Jeff Sevigny

The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.

Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating—Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

Amyloid PET Screening for Enrichment of Early-Stage Alzheimer Disease Clinical Trials: Experience in a Phase 1b Clinical Trial.

Amyloid positron emission tomography (PET) imaging is being investigated as a screening tool to identify amyloid-positive patients as an enrichment strategy for Alzheimer disease (AD) clinical trial enrollment. In a multicenter, phase 1b trial, patients meeting clinical criteria for prodromal or mild AD underwent florbetapir PET scanning at screening. PET, magnetic resonance imaging, and coregistered PET/magnetic resonance imaging scans were reviewed by 2 independent readers and binary visual readings tabulated. Semiquantitative values of cortical to whole cerebellar standard uptake value ratios were computed (threshold 1.10). Of 278 patients with an evaluable PET scan, 170 (61%) and 185 (67%) were amyloid-positive by visual reading and quantitative analysis, respectively; 39% were excluded from the study due to an amyloid-negative scan based on visual readings. More ApoE &egr;4 carriers than noncarriers were amyloid-positive (80% vs. 43%). Comparison of visual readings with quantitative results identified 21 discordant cases (92% agreement). Interreader and intrareader agreements from visual readings were 98% and 100%, respectively. Amyloid PET imaging is an effective and feasible screening tool for enrollment of amyloid-positive patients with early stages of AD into clinical trials.

First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab (BIIB037) in mild-to-moderate Alzheimer's disease

Aducanumab (BIIB037), a human monoclonal antibody selective for aggregated forms of amyloid beta, is being investigated as a disease‐modifying treatment for Alzheimers disease (AD).

Addendum: The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease

This corrects the article DOI: 10.1038/nature21361

Randomized, placebo-controlled, phase 1b study of anti-beta-amyloid antibody aducanumab (biib037) in prodromal ad/mild ad dementia: Interim results by patient subgroup

25 WFN15-1092 Dementia 2 Randomized, placebo-controlled, phase 1b study of anti-beta-amyloid antibody aducanumab (biib037) in prodromal ad/mild ad dementia: Interim results by patient subgroup J. Sevigny, P. Chiao, L. Williams, T. Chen, Y. Ling, J. O’Gorman, C. Hock, R. Nitsch, A. Sandrock. Clinical Development Neurodegeneration and Exp Med Clin Dev, Biogen, Cambridge, USA; Clinical Research MA Neurodegeneration and Exp Med Clin Dev, Biogen, Cambridge, USA; Drug Safety & Risk Management, Biogen, Cambridge, USA; Biostatistics Biometrics, Biogen, Cambridge, USA; Clinical Development MA MS Clin Dev Center, Biogen, Cambridge, USA; Biostatistics, Biogen, Cambridge, USA; Division of Psychiatry Research, Neurimmune Holding AG and University of Zurich, Zurich, Switzerland; Biogen, Development Sciences, Cambridge, USA

Pharmacokinetics of BIIB037 in people with mild-to-moderate Alzheimer's disease (AD) participating in a phase 1 dose-escalation trial

Background:A phase II 12-month trial of resveratrol for mild-moderate dementia due to Alzheimer’s disease (AD) will determine its safety and tolerability and putative effects on clinical outcomes, volumetric MRI, Aband tau levels in cerebrospinal fluid, and metabolic profiles. A history of metabolic syndrome or type 2 diabetes mellitus (T2D), particularly during midlife, is a well-known risk factor for AD in late life but underlying mechanisms are unknown.Methods: Exclusionary criteria include individuals consuming any resveratrol-containing supplement and subjects treated for T2D. Eligible subjects (50-90 year old men and women recruited from and/or referred to specialty clinics) with mild-moderate AD (MMSE 1226) were administered a baseline oral glucose tolerance test (OGTT, 75 g) after an overnight fast. Results will be compared to a repeat OGTT on the maximally tolerated resveratrol dose after 12 months. Resveratrol was synthesized, encapsulated, and packaged by Aptuit Laurus (now Catalent), initiated at 500 mg bymouth once daily, and will end with 1 g twice daily (with 500 mg increments every 3 months). Results: Five subjects (5/128 or 4%) revealed impaired fasting glycemia (110-125 mg/dl) and 38 subjects (38/ 125 or 30%) revealed impaired glucose tolerance at 2 hours (140-200 mg/ dl). Three subjects (3/128 or 2%) had findings consistent with a diagnosis of T2D (fasting glucose > 125 mg/dl) and 16 subjects (16/125 or 13%) had results consistent with T2D (glucose > 200 mg/dl) at 2 hours. The mean fasting glucose (+/S.E.) was 92 +/1 mg/dl. The mean glucose at 2 hours was 143 +/5 mg/dl. These data revealed a prevalence of impaired fasting glycemia or T2D at baseline of 6%. The prevalence of impaired glucose tolerance or T2D at 2 hours was 43%. Six subjects screen-failed due to newly-diagnosed or treated T2D.Conclusions:Due to this high prevalence, the OGTT may be considered for individuals with AD in order to optimize medical management of borderline or undiagnosed T2D. AD, a chronic inflammatory disorder may increase risk of co-incident impaired fasting glycemia, glucose intolerance, and T2D. Conversely, a glucoregulatory disturbance may promote AD. Treatment of this study cohort with resveratrol or placebo is in progress.