Winter 2022 Newsletter
By Jasmine (Sea) An, PharmD, PGY2 Geriatric Pharmacy Resident, and Lisa C Hutchison, PharmD, MPH
University of Arkansas for Medical Sciences (UAMS) College of Pharmacy
In June 2021, the U.S. Food and Drug Administration (FDA) approved the first-of-its-kind monoclonal antibody indicated for treatment of Alzheimer’s disease in patients with mild cognitive impairment or mild stage of disease. Despite this groundbreaking approval, controversy surrounds the drug.
Aducanumab (Aduhelm) is an anti-amyloid monoclonal antibody directed against aggregated amyloid beta (AAB) plaques, which is a defining pathophysiological feature of Alzheimer’s disease.1 Administration requires infusion over a 1-hour period every 4 weeks. The dose is slowly titrated to meet the goal dose (10 mg/kg) by the seventh infusion. According to the FDA label, no diagnostic tests are required to confirm the presence of AAB plaques prior to initiating this therapy. However, patients are required to obtain magnetic resonance imaging (MRI) at baseline and prior to their seventh and twelfth dose to screen for potential adverse events. The FDA label does not specify any contraindications.
Part of the controversy with aducanumab is the limited data available to evaluate the efficacy of aducanumab. Approval was based on two phase-3 trials. Phase-3 trials help confirm effectiveness and safety of investigational drugs. Both trials were terminated early due to clinical futility. However, Biogen, the manufacturer of aducanumab, subsequently conducted post hoc analysis of the data from the terminated trials to present to the FDA.
The two trials are called ENGAGE2 and EMERGE3. Both trials were 18-month, double-blind, randomized, placebo-controlled, parallel group studies. Patients received placebo, low-dose aducanumab (3 or 6 mg/kg), or high dose aducanumab (6 or 10 mg/kg). Some of the major exclusion criteria were:
- age over 85,
- transient ischemic attack or stroke within one year prior to screening,
- contraindications to having a brain MRI or PET scan, and
- use of medications with platelet antiaggregant or anticoagulant properties.2,3
The primary endpoint was changes from baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), and secondary endpoints were changes from baseline in Mini-Mental State Exam (MMSE), Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Alzheimer’s Disease Cooperative Study Activities of Daily Living MCI (ADCS-ADL-MCI). Both trials showed statistical reduction in AAB plaque compared to baseline. However, neither trial showed statistically significant difference in clinically useful endpoints for low-dose aducanumab.4 As for high-dose aducanumab, there were mixed results with the EMERGE trial showing statistical significance in the primary endpoint while the ENGAGE trial not showing any statistically significant difference.4
In addition to the question of efficacy, safety is another concern. Specifically, amyloid-related imaging abnormalities edema (ARIA-E) occurred in 35% of patients who received aducanumab compared to 3% from the placebo group.4 Even though ARIA-E was found to be reversible and non-significant, symptoms such as changes in mental state, confusion, and gait disturbances may be present. Other serious adverse reactions shown on imaging were microhemorrhage and amyloid-related imaging abnormalities-hemosiderin deposition (ARIA-H) which both had ≥10% higher risk compared to placebo. Other safety concerns were headaches, falls, and diarrhea.4
Aducanumab was FDA approved through accelerated approval and Biogen must conduct a fourth randomized clinical trial to prove that aducanumab actually slows the progression of Alzheimer’s disease measured in clinical results, not just in changes in AAB plaque. Other barriers to utilizing this medication include cost. Initially Biogen indicated the estimated cost was $56,000 per year (excluding cost of administration and imaging), but that figure was lowered to $28,200 per year as of January 2022.5 Because of the lack of clear clinical improvement and safety concerns, the Department of Veterans Affairs did not include aducanumab on its national formulary6, and other major health systems such as the Cleveland Clinic and Mount Sinai have affirmed their opposition to the drug as well.7 As of January 2022, the Centers for Medicare and Medicaid Services (CMS) made a draft decision to cover aducanumab only in studies approved by CMS or supported by the National Institutes of Health. This proposal is open to public comment for 30 days and final decision will be made by April 11.8
Despite finally having the first agent for treatment of Alzheimer’s disease, we cannot celebrate just yet. There is ambiguity in data, major safety concerns, and high potential to increase disparity in care. These issues must be considered prior to initiating aducanumab therapy.
- ADUHELM (aducanumab-avwa) . Biogen. Cambridge, MA. 2021.
- 221AD301 Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer’s Disease (ENGAGE). ClinicalTrials.gov identifier: NCT02477800. Updated September 2, 2021. Accessed September 17, 2021. https://clinicaltrials.gov/ct2/show/NCT02477800
- 221AD302 Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer’s Disease (EMERGE). ClinicalTrials.gov identifier: NCT02484547. Updated September 2, 2021. Accessed September 17, 2021. https://clinicaltrials.gov/ct2/show/NCT02484547
- Haeberlein SB, Hehn C, Tian Y et al. EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to Evaluate Aducanumab in Patients With Early Alzheimer’s Disease: Biogen Presentation. 2020.
- Terry M. Biogen Cuts Price of Much-Debated Alzheimer’s Drug in Half. BioSpace. December 20, 2021. Accessed January 3, 2022. https://www.biospace.com/article/biogen-cuts-price-of-alzheimer-s-drug-aduhelm-in-half/
- Kansteiner F. Biogen’s controversial Alzheimer’s med Aduhelm turned away by VA on efficacy and safety worries. FIERCE Pharma. August 11, 2021. Accessed September 3, 2021. https://www.fiercepharma.com/pharma/biogen-s-alzheimer-s-med-aduhelm-absent-from-veterans-association-formulary-efficacy-and
- Belluck P. Cleveland Clinic and Mount Sinai Won’t Administer Aduhelm to Patients. The New York Times. July 14, 2021. Accessed September 3, 2021. https://www.nytimes.com/2021/07/14/health/cleveland-clinic-aduhelm.html
- Mcginley L, Goldstein A. Medicare proposes covering expensive drug for early-stage Alzheimer’s, but with restrictions that will sharply limit use. The Washington Post. January 11, 2022. Accessed January 13, 2022. https://www.washingtonpost.com/health/2022/01/11/alzheimers-drug-aduhelm-medicare-coverage/