Aducanumab is not effective for mild cognitive impairment or mild Alzheimer's dementia and has major safety issues

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.

Synopsis

This is (finally!) the published report of the 2 trials that compared aducanumab with placebo for mild cognitive impairment (MCI) or mild Alzheimer's disease (AD). These studies were the basis for the FDA's approval of the drug over the strong objections of its advisory panel. The EMERGE (n = 1643) and ENGAGE (n = 1653) trials identified adults with mild AD or MCI, as well as evidence of amyloid deposition on a PET scan. This included patients with a Mini-Mental State Exam (MMSE) score between 24 and 30 (30 = normal), and a Clinical Dementia Rating Scale (CDRS) score of 0.5. Patients with evidence of intracranial pathology including microhemorrhages, hemorrhages, and infarcts were excluded. Only approximately one-quarter 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 half the patients completing the full 75-week follow-up. But the authors argue that the trials shouldn't have been stopped, and they present the data for those patients who completed the full study period. In this report, the results are given for all patients receiving at least one dose of the study drug. The authors found that the drugs successfully reduced amyloid deposition. However, although there were small and sometimes statistically significant changes in the MMSE, CDRS, and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-COG) scores, none of them came close to exceeding the minimum clinically important difference (MCID). This is the minimum the score would have to improve before a patient or caregiver was likely to notice the improvement. We performed a separate pooled analysis that found no statistically or clinically significant improvement for the MMSE and CDRS scales, and the improvement in the ADAS-COG score was far lower than the MCID of 3 points. With regard to harms, approximately one-quarter of the patients in the low-dose groups and more than one-third in the high-dose group developed amyloid-related imaging abnormalities with brain effusion or edema, while 16% in the low-dose group and 20% in the high-dose group developed brain microhemorrhages; these changes mandate temporary discontinuation of the drug. Serious or severe adverse events occurred in 16 patients and included gait disturbance, confusion, and seizures.