By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved a new, but controversial, treatment for Alzheimer’s disease (AD). Aducanumab is a recombinant human, immunoglobulin gamma (IgG1) monoclonal antibody that targets aggregated soluble and insoluble forms of amyloid beta, reducing plaque deposits. This therapeutic approach is in contrast to the currently available drugs for AD with limited benefit: acetylcholinesterase inhibitors, such as donepezil, and N-methyl-D-aspartate antagonists, such as memantine. The FDA approved aducanumab through the accelerated approval pathway based on surrogate markers typically used for anti-cancer drugs. This pathway is intended to provide earlier access to potentially valuable therapies for serious disease with an unmet need.1 Continued approval may be contingent on verification of clinical benefit in confirmatory trials. The approval ran counter to the recommendation of the agency’s Peripheral and Central Nervous System Drugs Advisory Committee, which did not support approval. Aducanumab is distributed as Aduhelm.
Aducanumab can be prescribed to treat AD.2
After an initial titration period (six doses), the recommended maintenance dose is 10 mg/kg (given by IV infusion over approximately one hour) every four weeks and at least 21 days apart.2 The titrations schedule should be 1 mg/kg for two doses, 3 mg/kg for two doses, 6 mg/kg for two doses, and 10 mg/kg for the seventh dose and beyond. Brain MRI should be performed before initiation of treatment and before doses 7 and 12. If there are 10 or more new microhemorrhages or more than two focal areas of superficial siderosis, treatment may be continued with caution only after clinical evaluation and a follow-up MRI demonstrating radiographic stabilization.2 Aducanumab is available in 100 mg/mL single-dose vials of 1.7 mL or 3 mL.
Aducanumab is the first drug that targets brain beta-amyloid that is believed to play a key role in the pathogenesis of AD.
Clinical benefit remains to be established. The clearance of amyloid is associated with amyloid-related imaging abnormalities (ARIA), including edema (ARIA-E) and hemosiderin deposition (microhemorrhage and superficial siderosis; ARIA-H).2 ARIA-E and/or ARIA-H were observed in 41% of aducanumab-treated subjects with a planned dose of 10 mg/kg vs. 10% treated with placebo.1 Incidence of ARIA-E was higher in those who carry the AD gene (APOE epsilon 4). Most ARIA were observed during titration. ARIA-E tends to resolve over time (week 12 to 20). In clinical trials, permanent discontinuation of the drug was required for radiographically severe ARIA-H and temporary dose suspension for moderate or severe ARIA-E and moderate ARIA-H.2 The most common symptom observed was headache (13%).2
The accelerated approval was based on review of the efficacy from two double-blind, randomized, placebo-controlled studies. The diagnosis of AD was based on confirmed presence of amyloid pathology and mild cognitive impairment or mild dementia stage of diseases consistent with stage 3 and 4. Subjects (n = 1,638 in study 1, n = 1,647 in study 2) were randomized to low dose (3 mg/kg or 6 mg/kg for APOE epsilon 4 carriers and noncarriers, respectively), high dose (10 mg/kg), or placebo for 18 months.2 APOE epsilon 4 carriers were later adjusted to 10 mg/kg. The primary endpoint was change from baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) score at week 78.4,5 CDR-SB assesses both cognitive and functional domains of AD disability. Secondary endpoints included change from baseline in Mini-Mental State Examination (MMSE) score, change from baseline in Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and change from baseline in Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment version) (ADCS-ADL-MCI) score.
Study 1 reached statistical difference for the high dose for all primary and secondary endpoints. However, the P values were not statistically controlled for multiple comparison (i.e., less strict statistical threshold). Study 2 did not reach statistical difference for CDR-SB. The FDA supported its case for approval from a subgroup analysis of participants enrolled in a biomarker portion of the study, which showed reduction in amyloid burden detected with PET and reduction of cerebrospinal fluid (CSF) tau proteins (total and phosphorylated) on high-dose aducanumab vs. placebo. Subgroup data at week 78 represented about 33% and 3.5%, respectively, of those assessed for primary and secondary endpoints at the same time. Significant reductions in amyloid deposits were observed for both subgroup studies (71% and 59%, respectively) for high-dose aducanumab vs. placebo, but significant reductions in CSF tau proteins (16%-23%) were observed only for study 1.
In recent years, pharmacologic interventions for AD have focused on anti-amyloid agents with the hope of reducing downstream tau pathology and cognitive decline.3,6 In the two clinical trials, aducanumab met the primary clinical outcome in one of the two studies. However, both studies were terminated based on a futility analysis.4,5 Ten of 11 members of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted against approval, with one abstention.7 However, the agency decided to grant an accelerated approval based, in large part, on a subgroup analysis of surrogate markers. The agency expects this will result in reduction in clinical decline and that benefit outweighed the risk of the drug. Subsequent to the FDA’s decision, three members of the Peripheral and Central Nervous System Drugs Advisory Committee resigned.7 The estimated cost is $56,000 per patient per year.
- U.S. Food & Drug Administration. FDA’s decision to approve new treatment for Alzheimer’s disease. June 7, 2021.
- Biogen. Aduhelm prescribing information. June 2021.
- Tolar M, Abushakra S, Hey JA, et al. Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval. Alzheimers Res Ther 2020;12:95.
- ClinicalTrials.gov. 221AD302 phase 3 study of aducanumab (BIIB037) in early Alzheimer’s disease (EMERGE).
- ClinicalTrials.gov. 221AD301 phase 3 study of aducanumab (BIIB037) in early Alzheimer’s disease (ENGAGE).
- Blennow K, Zetterberg H. Biomarkers for Alzheimer’s disease: Current status and prospects for the future. J Intern Med 2018;284:643-663.
- Chappell B. 3 experts have resigned from an FDA committee over Alzheimer’s drug approval. National Public Radio. June 11, 2021.