High-dose aducanumab delays clinical decline across multiple domains in early AD

Treatment with high-dose aducanumab shows less clinical decline across individual items or domains of cognition, function, and behaviour compared with placebo in patients with early symptomatic Alzheimer’s disease (AD), according to the EMERGE* study presented at AAIC 2021.

“Aducanumab is the first FDA-approved AD treatment that reduces amyloid beta [(Aβ)] plaques, a defining pathophysiological feature of AD,” said lead author Dr Sharon Cohen from Toronto Memory Program in Toronto, Ontario, Canada.

“Aducanumab is a monoclonal antibody against aggregated Aβ. Its efficacy was evaluated in two phase III studies, EMERGE and ENGAGE**. Despite early termination of these two trials, endpoints were analysed based on the prespecified statistical analysis plan,” Cohen noted.

This trial involved 1,643 patients (aged 50–85 years) with mild cognitive impairment or mild dementia with confirmed amyloid pathology, consistent with stages 3 and 4 AD. Participants were randomized to receive high- or low-dose aducanumab or placebo, but the current study only examined patients who received high-dose aducanumab (n=547; mean age 70.6 years) or placebo (n=548; mean age 70.8 years) intravenously every 4 weeks for 76 weeks. CDR*** domains and ADAS-Cog13⁺, ADCS-ADL-MCI⁺⁺, and NPI-10⁺⁺⁺ items were assessed. [AAIC 2021, abstract P57619]

At week 78, patients treated with high-dose aducanumab vs placebo showed lesser clinical decline across all six CDR domains, such as memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care (treatment difference, -28 percent, -24 percent, -25 percent, -23 percent, -24 percent, and -15 percent, respectively).

Aducanumab recipients also demonstrated less decline in the ADAS-Cog13 items, particularly word recognition, orientation, immediate and delayed word recall, and number cancellation at week 78 than the placebo recipients (treatment difference, -26 percent, -30, percent, -32 percent and -30 percent, and -51 percent, respectively).

Aducanumab-treated patients also showed less decline in daily function across all ADCS-ADL-MCI items, particularly in making a meal, cleaning room, using household appliances, reading >5 minutes, and watching television (treatment difference, -91 percent, -70 percent, -65 percent, -65 percent, and -50 percent, respectively) compared with placebo-treated patients at week 78.

The aducanumab arm also demonstrated a reduction in behavioural and psychiatric symptoms associated with AD, as shown by less decline in NPI-10 scores for agitation/aggression, apathy/indifference, and depression/dysphoria at week 78 than the placebo arm (treatment difference, -0.54 percent, -0.32 percent, -0.21 percent, respectively).

“In conclusion, the item-level analyses for each of the clinical endpoints are consistent with the results from the primary analysis … [that] demonstrated a statistically significant drug-placebo difference,” said Cohen.

“[Overall,] the aducanumab high-dose group showed a significant decline across all five clinical efficacy endpoints and this consistency of disease slowing is demonstrated across the broad range of cognitive, functional, and behavioural domains in early AD,” she added.

*EMERGE: 221AD302 phase 3 study of aducanumab (BIIB037) in early Alzheimer's disease

**ENGAGE: 221AD301 phase 3 study of aducanumab (BIIB037) in early Alzheimer's disease 

***CDR: Clinical Dementia Rating

⁺ADAS-Cog13: Alzheimer’s Disease Assessment Scale cognitive subscale 13 items

⁺⁺ADCS-ADL-MCI: Alzheimer’s Disease Cooperative Study-Activities of Daily Living-MCI