Kevin Booth

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.

Long-Term Extensions of Randomized Vaccination Trials of ACC-001 and QS-21 in Mild to Moderate Alzheimer’s Disease

OBJECTIVES Long-term safety and tolerability of ACC-001 (vanutide cridificar), an antiamyloid- beta therapeutic vaccine, was evaluated in subjects with mild to moderate Alzheimers disease. DESIGN Phase 2a extension studies of randomized parent trials were conducted in the United States, European Union, and Japan. METHODS Four immunizations of ACC-001 were administered at the same 3 dose levels (3, 10, and 30 μg) to subjects randomized in the parent studies; ACC-001 was administered with QS-21 adjuvant. Safety, tolerability, and immunogenicity were assessed during active treatment and 6-month follow-up. RESULTS ACC-001 + QS-21 was well tolerated in the United States (N=110) and European Union (N=50), and Japan (N=53) extension studies; safety profile was similar to that observed in the parent studies, and no new safety signals were identified. Overall, injection site reactions were the most common adverse event in these studies. Anti-amyloid antibody titers were elicited in all groups, with the highest titers observed in subjects who received ACC-001 + QS-21 in both the parent and extension studies. CONCLUSIONS Long-term exposure to ACC-001 + QS-21 was well tolerated in subjects with Alzheimers disease, suggesting that side effects do not pose a principal limitation for anti-amyloid active immunotherapy. The highest anti-amyloid-beta IgG titers are elicited during long-term therapy with ACC-001 + QS-21 compared with other regimens.

Safety, tolerability, and preliminary efficacy of SAM-531, a 5HT-6 antagonist, in subjects with mild-to-moderate Alzheimer's disease: Results from a phase 2a study

P1-457 SAFETY, TOLERABILITY, AND PRELIMINARY EFFICACY OF SAM-531, A 5HT-6 ANTAGONIST, IN SUBJECTS WITH MILD-TO-MODERATE ALZHEIMER’S DISEASE: RESULTS FROM A PHASE 2A STUDY Claudine Brisard, Beth Safirstein, Kevin Booth, Lisa Hua, Yves Brault, Sangeeta Raje, Steven Leventer, Pfizer Inc., Paris, France; MD Clinical, Hallandale Beach, FL, USA; Pfizer Inc., Collegeville, PA, USA. Contact e-mail: BRISARC@wyeth.com

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.

Biomarker pattern of ARIA-E participants in phase 3 randomized clinical trials with bapineuzumab

Objective To evaluate whether amyloid-related imaging abnormalities with edema/effusion (ARIA-E) observed in bapineuzumab clinical trials was associated with specific biomarker patterns. Methods Bapineuzumab, an anti-β-amyloid monoclonal antibody, was evaluated in patients with mild to moderate Alzheimer disease. Amyloid PET imaging, CSF biomarkers, or volumetric MRI (vMRI) were assessed. Results A total of 1,512 participants underwent one or more biomarker assessments; 154 developed incident ARIA-E. No differences were observed at baseline between ARIA-E and non-ARIA-E participants in brain amyloid burden by PET, the majority of vMRI measures, or CSF biomarkers, with the exception of lower baseline CSF Aβ42 in APOE ε4 noncarrier ARIA-E vs non-ARIA-E groups (bapineuzumab non-ARIA-E p = 0.027; placebo non-ARIA-E p = 0.012). At week 71, bapineuzumab-treated participants with ARIA-E vs non-ARIA-E showed greater reduction in brain amyloid PET, greater reductions in CSF phosphorylated tau (p-tau) (all comparisons p < 0.01), and total tau (t-tau) (all comparisons p < 0.025), and greater hippocampal volume reduction and ventricular enlargement (all p < 0.05). Greater reduction in CSF Aβ40 concentrations was observed for ARIA-E versus both non-ARIA-E groups (bapineuzumab/placebo non-ARIA-E p = 0.015/0.049). No group differences were observed at week 71 for changes in whole brain volume or CSF Aβ42. Conclusions Baseline biomarkers largely do not predict risk for developing ARIA-E. ARIA-E was associated with significant longitudinal changes in several biomarkers, with larger reductions in amyloid PET and CSF p-tau and t-tau concentrations, and paradoxically greater hippocampal volume reduction and ventricular enlargement, suggesting that ARIA-E in bapineuzumab-treated cases may be related to increased Aβ efflux from the brain and affecting downstream pathogenic processes.

A PROSPECTIVE, SYSTEMATIC LITERATURE REVIEW AND META-ANALYSES TO EVALUATE GLOBAL AND REGIONAL BRAIN VOLUMES BY STRUCTURAL MRI AS BIOMARKERS OF ALZHEIMER'S DISEASE (AD) PROGRESSION

and MMSE was found in the occipital lobes for the combined AD+MCI+HC (Pearson 0.82, p1⁄40.0465) and AD (Pearson 0.99, p1⁄40.01) groups. Conclusions:Based on relatively small number of studies, no apparent relationship between change on brain amyloid burden and cognition in AD was found. In contrast, the negative correlation seen in MCI suggests that PiB PET changes may be a useful biomarker in earlier disease phases. The significant finding in the correlation between changes in amyloid deposition in the occipital lobe and MMSE warrants further study. Limitation included the paucity of studies having longitudinal data on both brain amyloid burden and clinical measures and heterogeneity amongst studies.

POOLED AMYLOID PET BASELINE DATA FROM THE BAPINEUZUMAB IV PHASE III TRIALS

mL (n1⁄4516), 5.86 (1.10) mL (n1⁄4518) and 50.56 (22.89) mL (n1⁄4517), respectively. The left hippocampus volume (LHV) was 0.117 mL (95% CI: 0.088-0.145) smaller than the right hippocampus volume (RHV) with volumes of 2.87 (0.56) mL (n1⁄4518) and 2.99 (0.59) mL (n1⁄4518), respectively. Mild AD subjects (MMSE 21) had a larger brain volume (95% CI: 16.392-51.390) and LHV (95% CI: 0.012-0.206) than moderate AD patients (MMSE 20). In contrast significant differences were not observed between mild and moderate AD subjects in the RHVand total hippocampus volume or ventricular volume. Whole brain and ventricles volume were not impacted by APOE4 status of subjects whereas a difference was found for LHV (95% CI:0.074-0.278), RHV (95% CI:0.064-0.283) and total (95% CI:0.148-0.553) hippocampus volume with APOE4-carriers presenting with more atrophied structures. Conclusions: These data from a partial sample of EPOCH trial participants showed differences in whole brain atrophy stage between mild and moderate AD patients and a higher hippocampal atrophy in APOE4-carriers They also suggest that the left hippocampus is more vulnerable to atrophy than the right hippocampus. A comparison of our study brain parameters to ADNI data will also be presented.

Depression in patients screened for Alzheimer's disease clinical trials

Background: Depression is a common comorbidity in patients with AD. In two recent clinical trials for treatment of mild to moderate AD, patients with a medical history of depression were permitted to participate except those with current major depressive disorder. The prevalence of depression and clinical characteristics of these patients were investigated. Methods: A total of 2490 patients with AD who reported their medical history at a screening visit of two trials between December 2007 and October 2011 were included (ClinicalTrials.gov identifiers NCT00667810 and NCT00676143). The prevalence of a past medical history of depression was described for the overall patient sample and for patient subgroups defined by race, gender, and age at AD diagnosis. Onset of depression in relation to date of AD diagnosis was described. A statistical-modeling approach was used to identify the AD patient subgroup with the highest prevalence of depression. Results:Approximately 27% of patients reported a past medical history of depression at screening. Prevalence of depression was 33% in subjects with a diagnosis of AD at or before age 65 and 24% in those with a diagnosis of AD after age 65, with 31% in women, 22% in men, 33% in whites, and 15% in other races. The prevalence did not vary with ApoE e4 carrier status or MMSE scores (<21 vs 21). The statistical model estimated that white women with a diagnosis of AD would have the highest estimated prevalence of depression (45%). Approximately 89% of patients who had medical history of depression reported concurrent depression at screening. In comparing the time of concurrent depressive onset and diagnosis of AD in these patients, we found that depression occurred prior to AD diagnosis in approximately 44% of these patients. The percentage of women (49%) whose depressive onset preceded the diagnosis of AD was higher than that for men (34%). Conclusions: Depression was common among AD patients who were screened for these two clinical trials. Prevalence of depression was found to be highest among patients with diagnosis of AD at or before age 65, women, and whites in our AD patient sample.

A comparison of Neuropsychological Test Battery (NTB) and ADAS-cog performance in an Alzheimer's disease clinical trial

Background: It has been suggested that the ADAS-Cog is not uniformly sensitive to measuring cognitive decline in Alzheimer disease across mild and moderate patients. As a result, the NTB (neuropsychological test battery) was introduced as an alternative which measures cognitive decline in both mild and moderate patients equally well (Harrison et al, Arch Neurol 64:1323-9, 2007). Methods: The psychometric properties of NTB are examined in two randomized, double-blind trials; one 12-week placeboand active-controlled (w 350 patients) and the other 24-week placebo-controlled (w 330). The test-retest reliability, ratio of within subject variability to between subject variability, and internal consistency of NTB in addition to correlation of NTB with other cognitive and functional measures are evaluated using data from the placebo patients. The sensitivities of NTB and ADAS-Cog are assessed as a function of baseline MMSE (Mini-Mental State Examination) scores using data from the active and the placebo arms. Results: It is confirmed that the NTB has good psychometric properties. Although the NTB and ADAS-Cog are equally sensitive in detecting change in the overall population, differences are observed when stratified by baseline MMSE scores. While the NTB is more sensitive than ADAS-Cog among the mild patients, the reverse is observed among the moderate patients. Conclusions: The NTB has good psychometric properties. Based on two studies of relatively short duration, both the NTB and ADAS-Cog are shown to be good instruments for detecting drug effects on cognitive decline among AD patients. The sensitivity of these instruments needs to be evaluated in validation studies of longer duration.