Clinical Question

Is aducanumab (Aduhelm) safe and effective for the treatment of mild cognitive impairment or mild Alzheimer disease?

Bottom Line

This drug was approved by the U.S. Food and Drug Administration (FDA) after its advisory panel voted 10 to 1 against approval, with three members resigning in protest after the FDA decision became public. The drug costs $56,000 per year, which does not include the cost of regular magnetic resonance imaging, physician fees, and the management of complications. This drug has no meaningful impact on symptoms. (Level of Evidence = 1b−)

Synopsis

A report was published on two trials that compared aducanumab with placebo for mild cognitive impairment or mild Alzheimer disease. The studies were the basis for the FDA's approval of the drug over the strong objections of its advisory panel. The EMERGE (n = 1,643) and ENGAGE (n = 1,653) trials identified adults with mild Alzheimer disease or mild cognitive impairment, and evidence of amyloid deposition on positron emission tomography scan. The trials included patients with a Mini-Mental State Examination (MMSE) score between 24 and 30 (30 = normal) and a Clinical Dementia Rating Scale score of 0.5. Patients with evidence of intracranial pathology, including microhemorrhages, hemorrhages, and infarcts, were excluded. Approximately one-fourth of screened patients met these criteria. Patients in each study were randomized to receive placebo, low-dose aducanumab, or high-dose aducanumab, with the dose differing according to the presence or absence of apolipoprotein E4. The trials were halted early for futility, with slightly more than one-half of patients completing the full 75-week follow-up. The authors argue that the trials should not have been stopped, and they presented the data for those patients who completed the full study period. In the report, the results are given for all patients receiving at least one dose of the study drug. The authors found that aducanumab successfully reduced amyloid deposition. Although there were small and sometimes statistically significant changes in the MMSE, Clinical Dementia Rating Scale, and Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-COG) scores, none came close to exceeding the minimum clinically important difference. This is the minimum the score would have to improve before a patient or caregiver is likely to notice improvement.

A separate pooled analysis (https://www.aafp.org/afp/2022/0400/p353.html) showed no statistically or clinically significant improvement in the MMSE and Clinical Dementia Rating Scale scores, and the improvement in the ADAS-COG score was far lower than the minimum clinically important difference of 3 points. With regard to harms, approximately one-fourth of the patients in the low-dose group and more than one-third in the high-dose group developed amyloid-related imaging abnormalities with brain effusion or edema, whereas 16% in the low-dose group and 20% in the high-dose group developed brain microhemorrhages; these changes mandated temporary discontinuation of the drug. Serious or severe adverse events occurred in 16 patients and included gait disturbance, confusion, and seizures.

Study design: Randomized controlled trial (double-blinded)

Funding source: Industry

Allocation: Uncertain

Setting: Outpatient (specialty)

Reference: Haeberlein SB, Aisen PS, Barkhof F, et al. Two randomized phase 3 studies of aducanumab in early Alzheimer’s disease. J Prev Alzheimers Dis. 2022;9(2):197-210.

Editor's Note: Dr. Ebell is deputy editor for evidence-based medicine for AFP and cofounder and editor-in-chief of Essential Evidence Plus, published by Wiley-Blackwell.