#AAIC21 – New Analyses Support Aduhelm’s Effects on Cognition
In clinical trials of the Alzheimer’s treatment Aduhelm (aducanumab), participants who experienced a greater reduction in brain levels of amyloid plaques — the abnormal protein clumps targeted by the treatment — tended to also experience a greater treatment benefit, in terms of cognition and functional ability, according to new analyses.
The findings broadly support Aduhelm’s proposed mechanism of action, whereby removing amyloid plaques prevents damage in the brain and, consequently, cognitive problems.
Aduhelm, which was developed by Biogen and Eisai, was recently granted accelerated approval by the U.S. Food and Drug Administration as a treatment for individuals with mild cognitive impairment or early Alzheimer’s.
The active agent in Aduhelm is an antibody that targets amyloid plaques. These plaques are abnormal clumps of protein that form in the brains of people with Alzheimer’s, and are thought to drive disease progression and brain cell death. By targeting specific regions of the clumped-up protein, Aduhelm is thought to break up amyloid plaques, thereby preventing damage to the brain and subsequent symptoms.
To test this idea, researchers at Biogen conducted analyses using data from three prior clinical trials of Aduhelm: the Phase 1 PRIME trial (NCT01677572), and two Phase 3 trials called ENGAGE (NCT02477800) and EMERGE (NCT02484547).
In the Phase 3 trials, participants were titrated to either a low (3 or 6 mg/kg) or a high (10 mg/kg) dose of Aduhelm, and followed for 78 weeks (about a year and a half). In PRIME, participants were given varying doses of Aduhelm, from 1 to 10 mg/kg, and followed for 54 weeks.
Prior analyses from these trials suggested that the treatment slowed the decline in cognition and function in PRIME and in EMERGE, but not in ENGAGE.
In the new analyses, the researchers conducted statistical tests to see whether trial participants who experienced a greater decrease in amyloid plaques in their brains, as assessed by positron emission tomography scan, also experienced a greater slowing in decline of cognition and function, as measured using a battery of standardized tests.
The team presented its findings at the 2021 Alzheimer’s Association International Conference (AAIC), held late last month in Denver and online, in a poster, “Reductions in Biomarkers of Alzheimer’s Disease Pathophysiology Following Treatment with Aducanumab Were Associated with Slowing in Clinical Decline.”
Participant-level analyses showed that a greater decline in brain amyloid plaques “was associated with lesser decline in all key clinical measures in EMERGE,” the researchers reported. Data from PRIME did show a similar correlation, but no such association was found in the data for ENGAGE.
Additional analyses at the group level also found evidence of this kind of association in data from EMERGE and PRIME, but not from ENGAGE. In particular, data from the high-dose group in ENGAGE did not show a statistically meaningful association.
Group-level analyses that included clinical data for two investigational therapies that target amyloid plaques — lecanemab (BAN2401) and donanemab (LY3002813) — showed an association between plaque reduction and improved clinical outcomes, comparable to what was seen in EMERGE and PRIME.
In a final analysis, the researchers compared participants whose plaque levels went below a threshold, at which point they could be considered “amyloid negative,” to those who did not, using data from participants in the Aduhelm trials.
“In all 3 studies, a smaller magnitude of decline across key clinical measures was observed in patients for whom [amyloid] plaque levels were lowered to a threshold considered to be amyloid negative (relative to those who did not reach this threshold),” they wrote.
Collectively, the results indicate that these therapies are working as intended: reducing amyloid plaques, thereby lessening brain damage and slowing the progression of symptoms.
“The clinical trial results Biogen shared about our joint asset, Aduhelm, at AAIC are important as we believe the data will help inform the scientific community as we continue to explore the strong scientific rationale behind the amyloid beta pathway as one of the earliest changes that occur in Alzheimer’s disease,” Lynn Kramer, MD, chief clinical officer in the neurology business group at Eisai, said in a press release.
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