The BACE inhibitor verubecestat was previously found to reduce amyloid load as assessed by 18F-flutemetamol positron emission tomography (PET) composite cortical standard uptake value ratio (SUVr) in patients with mild-to-moderate Alzheimer’s disease (AD) in a substudy of the EPOCH trial. Here, we report on additional analyses relevant to the EPOCH PET data, to help inform on the use of PET for assessing amlyloid load in AD clinical trials. The analyses addressed (1) identification of an optimal 18F-flutemetamol reference region, (2) determination of the threshold to characterize the magnitude of the longitudinal change, and (3) the impact of partial volume correction (PVC). Pons and subcortical white matter were evaluated as reference regions. The SUVr cutoffs and final reference region choice were determined using 162 18F-flutemetamol PET scans from the AIBL dataset. 18F-flutemetamol SUVrs were computed at baseline and at Week 78 in EPOCH participants who received verubecestat 12 mg (n = 14), 40 mg (n = 20), or placebo (n = 20). Drug effects on amyloid load were computed using either Meltzer (MZ), or symmetric geometric transfer matrix (SGTM) PVC and compared to uncorrected data. The optimal subcortical white matter and pons SUVr cutoffs were determined to be 0.69 and 0.62, respectively. The effect size to detect longitudinal change was higher for subcortical white matter (1.20) than pons (0.45). Hence, subcortical white matter was used as the reference region for the EPOCH PET substudy. In EPOCH, uncorrected baseline SUVr values correlated strongly with MZ PVC (r2 = 0.94) and SGTM PVC (r2 = 0.92) baseline SUVr values, and PVC did not provide improvement for evaluating treatment effects on amyloid load at Week 78. No change from baseline was observed in the placebo group at Week 78, whereas a 0.02 and a 0.04 decrease in SUVr were observed in the 12 mg and 40 mg arms, with the latter representing a 22

The Down syndrome (DS) population is aging rapidly with a life expectancy of nearly 60 years of age compared to 25 years of age in 1980. There are approximately 210,000 people with DS in the USA and about 85,000 are >30 years of age. 1 With longevity comes a high risk of Alzheimer’s disease (AD). The lifetime risk of AD is estimated to be >90% , 2 and is the leading cause of death for adults with DS. 3 Symptoms of DS associated AD (DS-AD) appear at approximately 45 to 55 years of age with early biomarker changes occurring a decade or more earlier at about 35 years of age. 4 Recent fluid biomarker and amyloid imaging data show that AD pathogenesis in individuals with DS are similar to AD biomarkers in individuals with late-onset AD. 5 Published data using the tau positron emission tomography (PET) imaging agent flortaucipir provide data on tau accumulation in DS-AD that correlates with amyloid burden 6 and cognitive decline 7 . The LIFE-DSR study is a multi-center natural history study recruiting 270 adults with DS. Participants, age 25 or older, are followed at 16-month intervals over 32-months. Data collected includes cognitive, behavioral, and functional from a range of common developmental disability assessment tools. Plasma and buffy coat samples are banked for prospective molecular and genetic analyses. Two longitudinal sub-studies will be added to the LIFE-DSR protocol. First is a tau PET sub-study using the tracer 18 F-MK-6240. Second is a cerebrospinal fluid (CSF) biomarkers sub-study. Both sub-studies will enroll 30 LIFE-DSR participants with similar demographics (age >= 35 years), collecting data twice every 16 months. Data from the tau PET and CSF sub-studies will be compared with the clinical and fluid biomarker data collected under the LIFE-DSR protocol. Inclusion of PET and CSF sub-studies will enrich the LIFE-DSR study and improve our ability to understand and assess clinical features, imaging, and genetic markers of DS-AD progression and provide a basis for the development of endpoints for clinical trials to potentially develop more effective treatments. This is the first use of the next generation PET tau radiotracer, 18 F-MK-6240 in DS.

Verubecestat, a BACE1 inhibitor that reduces Aβ levels in the cerebrospinal fluid of humans, was not effective in a phase 3 trial (EPOCH) of mild-to-moderate AD and was associated with adverse events. To assist in the development of BACE1 inhibitors, we report detailed safety findings from EPOCH. EPOCH was a randomized, double-blind, placebo-controlled 78-week trial evaluating verubecestat 12 mg and 40 mg in participants with mild-to-moderate AD diagnosed clinically. The trial was terminated due to futility close to its scheduled completion. Of 1957 participants who were randomized and took treatment, 652 were assigned to verubecestat 12 mg, 652 to verubecestat 40 mg, and 653 to placebo. Adverse events and relevant laboratory, vital sign, and ECG findings were assessed. Verubecestat 12 mg and 40 mg were associated with an increase in the percentage of participants reporting adverse events versus placebo (89 and 92% vs. 82%), although relatively few participants discontinued treatment due to adverse events (8 and 9% vs. 6%). Adverse events that were increased versus placebo included falls and injuries, suicidal ideation, weight loss, sleep disturbance, rash, and hair color change. Most were mild to moderate in severity. Treatment differences in suicidal ideation emerged within the first 3 months but did not appear to increase after 6 months. In contrast, treatment differences in falls and injuries continued to increase over time. Verubecestat was associated with increased risk for several types of adverse events. Falls and injuries were notable for progressive increases over time. While the mechanisms underlying the increased adverse events are unclear, they may be due to BACE inhibition and should be considered in future clinical development programs of BACE1 inhibitors. ClinicalTrials.gov NCT01739348 , registered on 29 November 2012.

The BACE inhibitor verubecestat (MK-8931) demonstrated cognitive and functional decline relative to placebo in a 2-year Phase 3 trial of individuals with prodromal AD (NCT01953601). Disease progression modeling was used to investigate the temporal pattern of the cognitive and functional deficits and dose- or exposure-dependency in the Results. Disease progression models for the clinical efficacy outcomes (ADAS-cog13, ADAS-cog11, CDR-SB, ADCS-ADL) were developed using a similar Methodology to an established ADAS-cog disease progression model (Ref 1). Parameters describing placebo response were first estimated and fixed based on the published model and using the trial data from the placebo arm. Then Akaike Information Criteria (AIC) were used to select among alternative drug effect models (effects on the underlying progression rate vs an offset with no change in underlying progression rate). The best model was then tested for dose- and exposure-dependency in the drug effect. Models describing the drug effect as a detrimental offset occurring early in therapy without a change in underlying progression rate resulted in a large drop in AIC for ADAS-cog13 (-129), ADAS-cog11 (-105.7), and CDR-SB (-21.9) and a moderate drop in ADCS-ADL (-6.9) indicating a statistically favorable model (<−10.8 corresponds to p<0.001 for a nested comparison with 1df), while inclusion of a drug effect of altered progression rate resulted in little change in AIC. Addition of dose- or exposure-dependency on the offset drug effect term resulted in little change in AIC for all 4 endpoints suggesting a lack of significant difference in drug effects across doses and drug exposures investigated. The magnitude of the drug effect offset at the 12 and 40 mg doses was estimated as 1.9 and 2.5 for ADAS-cog13, 1.4 and 1.9 for ADAS-cog11, 0.27 and 0.37 for CDR-SB, and −0.53 and −0.43 for ADCS-ADL, respectively. Overall, these Results indicate that the detrimental verubecestat drug effect in APECS occurred rapidly and did not alter the underlying disease progression rate, but rather acted as an offset. This drug effect was similar in magnitude across the doses and range of drug exposures studied. Ref 1. Clin Pharmacol Ther. 2015 Mar;97(3):210-4.

In a recent Phase-3 trial (APECS) verubecestat was associated with poorer clinical outcomes compared with placebo in prodromal AD subjects. The subjects were screened using amyloid PET imaging and a subgroup of patients participated in a tau PET substudy. Here we report on the characteristics of neurofibrillary tangle (NFT) distribution in these prodromal AD subjects. Participants 50–85 years of age with prodromal AD/amnestic mild cognitive impairment due to AD were randomized in a double-blind, 24-month, placebo-controlled trial of verubecestat (12mg and 40mg). Subjects had a MMSE score between 24–30 and a positive Aβ imaging PET scan at screening. After 1 year in the trial, thirteen participants (3 females and 10 males) participated in a tau PET imaging substudy. Participants underwent 30 min (80 – 110 min post-tracer injection) brain PET scans with [18F]MK-6240. PET scans were obtained at multiple sites, but centrally collected and quality controlled by Bioclinica. The image processing including motion correction, spatial coregistration to 3D T1 MRI, normalization and smoothing were performed consistently across subjects. Cortical and subcortical SUVRs were calculated with cerebellar gray matter as reference. At the time of scanning 4 subjects were on placebo, 3 and 6 subjects had received 12 mg or 40 mg verubecestat for 12 months, respectively. Subjects age ranged between 55–87 year old and MMSE score between 23-29. There was no significant difference in cortical gray matter, parahippocampal and ambient gyri SUVRs between treatment groups. A positive [18F]MK-6240 signal was observed in hippocampal and limbic regions of all patients with SUVR ranging from 1 to > 3. Different patterns of NFT cortical distribution were observed, with 6 subjects showing levels consistent with Braak V-VI in typical brain regions known for NFT accumulation while the other subjects showed less NFT. In this limited sample size, both higher global and regional SUVRs tended to correlate with worse cognitive scores. In the APECS trial, prodromal amyloid positive subjects exhibited positive [18F]MK-6240 PET scan indicating the presence of NFT pathology. The diversity of brain NFT distribution pattern suggests that these prodromal subjects were at different stages on the AD pathological continuum.

In the phase-3 APECS trial, the BACE inhibitor verubecestat failed to improve clinical outcomes in participants with prodromal AD and was associated with worsening on some measures, notably cognition. Worsening relative to placebo was apparent early but did not progress further over time. We performed analyses to evaluate whether this early-onset worsening of cognition was consistent across participant subgroups and cognitive domains, and the possible relationship with adverse events. Participants aged 55–85 years who had memory impairment and elevated brain amyloid but without significant functional impairment were randomized in a double-blind, placebo-controlled, 104-week trial of verubecestat 12mg and 40mg. Cognition was assessed by the ADAS-Cog13 and a 3-domain composite cognition score (CCS-3D) which included tests of episodic memory, executive function, and attention/processing speed. Analyses were exploratory and intended to be hypothesis-generating. As previously reported, total score on the ADAS-Cog13 and CCS-3D worsened in each verubecestat group relative to placebo at the earliest evaluation time point of Week-13. There was no observed effect of age, baseline severity, APOE4 genotype, use of AD treatment at baseline, PET brain amyloid load, or MRI brain volume on treatment response on the ADAS-Cog13 at Week-13. There did not appear to be a relationship among groupings of adverse events (e.g. those potentially related to cognition, psychiatric adverse events, or falls) within the first 13 weeks and treatment response on the ADAS-Cog13 at Week-13. Analysis of components of CCS-3D suggested that the Week-13 verubecestat worsening relative to placebo was driven by worse scores on episodic memory and attention/processing speed domains. In contrast, verubecestat was associated with better performance on letter and category fluency tests in the executive function domain at Week-13. The early-onset worsening of cognition by verubecestat in participants with prodromal AD was consistent across subgroups and did not appear to be influenced by adverse events. Verubecestat appeared to have differential effects on different cognitive domains at Week-13, but this could be a chance finding given the large number of exploratory comparisons performed. If replicated in other data sets, this observation might provide insights into the role of BACE inhibition in cognition.

INTRODUCTION:We evaluated the selective M1 muscarinic positive allosteric modulator, MK-7622, as adjunctive cognitive enhancing therapy in individuals with Alzheimer's disease.METHODS:A randomized, double-blind, proof-of-concept trial was performed. Participants with mild-to-moderate Alzheimer's disease, being treated with an acetylcholinesterase inhibitor, were randomized 1:1 to 45 mg of MK-7622 or placebo for 24 weeks. Endpoints included the mean change from baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) at 12 weeks and Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory at 24 weeks.RESULTS:Two hundred forty participants were randomized. The trial was stopped for futility after meeting prospectively defined stopping criteria. MK-7622 did not improve cognition at 12 weeks (group difference in ADAS-Cog11: 0.18 [95% confidence interval: -1.0 to 1.3]) or function at 24 weeks (group difference in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory: 0.06 [95% confidence interval: -2.4 to 2.5]). More participants taking MK-7622 discontinued study medication because of adverse events than those taking placebo (16% vs 6%) and who experienced cholinergically related adverse events (21% vs 8%).DISCUSSION:MK-7622 (45 mg) does not improve cognition or function when used as adjunctive therapy in mild-to-moderate Alzheimer's disease.

β-Amyloid (Aβ) peptides are thought to be critically involved in the etiology of Alzheimer’s disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aβ, and BACE1 inhibition is thus an attractive target for the treatment of AD. We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys. Chronic treatment of rats and monkeys with verubecestat achieved exposures >40-fold higher than those being tested in clinical trials in AD patients yet did not elicit many of the adverse effects previously attributed to BACE inhibition, such as reduced nerve myelination, neurodegeneration, altered glucose homeostasis, or hepatotoxicity. Fur hypopigmentation was observed in rabbits and mice but not in monkeys. Single and multiple doses were generally well tolerated and produced reductions in Aβ40, Aβ42, and sAPPβ in the CSF of both healthy human subjects and AD patients. The human data were fit to an amyloid pathway model that provided insight into the Aβ pools affected by BACE1 inhibition and guided the choice of doses for subsequent clinical trials.

AD endpoints are translated and culturally adapted for multiregional trials with the intent of preserving their cognitive and functional concepts. However, data supporting performance of AD endpoints across countries and cultures are sparse. To examine the potential influence of culture on the measurement of cognition and function, we evaluated regional variability in the ADAS-Cog and the ADCS-ADL using baseline data from a global trial of subjects with mild-to-moderate AD. Mild-to-moderate AD subjects (n=2,221) were recruited from 21 countries for a double-blind, placebo-controlled randomized clinical trial. Countries were grouped into one of six geographic regions. To assess ADAS-Cog and ADCS-ADL item scores across regions, data were stratified according to disease severity (mild, MMSE= 21-26; moderate, MMSE= 15-20). To present the data graphically, standardized z-scores were calculated within each stratum. These standardized z-scores were then pooled across disease severity and re-standardized. ADAS-Cog: The largest absolute z-scores were observed in the Middle East, South America and the Far East, primarily in the Commands, Praxis, and Naming items. The Middle East and South American z-scores indicate subjects tended to perform worse than the overall study population mean, while Far East and Oceania performed better than average. Absolute z-scores for North America and the European Union were the smallest, though this observation may be due, in part, to the sample sizes of these regions comprising a large proportion of the total on which the standardized scores were based. ADCS-ADL: The Middle East and South American z-scores were consistently lower than the mean (suggesting more functional impairment) in basic activities and activities related to communication and engagement. Oceania z-scores were consistently larger than average indicating reduced functional impairment. Assuming no true underlying interaction between geographic region and cognitive and functional performance, these data suggest there may be residual variance in the measurement of cognition and function related to cultural differences across regions. Future evaluation of the psychometric characteristics of the endpoints by region may provide further insight into the influence of cultural variability on measurement error.

It remains an open question whether the failed efficacy trials for the gamma secretase inhibitors (semagacestat and avagacestat) and, at most, modest findings for antibodies targeting soluble Aβ (solanezumab) demonstrate that the amyloid hypothesis has been disproven. A model-based analysis was conducted to characterize the degree of modulation of Aβ tested in these trials to inform this question. A semi-mechanistic mathematical pharmacokinetic/pharmacodynamic model describing inhibition of brain Aβ production and distribution to CSF previously developed to describe CSF Aβ biomarker data from the BACE inhibitor verubecestat (MK-8931) Phase 1 program was extended to semagacestat, avagacestat, and solanezumab. Clinical data on CSF Aβ levels and drug exposure over time were digitized from the public domain. The model-estimated median steady-state % reduction (averaged over the dosing interval) in brain Aβ40 was 29.5%, 14.8%, 70.8%, and 86.8% for daily administered 50 mg avagacestat, 140 mg semagacestat, 12 mg and 40 mg verubecestat. Thus the two gamma secretase inhibitor trials likely tested a degree of Aβ reduction that was less than that associated with human genomic evidence (∼50% Aβ increase with early onset due to trisomy 21 and 40% Aβ reduction with protective BACE1 mutant). Given the genomic alterations are present at birth, it is likely that a therapeutic intervention would require a greater level of perturbation to be effective. Alterations in free and total Aβ in plasma and CSF with solanezumab were well described by a model with slowed clearance of the Aβ-mAb complex and suggested limited CNS penetration and modulation of CSF Aβ. Overall, these results indicate that the completed trials did not robustly test the amyloid hypothesis. Ongoing verubecestat trials of 12 and 40 mg are testing a substantially greater reduction in brain production of Aβ and therefore will constitute a more robust test of the amyloid hypothesis.

Volumetric MRI is a well suited and sensitive biomarker to monitor neurodegenerative processes in Alzheimer’s Disease (AD) patients. Verubecestat (MK-8931), a potent inhibitor of beta secretase (BACE), is being assessed in a Phase 2/3 trial of mild-to-moderate AD subjects (EPOCH study - NCT01739348). We present analyses of baseline volumetric MR images from an initial partial sample of study participants. The relationship between brain anatomical parameters, cognitive status and APOE4 status of the patients is also examined. Participants between ≥ 55 and ≤ 85 years of age with probable AD and an MMSE score ≥ 15 and ≤ 26 were enrolled. Most subjects received an MRI scan at baseline. Using a standardized imaging protocol 3D T1-weighted MRI sequences were collected on various 1.5T and 3T MRI scanners from more than 200 centers worldwide. Images were centrally collected and quality controlled, and then segmented using Freeesurfer at Bioclinica. The mean (S.D.) of the whole brain, hippocampus and ventricles volume were 975.75 (101.78) mL (n=516), 5.86 (1.10) mL (n=518) and 50.56 (22.89) mL (n=517), 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 (n=518) and 2.99 (0.59) mL (n=518), 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 RHV and 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. 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.

Verubecestat (MK-8931) is a potent, oral beta-secretase 1 inhibitor currently in development for treatment of Alzheimer’s disease (AD). Verubecestat reduces Aβ levels by over 80% in cerebrospinal fluid (CSF) and brain of rodents and primates, and as well as CSF in subjects with AD. Verubecestat is therefore being evaluated for its ability to slow AD progression. A Phase II/III trial (EPOCH) is testing verubecestat in mild-to-moderate AD and has completed enrollment. Baseline clinical characteristics are presented below. EPOCH (clinicaltrials.gov NCT01739348) is an ongoing randomized, double-blind, placebo-controlled trial in mild-to-moderate AD. Key entry criteria included: diagnosis of probable AD (based on NINCDS-ADRDA and DSM-IV-TR criteria); MMSE of 15-26; MRI/CT findings consistent with AD; a trial partner with frequent contact with participant; and no uncontrolled medical conditions. Use of a stable dose of acetylcholinesterase inhibitors (AChEI) and memantine is permitted. Exclusion criteria included modified Hachinski>4, severe white matter disease, and other active neurological/psychiatric disorders. Co-primary outcome measures are change from baseline in ADAS-Cog and ADCS-ADL scores at Week 78. 2,211 participants were randomized between 2012 and 2015 from 239 sites in 21 countries worldwide, with 44% recruited from US/Canada, 31% from Europe/Australia/New Zealand, 13% from Japan, and 12% from other countries. Screening failure was 34%. Preliminary baseline demographic data include the following: 55% female, mean (SD) age of 71.8 (7.5) years, 80% white race (17% Asian, 3% other) and 10% Hispanic or Latino. Most participants (89%) had been diagnosed with AD for at least six months before study entry. Most (88%) were on AChEI and/or memantine therapy. Regarding education level, 40% had 16 or more years.Enrollment was balanced regarding baseline disease severity: 48% mild (MMSE ≥21) and 52% moderate (MMSE ≤ 20). Approximately 62% were APOE4 positive. Mean (SD) baseline scores for the key efficacy measures were ADAS-Cog: 21.4 (7.5), ADCS-ADL: 62.6 (10.0), CDR-SB: 5.4 (2.2) and MMSE: 20.3 (3.3). Baseline characteristics of the population included in the EPOCH trial are similar to those from prior published trials in participants with mild-to-moderate AD. Trial results will be available in 2017.

To evaluate, in amnestic MCI, whether regional amyloid positivity is associated with lower cognitive performance in cognitive domains relevant to that anatomic region. Amyloid PET data and baseline cognitive performance were analyzed from the ongoing MK-8931-019 (APECS) trial of verubecestat. Trial participants were screened using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Delayed Memory Index (DMI) ≤85 to define memory impairment; only those with memory impairment underwent PET. PET positivity was determined by visual read in accordance with approved labelling. Six regions were examined in this exploratory analysis (frontal, parietal, temporal, cingulate, striatal, precuneus). Cognitive performance was assessed using five RBANS index scores (immediate memory, delayed memory, language, attention, visuospatial). For each anatomical region, the mean RBANS scores for PET negative vs. positive were compared. The impact of number of additional PET positive regions on RBANS score was also assessed. Of the 765 individuals analyzed, 556 (73%) were PET positive. Baseline age, education, MMSE and ADCS-ADL were similar between PET positive and negative individuals. Within PET positives, 69% were positive for all six regions; 20% for 3-5 regions; 11% for 1 or 2 only. The frontal region was most often positive (94%), while temporal and striatal were least frequently positive (77%). Regardless of anatomic region studied, PET positive individuals had worse performance on the immediate memory index (IMI) and DMI as compared to PET negative (e.g for frontal region, mean DMI difference 9.1, 95%CI (7.01-11.2); IMI difference 9.25, 95%CI (6.95-11.56). There were no nominal differences in attention, language, or visuospatial performance. For both immediate and delayed memory, scores tended to decline as the number of positive PET regions increased; this pattern was not observed for the other cognitive domains. Immediate and delayed memory performance were lower among PET positive individuals for all regions, with performance on these indices also declining as the number of amyloid positive regions increased. Otherwise, there was no clear relationship between domain-specific cognitive performance and regional amyloid burden.

Alzheimer's disease (AD) is the most common neurodegenerative dementia in the elderly. The pathognomonic senile plaques found in brains of AD patients are comprised largely of aggregated amyloid-β (Aβ) peptide. Several forms of soluble Aβ oligomers have been identified and there is increasing evidence that these soluble oligomers are toxic Aβ species. An Aβ oligomer-specific assay which detects endogenous oligomers from cerebrospinal fluid (CSF) or from histologically confirmed human AD and healthy control subjects was previously developed and reported (J. Neuroscience 34:2884). Using this assay, a robust 3-5 fold increase in Aβ oligomers was observed in the CSF of AD patients (N=63) vs. age-matched healthy controls (N=54) from 2 commercial sources, as well as from SEC-fractionated aqueous supernatants of AD compared to non-AD cortex. To further confirm assay utility to measure Aβ oligomers, and the correlation of these species with other AD-relevant endpoints, we evaluated CSF samples from subsets of two additional unique cohorts of HC and AD, including samples from the Australian Imaging Biomarkers and Lifestyle Study of Aging (AIBL) and the Oxford Project to Investigate Memory and Ageing (OPTIMA) studies (J Alzheimers Dis. 44:525-539). These cohorts provide critical genotype, biochemical, imaging, cognitive and functional data with which to assess oligomers as potential surrogates of disease state. The ability of oligomers to differentiate between HC and AD, and the assessment of their performance in comparison with amyloid and tau, will be reported.

Prior studies have demonstrated that the CSF Tau to Amyloid ß(42) ratio (Tau/Aβ42) can distinguish patients with mild to moderate AD from healthy elderly control (HC) subjects. We hypothesized that a cutoff with at least 80% sensitivity and 60% specificity could be identified using Luminex® xMAP® Tau/Amyloid ß(42) assays to discriminate between AD and HC subjects. CSF samples were collected from 188 HC and 155 mild to moderate AD subjects from five sites and assayed using the Tau/Amyloid ß(42) assay. A two-step approach was used to determine cutoff. First, a range of possible cutoff values was determined that distinguish AD from HC subjects with at least 80% sensitivity and 60% specificity. Second, results from amyloid PET imaging were used to select a specific cutoff within this range. Briefly, amyloid deposition status assessed with PET by visual read and CSF Tau/Aβ42 were both obtained from a heterogeneous group of 95 subjects (including HC, mild to moderate AD, amnestic MCI and other subjects). The CSF Tau/Aβ42 value within the window that met sensitivity and specificity criteria and maximized concordance with amyloid PET was chosen as the final cutoff. A CSF Tau/Aβ42 ratio value of 0.215 provides an estimated 77.7% (72.3%, 100%) specificity and 94.8% (91.1%, 100%) sensitivity to discriminate AD from HC and maximized concordance with PET. Concordance with PET visual reads was 86.9% (80.7%, 91.9%) in a population that is 50% PET positive [values are given as estimates with (95% CI)]. The Tau/Aβ42 ratio performed better than either Tau or Aβ42 alone. The levels of concordance between tau/Aβ42 and PET SUVR scores using either flutemetamol or PiB were similar to those observed with flutemetamol visual reads. In this study, the Luminex xMAP Tau/Amyloid ß(42) assay was used to identify a threshold ratio value of CSF Tau/Aβ42 with acceptable sensitivity and specificity for distinguishing HC from AD. This threshold is highly correlated with the results of PET amyloid imaging, with an estimated concordance rate of 86.9%. Overall, these results indicate that the Luminex xMAP Tau /Aβ42 assay may have clinical utility for identifying subjects with AD.

BACKGROUND:Current antipsychotic treatments have little impact on the cognitive deficits associated with schizophrenia. It has been proposed that agents which promote histamine release may enhance cognition. We evaluated whether the H3 inverse agonist MK-0249 might improve cognitive deficits in patients with schizophrenia. METHODS:Outpatients (N=55) with schizophrenia between ages 21 and 55 who were clinically stable, experienced no more than mild to moderate overall symptoms (PANSS score total 36-75), and were taking a stable dose of antipsychotic medication were randomized to MK-0249 10mg and placebo in a multi-center, randomized, double-blind, 2-period (4-weeks per period), cross-over study. The primary efficacy endpoint was the mean change from baseline at 4-weeks of treatment in the total cognitive score on the Brief Assessment of Cognition in Schizophrenia (BACS) Battery. Other assessments of cognition were also performed. RESULTS:A total of 46 patients completed the study. MK-0249 10mg did not demonstrate a statistically significant difference compared to placebo in the mean change from baseline in the total cognitive score on the BACS battery after 4-weeks of treatment (-0.1, 95% CI: -2.3, 2.1) or with regard to secondary measures of attention/processing speed, episodic memory, or working memory after 4-weeks of treatment. The incidence of adverse events was greater during the MK-0249 treatment period (25/52 patients, 48.1%) compared to the placebo treatment period (15/51 patients, 29.4%). CONCLUSION:MK-0249 10mg once daily was not superior to placebo in the treatment of cognitive impairment in patients with schizophrenia after 4-weeks. (Clinicaltrials.gov: NCT00506077).

Compelling evidence implicates the abnormal accumulation of Aβ in the pathogenesis of Alzheimer's disease (AD). Inhibition of BACE1 to reduce Aβ production is a promising approach to test the amyloid hypothesis. In prior studies in healthy volunteers, the BACE1 inhibitor MK-8931 was generally well-tolerated and resulted in a dose-dependent reduction of CSF Ab. Here we report the initial characterization of the pharmacodynamics of MK-8931 in AD patients. Randomized, double-blind, placebo-controlled, multiple-dose study in mild-to-moderate AD patients. Subjects were administered 12, 40 or 60-mg MK-8931 or placebo (n=8 per dose; n=6 for placebo) daily for 7days. CSF Aβ40, Aβ42 and sAPPβ concentrations were determined over 36 hours postdose on Day7 using samples collected via lumbar catheterization. A semi-mechanistic mathematical model was developed to describe Ab 40, Ab 42 and sAPP b modulation in CSF and used to generate dose-response profiles for AD patients. Following placebo administration, mean CSF concentrations of Aβ40, Aβ42 and sAPP b increased relative to baseline. By contrast, administration of MK-8931 resulted in a dose-dependent and sustained reduction in CSF Ab levels with mean percent reduction from baseline of up to: Aβ40=84%, Aβ42=81%, and sAPPβ=88%. CSF modulation of Ab 40, Ab 42 and sAPP b was best described by a sigmoid Emax model and transit compartments accounted for the delay between brain and lumbar CSF Ab. Based on dose-response profiles generated using this model, t argeted CSF A b reductions between 50–75% and between 75–100% from baseline are predicted to be achieved in AD patients at dose levels of 12 and 40mg MK-8931, respectively. This study is the first demonstration of a pharmacodynamic effect of BACE1 inhibition in AD patients. Multiple doses of 12 to 60-mg MK-8931 resulted in a dose-dependent reduction in CSF A β, similar to that observed in healthy volunteers and have enabled robust dose-response modeling. Dose-response profiles predict that 12 and 40mg MK-8931 will inhibit Aβ production by >50% and >75%, respectively, in the majority of AD patients. Thus, MK-8931 presents a unique opportunity to test the amyloid hypothesis of AD pathogenesis. Ref 1: Forman et al. 2012 AAIC abstract.