Aducanumab produced a clinically meaningful benefit in association with amyloid lowering

Abstract

Aducanumab is a monoclonal antibody targeting amyloid beta protein (Aß), a defining feature of the biology of Alzheimer’s disease (AD) [1]. Laboratory studies showed high affinity of aducanumab for the neurotoxic oligomeric species of Aß [2]. Following a promising phase 1B trial [3], the sponsor (Biogen) implemented two phase 3 studies—EMERGE and ENGAGE. A planned futility analysis concluded that the treatment was not beneficial, and the trials were terminated. With the accrual of additional blinded data, the prespecified analysis of the primary outcome—Clinical Dementia Rating Sum of Boxes (CDR-sb)—showed that the EMERGE trial met its primary outcome and the ENGAGE trial did not. Biogen submitted the data to the US Food and Drug Administration (FDA) for review and possible marketing approval, setting the stage for a vigorous dialogue on aducanumab [4, 5]. The CDR-sb, comprising the primary outcome of ENGAGE and EMERGE, is a composite measure with cognitive and functional components including home activities, problem solving, and community engagement—skills highly valued by patients [6]. In EMERGE, aducanumab treatment resulted in a significant 22% slowing of decline on the CDR-sb [7]. This instrument has a restricted range (0–18); small changes reflect meaningful clinical alterations. In both trials, participants who received at least 14 doses of the highest dose of aducanumab showed similar levels of slowing on the CDR-sb (30% in EMERGE, 27% in ENGAGE). In EMERGE, all secondary measures including the Mini Mental State Examination, Alzheimer’s Disease Assessment Scale-cognitive subscale, and the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS ADL) scale showed statistically significant drugplacebo differences. The ADCS-ADL scale showed a robust 40% slowing of functional decline in the treatment group compared to the placebo group [7]. The Neuropsychiatric Inventory (NPI) that assesses an array of behavioral changes common in AD showed an 87% reduction from baseline scores in the high dose group of EMERGE [8]. There was a corresponding 84% reduction in caregiver distress. Disease-modifying therapies change the trajectory of disease progression; benefits observed in trials are anticipated to increase with long-term treatment. Extending the mild cognitive impairment stage of AD and delaying the dementia stage is very meaningful for a 68year-old grandmother seeking to preserve daily activities, hobbies, and community and family engagement. Amyloid plaques measured by amyloid positron emission tomography (PET) were markedly decreased by aducanumab in both trials. Phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) and medial temporal neurofibrillary tangles measured by tau PET in a small subset of patients were reduced as predicted by “the amyloid hypothesis.” Phosphorylated tau is closely linked to cognitive decline [1]. Statistically significant correlations were present between Aß reduction and the