Jianing Di

Amyloid-β 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials

Objective: To evaluate the effects of bapineuzumab on brain β-amyloid (Aβ) burden using 11C-Pittsburgh compound B (11C-PiB)-PET. Methods: Two phase 3 clinical trials, 1 each in apolipoprotein APOE ε4 carriers and noncarriers, were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Aβ monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks. PET substudies assessed change in brain fibrillar Aβ over 71 weeks using an 11C-PiB-PET standardized uptake value ratio (SUVr) global cortical average (GCA) comprising the average SUVr from 5 cortical regions of interest with cerebellar gray matter as the reference region. Results: A total of 115 carriers and 39 noncarriers were analyzed. The difference (δ) in mean baseline to 71 week change in 11C-PiB-PET GCA between bapineuzumab and placebo was significant in carriers (0.5 mg/kg vs placebo δ = −0.101; p = 0.004) and in pooled analyses of both carriers and noncarriers (0.5 mg/kg vs placebo δ = −0.068; p = 0.027; 1.0 mg/kg vs placebo δ = −0.133; p = 0.028) but not in the noncarrier trial separately. Analyses by individual region of interest and in mild disease yielded findings similar to the main trial results. Conclusions: The 11C-PiB-PET imaging results demonstrated reduction of fibrillar Aβ accumulation in patients with Alzheimer disease treated with bapineuzumab; however, as no clinical benefit was observed, the findings are consistent with the hypotheses that bapineuzumab may not have been initiated early enough in the disease course, the doses were insufficient, or the most critical Aβ species were inadequately targeted.

Changes in Brain Volume with Bapineuzumab in Mild to Moderate Alzheimer’s Disease

BACKGROUND Bapineuzumab, an anti-amyloid-β monoclonal antibody, was evaluated in two placebo-controlled trials in APOE*ɛ4 carriers and noncarriers, respectively, with Alzheimers disease. OBJECTIVES A volumetric magnetic resonance imaging substudy was performed to determine if bapineuzumab altered brain volume rate of change. METHODS Bapineuzumab dosages included 0.5 mg/kg in carriers and 0.5 or 1.0 mg/kg in noncarriers, every 13 weeks for 78 weeks. Volumetric outcomes included annualized brain, ventricular, and mean hippocampal boundary shift integrals (BBSI; VBSI; HBSI) up to Week 71. Treatment differences were estimated using mixed models for repeated measures. RESULTS For BBSI and HBSI, there were no significant treatment-related differences within either study, but, compared to pooled carriers and noncarriers receiving placebo, noncarriers receiving1.0 mg/kg bapineuzumab had greater increases in these measures. Bapineuzumab-treated patients showed significantly greater VBSI rates compared with placebo for 0.5 mg/kg in carriers and 1.0 mg/kg (but not 0.5 mg/kg) in noncarriers. CONCLUSIONS Bapineuzumab produced an increase in ventricular volume compared with placebo. Etiology for this increase is unclear but may be related to amyloid-β clearance or its consequences.

Central Review of Amyloid-Related Imaging Abnormalities in Two Phase III Clinical Trials of Bapineuzumab in Mild-To-Moderate Alzheimer’s Disease Patients

BACKGROUND Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]). OBJECTIVES To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimers disease randomized to bapineuzumab IV or placebo during two Phase III trials (APOE ɛ4 allele carriers or noncarriers). METHODS Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE ɛ4 noncarriers and 1,121 carriers by independent neuroradiologists. Assessment of ARIA-E, ARIA-H, intracerebral hemorrhages, and age-related white matter changes is described. RESULTS In the Final Read, treatment-emergent ARIA-E were identified in 242 patients including 76 additional cases not noted previously in real time. Overall, incidence proportion of ARIA-E was higher in carriers (active 21.2%; placebo 1.1%) than in noncarriers (pooled active 11.3%; placebo 0.6%), and was more often identified in homozygote APOE ɛ4 carriers than heterozygotes (34.5% versus 16.9%). Incidence rate of ARIA-E increased with increased dose in noncarriers. Frequency of ARIA-E first episodes was highest after the first and second bapineuzumab infusion and declined after repeated infusions. Incidence of total HDs <10 mm (cerebral microhemorrhages) was higher in active groups versus placebo. CONCLUSION ARIA was detected more often on MRI scans when every scan was reviewed by trained neuroradiologists and results adjudicated. There was increased incidence of ARIA-E in bapineuzumab-treated carriers who had a microhemorrhage at baseline. ARIA-E was a risk factor for incident ARIA-H and late onset ARIA-E was milder radiologically. Age-related white matter changes did not progress during the study.

EVALUATION OF CEREBRAL GRAY MATTER AND PONS AS REFERENCE REGIONS FOR AMYLOID PET: RESULTS FROM A BAPINEUZUMAB SUBCUTANEOUS PHASE 2 TRIAL

ensure comparability and spatial correlations were assessed both voxelwise and using regions of interest (ROIs) from the AAL atlas. Results: Developmental effects showed reductions in GMwith advancing age that were highly correlated with both metabolism and A. All three maps (Figure, top row) showed significant spatial correlation, on a voxelwise level (GM-FDG, r 1⁄4 0.264; FDG-Ab, r1⁄4 0.546; GM-Ab, r1⁄4 0.336, all p<0.001; Figure, middle row) or with AAL ROIs (pruning-FDG, r 1⁄4 0.563; FDG-Ab, r 1⁄4 0.634; pruning-Ab, r 1⁄4 0.641, all p<0.001; Figure, bottom row). Conclusions: The regions that are prone to Ab already share common features in early life: they are very metabolically active in young adults and also show age-related gray matter reduction (“pruning”) in childhood. While these topographical correlations do not define causal relationships, they support theories that synaptic activity influences Ab deposition. In particular, these data suggest that early life pruning may result in neural systems in association cortex that are metabolically stressed and thereby susceptible to Ab deposition.

Assessing the Cumulative Exposure Response in Alzheimer’s Disease Studies

To assess long-term cumulative benefit of a treatment, relationship betwe en cumulative drug exposure and outcomes could be explored to understand the dose response. However, cumulative exposure corresponds to the longitudinal profile of an outcome, which is often heavily confounded with natural disease progression and missing data. A model-based approach is developed to account for the confounding factors. In particular, the observed measures are adjusted by the projected disease progression at the corresponding time points before exposure response is assessed. The proposed approach introduces new insights to the interpretation of exposure data. In the presented case study, the proposed method identified various degrees of potential efficacy trend favoring higher level of cumulative exposure in active drug.

Pooled biomarker analyses of phase 2 studies of vanutide cridificar vaccine (ACC-001) in mild-to-moderate and early Alzheimer’s disease

-23%, and -60%). For the combination drug treatment arms, we observed a significant broad dose response in the presence of high dose antibody and varying dose levels of BACE inhibitor (from -33% through -84%). The combination drug treatments of a high dose BACE inhibitor in the presence of varying dose levels of Ab antibody revealed a significant, yet steeper dose response (from -60% through -84%). Several of the of drug combination treatments resulted in significant synergistic lowering of deposited Ab. The longitudinal study demonstrated significant time dependent effects on plaque removal that was detected as early as 4weeks and the combination therapy showed a continual significant reduction over time that resulted in a dramatic reduction of deposited Ab as compared to the time zero cohort. Conclusions: The combination therapy studies demonstrated significant dose-response and longitudinal relationships for the plaque specific antibody and BACE inhibitor that further support/enable the rationale for utilizing combinational anti-amyloid therapies in the clinic.

AMYLOID BURDEN-RELATED PERFORMANCE DIFFERENCES ON COGNITIVE AND FUNCTIONAL INSTRUMENTS ACROSS ALZHEIMER'S DISEASE PATHOPHYSIOLOGIC STAGES

with mild AD and age-/gender-matched cognitively healthy controls (CHc). Methods: 61 right handed persons (mild AD1⁄432; diagnosed according to NIAAA criteria, & CDR 1⁄4 1 & CHc1⁄429) were recruited after informed written consent. All subjects underwent detailed neurocognitive assessment including VFT (category: fruits, animals & vegetables) followed by neuroimaging (structural and resting state fMRI). Resting state fMRI was decomposed into independent components using independent component analysis. Group ENwas visually identified from obtained components.We performed regression analysis to examine the link between VFT (scores) performance and RSFC of EN, correcting for age and gender variations. Results: We found a significant positive relation between VFT scores and RSFC of regions under EN among the whole group (CHc and mild AD patients) after correcting for age and gender effects. There was a significant difference (but uncorrected at p <0.01) between groups in RSFC of EN. Mild AD patients performed significantly poorer in VFT task. Conclusions: A link exists between RSFC of EN and executive performance (as assessed by VFT). Both measures being sensitive biomarkers for AD may be helpful for objectively diagnosing early AD and monitoring its progression.