Two global, phase 3 trials assessing the investigational anti-amyloid agent aducanumab (Biogen, Eisai) for the treatment of Alzheimer's disease (AD) dementia are being scrapped because of futility, the manufacturers announced earlier today.
In a statement released by Biogen, an independent data monitoring committee advised that the drug was "unlikely to meet primary endpoints" in either the ENGAGE or EMERGE randomized controlled trials.
The trials were designed to assess the efficacy and safety of the drug in patients with mild cognitive impairment from AD and mild AD dementia. The companies note that the committee's recommendation for stoppage was not based on safety concerns.
"This disappointing news confirms the complexity of treating Alzheimer's disease and the need to further advance knowledge in neuroscience," Michel Vounatsos, chief executive officer at Biogen, said in a press release.
The company notes that it still plans to present detailed data from the studies at upcoming medical meetings "to inform ongoing research."
"On behalf of the millions of people living with Alzheimer's disease and their families that we serve and represent, the Alzheimer's Association is disappointed" to hear about today's report, Maria C. Carrillo, PhD, the organization's chief science officer, said in a statement.
However, "it is important to note that much of the knowledge we have gained about potential new treatments, and how to properly conduct clinical trials in people with and at risk for Alzheimer's disease, has been from clinical trials that have not met their endpoints," she added.
She noted that her organization looks forward to the upcoming release of full trial data for aducanumab. "Learnings from these trials will eventually lead to therapies that successfully slow, stop, or prevent this devastating disease in the future."
Fast Track Designation, Early Promise
Aducanumab, which has also been known as BIIB037, is an anti-amyloid-beta (Aß) human monoclonal antibody.
The phase 3 ENGAGE and EMERGE trials were randomized, double-blind, placebo-controlled, parallel-group studies. The primary outcome was efficacy of monthly doses of aducanumab vs placebo in reducing cognitive and functional impairment, as measured by score changes on the Clinical Dementia Rating-Sum of Boxes.
According to clinicaltrials.gov, the estimated enrollment for ENGAGE was 1605 participants between the ages of 50 and 85 years from 181 locations in the United States, Canada, United Kingdom, Australia, Austria, Denmark, France, Germany, Italy, Japan, Korea, Portugal, Spain, and Taiwan. The trial start date was August 2015; the estimated primary completion and estimated full study completion dates were in 2020 and 2022, respectively.
The estimated enrollment for EMERGE was also 1605 participants, but from 192 locations in the United States, Canada, Belgium, Finland, France, Germany, Italy, Japan, Netherlands, Poland, Spain, Sweden, and Switzerland. This trial started in September 2015 and had about the same estimated completion dates as ENGAGE.
As reported in late 2016 by Medscape Medical News, the drug showed promise in earlier trials, such as in the phase 1b PRIME trial. Clinical, safety, and biomarker results at 24 months, which were presented at the Clinical Trials on AD (CTAD) meeting in 2016, were positive — including a dose-dependent reduction of Aß on amyloid-positron emission tomography (amyloid-PET).
However, today's statement notes that along with ENGAGE and EMERGE, a long-term extension study from PRIME and the phase 2 EVOLVE study will also be discontinued.
"Initiation of the aducanumab phase 3 secondary prevention trial will be assessed while the data from ENGAGE and EMERGE are further evaluated," the company reports.
The US Food and Drug Administration had granted Fast Track designation for aducanumab's development.
Time to "Move On" from Amyloid?
In the press release, Vounatsos noted that "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."
This includes continued research into its novel anti-amyloid agent known as BAN2401.
Results from an 856-patient phase 2 study presented at last year's Alzheimer's Association International Conference (AAIC) showed a significant reduction in amyloid at 18 months with a high dose of the drug, as reported by Medscape Medical News. However, phase 3 study information for this drug has not been released.
The phase 3 trials CREAD 1 and CREAD 2, which assessed the anti-amyloid antibody crenezumab (Roche), was stopped in January of this year based on futility analyses; and the phase 3 EXPEDITION trial of solanezumab (Eli Lilly & Co) failed to meet its primary endpoint in results released in 2016.
After EXPEDITION, many experts wondered publicly if it was time to move on from evaluating AD and amyloid.
At the 2018 AAIC meeting, Carrillo didn't dismiss the possibility of anti-amyloid strategies, but told Medscape Medical News that approaches that combine agents with other treatments and/or lifestyle interventions may end up being the best option.
"The scientific community is in agreement that combination therapy may be the future," she said at the time. "To be able to delay the disease even for a year can have a huge impact on lives."
In today's statement, Carrillo stressed that all potential treatment targets need to advance, and again reiterated that combining approaches should be explored.
"No stone can be left unturned. That said, all currently pursued treatments that are considered safe should be continued to determine their efficacy," she noted.
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Cite this: Hopes Dashed for Aducanumab in Alzheimer's Disease - Medscape - Mar 21, 2019.