Joanne Bell

Neuropsychiatric symptoms in Alzheimer's disease: Past progress and anticipation of the future

Neuropsychiatric symptoms (NPS) in Alzheimers disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimers first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimers Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimers Research and Treatment (ISTAART). The NPS‐PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome‐specific synthetic reviews and recommendations prepared by NPS‐PIA workgroups on depression, apathy, sleep, agitation, and psychosis.

PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease.

ObjectiveTo evaluate the safety and tolerability of PF-04494700, an oral inhibitor of receptor for advanced glycation end products, in patients with mild-to-moderate dementia of the Alzheimer type. MethodsPatients aged 50 years and older who met the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimers Disease and Related Disorders Association criteria for Alzheimer disease with an Mini-Mental State Examination (MMSE) score between 12 and 26 (inclusive) were randomized to 10 weeks of double-blind treatment with either a 10 mg “low dose” of PF-04494700 (after a 6-d loading dose of 30 mg/d), a 20 mg “high dose” of PF-04494700 (after a loading dose of 60 mg/d), or placebo. Safety measures included adverse events, laboratory tests, vital signs, and 12-lead electrocardiogram. ResultsTwenty-seven patients received PF-04494700 30/co mg (female: 63%; mean age: 74.6 y; mean MMSE: 21.1), 28 patients received PF-04494700 60/20 mg (female: 57%; mean age: 76.6 y; mean MMSE: 21.6), and 12 patients received placebo (female: 67%; mean age: 74.1 y; mean MMSE: 19.2). A higher proportion of patients completed 10 weeks of double-blind treatment on both the “low-dose” regimen of PF-04494700 (88.9%) and the “high-dose” regimen (85.7%) than patients who were on placebo (66.7%). Discontinuation owing to adverse events and incidence of severe adverse events, respectively, were lower in the “low-dose” regimen (7.4%, 11.1%) and the “high-dose” regimen (3.6%, 10.7%) compared with placebo (25.0%, 16.7%). There were no clinically meaningful differences in vital signs, laboratory test results, or mean electrocardiogram parameters in patients treated with PF-04494700. PF-04494700 had no consistent effect on plasma levels of &bgr;-amyloid, inflammatory biomarkers, or secondary cognitive outcomes. ConclusionsTen weeks of treatment with PF-04494700 was safe and well tolerated in patients with mild-to-moderate Alzheimer disease, indicating the feasibility of a larger long-term efficacy trial.

Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease

Objective: To examine safety, tolerability, and efficacy of PF-04494700, an inhibitor of the receptor for advanced glycation end products (RAGE), in mild to moderate Alzheimer disease (AD). Methods: Double-blind, placebo-controlled trial at 40 academic centers (United States). Subjects with AD and Mini-Mental State Examination score 14–26 were randomized to PF-04494700 60 mg/day × 6 days, then 20 mg daily (high dose); 15 mg/day × 6 days, then 5 mg daily (low dose); or placebo, for 18 months. Clinical and laboratory measures were used to evaluate safety and tolerability. The primary efficacy measure was the Alzheimers Disease Assessment Scale–cognitive (ADAS-cog). Secondary measures assessed clinical stage, function, behavior, MRI, and CSF biomarkers. Results: A total of 399 subjects were randomized. In a prespecified interim analysis, when 50% of subjects had completed the 6-month visit, the high dose was associated with confusion, falls, and greater ADAS-cog decline and was discontinued. A second prespecified analysis compared low-dose and placebo groups for futility and safety approximately 12 months after all subjects were randomized. This analysis met criteria for futility, and treatment was discontinued. There were no safety concerns in the low-dose group. Analyses including post-futility data showed decreased decline on the ADAS-cog in the low-dose group at month 18. Other clinical and biomarker measures showed no differences between low-dose treatment and placebo. Conclusions: PF-04494700 at 20 mg/d was associated with increased adverse events and cognitive decline. At 5 mg/d, PF-04494700 had a good safety profile. A potential benefit for this low dose on the ADAS-cog is not conclusive, because of high dropout and discontinuation rates subsequent to the interim analyses. Classification of evidence: This study provides Class I evidence that in patients with AD high-dose PF-04494700 increased cognitive decline at 6 months and Class IV evidence that low-dose PF-04494700 slowed cognitive decline at 18 months.

A novel BACE inhibitor (PF-05297909): A two-part adaptive design to evaluate safety, pharmacokinetics and pharmacodynamics for modifying beta-amyloid in a first-in-human study

BackgroundThe accumulation of amyloid beta (Aβ) peptides is believed to be a central contributor to the neurodegeneration seen in the Alzheimers disease (AD) brain. Given the central role of Aβ42 in AD pathogenesis, a therapeutic strategy to lower central Aβ42 (and Aβ40) levels via inhibition of BACE was adopted in a first in human trial in a 2-part adaptive design.MethodsPart 1 evaluated PF-05297909 plasma PK and the PK/PD relationship for the reduction of plasma Aβ40, Aβ42 and AβX levels; Part 2 evaluated the exposure-response relationship between PF-05297909 and CSF levels of Aβ40, Aβ42 and AβX. Sufficient safety and tolerability, plasma exposure and reduction in plasma Aβ were necessary to initiate Part 2. Part 1 was a sequential parallel group dose escalation (25, 100, 250 and 325 mg) with n=8 (6:2, active:placebo) healthy volunteers (HV) in each cohort. Part 2 consisted of 3 cohorts of n=8 (6:2, active:placebo) HV. Doses selected for Part 2 started with the highest safe dose in Part 1 and then adapted for subsequent cohorts. The PK/PD relationship between PF-05297909 and Aβ42 was determined using a non-linear mixed effects (NLME) analysis. The doses for Part 2 - cohort 2 and 3 were to be chosen to improve the relative standard error in the estimate of the BACE IC50 as quantified by evaluating the determinant of the Fisher information matrix for the NLME model.ResultsPF-05297909 was well-tolerated. Reduction in plasma Aβ (Aβ40 and Aβ42) was exposure related with an apparent maximum at the 250 mg dose with a greater duration of activity at the 325 mg dose of PF-05297909. A 325 mg dose was selected for Part 2 - cohorts 1 and 2 without further cohorts being run, as stopping criteria for futility were met following analysis of cohort 2. A PK/PD relationship in CSF was not observed.ConclusionsThe adaptive designed PF-05297909 FIH study allowed efficient testing of safety and of the PK/PD relationship between PF-05297909 exposure and Aβ (Aβ40 and Aβ42). PF-05297909 was safe and well tolerated in HV at exposures tested. A robust effect on plasma Aβ did not translate to CSF pharmacodynamic effects.

A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects with mild to moderate Alzheimer’s disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil

BackgroundSymptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer’s disease (AD) trials. SAM-760 is a potent and selective 5-HT6 receptor antagonist that has demonstrated central 5-HT6 receptor saturation in humans at a dose of 30 mg.MethodsThis was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD. The study included an interim analysis with stopping rules for futility or efficacy after 180 subjects completed the week 12 visit. Up to 342 subjects with AD (Mini-Mental State Examination (MMSE) score 10–24) and neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI) total score ≥ 10) were to be enrolled if the study continued after the interim analysis. After a 4-week, single-blind, placebo run-in period, subjects entered the 12-week double-blind period and were randomized to either SAM-760 or placebo. The primary and key secondary efficacy endpoints were the change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog13) and NPI total scores. Mixed models for repeated measures were used to analyze the data.ResultsAt the interim analysis, when 186 subjects had been randomized and 163 had completed the week 12 visit, the study met futility criteria and was stopped. The mean week 12 treatment difference was 0.70 points (P = 0.43) for ADAS-cog13 and 2.19 points (P = 0.20) for NPI score, both of which were numerically in favor of placebo. Other secondary endpoints did not demonstrate any significant benefit for SAM-760. In total, 46.2% of SAM-760 subjects reported adverse events (AE) versus 44.7% for placebo, and there were 5 (5.5%) serious AEs in the SAM-760 group versus 3 (3.2%) for placebo. There were two deaths, one prior to randomization and one in the SAM-760 group (due to a traffic accident during washout of active treatment).ConclusionsSAM-760 was safe and well tolerated, but there was no benefit of SAM-760 on measures of cognition, neuropsychiatric symptoms, or daily function. Differences in trial design, study population, region, or pharmacological profile may explain differences in outcome compared with other 5-HT6 receptor antagonists.Trial registrationClinicaltrials.gov, NCT01712074. Registered 19 October 2012.

Cross-species analysis of cerebrospinal fluid (CSF) beta-amyloid reductions by the BACE1 inhibitor PF-05297909 indicates species differences in PK/PD relationships: Relevance to clinical translation

reversed Ab oligomer-damaged long-term potentiation (LTP) at concentrations that did not interfere normal high frequency stimulation-induced LTP. Moreover, bis(heptyl)-cognitin prevented Ab oligomer-induced reduction of neurite length and synaptic quantity in mature hippocampal neurons. In contrast, tacrine could not reverse synaptic impairments in these models. Under oligomerization condition, bis(heptyl)-cognitin reduced the amount of Ab oligomer as evidenced by dot blot assay and immunoblot analysis. Finally, bis(heptyl)-cognitin was shown to alter Ab self-assembling as demonstrated by circular dichroism spectroscopy and transmission electron microscopy. Conclusions: All these results not only offer a modality as to how dimeric agents protect against Ab oligomer-induced synaptic impairments, but also offers a strong support for the beneficial therapeutic effects of bis(heptyl)-cognitin in the treatment of AD.

A five-way crossover study to evaluate the single-dose effects of a novel 5-HT6 receptor antagonist, PF-07212377 (SAM-760), on reversing psychomotor and cognitive deficits induced by scopolamine

THE SINGLE-DOSE EFFECTS OFA NOVEL 5-HT6 RECEPTOR ANTAGONIST, PF-07212377 (SAM-760), ON REVERSING PSYCHOMOTOR AND COGNITIVE DEFICITS INDUCED BY SCOPOLAMINE Joanne M. Bell, Thomas A. Comery, Peter Lockwood, Yifan Huang, Grace Vandal, Paul Maruff, James Kupiec, Pfizer, Groton, Connecticut, United States; Pfizer Global Research and Development, Groton, Connecticut, United States; 3 Pfizer, Groton, Connecticut, United States; 4 Pfizer, Melbourne, Australia.

Sydney Multisite Intervention of LaughterBosses and ElderClowns (SMILE): results from a clustered randomised controlled trial

Abstract from the International Psychogeriatric Association Reinventing Aging through Innovation 15th International Congress, 6-9 September 2011, The Hague, Netherlands.Use of prescription medications for various conditions is highly prevalent in older adults, often leading to the use of multiple medications. The resulting polypharmacy is widely recognized as a risk factor for many negative outcomes, but less is known about the risks of specific types of medication upon cognitive functions. Benzodiazepines are commonly prescribed for the treatment of anxiety and insomnia, among other conditions. While dependency with continued use has been the subject of much concern over this type of medication, other literature has suggested an increased risk of cognitive impairment with chronic use of benzodiazepines. The nature of the cognitive changes and the domains of cognitive function most likely to be affected have differed across various studies. Here we describe the associations between measures of various domains of cognitive functioning and benzodiazepine use in 2879 older Canadian adults from the Canadian Study of Health and Aging (CSHA; 64.3% female, mean age 81.0 years, SD=7.44). These people underwent a comprehensive medical and psychosocial evaluation that included a record of medications used, in addition to a complete personal and medical history. The CSHA was a community-based epidemiological study of the prevalence of dementia and its associated risk factors in over 10,000 Canadians. Benzodiazepines were classified according to their half-life: short (under 12 hours), medium (12 to 40 hours) or long half-life (over 40 hours); 35 elderly people were excluded since they were taking more than one class of benzodiazepine. A comprehensive neuropsychological battery that assessed the major domains of cognitive functioning was administered to all participants who completed the CSHA clinical assessment. Neuropsychological test scores for the domains of short- and long-term memory, abstract reasoning, judgement, visuoconstruction, and language formed were the primary independent variables, while gender, age, and years of education were used as covariates in logistic regression models predicting use of each class of drug. Education was not a significant covariate for any analysis. Gender proved to be a significant covariate in the case of the medium-half life drugs, but not for the other two classes. Age was a significant covariate for the majority of test scores for the short and long half-life drugs. After controlling for the covariates, the results showed a broader range of cognitive impairments with the use of short half-life benzodiazepines than with the medium half-life or the long half-life benzodiazepine compounds. Six cognitive measures, assessing abstract reasoning and comprehension, verbal fluency, verbal memory, and visuoconstruction skills (BlockDesign), showed poorer performance among those who used short half-life benzodiazepines, two measures, those of abstract reasoning and comprehension, showed impaired performance by those using medium half-life benzodiazepines, and three measures, for abstract reasoning, verbal memory, and visuoconstruction skills, showed lower performance by those taking long halflife benzodiazepines. Wechsler Similarities, the measure of abstract reasoning, was the only showing significant differences common across all three drug class models. Results are discussed in terms of both the relative extent of lower neuropsychological test scores and the context of increasing evidence of impaired functioning associated with benzodiazepine use.

Single- and multiple-dose safety, tolerability and pharmacokinetics of a Novel 5HT6 receptor full antagonist (SAM-760) for the treatment of the symptoms of Alzheimer's disease in healthy young adults and elderly subjects

plus Caregiver Input (CIBIC+), and the change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) score at Week 24 (intention-to-treat [ITT], mixed model repeated measures [MMRM] analyses). Secondary endpoints included the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), Mini-Mental State Examination (MMSE), Alzheimer’s Disease Cooperative Study Group-Activities of Daily Living Inventory (ADCS-ADL) and Cornell Scale for Depression in Dementia (CSDD). Safety and tolerability were also assessed. Results: Study completion rates were: SB-742457 15 mg/ day, 88%; 35 mg/day, 89%; donepezil, 86%; placebo, 81%. No statistically significant differences from placebo were observed for either dose of SB742457 with CIBIC+ or ADAS-Cog (Table 1). A statistically significant difference from placebo was observed for donepezil at Week 24 for CIBIC+ but not ADAS-Cog (Table 1). No statistically significant differences from placebo were observed for any treatment for ADCS-ADL or CSDD (Table 2). Statistically significant differences from placebo were observed for MMSE at Week 24 for donepezil but not for either dose of SB-742457 (Table 2). The incidence of AEs was similar in the SB-742457 (29% for 15mg and 35mg) and placebo groups (31%) and higher in the donepezil group (43%). Overall, the most common AEs were headache, nasopharyngitis, dizziness and influenza across treatment groups. Conclusions: The study failed to detect any efficacy for SB-742457 as monotherapy. Marginal efficacy was observed for donepezil on global function and MMSE but not on ADAS-Cog, activities of daily living or mood, indicating limited assay sensitivity of the study. Both treatments were generally safe and well tolerated. The limited assay sensitivity of this study warrants consideration in the design of future short-term monotherapy studies.

Early evaluation of the safety, tolerability and pharmacokinetics of a novel 5HT6 receptor full antagonist for the treatment of the symptoms of mild-to-moderate dementia of the Alzheimer type

day. It has not been generally assumed that a further dose increase will show such dose-response in more advanced AD patients due to greater loss of cholinergic neurons. To investigate whether a donepezil dosage >10 mg/day could confer additional benefit to patients with more advanced AD who were already on 10 mg/day, a once daily 23 mg extended-release donepezil HCl tablet with dose-proportional lower Cmax and delayed Tmax was developed. Methods: Patients with moderate-to-severe AD (MMSE 0-20) treated 3 months with donepezil immediate release 10 mg/day (10mg) were enrolled in a 24-week, double-blind, parallel-group trial comparing donepezil 23 mg/day extended-release tablets (23mg) with continued treatment with donepezil 10mg. Concomitant memantine was allowed. 1467 patients were randomized, 2:1, to 23mg and 10mg, respectively. Change from baseline (BL) in Severe Impairment Battery (SIB) score and scores at week 24 on the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC+) scale were co-primary efficacy assessments. Here, we report on post-hoc analyses of these endpoints based on disease severity by BL MMSE. Results: Among the full ITT population (n 1⁄4 1369), change from BL in SIB favored 23mg over 10mg: 2.6 versus 0.4, P 1⁄4 .0001. At week 24, CIBIC+ was 4.23 for 23mg versus 4.29 for 10mg, P 1⁄4 .1789. Treatment differences between 23mg and 10mg among patients selected to match the populations in published trials of memantine (MMSE 3-14 [n 1⁄4 732] and 5-14 [n1⁄4 680]) were: SIB 3.1 (P1⁄4 .0005) and 2.6 (P1⁄4 .0034), respectively; CIBIC+ 0.10 (P 1⁄4 .0508) and 0.11 (P 1⁄4 .0469), respectively. Patients comprising most of the more impaired end of the moderate-to-severe spectrum (eg, MMSE 0-16; 71% of ITT population) showed greater benefit with 23mg treatment than with continued 10mg treatment on both the SIB and the CIBIC+. The enhanced efficacy observed in patients with lower BL MMSE treated with 23mg was not associated with an increased AE rate versus the full 23mg group. Conclusions: More advanced AD patients (eg, MMSE 0-16) treated with donepezil 23 mg/day extended-release tablets demonstrated significant cognitive and global improvement relative to those treated with 10 mg/day.