At the 12th Clinical Trials in Alzheimer’s Disease conference in San Diego, CA, detailed data from the EMERGE (NCT02484547) and ENGAGE (NCT02477800)clinical trials of aducanumab (Biogen, Cambridge, MA) for Alzheimer’s disease (AD) were presented. Last October it was announced that submission to the Food and Drug Administration (FDA) for approval would be pursued based on positive results in the EMERGE trial and supporting data from post hoc analysis of a subset of participants in the ENGAGE trial, even though ENGAGE overall had negative results. The news that these trials, which had been discontinued for futility, were now being considered as evidence for approval created great interest among the AD community and great interest in the presentation of more detailed data.
The positive results seen in the EMERGE trial include 23% reduction in the Clinical Dementia Rating=Sum of Boxes (CDR-SB) score for participants given the higher of 2 aducanumab doses (n= 547) compared with those given placebo (n = 548) after 78 weeks of treatment (P = .01). On the Mini-Mental Status Examination (MMSE), participants given the higher dose of aducanumab had 15% improvement compared with those given placebo (P = .06). Similarly, the treatment with higher dose of aducanumab vs placbo resulted in 27% and 40% improvement on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Alzheimer's Disease Cooperative Study/Activities of Daily Living for MCI (ADCS/ADL/MI) scores, respectively (P = .0998 and P = .0009, respectively). Longitudinally, the difference for those treated with aducanumab vs placebo increased over time.
A small subset of participants had amyloid-PET scans and/or cerebrospinal fluid (CSF) levels of tau and phosphorylated tau measured. Those treated with aducanumab had statistically significant reductions in both biomarkers compared with those treated with placebo, although sample sizes for these measures were small. This suggests that clearing amyloid with aducanumab, a monoclonal antibody to ß-amyloid aggregates, removes amyloid as shown in earlier trials and may also have a downstream effect of lowering tau levels.
These data represent the first positive phase 3 clinical trial result for AD in approximately 2 decades, and the first positive result for a disease-modifying agent in AD. Participants given the lower dose of aducanumab did not have statistically significant change on any of these measures vs placebo.
The explanation given for the negative results in the ENGAGE trial that would seem to contradict the above findings rests upon the facts that 1) both trials were discontinued early because of interim futility analysis of a subset of the data, and 2) the dose given in the ENGAGE study was changed during the course of the study. As a result of this first fact, the datasets for people who received the drug for 50 weeks or more (when statistically significant separation from placebo began to occur) was lower than needed to power the study. Because of the second fact, the dose received in ENGAGE was highly variable. On that basis, post-hoc analysis of people who received 14 doses of 10 mg compared with those who received placebo was done and supports the positive findings of EMERGE.
In both trials, the most common adverse events were transient amyloid-related imaging abnormalities-edema (ARIA-E) and headache.
A plan to begin redosing people who participating in the trials is under development so that most trial participants can reinitiate treatment on an open-label basis if they choose to do so. The manufacturer, Biogen, plans to submit a biologics license application to the Food and Drug Administration in the first quarter of 2020.
Although many questions remain, and independent statistical analysis of the data is needed to properly interpret these findings, if proven, clinical improvement and change in biomarkers hold promise for aducanumab. If proven effective, aducanumab could be the agent that ushers in a new era of disease-modifying treatment in AD.
Kelly G. Gwathmey, MD
Jennifer E. Fugate, DO
Olivia Reese; Rimas V. Lukas, MD; and Katherine S. Carroll, MD