Last Review Date: 10/03/2023

Date of Origin: 07/01/2021

Dates Reviewed: 07/2021, 06/2022, 06/2023, 10/2023

1. Description of Procedure or Service ¹

Aduhelm™ (aducanumab-avwa) is a recombinant human immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta which is potentially a disease-modifying treatment.

2. Policy

Aduhelm™ (aducanumab-avwa) is considered not medically necessary for all indications including treatment of Alzheimer’s Disease (AD).

Note: There is insufficient clinical evidence for demonstrated efficacy

3. Key Points ^1,5,6,9

Alzheimer’s disease is a fatal neurodegenerative brain disease with progressive accumulation of plaques in the brain that contain beta-amyloid protein and neurofibrillary tangles of phosphorylated tau protein.  Current treatment options for AD focus on supportive management and includes the treatment of dementia with medications that are not disease-modifying (e.g., donepezil, rivastigmine, galantamine, memantine, etc.).. Aducanumab promotes the clearance of beta-amyloid plaques from the brain, however, the role of beta-amyloid protein in disease is not well understood. At this time, aducanumab is not addressed in any clinical guidelines by U.S. or non-U.S. based organizations, though, the Institute for Clinical And Economic Review (ICER) did assess the effectiveness and value of aducanumab for Alzheimer’s disease in a draft evidence report in May 2021 and they concluded that the current available evidence is insufficient to determine the net health benefit of aducanumab⁹.

4. Clinical Trials and FDA Review ^1,5,6,9

Initial efficacy was studied in a small, double-blind, randomized, placebo-controlled, dose ranging Phase 1b study titled the PRIME (Study 3, NCT 01677572). The effects of Aduhelm in patients with Alzheimer’s disease (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), were favorable though there was differential loss to follow-up in the high-dose and placebo groups due to study withdrawal and treatment discontinuation.

Subsequent confirmatory efficacy was then evaluated in two identical double-blind, randomized, placebo-controlled, parallel group studies (Study 1, NCT 02484547 and Study 2, NCT 02477800) in patients with early Alzheimer’s disease (patients with confirmed presence of amyloid pathology and mild cognitive impairment or mild dementia stage of disease, consistent with Stage 3 and Stage 4 Alzheimer’s disease, stratified to include 80% Stage 3 patients and 20% Stage 4 patients). In both trials and at all doses, aducanumab effectively removed beta-amyloid, though during the trials the trial protocol was amended such that the high-dose group was titrated to 10 mg/kg, regardless of APOE 𝜀𝜀4 status. In March 2019, ENGAGE and EMERGE were both terminated based on an interim analysis for futility. Subsequent analyses showed a possible positive effect in the EMERGE trial, though the results from ENGAGE failed to corroborate this with regard to improvement in the primary clinical endpoint (Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB)) within the high-dose group when compared with placebo. Secondary endpoint analysis was consistent with regard to the disparity in clinical effect found in the primary endpoint result for each trial respectively. An external panel of experts on the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, overwhelmingly voted in November 2020, that the clinical data did not support the approval of aducanumab. The FDA approved aducanumab on June 07, 2021 as a fast-track approval via the accelerated approval pathway. Accelerated approval is intended to expedite drugs to market with surrogate evidence in the rare situations where the preferred method of measuring actual clinical endpoints would simply take too long. The trials for aducanumab did include effect on clinical endpoints.

Study 3, PRIME (NCT01677572): “A Randomized, Double-Blinded, Placebo-Controlled Multiple Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB037 in Subjects With Prodromal or Mild Alzheimer's Disease”.

• In Study 3, 197 patients were randomized to receive a fixed dose of Aduhelm 1 mg/kg (n=31), 3 mg/kg (n=32), 6 mg/kg (n=30), 10 mg/kg (n=32), titration of Aduhelm to 10 mg/kg over 44 weeks (n=23), or placebo (n=48) for 12 months. Clinical assessments in Study 3 were exploratory. Results for clinical assessments were directionally aligned with the findings from Study 1, with less change from baseline in CDR-SB and MMSE scores at 1 year in the Aduhelm 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]).

Study 1, EMERGE (NCT02484547): “A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects With Early Alzheimer's Disease”

• In Study 1, 1638 patients were randomized 1:1:1 to receive Aduhelm low dose, Aduhelm high dose, or placebo.  The primary efficacy endpoint was the change from baseline on the CDR-Sum of Boxes (CDRSB) at Week 78. In Study 1, treatment with Aduhelm high dose demonstrated reduced clinical decline, as evidenced by a statistically significant treatment effect on change from baseline in CDR-SB compared to placebo (-0.39 [-22%], p = 0.0120). Differences from placebo observed in the Aduhelm low dose group numerically favored Aduhelm but were not statistically significant.

Study 2, ENGAGE (NCT02477800): “A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects With Early Alzheimer's Disease”

• In Study 2, 1647 patients were randomized 1:1:1 to receive Aduhelm low dose, Aduhelm high dose, or placebo. At baseline, the mean age of patients was 71 years, with a range of 50 to 85 years. No statistically significant differences were observed between the Aduhelm-treated and placebo-treated patients on the primary efficacy endpoint, the change from baseline in CDR-SB score at 78 weeks.

5. Billing Code/Availability Information

HCPCS Code:

• J0172 – Injection, aducanumab-avwa, 2 mg; 1 billable unit = 2 mg

NDC:

• Aduhelm 170 mg/1.7 mL (100 mg/mL) solution in a single-dose vial: 64406-0101-xx
• Aduhelm 300 mg/3 mL (100 mg/mL) solution in a single-dose vial: 64406-0102-xx

6. References

1. Aduhelm [package insert]. Cambridge, MA; Biogen, Inc; August 2023. Accessed September 2023.
2. McKhann GM, Knopman DS, Chertklow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.  Alzheimers Dement. 2011;7(3):263. Epub 2011 Apr 21. 
3. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):280. Epub 2011 Apr 21.
4. Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016 Sep 1;537(7618):50-6. doi: 10.1038/nature19323. Update in: Nature. 2017 Jun 21;546(7659):564.
5. Biogen. 221AD302 Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer's Disease (EMERGE). Available from: https://clinicaltrials.gov/ct2/show/NCT02484547?term=NCT02484547&draw=2&rank=1. Accessed May 10, 2023.
6. Biogen. 221AD301 Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer's Disease (ENGAGE). Available from: https://clinicaltrials.gov/ct2/show/NCT02477800?term=NCT02477800&draw=2&rank=1. Accessed May 10, 2023.
7. O'Bryant SE, Lacritz LH, Hall J, et al. Validation of the new interpretive guidelines for the clinical dementia rating scale sum of boxes score in the national Alzheimer's coordinating center. Arch Neurol. 2010 Jun;67(6):746-9. doi: 10.1001/archneurol.2010.115.
8. Skinner J, Carvalho, JO, Potter GG, et al. The Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-Plus): an expansion of the ADAS-Cog to improve responsiveness in MCI. Brain Imaging Behav. 2012 Dec;6(4):489-501. doi: 10.1007/s11682-012-9166-3.
9. Salloway S, Chalkias S, Barkhof F, et al. Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease. JAMA Neurol. 2022 Jan 1;79(1):13-21. doi: 10.1001/jamaneurol.2021.4161.
10. Lin GA, Whittington MD, Synnott PG, et al. Aducanumab for Alzheimer’s Disease: Effectiveness and Value; Final Evidence Report and Meeting Summary. Institute for Clinical and Economic Review, August 5, 2021. https://icer.org/assessment/alzheimers-disease-2021/.
11. Lin GA, Whittington MD, Wright A, et al. Beta-Amyloid Antibodies for Early Alzheimer’s Disease: Effectiveness and Value; Draft Evidence Report. Institute for Clinical and Economic Review, December 22, 2022. https://icer.org/assessment/alzheimers-disease-2022/#timeline.

Appendix 1 – Covered Diagnosis Codes

Appendix 2 – Centers for Medicare and Medicaid Services (CMS)

Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determination (NCD), Local Coverage Articles (LCAs), and Local Coverage Determinations (LCDs) may exist and compliance with these policies is required where applicable. They can be found at: https://www.cms.gov/medicare-coverage-database/search.aspx. Additional indications may be covered at the discretion of the health plan.

Medicare Part B Covered Diagnosis Codes (applicable to existing NCD/LCA/LCD): N/A