MMSE) score of 21 - 30 (see Appendix C); or
      3. Montreal Cognitive Assessment (MoCA) score of greater than or equal to 16 (see Appendix D); and

   5. Member must meet one of the following criteria:

      1. Have a positron emission tomography (PET) scan confirming the presence of amyloid pathology; or
      2. Have results from a lumbar puncture confirming at least one of the following detected in cerebrospinal fluid (CSF) as determined by the lab assay:
         
         
         1. Presence of elevated phosphorylated tau (P-tau) protein and/or elevated total tau (T-tau) protein, and reduced beta amyloid-42 (AB42); or
         2. Low AB42/AB40 ratio; or
         3. Elevated P-tau/AB42 ratio; or
         4. Elevated T-tau/AB42 ratio; and 
   6. Member must have a recent brain magnetic resonance imaging (MRI) within one year prior to initiating treatment; and 
   7. Member meets one of the following regarding apolipoprotein E ε4 (ApoE ε4) status:
       
      1. Genotype testing for ApoE ε4 status has been performed prior to initiation of treatment to inform member of the risk of developing ARIA; or
      2. Genotype testing has not been performed and the prescriber has informed the member that it cannot be determined if they are ApoE ε4 homozygous and may be at higher risk for ARIA; and
   8. Member must currently be enrolled in a randomized controlled trial conducted under an investigational new drug (IND) application or National Institutes of Health (NIH)-supported trial.

   Aetna considers all other indications as experimental, investigational, or unproven.

4. Continuation of Therapy

   Aetna considers continuation of aducanumab-avwa (Aduhelm) therapy medically necessary for treatment of Alzheimer's disease (AD) [except as outlined in Section I for exclusions] when criteria are met. Note: The first two reauthorizations will each be for 6 months duration; the third and all subsequent authorizations will be for 12 months duration.

   1. Criteria for Continuation of Therapy at 6 months following initiation:

      Continued use of the requested medication at 6 months following initiation is considered medically necessary when all of the following criteria are met:

      1. Member has met all initial authorization criteria at the time of initial approval; and
      2. Member has been evaluated for evidence of amyloid-related imaging abnormalities (ARIA) on MRI prior the 5th dose (first dose of 6 mg/kg) and the 7th dose (first dose of 10 mg/kg) (see Appendix E)
         
         

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

            1. Dosing may continue at current dose and schedule for members that meet the following criteria: 

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

            2. Dosing should be suspended until MRI demonstrates radiographic resolution and symptoms resolve for members that meet any of the following criteria:
               
               
               1. Member has mild ARIA-E on MRI and has moderate or severe clinical symptoms; or
               2. Member has moderate ARIA-E on MRI and is asymptomatic or has mild, moderate, or severe clinical symptoms; or
               3. Member has severe ARIA-E on MRI and is asymptomatic or has mild, moderate, or severe clinical symptoms; or

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

            1. Dosing may continue at current dose and schedule for members that meet the following criteria:

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

            2. Dosing should be suspended until MRI demonstrates radiographic resolution or stabilization and symptoms resolve for members that meet any the following criteria:

               1. Member has mild ARIA-H on MRI and is symptomatic; or
               2. Member has moderate ARIA-H on MRI and is asymptomatic or symptomatic; or
               3. Member has severe ARIA-H on MRI and is asymptomatic or symptomatic; and

         3. Member continues to be enrolled in a randomized controlled trial conducted under an investigational new drug (IND) application or National Institutes of Health (NIH)-supported trial.

   2. Criteria for Continuation of Therapy at 12 months following initiation:

      Continued use of the requested medication at 12 months following initiation is considered medically necessary when all of the following criteria are met:

      1. Member has met all initial authorization criteria at the time of initial approval; and
         
      2. Member has been evaluated for evidence of amyloid-related imaging abnormalities (ARIA) on MRI prior to the 9th dose (third dose of 10 mg/kg) and the 12th dose (sixth dose of 10 mg/kg) (Appendix E):
         
         

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

            1. Dosing may continue at current dose and schedule for members that meet the following criteria:

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

            2. Dosing should be suspended until MRI demonstrates radiographic resolution and symptoms resolve for members that meet any of the following criteria:

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

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

            1. Dosing may continue at current dose and schedule for members that meet the following criteria:

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

            2. Dosing should be suspended until MRI demonstrates radiographic resolution or stabilization and symptoms resolve for members that meet any the following criteria:

               1. Member has mild ARIA-H on MRI and is symptomatic; or
               2. Member has moderate ARIA-H on MRI and is asymptomatic or symptomatic; or
               3. Member has severe ARIA-H on MRI and is asymptomatic or symptomatic; and

         3. Member continues to be enrolled in a randomized controlled trial conducted under an investigational new drug (IND) application or National Institutes of Health (NIH)-supported trial.

   3. Criteria for Continuation of Therapy for reauthorizations beyond initial 18 months of therapy:

      Continued use of the requested medication for all subsequent times (beyond the first two reauthorizations at 6 and 12 months following initiation) is considered medically necessary when all of the following criteria are met:

      1. Member has met all initial authorization criteria at the time of initial approval; and
      2. Member meets either of the following criteria:
         
         

         1. Member has had a positive clinical response as evidenced by stabilization in score in any of the following measures:

            1. CDR-GS (i.e., score of 0.5 or 1); or
            2. MMSE (i.e., score of 21 – 30); or
            3. MoCA (i.e., score of greater than or equal to 16); or

         2. Member continues to be enrolled in a randomized controlled trial conducted under an investigational new drug (IND) application or National Institutes of Health (NIH)-supported trial.

5. Related CMS Coverage Guidance

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

   Code of Federal Regulations (CFR):

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

   
   
   

   Internet-Only Manual (IOM) Citations:

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

   
   
   

   Medicare Coverage Determinations:

   Centers for Medicare & Medicaid Services (CMS), Medicare Coverage Database [Internet]. Baltimore, MD: CMS; updated periodically. Available at: Medicare Coverage Center. Accessed November 7, 2023.

6. Related Policies

   1. CPB 0071 - Positron Emission Tomography (PET)
   2. CPB 0140 - Genetic Testing
   3. CPB 0349 - Alzheimer's Disease Tests
   4. CPB 0788 - Alzheimer's Disease: Experimental Treatments
   5. CPB 1026 - Lecanemab-irmb (Leqembi)
   6. CPB 1066 - Donanemab-azbt (Kisunla)

Dosage and Administration

Aducanumab-avwa is available as Aduhelm and supplied for injection as 170 mg/1.7 mL (100 mg/mL) and 300 mg/3 mL (100 mg/mL) solution in single-dose vials for intravenous use only.

Titration is required for treatment initiation (see Table 1 below).

Dosage and administration instructions outlined in the label include the following:

• Confirm the presence of amyloid beta pathology prior to initiating treatment;
• Titration is required for treatment initiation;
• The recommended maintenance dosage is 10 mg/kg administered as an intravenous infusion over approximately one hour every four weeks;
• Obtain a recent (within one year) brain MRI prior to initiating treatment;
• Obtain MRIs prior to the 5th, 7th, 9th, and 12th infusions; if radiographically observed amyloid related imaging abnormalities (ARIA) occurs, treatment recommendations are based on type, severity, and presence of symptoms;
• Dilution in 100 mL of 0.9% Sodium Chloride Injection, USP, is required prior to administration;
• Administer as an intravenous infusion over approximately one hour via a 0.2 or 0.22 micron in-line filter.

Note: Per the Prescribing Information, enhanced clinical vigilance for ARIA is recommended during the first 8 doses of treatment with Aduhelm, particularly during titration. Risk of ARIA, including symptomatic ARIA, was increased in apolipoprotein E ε4 (ApoE ε4) homozygotes compared to heterozygotes and noncarriers. If an individual experiences symptoms which could be suggestive of ARIA, clinical evaluation should be performed, including MRI testing if indicated.

Table 1: Infusion Dosing Schedule

IV Infusion (every 4 weeks)	Aduhelm Dosage (administer over approximately one hour)
Infusion 1 and 2	1 mg/kg
Infusion 3 and 4	3 mg/kg
Infusion 5 and 6	6 mg/kg
Infusion 7 and beyond	10 mg/kg

Recommendations for Dosing Interruptions in Persons with Amyloid Related Imaging Abnormalities (ARIA)

Per the label, if dosing is resumed following a temporary suspension, dosing may resume at that same dose and titration schedule prior to the dosing suspension. The benefits of reaching and maintaining the 10 mg/kg dosage should be considered when evaluating a potential dose suspension.

Table 2: ARIA-E Severity on MRI

Clinical Symptom Severity	ARIA-E Severity on MRI
	Mild	Moderate	Severe
Asymptomatic	May continue dosing at current dose and schedule	Suspend dosingFootnote1*	Suspend dosingFootnote1*
Mild	May continue dosing based on clinical judgment	Suspend dosingFootnote1*
Moderate or Severe	Suspend dosingFootnote1*

Footnote1* Suspend until MRI demonstrates radiographic resolution and symptoms, if present, resolve; consider a follow-up MRI to assess for resolution 2 to 4 months after initial identification. Resumption of dosing should be guided by clinical judgment. 

Table 3: ARIA-H Severity on MRI

Clinical Symptom Severity	ARIA-H Severity on MRI
	Mild	Moderate	Severe
Asymptomatic	May continue dosing at current dose and schedule	Suspend dosingFootnote2**	Suspend dosingFootnote3***
Symptomatic	Suspend dosingFootnote2**	Suspend dosingFootnote2**

Footnote2** Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; resumption of dosing should be guided by clinical judgment; consider a follow-up MRI to assess for stabilization 2 to 4 months after initial identification.

Footnote3*** Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; use clinical judgment in considering whether to continue treatment or permanently discontinue Aduhelm.

In persons who develop intracerebral hemorrhage greater than 1 cm in diameter during treatment with Aduhelm, suspend dosing until MRI demonstrates radiographic stabilization and symptoms, if present, resolve. In Studies 1 and 2, dosing was permanently discontinued in patients who developed intracerebral hemorrhage greater than 1 cm in 4 diameter. Use clinical judgment in considering whether to continue treatment or permanently discontinue Aduhelm.

Source: Biogen, 2023

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
0445U	β-amyloid (Abeta42) and phospho tau (181P) (pTau181), electrochemiluminescent immunoassay (ECLIA), cerebral spinal fluid, ratio reported as positive or negative for amyloid pathology
62270	Spinal puncture, lumbar, diagnostic
70551	Magnetic resonance (eg, proton) imaging, brain (including brain stem); without contrast material
70552	with contrast material(s)
70553	without contrast material, followed by contrast material(s) and further sequences
78608	Brain imaging, positron emission tomography (PET); metabolic evaluation
78811	Positron emission tomography (PET) imaging; limited area (eg, chest, head/neck)
78814	Positron emission tomography (PET) with concurrently acquired computed tomography (CT) for attenuation correction and anatomical localization imaging; limited area (eg, chest, head/neck)
81401	Molecular pathology procedure, Level 2 common variants (eg, R3500Q, R3500W) APOE (apolipoprotein E) (eg, hyperlipoproteinemia type III, cardiovascular disease, Alzheimer disease)
81405	Molecular pathology procedure, Level 6 full gene sequence PSEN1 (presenilin 1) (eg, Alzheimer disease)
81406	Molecular pathology procedure, Level 7 full gene sequence APP (amyloid beta [A4] precursor protein) (eg, Alzheimer disease), full gene sequence PSEN2 (presenilin 2 [Alzheimer disease 4]) (eg, Alzheimer disease)
96365 – 96368	Intravenous infusion administration
HCPCS codes covered if selection criteria are met:
J0172	Injection, aducanumab-avwa, 2 mg
Other HCPCS codes related to the CPB:
A9586	Florbetapir f18, diagnostic, per study dose, up to 10 millicuries
A9598	Positron emission tomography radiopharmaceutical, diagnostic, for non-tumor identification, not otherwise classified
J0174	Injection, lecanemab-irmb, 1 mg
J0175	Injection, donanemab-azbt, 2 mg
Q9982	Flutemetamol F18, diagnostic, per study dose, up to 5 millicuries
S3852	DNA analysis for APOE epsilon 4 allele for susceptibility to Alzheimer's disease
ICD-10 codes covered if selection criteria are met:
G30.0 - G30.9	Alzheimer's disease
G31.84	Mild cognitive impairment of uncertain or unknown etiology [due to AD or mild AD dementia]
ICD-10 codes not covered for indications listed in the CPB:
D69.0 – D69.9	Purpura and other hemorrhagic conditions
G23.0 – G23.9	Other degenerative diseases of basal ganglia
G31.01 – G31.9	Other degenerative diseases of nervous system, not elsewhere classified [Except G31.84]
G32.0 – G32.89	Other degenerative disorders of nervous system in diseases classified elsewhere
R79.1	Abnormal coagulation profile
Z79.01	Long term (current) use of anticoagulants
Z79.02	Long term (current) use of antithrombotics/antiplatelets
Z86.69	Personal history of other diseases of the nervous system and sense organs [seizures]
Z86.73	Personal history of transient ischemic attack (TIA), and cerebral infarction without residual deficits

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Background

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

• Aduhelm is an amyloid beta-directed antibody indicated for the treatment of Alzheimer’s disease. Treatment with Aduhelm should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. This indication is approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with Aduhelm. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).

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

Biogen sponsored several clinical trials evaluating the efficacy of aducanumab for the treatment of Alzheimer's disease (AD). Two relatively large-scale randomized, double-blind, placebo-controlled trials were underway, the EMERGE and ENGAGE. However, in March 2019, both the EMERGE and ENGAGE trials were discontinued based on results of a futility analysis conducted by an independent data monitoring committee, which indicated that the trials were unlikely to meet their primary endpoint upon completion. The recommendation to stop the studies was not based on safety concerns (Biogen, 2019b).

In October 2019, Biogen, in consultation with the FDA, announced that they had conducted new data analysis from the EMERGE and ENGAGE trials, which included additional data that became available after the pre-specified futility analysis. The new data analyses showed aducanumab to be effective in decreasing brain amyloid and reducing clinical decline as assessed by the pre-specified primary endpoint Clinical Dementia Rating-Sum of Boxes (CDR-SB). In both studies, the safety and tolerability profile of aducanumab was consistent with prior studies of aducanumab (Biogen, 2019a).

On June 7, 2021, the U.S. FDA announced the approval of Biogen's Aduhelm (aducanumab) for the treatment of Alzheimer's disease. Aduhelm was approved using the accelerated approval pathway based on the review of efficacy in three studies, representing a total of 3482 patients, and the study's surrogate endpoint, reduction of amyloid beta plaque in the brain, a hallmark of Alzheimer’s disease (FDA, 2021). Per the FDA, accelerated approval can be based on the drug’s effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients, with a required post-approval trial to verify that the drug provides the expected clinical benefit. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials. A timeline for the completion of the confirmatory trial is not available. 

The FDA approval was based on the new data analysis of the efficacy of aducanumab in the two randomized, double-blind, placebo-controlled, parallel group, Phase 3 clinical trials, EMERGE (NCT02484547) and ENGAGE (NCT02477800) which included patients with confirmed presence of amyloid pathology and mild cognitive impairment or dementia consistent with Stage 3 and Stage 4 Alzheimer's disease. The effects of aducanumab were also supported by an exploratory, double-blind, randomized, placebo-controlled, dose-ranging study, PRIME (NCT 01677572) which included patients with confirmed presence of amyloid pathology and prodromal or mild dementia stage of disease, consistent with Stage 3 and Stage 4 Alzheimer’s disease, with an enrolled distribution of 43% Stage 3 patients and 57% Stage 4 patients, followed by an optional, dose-blind, long-term extension period (Biogen, 2023).

In the EMERGE trial (n=1638) and ENGAGE trial (n=1647) patients (age range 50 to 85 years) were randomized to receive aducanumab low dose (3 or 6 mg/kg for ApoE ε4 carriers and noncarriers, respectively), high dose (10 mg/kg), or a placebo every 4 weeks for 18 months, followed by an optional, dose-blind, long-term extension period. 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. Clinical trial inclusion criteria for both trials included a requirement for a Clinical Dementia Rating (CDR) global score of 0.5, a Repeatable Battery for Assessment of Neuropsychological Status (RBANS) delayed memory index score ≤ 85, and a Mini-Mental State Examination (MMSE) score of 24 to 30 (Biogen, 2023). 

In the EMERGE trial, a subgroup of 488 patients were enrolled in the amyloid PET sub-study; of these, 302 were evaluated at week 78. The primary efficacy endpoint was the change from baseline on the CDR-Sum of Boxes (CDRSB) at Week 78. Treatment with aducanumab high dose demonstrated reduced clinical decline, as evidenced by a statistically significant treatment effect on change from baseline in CDR-SB compared to placebo (p = 0.0120). Secondary efficacy endpoints included the change from baseline in MMSE score at Week 78, the change from baseline in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13) at Week 78, and the change from baseline in the Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory (Mild Cognitive Impairment version) (ADCS-ADL-MCI) score at Week 78. Statistically significant differences from placebo were observed in the aducanumab high dose group on all secondary efficacy endpoints evaluated. The estimate of the treatment effect favored aducanumab across most prespecified subgroups of interest for the secondary efficacy endpoints. The Neuropsychiatric Inventory-10 item (NPI-10) was the only tertiary endpoint that assessed efficacy. Differences from placebo observed in the aducanumab low dose group numerically favored aducanumab but were not statistically significant (Biogen, 2022). When compared to patients receiving placebo, patients who received high-dose aducanumab experienced a 23% greater improvement in CDR-SB score (p=0.01), 15% greater improvement in MMSE (p=0.06), 27% greater improvement in ADAS-Cog 13 score (p=0.01), 40% greater improvement in ADCS-ADL-MCI score (p=0.001) (Biogen, 2019a).

In the ENGAGE trial, a subgroup of 585 patients were enrolled in the amyloid PET subgroup; of these, 374 were evaluated at week 78. No statistically significant differences were observed between the aducanumab-treated and the placebo-treated patients on the primary efficacy endpoint, the change from baseline in CDR-SB score at 78 weeks.

The PRIME, Phase I, trial included 197 patients (age range 51 to 91 years) who were randomized to receive a fixed dose of aducanumab 1 mg/kg (n=31), 3 mg/kg (n=32), 6 mg/kg (n=30), 10 mg/kg (n=32), titration of aducanumab to 10 mg/kg over 44 weeks (n=23), or placebo (n=48) for 12 months. Clinical assessments in the trial were exploratory. Results for clinical assessments were directionally aligned with the findings from the EMERGE trial, with less change from baseline in CDR-SB and MMSE scores at 1 year in the aducanumab 10 mg/kg fixed-dose group than in patients on placebo (CDR-SB: -1.26, 95% CI [-2.356, -0.163]; MMSE: 1.9, 95% CI [0.06, 3.75]). Trial inclusion criteria required participants to be ambulatory, and for prodromal AD, have a MMSE score between 24 and 30, a global Clinical Dementia Rating Scale (CDR) score of 0.5, objective memory loss defined as a free recall score of ≤27 on the Free and Cued Selective Reminding Test (FCSRT), and absence of significant levels of impairment in other cognitive domains; or for mild AD, have a MMSE score between 20 and 26, a global CDR score of 0.5 or 1.0, and have a positive florbetapir positron emission tomography (PET) amyloid scan (Biogen, 2023).

Per the FDA, the results from these clinical trials support the accelerated approval of Aduhelm, which is based on the surrogate endpoint of reduction of amyloid beta plaque in the brain. Amyloid beta plaque was quantified using positron emission tomography (PET) imaging to estimate the brain levels of amyloid beta plaque in a composite of brain regions expected to be widely affected by Alzheimer’s disease pathology compared to a brain region expected to be spared of such pathology (FDA, 2021).

With the attention surrounding the FDA approval of the first novel therapy approved for targeting amyloid beta plaques in the brain, the FDA issued a subsequent press release stating in part, "...the data included in the applicant’s submission were highly complex and left residual uncertainties regarding clinical benefit. There has been considerable public debate on whether Aduhelm should be approved. As is often the case when it comes to interpreting scientific data, the expert community has offered differing perspectives. At the end of the day, we followed our usual course of action when making regulatory decisions in situations where the data are not straightforward. We examined the clinical trial findings with a fine-tooth comb, we solicited input from the Peripheral and Central Nervous System Drugs Advisory Committee, we listened to the perspectives of the patient community, and we reviewed all relevant data. We ultimately decided to use the Accelerated Approval pathway—a pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit. In determining that the application met the requirements for Accelerated Approval, the Agency concluded that the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy. The late-stage development program for Aduhelm consisted of two phase 3 clinical trials. One study met the primary endpoint, showing reduction in clinical decline. The second trial did not meet the primary endpoint. In all studies in which it was evaluated, however, Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion. It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline"(Cavazzoni, 2021).

Aduhelm carries a boxed warning for amyloid related imaging abnormalities (ARIA). Per the label, monoclonal antibodies directed against aggregated forms of beta amyloid, including Aduhelm, can cause ARIA, characterized as ARIA with edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and ARIA with hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with Alzheimer’s disease. ARIA-H associated with monoclonal antibodies directed against aggregated forms of beta amyloid generally occurs in association with an occurrence of ARIA-E. ARIA-H of any cause and ARIAE can occur together. ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, rarely can occur. When present, reported symptoms associated with ARIA may include headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms associated with ARIA usually resolve over time. The risk of ARIA, including symptomatic and serious ARIA, is increased in apolipoprotein E ε4 (ApoE ε4) homozygotes. In addition to ARIA, intracerebral hemorrhages greater than 1 cm in diameter have occurred in patients treated with Aduhelm.

In clinical studies, symptomatic ARIA occurred in 10% (110/1105) of patients treated with Aduhelm. Serious symptoms associated with ARIA were reported in 0.3% of patients treated with Aduhelm. Clinical symptoms associated with ARIA resolved in 88% of patients during the period of observation. Overall, recurrent episodes of ARIA-E were less frequently symptomatic (12%) compared with initial episodes of ARIA-E (25%). Including asymptomatic radiographic events, ARIA was observed in 41% (454/1105) of patients treated with Aduhelm 10mg/kg compared to 10% (111/1087) of patients on placebo in clinical studies. ARIA-E was observed in 35% (387/1105) of patients treated with ADUHELM 10 mg/kg compared with 3% (29/1087) of patients on placebo. ARIA-H was observed in 28% (312/1105) of patients treated with ADUHELM compared to 9% (94/1087) of patients on placebo. There was no increase in isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) for Aduhelm compared to placebo.

An additional warning and precaution includes risk of hypersensitivity reactions. Angioedema and urticaria have occurred. If a hypersensitivity reaction occurs, the infusion should be promptly discontinued and initiate appropriate therapy. The most common adverse reactions (at least 10% and higher incidence compared to placebo) include ARIA-Edema, headache, ARIA-H microhemorrhage, ARIA-H superficial siderosis, and fall (Biogen, 2023).

Per the label, approximately 15% of Alzheimer’s disease patients are ApoE ε4 homozygotes. In the clinical trials, among patients with a known ApoE ε4 genotype, 17% (182/1103) of patients in the Aduhelm group were ApoE ε4 homozygotes, 51% (564/1103) were heterozygotes, and 32% (357/1103) were noncarriers. The incidence of symptomatic ARIA was found to be higher in ApoE ε4 homozygotes (16%) than in heterozygotes (11%) and noncarriers (5%) among patients treated with Aduhelm. However, the incidence of serious adverse reactions with ARIA-E, including risk of death, persistent or significant disability or incapacity, hospitalization, or other medically important event that may require intervention to prevent serious outcomes, was similar for ApoE ε4 carriers and noncarriers (2% in homozygotes, 1% in heterozygotes, 2% in noncarriers). The recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers. However, testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Prescribers should inform patients that if genotype testing is not performed they can still be treated with Aduhelm; however, it cannot be determined if they are ApoE ε4 homozygotes and at a higher risk for ARIA. An FDA-authorized test for detection of ApoE ε4 alleles to identify patients at risk of ARIA if treated with Aduhelm is not currently available. Currently available tests used to identify ApoE ε4 alleles may vary in accuracy and design (Biogen, 2023).

In a systematic review and meta-analysis, Ebell and colleagues (2024) evaluated clinically meaningful benefits and harms of monoclonal antibodies targeting amyloid for the treatment of Alzheimer disease. These investigators carried out a literature search using PubMed, Cochrane CENTRAL, and 5 trial registries, as well as the reference lists of identified studies related to monoclonal antibodies. Randomized controlled trials comparing a monoclonal antibody with placebo at a dose consistent with that used in phase 3 trials or for U.S. FDA approval were included. Studies had to report at least 1 clinically relevant benefit or harm. Data were extracted independently by at least 2 researchers for random effects meta-analysis. Changes in cognitive and functional scales were compared between groups, and each difference was assessed to determine if it met the minimal clinically important difference (MCID), defined as the smallest change in a scale measuring cognition or function that is noticeable by the patient or their caregiver. The investigators identified 87 studies from PubMed and 71 from other sources, of which 16 were duplicates. A total of 142 records were screened and 41 underwent full text review. Exclusions included some studies that used subtherapeutic doses, studied an anti-Tau antibody, or were phase 1 studies. A total of 19 publications with 23,202 total participants that evaluated 8 anti-amyloid antibodies were used for final analysis. Most were 18 to 19 months in duration, and enrolled patients with mild cognitive impairment or with mild or moderate Alzheimer disease. Their analysis revealed small improvements over placebo in the Alzheimer's Disease Assessment Scale (ADAS)-Cog-11 to -14 score (standardized mean difference = -0.07; 95% CI, -0.10 to -0.04), Mini Mental State Examination score (0.32 points; 95% CI, 0.13 to 0.50), and Clinical Dementia Rating-Sum of Boxes scale score (mean difference =-0.18 points; 95% CI, -0.34 to -0.03), and the combined functional scores (standardized mean difference = 0.09; 95% CI, 0.05 to 0.13). None of the changes, including those for lecanemab, aducanumab, and donanemab, exceeded the MCID. Harms included significantly increased risks of amyloid-related imaging abnormalities (ARIA)-edema (relative risk [RR] = 10.29; number needed to harm [NNH] = 9), ARIA-hemorrhage (RR = 1.74; NNH = 13), and symptomatic ARIA-edema (RR = 24.3; NNH = 86). The investigators acknowledged limitations to their analysis. "All studies enrolled participants who underwent positron emission tomography scanning and/or cerebrospinal fluid analyses for amyloid, studies that are not typically done in current routine clinical practice. The included studies reported average changes on standard cognitive and functional scales, but did not report the percentage of participants achieving clinically meaningful differences in cognition or function from baseline. Such data would be more interpretable for clinicians and patients. Finally, studies had different inclusion criteria for severity of disease at baseline, which is a source of potential heterogeneity." The investigators concluded that although monoclonal antibodies targeting amyloid provide small benefits on cognitive and functional scales in patients with Alzheimer dementia, these improvements are far below the MCID for each outcome and are associated with significant harms.

Cerebrospinal Fluid (CSF) Biomarkers of Alzheimer Disease

Fagan et al. (2006) state that amyloid-beta(42) (Abeta(42)), a central component of amyloid plaques which appears central to the pathogenesis of Alzheimer's disease, is decreased in the cerebrospinal fluid (CSF) in persons with dementia of the Alzheimer's type. The authors hypothesize that this decrease may reflect plaques acting as an Abeta(42) "sink," hindering transport of soluble Abeta(42) between brain and CSF. The authors compared the in vivo brain amyloid load (via positron emission tomography imaging of the amyloid-binding agent, Pittsburgh Compound-B [PIB]) with CSF Abeta(42) and other measures (via enzyme-linked immunosorbent assay) in clinically characterized research subjects. Subjects fell into two non-overlapping groups: those with positive PIB binding had the lowest CSF Abeta(42) level, and those with negative PIB binding had the highest CSF Abeta(42) level. No relation was observed between PIB binding and CSF Abeta(40), tau, phospho-tau(181), plasma Abeta(40), or plasma Abeta(42). Importantly, PIB binding and CSF Abeta(42) did not consistently correspond with clinical diagnosis; three cognitively normal subjects were PIB-positive with low CSF Abeta(42), suggesting the presence of amyloid in the absence of cognitive impairment (ie, preclinical AD). The authors concluded that these observations suggest that brain amyloid deposition results in low CSF Abeta(42), and that amyloid imaging and CSF Abeta(42) may potentially serve as antecedent biomarkers of (preclinical) AD.

Schindler et al. (2018) state that levels of amyloid β peptide 42 (Aβ42), total tau, and phosphorylated tau-181 are well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, but variability in manual plate-based assays has limited their use. The authors examined the relationship between CSF biomarkers, as measured by a novel automated immunoassay platform, and amyloid positron emission tomography (PET). CSF samples from 200 individuals underwent separate analysis for Aβ42, total tau, and phosphorylated tau-181 with automated Roche Elecsys assays. Aβ40 was measured with a commercial plate-based assay. PET with Pittsburgh Compound B was performed less than 1 year from CSF collection. The results showed that the ratios of CSF biomarkers (total tau/Aβ42, phosphorylated tau-181/Aβ42, and Aβ42/Aβ40) best discriminated Pittsburgh Compound B-positive from Pittsburgh Compound B-negative individuals. The authors concluded that CSF biomarkers and amyloid PET reflect different aspects of Alzheimer's disease brain pathology, and therefore, less-than-perfect correspondence is expected. Automated assays are likely to increase the utility of CSF biomarkers.

An UpToDate review on "Mild cognitive impairment: Prognosis and treatment" (Petersen, 2020) states that "a number of smaller studies have examined the use of cerebrospinal fluid (CSF) markers for predicting conversion from MCI [mild cognitive impairment] to dementia". The CSF biomarkers most often found to be predictive include increased levels of tau or tau protein phosphorylated at Thr 181 and lower levels of amyloid beta 42 (Aß42) peptide, a low ratio of Aß42 to Aß40 levels, and a low ratio of Aß42 to tau levels.

In December 2022, the FDA granted premarket notification for Roche Diagnostics' Elecsys β-Amyloid (1-42) CSF II and Elecsys phospho-tau (181P) CSF. These in vitro electrochemiluminescence immunoassays are indicated for the measurement of the β-amyloid (1-42) (Abeta42) and phospho-tau (181P) (pTau181) protein concentrations in cerebrospinal fluid (CSF) from adult patients aged 55 years and older being evaluated for Alzheimer's disease (AD) and other causes of cognitive impairment to generate a pTau181/Abeta42 ratio value. A negative result, defined as pTau181/Abeta42 ratio value below cut-off or an Abeta42 value above the measuring range, is consistent with a negative amyloid positron emission tomography (PET) scan result. A negative result reduces the likelihood that a patient’s cognitive impairment is due to AD. A positive result, defined as pTau181/Abeta42 ratio value above cut-off, is consistent with a positive amyloid PET scan result. A positive result does not establish a diagnosis of AD or other cognitive disorder. The pTau181/Abeta42 ratio result is used as an adjunct to other clinical diagnostic evaluations. There are limitations for use. The performance of the pTau181/Abeta42 ratio has not been established for predicting development of dementia or other neurologic conditions, and monitoring responses to therapies.

Genetic Mutations in Early-Onset Alzheimer Disease

An UpToDate review on "Genetics of Alzheimer disease" (Sherva and Kowall, 2020) states that genetic basis of AD resulted from studies of families displaying autosomal dominant inheritance of the disorder. Early studies facilitated the eventual identification of causative mutations in the following genes: amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), which collectively account for less than 1 percent of all AD cases and 60 to 70 percent of early-onset AD. The authors state that more than 30 mutations in this gene have been described in association with AD, accounting for 10 to 15 percent of early familial AD. "Nearly all pathogenic APP mutations identified so far cluster around the three major processing sites that are relevant to the generation of amyloidogenic Aß, increasing production of Aβ, or altering the ratio of Aβ42 to Aβ40". The PSEN1 gene has been associated with more than 150 mutation AD, accounting for up to 50 percent of early-onset familial AD. "Most mutations in PSEN1 increase the generation of the highly fibrillogenic Aβ42 species, alter the kinetics of Aβ peptide turnover, and enhance accumulation of Aβ in the brain. Blood and cerebrospinal fluid (CSF) levels of Aβ are also elevated". The PSEN2 gene is rarer, as fewer than 20 mutations of this gene have been described in early-onset familial AD. "Similar to PSEN1 mutations, PSEN2 mutations alter the cleavage activity of γ-secretase and increase the ratio of Aβ42 to Aβ40". The authors summarize by stating, "APP, PSEN1, and PSEN2 mutations account for approximately two-thirds of familial autosomal dominant AD and less than 10 percent of early-onset AD overall. Rare variants at other loci may contribute to early-onset AD risk, including some that overlap with late-onset AD (LOAD; eg, SORL1, TREM2) and others related to the endolysosomal pathway (eg, RUFY1, PSD2, TCIRG1, RIN3)."

Montreal Cognitive Assessment (MoCA)

The Montreal Cognitive Assessment (MoCA) is a widely used screening tool designed to detect subtle cognitive deficits that characterize mild cognitive impairment (MCI). Similar to the Mini-Mental Status Exam (MMSE), the MoCA is scored on a 30-point scale, with items that assess delayed word recall (5 points), visuospatial/executive function (7 points; includes clock-drawing), language (6 points), attention/concentration (6 points), and orientation (6 points). "The MoCA exhibits a pooled sensitivity of 91 percent and a pooled specificity of 81 percent for identifying dementia, and a pooled sensitivity of 89 percent and a pooled specificity of 75 percent for identifying MCI. Studies examining head-to-head performance of patients on the MMSE and MoCA have shown that the MoCA is more difficult; MoCA scores are consistently lower than those obtained on the MMSE. The MoCA appears to be more sensitive than the MMSE for detecting MCI, though perhaps slightly less specific." "There are fewer data regarding the magnitude of annual decline in patients with baseline cognitive impairment. One small study showed a one-point decline on the MoCA in patients with prodromal to mild AD over a one-year interval. A larger study that spanned three years reported no detectable decline in MCI and an average decline of 2.5 points in dementia over that interval. Further work is needed to more clearly define expected rates of decline on the MoCA in patients with neurodegenerative disease and other conditions. The MoCA is freely accessible for clinical use at the MoCA website; whereas MMSE users must now register for permission and pay a fee to use the assessment tool (Mendez, 2019). See Appendix D for MoCA scoring definition.

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Appendix

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

• Cognitive concern reflecting a change in cognition reported by patient or information or clinician (i.e. historical or observed evidence of decline over time)
• Objective evidence of impairment in more or more cognitive domains, typically including memory (i.e., formal or bedside testing to establish level of cognitive function in multiple domains)
• Preservation of independence in functional abilities
• Not demented

Source: Albert et al (2011)

Appendix B: Clinical Dementia Rating (CDR) Scale

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

• 0 = Normal
• 0.5 = Very Mild Dementia
• 1 = Mild Dementia
• 2 = Moderate Dementia
• 3 = Severe Dementia.

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

Appendix C: Mini-Mental Status Exam (MMSE)

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

• 25 - 30 suggests normal cognition
• 20 - 24 suggests mild dementia
• 13 - 20 suggests moderate dementia
• Less than 12 suggests severe dementia.

Source: Folstein, Folstein, and McHugh (1975)

Appendix D: Montreal Cognitive Assessment (MoCA)

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

• Mild Cognitive Impairment: 19 - 25
• Mild Dementia: 11 - 21
• Normal: 26 and above.

Source: Nasreddine et al, 2019; Nasreddine, 2021

Appendix E: ARIA MRI Classification Criteria

Table 4: ARIA MRI Classification Criteria

ARIA Type	Radiographic Severity
	Mild	Moderate	Severe
ARIA-E	FLAIR  hyperintensity confined to sulcus and or cortex/subcortical white matter in one location < 5 cm	FLAIR hyperintensity 5 to 10 cm, or more than 1 site of involvement, each measuring < 10 cm	FLAIR hyperintensity measuring > 10 cm, often with significant subcortical white matter and/or sulcal involvement. One or more separate sites of involvement may be noted.
ARIA-H microhemorrhage	≤ 4 new incident microhemorrhages	5 to 9 new incident microhemorrhages	10 or more new incident microhemorrhages
ARIA-H superficial siderosis	1 focal area of superficial siderosis	2 focal areas of superficial siderosis	> 2 focal areas of superficial siderosis

Source: Biogen, 2022

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References