Biogen has resurrected aducanumab for the treatment of early Alzheimer’s disease—after scrapping studies in March 2019 based on a futility analysis—because new data from more patients showed promising outcomes.
The positive results were driven mainly by exposure to high-dose aducanumab in a larger dataset than that available at the time of the futility analysis. Based on discussions with the FDA, Biogen plans to file for approval of aducanumab in early 2020.
The new analysis showed that the phase 3 EMERGE study met its primary endpoint—a significant reduction in clinical decline in patients with early Alzheimer’s disease. Biogen believes that results from a subset of patients in the phase 3 ENGAGE study who received sufficient exposure to high-dose aducanumab support the EMERGE findings.
Patients who received aducanumab experienced significant benefits on measures of cognition and function such as memory, orientation, and language. Patients also benefitted on activities of daily living, including conducting personal finances; performing household chores such as cleaning, shopping, and laundry; and independently traveling out of the home.
If approved, aducanumab would become the first therapy to reduce the clinical decline of Alzheimer’s disease. It would also be the first therapy to demonstrate that removing amyloid beta in the brain resulted in better clinical outcomes.
The futility analysis that led to the discontinuation of EMERGE and ENGAGE in March 2019, relied on data available as of December 26, 2018. Later, however, additional data from these studies became available. Extensive analysis of this larger dataset showed a different outcome than the outcome predicted by the futility analysis.
The new analysis showed that aducanumab is pharmacologically and clinically active as determined by dose-dependent effects in reducing brain amyloid and in reducing clinical decline as assessed by the prespecified primary endpoint, the Clinical Dementia Rating–Sum of Boxes (CDR–SB).
In EMERGE, patients treated with high-dose aducanumab showed a significant reduction of clinical decline from baseline in CDR-SB scores at 78 weeks (23% versus placebo). High-dose patients also showed a consistent reduction of clinical decline as measured by the Mini-Mental State Examination (15% versus placebo), the AD Assessment Scale–Cognitive Subscale 13 Items (27% versus placebo), and the AD Cooperative Study–Activities of Daily Living Inventory Mild Cognitive Impairment Version (40% versus placebo). Imaging demonstrated that amyloid plaque burden was reduced with low- and high-dose aducanumab compared to placebo at 26 and 78 weeks.
In both studies, the most commonly reported adverse events were amyloid-related imaging abnormalities and headache.
Multiple factors contributed to greater exposure to high-dose aducanumab in the new analysis of the larger dataset, including data on more patients, longer exposure to the high dose, the timing of protocol amendments that allowed more patients to receive high doses, and the timing and prespecified criteria of the futility analysis.
Since October 2017, Biogen and Eisai have collaborated on the development and commercialization of aducanumab globally.
Source: Biogen, October 22, 2019