Michel VounatsosMichel Vounatsos, MBA
In a joint announcement, Biogen and Eisai have declared the discontinuation of the ENGAGE and EMERGE phase 3 clinical trials, which were intended to evaluate the efficacy and safety of aducanumab in patients with mild cognitive impairment (MCI) due to Alzheimer disease and mild Alzheimer dementia.1

After a futility analysis was conducted by an independent data monitoring committee, it was determined that aducanumab was unlikely to meet their primary end point upon the completion of the study period, and the decision was made to halt the trials. At the time of the recommendation to stop, there were no safety concerns of note.

As part of the verdict, the EVOLVE phase 2 safety study and the long-term extension of the PRIME phase 1b study of aducanumab will also be discontinued. The beginning of a planned phase 3 secondary prevention trial will continue to be assessed while the data from ENGAGE and EMERGE are further appraised, the companies stated.

“This disappointing news confirms the complexity of treating Alzheimer’s disease and the need to further advance knowledge in neuroscience.  We are incredibly grateful to all the Alzheimer’s disease patients, their families and the investigators who participated in the trials and contributed greatly to this research,” said Michel Vounatsos, MBA, the chief executive officer at Biogen, in a statement. “Biogen’s history has been based on pioneering innovation, learning from successes and setbacks.”

“Driven by our steadfast commitment to patients and our strong business foundation, we will continue advancing our pipeline of potential therapies in Alzheimer’s disease and innovative medicines for patients suffering from diseases of high unmet need,” Vounatsos added.

Biogen announced that the data which was collected from the ENGAGE and EMERGE trials will be presented at future medical meetings with the hope of potentially informing further research in the area.

The trials were global and multicenter in nature, as well as randomized, double-blind, placebo-controlled and parallel-grouped. Both trials had the primary end point of the change in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score to assess the efficacy of a monthly dose of the trial agent. Secondary objectives included clinical progression as measured by Mini-Mental State Examination (MMSE), AD Assessment Scale-Cognitive Subscale (ADAS-Cog 13), and AD Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL-MCI).

Aducanumab, otherwise known as BIIB037, is an investigational compound which was licensed by Biogen from Neurimmune through a collaboration and license agreement. Since 2017, Biogen and Eisai have collaborated on the development and commercialization of the agent, and it had previously been granted a Fast Track designation from the FDA. It is a human monoclonal antibody derivative from a de-identified collection of B cells which were amassed from healthy older subjects with no cognitive impairment or elderly patients who were impaired and had unusually slow declines in cognition. They were collected using Neurimmune’s Reverse Translational Medicine (RTM) technologic platform.

In previous trials, the product was assessed in healthy volunteers (NCT02782975), and in patients with Alzheimer in both the United States  (NCT01397539) and Japan (NCT02434718).

The PRIME trial had announced its interim results from the first 165 patients, which revealed that all doses of the trial drug, administered intravenously, were shown to significantly reduce amyloid plaques in a time- and dose-dependent manner in comparison to baseline. As measured by CDR-SB and the MMSE, there were signs that the treatment slowed cognitive decline, though the trial was not powered to measure this effect. In total, 40 patients had discontinued treatment in the first year.2
REFERENCE
1. Biogen and Eisai to Discontinue Phase 3 ENGAGE and EMERGE Trials of aducanumab in Alzheimer’s Disease [press release]. Cambridge, MA: Biogen; Published March 21, 2019. globenewswire.com/news-release/2019/03/21/1758398/0/en/Biogen-and-Eisai-to-Discontinue-Phase-3-ENGAGE-and-EMERGE-Trials-of-aducanumab-in-Alzheimer-s-Disease.html. Accessed March 21, 2019.
2. Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537(7618):50-56.
doi: 10.1038/nature19323.