CMAJ : Canadian Medical Association Journal | 2021
Should Canadian patients look forward to aducanumab for Alzheimer disease?
Abstract
E1430 CMAJ | SEPTEMBER 13, 2021 | VOLUME 193 | ISSUE 36 © 2021 CMA Joule Inc. or its licensors I n Canada, 190 000 people are living with mild Alzheimer-type dementia and 532 000 to 799 000 people are living with amnestic mild cognitive impairment.1–4 Developing treatments for Alzheimer disease is challenging, with few effective therapies that only target symptoms. Although the US Food and Drug Administration (FDA) approved aducanumab on June 7, 2021 — the first new treatment for Alzheimer disease since 2003 — its approval was controversial.5 Aducanumab is a human monoclonal immunoglobulin (Ig) G1 antibody that selectively targets amyloid-β aggregates (including soluble oligomers and insoluble fibrils) and clears amyloid plaques from the brain via a microglia-mediated phagocytic process.6 Biogen sponsored ENGAGE (NCT02477800) and EMERGE (NCT02484547) , which are both phase 3, parallel group, placebocontrolled randomized trials involving aducanumab. Both trials enrolled patients aged 50 to 85 years with mild cognitive impairment or mild dementia caused by Alzheimer disease who had a positron emission tomography (PET) scan that showed brain amyloid pathology. Patients were randomized to receive lowdose aducanumab, high-dose aducanumab or placebo for 18 months. Because of concern that carriers of apolipoprotein E (ApoE) episilon-4 could be at higher risk of developing amyloidrelated imaging abnormalities (ARIA), than noncarriers, Biogen stratified patients by ApoE episolon-4 status.7 For example, ApoE epsilon-4 carriers who were randomized to high-dose aducanumab received 6 mg/kg and noncarriers received 10 mg/kg after a 24-week titration period.8 However, the protocol was amended after a phase 1b randomized trial (completed after phase 3 trials began) established that it was safe to administer a 10 mg/kg dose to ApoE epsilon-4 carriers randomized to the high-dose aducanumab group.8 ENGAGE and EMERGE were both terminated for futility on Mar. 21, 2019, after a prespecified interim analysis, but Biogen successfully argued in support of aducanumab’s potential efficacy as a disease-modifying therapy based on posthoc analyses, and the FDA approved aducanumab for use in people with mild cognitive impairment or mild dementia caused by Alzheimer disease.5,8 The FDA’s approval of aducanumab went against the recommendation of its independent Peripheral and Central Nervous System Drugs advisory committee, which recommended to the FDA that aducanumab not be approved because of lack of efficacy. Some trial analyses were conducted in close collaboration with the FDA, which may be perceived to have influenced the FDA’s decision.5,8 The FDA’s approval of aducanumab was also atypical because it was approved through the Accelerated Approval pathway, which is intended for drugs that are for a “serious or life-threatening illness that may provide meaningful therapeutic benefit over existing treatments when the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients and there remains some uncertainty about the drug’s clinical benefit.”5 Although aducanumab resulted in statistically significant timeand dose-dependent reductions in brain amyloid plaque compared with placebo, as measured by PET and other biomarkers in EMERGE and ENGAGE, the association between reduced amyloid levels and improvement in cognitive outcomes is uncertain.8,9 Furthermore, the accumulation of amyloid-β (i.e., the amyloid hypothesis) may not be the sole cause of Alzheimer disease, which makes its appropriateness as a surrogate end point questionable.8,9 Reliance on a surrogate end point, as opposed to primary and secondary clinical outcomes, was also important because of the uncertain clinical significance of clinical outcomes seen in the EMERGE trial. In the ENGAGE trial, neither statistically nor clinically significant treatment differences were found for primary or secondary clinical outcomes. For example, the minimum clinically important difference (i.e., the threshold above which clinicians, COMMENTARY