Aducanumab currently sits before the FDA for review for the treatment of Alzheimer disease, with a PDUFA date set for June 7, 2021.
The design of the phase 3b redosing study of the investigational Alzheimer disease (AD) agent aducanumab was presented at the 2021 American Academy of Neurology (AAN) Annual Meeting, April 17-22. The trial, dubbed EMBARK (NCT04241068), is currently enrolling by invitation patients who were actively participating in the clinical trial program when the PRIME, EVOLVE, EMERGE, and ENGAGE studies were terminated early in March 2019.1
EMBARK will be an open-label, single-arm clinical safety study with a 24-month treatment period. It will evaluate the long-term safety and efficacy of aducanumab in participants with AD, who will be titrated to receive 10-mg/kg aducanumab by intravenous infusion every 4 weeks. In total, it will include an 8-week screening period, a 100-week treatment period, and an 18-week safety and follow-up visit after the final dose.
The poster was presented by Carmen Castrillo-Viguera, MD, senior medical director, Clinical Development, Biogen, and the authors of the poster included Samantha Budd Haeberlein, PhD, senior vice president and head, Neurodegeneration Development Unit, Biogen. She and colleagues noted that “further analyses of the phase 3 studies were conducted post-futility announcement using data from all randomized and dosed participants collected through April 1, 2019, with data after March 20, 2019, censored for efficacy analysis,” and that the final dataset revealed that EMERGE had met both its primary and secondary end points, while post-hoc analyses from the high-dose group in ENGAGE supported the EMERGE data.
“EMBARK is expected to be one of the largest clinical trials in AD, with a planned enrollment of 2400 participants. EMBARK will provide further information on the long-term safety and efficacy of aducanumab,” Castrillo-Viguera et al. wrote. As of March 9, 2021, there have been 1705 participants screened and 1361 enrolled across 301 active sites in 20 countries.
The primary end points include the number of participants with adverse events (AEs); serious AEs; AEs leading to treatment discontinuation or study withdrawal; amyloid-related imaging abnormality-edema (ARIA) or amyloid-related imaging abnormality-hemorrhage or superficial siderosis; and the number of participants with anti-aducanumab antibodies.
The exploratory efficacy and pharmacodynamic data will be collected from the population of patients who receive at least 1 dose during the study period and those who have positron emission tomography (PET) or other cerebrospinal fluid (CSF) data. “Efficacy analyses will consider the prior exposure to aducanumab (length and dose level), the length of the wash-out period, and participants’ demographics and other disease characteristics,” the group wrote.
The safety population of EMBARK will include those who receive at least 1 dose of aducanumab during the study period, with those participants who additionally have at least 1 follow-up MRI being included in the safety MRI population.
There will be 3 longitudinal substudies of the biomarkers amyloid-beta (Aß) and tau, measured by PET, as well as CSF. Aß PET will be measured at the new baseline, as well as at week 102, while tau PET and CSF measures will be taken at baseline, week 52, and week 102. Cognitive and functional outcomes will be measured at new baseline, week 25, week 53, week 78, and week 102, as will health economics and outcomes research (HEOR) data. Safety MRI monitoring will take place at all time points.
“EMBARK will shed light on the effect of prolonged treatment interruption and improve our understanding of the durability of treatment effect,” Castrillo-Viguera et al. wrote. “Large imaging and fluid biomarker substudies will provide a deeper understanding of the durability of aducanumab’s effect following a treatment gap, after prolonged exposure, and, potentially, the correlation between biomarkers and clinical outcomes.
Biogen and Eisai’s aducanumab is currently before the FDA for review of a biologics license application, with a Prescription Drug User Fee Act (PDUFA) action date that was recently pushed from March 7, 2021 to June 7, 2021. As part of the process with the FDA, Biogen had submitted a response to an information request which consisted of additional clinical data and analyses—deemed a Major Amendment to the application—resulting in the need for additional review time. The application was originally submitted in July 2020 and was first accepted for review the following month.2
“We are committed to working with the FDA as it completes its review of the aducanumab application. We want to thank the FDA for its continued diligence during the review,” said Michel Vounatsos, chief executive officer, Biogen, in a statement at the time.
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