Biogen is planning to seek approval for aducanumab, an injectable treatment under investigation for patients with early Alzheimer’s disease, following a new analysis of Phase 3 studies supporting meaningful benefits for patients’ cognition and daily life abilities.
After meeting with the U.S. Food and Drug Administration (FDA), Biogen plans to submit a Biologics License Application in early 2020. The company is also consulting with other regulatory authorities in other countries, including Europe and Japan. If accepted, aducanumab would become the first therapy to reduce the clinical decline of Alzheimer’s disease.
The decision came after the analysis of a larger dataset of Phase 3 clinical trials ENGAGE (NCT02477800) and EMERGE (NCT02484547), showing that monthly vein infusions of aducanumab reduced the clinical decline of patients with early Alzheimer’s.
Both trials were halted in March after a monitoring committee analyzed data from the first 18 months of the studies and determined that aducanumab was not likely to produce meaningful benefits for patients.
However, Biogen reconsidered when an additional three months of data became available after the trials were discontinued. The new analysis showed that EMERGE met its primary efficacy measure, or endpoint, with aducanumab resulting in benefits for cognition and function, including memory, orientation, and language, as well as activities of daily living.
An important piece of new data showed that a group of patients from ENGAGE who received sufficient exposure to high-dose aducanumab also experienced significant benefits. Biogen believes it was largely due to these patients that the results actually proved more positive than at the time of the trials’ halt.
In addition, aducanumab was able to reduce brain amyloid — a hallmark of the disease — in a dose-dependent manner.
While under review by the FDA, the company said it will work “with a sense of urgency” to offer aducanumab to eligible participants previously enrolled in ENGAGE and EMERGE and the long-term extension of the PRIME trial (NCT01677572), and the safety study EVOLVE (NCT03639987).
“With such a devastating disease that affects tens of millions worldwide, today’s announcement is truly heartening in the fight against Alzheimer’s. This is the result of groundbreaking research and is a testament to Biogen’s steadfast determination to follow the science and do the right thing for patients,” Michel Vounatsos, Biogen’s CEO, said in a press release. “We are hopeful about the prospect of offering patients the first therapy to reduce the clinical decline of Alzheimer’s disease and the potential implication of these results for similar approaches targeting amyloid beta.”
Aducanumab (BIIB037) is an investigational human monoclonal antibody that works by targeting the protein amyloid beta, particularly when its toxic form is organized in clusters, which are thought to be the underlying cause of Alzheimer’s.
Aducanumab was developed by Neurimmune and later licensed by Biogen under a collaborative development and license agreement. Since October 2017, Biogen and Eisai have collaborated on the development and commercialization of aducanumab globally.
EMERGE and ENGAGE were two Phase 3 multi-center, randomized trials designed to evaluate the efficacy and safety of two dosing regimens of aducanumab in patients with mild Alzheimer’s disease or mild cognitive impairment due to the disease. The studies enrolled 1,638 and 1,647 patients respectively, ages 50–85.
The primary objective of the studies was to evaluate the efficacy of monthly intravenous injections of aducanumab, as compared to placebo, in reducing cognitive and functional impairment as measured by changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB score).
Secondary objectives assessed the effect on 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 (mild cognitive impairment version) (ADCS-ADL-MCI).
In EMERGE, patients treated with high-dose aducanumab showed a 23% reduction in clinical decline in CDR-SB scores at 78 weeks, compared to placebo. This matched positive effects on other secondary endpoints, including ADAS-Cog 13 (27% reduction vs. placebo) and ADCS-ADL-MCI (40% reduction vs. placebo).
Clinical benefits were further supported by a reduction in amyloid plaque burden in the brain, compared to placebo, at 26 and 78 weeks.
Results from ENGAGE, specifically those of patients who achieved sufficient exposure to high-dose aducanumab, also support these findings, Biogen reports. Data from these patients were decisive to dispute the prior futility analysis recommending the trials’ discontinuation on March 21, Biogen reports.
This futility analysis was based on earlier and smaller datasets — 1,748 patients who had completed 18 months of treatment. The new analysis supporting aducanumab’s benefits was enriched by multiple factors, including data on a greater number of patients, a longer duration of exposure to high dose, and a greater proportion of patients to receive high dose.
In both studies, the safety profile of aducanumab was consistent with prior studies. The most commonly reported adverse events were amyloid-related imaging abnormalities-edema (ARIA-E) and headache, which did not result in any symptoms in most patients and generally resolved within 4 to 16 weeks, typically without complications.
Biogen plans to share more details about the trial results at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting taking place Dec. 4–7 in San Diego.
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