Tianle Chen

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.

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

This corrects the article DOI: 10.1038/nature21361

Impact of Reference/Target Region Selection on Amyloid PET Standard Uptake Value Ratios in the Phase 1b PRIME Study of Aducanumab.

SUV ratios (SUVRs) are commonly used to quantify tracer uptake in amyloid-β PET. Here, we explore the impact of target and reference region-of-interest (ROI) selection on SUVR effect sizes using interventional data from the ongoing phase 1b PRIME study (NCT01677572) of aducanumab (BIIB037) in patients with prodromal or mild Alzheimer disease. Methods: The florbetapir PET SUVR was calculated at baseline (screening) and at weeks 26 and 54 for patients randomized to receive placebo and each of 4 aducanumab doses (1, 3, 6, and 10 mg/kg) using the whole cerebellum, cerebellar gray matter, cerebellar white matter, pons, and subcortical white matter as reference regions. In addition to the prespecified composite cortex target ROI, individual cerebral cortical ROIs were assessed as targets. Results: Of the reference regions used, subcortical white matter, cerebellar white matter, and the pons, alone or in combination, generated the largest effect sizes. The use of the anterior cingulate cortex as a target ROI resulted in larger effect sizes than the use of the composite cortex. SUVR calculations were not affected by correction for brain volume changes over time. Conclusion: Dose- and time-dependent reductions in the amyloid PET SUVR were consistently observed with aducanumab only in cortical regions prone to amyloid plaque deposition, regardless of the reference region used. These data support the hypothesis that florbetapir SUVR responses associated with aducanumab treatment are a result of specific dose- and time-dependent reductions in the amyloid burden in patients with Alzheimer disease.

24-MONTH ANALYSIS OF CHANGE FROM BASELINE IN CLINICAL DEMENTIA RATING SCALE COGNITIVE AND FUNCTIONAL DOMAINS IN PRIME: A RANDOMIZED PHASE 1B STUDY OF THE ANTI–AMYLOID BETA MONOCLONAL ANTIBODY ADUCANUMAB

blind dose. Target dose and titration schemes were modelled based on all available data with mAb targeting aggregated amyloid, to achieve maximum amyloid reduction while maintaining safety and tolerability. Protocol measures included MRI monitoring and dosing algorithm. Results:As of January 16, 2018, OLE duration ranged 12–101 weeks (median: 63.9 weeks). 103/154 patients received 1200mg gantenerumab for 1–81 weeks. ARIAs were detected in 47/133 patients with a post-baseline MRI; 38 patients had ARIA-E, 61% of whom had ARIA-H. ARIA-E incidence increased with dose (Table), with overall rate 28.6%. Most ARIAs (84%) were asymptomatic and non-serious. Incidence (79%) and severity of adverse events (including ISRs) remained comparable to SCarlet RoAD low-dose double-blind treatment. Conclusions: This updated Scarlet RoAD OLE safety analysis showed no new or unexpected findings with longer exposure to high-dose gantenerumab. ARIA-E rate increased with dose, but the titration appeared to reduce ARIA-E risk with overall incidence <30%. ARIAs appeared manageable with implemented protocol measures. These data support the use of titration to high-dose gantenerumab in the phase 3 GRADUATE program. 1. Andjelkovic, CTAD 2017.

24-MONTH ANALYSIS OF APOE ε4 CARRIERS IN PRIME: A RANDOMIZED PHASE 1B STUDY OF THE ANTI–AMYLOID BETA MONOCLONAL ANTIBODY ADUCANUMAB

P1-041 24-MONTH ANALYSIS OFAPOE ε4 CARRIERS IN PRIME: A RANDOMIZED PHASE 1B STUDYOF THEANTI–AMYLOID BETA MONOCLONAL ANTIBODY ADUCANUMAB Philip von Rosenstiel, Carmen Castrillo-Viguera, Sarah Gheuens, Tianle Chen, John O’Gorman, Ping Chiao, Guanfang Wang, Christian von Hehn, LeAnne Skordos, Christoph Hock, RogerM. Nitsch, Samantha Budd Haeberlein, Alfred Sandrock, Biogen, Cambridge, MA, USA; Cytel, Cambridge, MA, USA; Neurimmune Holding AG, Zurich, Switzerland. Contact e-mail: philipp.vonrosenstiel@ biogen.com

CLINICAL DEMENTIA RATING-SUM OF BOXES RESPONDER ANALYSIS IN PRIME: A RANDOMIZED PHASE 1B STUDY OF THE ANTI-AMYLOID BETA MONOCLONAL ANTIBODY ADUCANUMAB (BIIB037)

logical and age-related disorders and 3) report and comment on the clinical utility of the biomarker signature. In this analysis, we expand on Lunnon et al. 2012 and address all of these concerns. Methods:We obtained sixteen gene expression data sets, including two additional AD data sets, neurological, autoimmune, diabetes and arterial related disorders from public and in-house sources. All predictive modelling was performed using the R package ‘caret’ with 1000 bootstrap resamples used to evaluate model performance. We re-developed the Random Forest (RF) AD classification model published in Lunnon et al. 2012, using 79 AD-cases and 79 controls for training.We evaluated themodel in two independent AD datasets, generated using two different microarray platforms (Illumina N1⁄4221 and Affymetrix N1⁄439). To assess specificity for AD, the two AD expression sets and all Non-AD data were combined and used as a large test/validation dataset totalling 1839 samples, on which, the AD RF classifier was tested for its ability to predict AD from non-AD. Results: The AD RF classification model achieved a training accuracy of 88%, and a mean test accuracy of 68.88% (95% CI, 62.74-74.51%) within the first independent AD dataset (Illumina) and 59.52%(95% CI, 45.79-74.34%) in the second independent AD dataset (Affymetrix). When evaluating the AD classification model’s ability to discriminate AD samples from non-AD samples, the model achieved a mean accuracy of 59.7% (95% CI, 55.13-64.08) and equated to a PPV of 0.6, NPV of 0.4, positive Clinical Utility Index of 0.39 and a negative Clinical Utility Index of 0.22. Conclusions: In its current form, the AD classification model’s clinical utility is ‘poor’ in AD discovery (confirmation) and a ’poor’ predictor for screening (ruling out) AD. Further investigations and comparisons of signatures in larger AD datasets and other disorders are required.

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