A multicenter, double-blind, placebo-controlled trial of the PDE9A inhibitor, PF-04447943, in Alzheimer's disease.

BACKGROUND: PF-04447943 is a potent, selective phosphodiesterase 9A (PDE9A) inhibitor that elevates guanoscine 3',5' - cyclic monophosphate (cGMP) in brain and cerebrospinal fluid. PDE9A inhibition enhances synaptic plasticity and improves memory in preclinical cognition models, and prevents decreases in dendritic spine density in transgenic mice that overexpress amyloid precursor protein (APP) leading to high levels of amyloid beta (Aß) production (Tg2576). OBJECTIVE: This Phase 2 multicenter study was designed to assess the efficacy, safety and pharmacokinetics of PF-04447943 compared with placebo in mild to moderate probable Alzheimer's disease (AD). METHODS: Subjects in overall good health with Mini Mental State Examination (MMSE) scores of 14-26 were randomized to 12 weeks treatment with PF-04447943 25 mg q12h (n=91) or placebo (n=100). Concomitant acetylcholinesterase inhibitor or memantine use was excluded. The primary outcome was the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog). The Neuropsychiatric Inventory (NPI), Clinical Global Impression-Improvement scale (CGI-I) and standard safety measures were secondary outcomes. RESULTS: Completion rates were similar, 87% PF-04447943 vs 92% placebo. At week 12 the mean (SE) baseline adjusted decrease from baseline in ADAS cog for PF-04447943-treated patients was -1.91 (0.54). Placebo treated patients had a change of -1.60 (0.50). The difference between treatments was -0.31 (90% CI of -1.52, 0.90). Corresponding values for the NPI were -2.86 (0.72) vs -2.70 (0.67) with a treatment difference of -0.16 (90% CI of -1.78, 1.48). Neither these changes nor the distribution of CGI-I scores were statistically significantly different between groups. The incidence of serious adverse events (AEs) was similar between groups with 2 deaths in the placebo group. The PF-04447943 group reported more gastrointestinal AEs including diarrhea (5.5% vs 3%) and nausea (5.5% vs 1%) and had a higher rate of discontinuation due to AEs (6.6% vs 2%). CONCLUSIONS: Although generally safe and well-tolerated, 12 weeks PF-04447943 treatment did not improve cognition, behavior, and global change compared with placebo.

Phase II crossover trial of varenicline in mild-to-moderate Alzheimer's disease.

BACKGROUND: Evidence supports a role of α4ß2 receptors in Alzheimer's disease (AD). METHODS: This Korean, multicenter, double-blind, two-period (6 weeks each), crossover study randomized participants to the order in which they received varenicline (1 mg twice daily) and placebo. Assessments included AD Assessment Scale-Cognitive Subscale (ADAS-Cog) 75, Neuropsychiatric Inventory (NPI), adverse events (AEs) and Columbia-Suicide Severity Rating Scale (C-SSRS). RESULTS: For varenicline versus placebo (n = 66 randomized), there was no significant difference in the week 6 least square (LS) mean ADAS-Cog 75 total score (primary endpoint; 18.07 vs. 18.49; p = 0.3873) and a slight worsening in the week 6 LS mean NPI (3.82 vs. 2.55; p = 0.0468), primarily driven by decreased appetite/eating. Common treatment-related AEs were nausea (23.3; 3.4%), vomiting (15.0%; 0) and decreased appetite (15.0; 6.8%). CONCLUSIONS: Varenicline did not improve cognition, behavior or global change in this population. The most frequent varenicline-associated AEs were gastrointestinal; psychiatric AEs were rare and similar between the groups.

Pharmacokinetics, safety, and tolerability following multiple oral doses of varenicline under various titration schedules in elderly nonsmokers.

This study was designed to investigate the multiple-dose pharmacokinetics, safety, and tolerability of the selective α4ß2 nicotinic acetylcholine partial agonist, varenicline, in elderly (65-85 years old) nonsmokers. Fifty male and female subjects with normal renal function for their age were randomized to receive varenicline or placebo once or twice daily for 3 weeks in an investigator- and subject-blinded parallel-group design. Treatment regimens included weekly titration (n = 14; days 1-7, 0.5 mg once daily; days 8-14, 0.5 mg twice daily; days 15-21, 1 mg twice daily); 2-week twice-daily titration (n = 13; days 1-14, 0.5 mg once daily; days 15-21, 0.5 mg twice daily); 2-week once-daily titration (n = 13; days 1-14, 0.5 mg once daily; days 15-21, 1 mg once daily); and placebo (n = 10). Approximate dose-proportional increases in systemic exposure of varenicline at steady state, based on maximum concentration and area under the plasma concentration-time curve over the 24-hour period at steady state, were observed across the dose range of 0.5 to 2 mg/d. Median time to maximum concentration was 3 hours. Mean elimination half-life was estimated to be approximately 24 to 32 hours and independent of dose. Varenicline was considered to be safe and well tolerated in this elderly nonsmoking population.

Predicting cognitive decline in Alzheimer's disease: an integrated analysis.

BACKGROUND: Numerous patient- and disease-related factors increase the risk of rapid cognitive decline in patients with Alzheimer's disease (AD). The ability of pharmacological treatment to attenuate this risk remains undefined. METHODS: Pooled data from 14 randomized clinical studies of donepezil in the treatment of AD (N = 3748) were analyzed to identify predictors of fast decline and determine the effect of donepezil on the risk of fast decline. RESULTS: Young age and more severe baseline cognitive, global, or behavioral status were identified as independent predictors of faster decline in placebo-treated patients. Multivariate models indicated that donepezil treatment was associated with a 39% to 63% reduction in the risk of faster decline. CONCLUSIONS: These results correspond with previous findings, indicating relationships between age or baseline disease severity and rates of cognitive decline. Furthermore, they suggest that symptomatic therapy for AD could reduce the likelihood of faster decline in treated patients.

Effects of donepezil on activities of daily living: integrated analysis of patient data from studies in mild, moderate and severe Alzheimer's disease.

BACKGROUND: We aimed to develop a standardization method to pool data recorded on different activities of daily living (ADL) scales in order to reduce variability of functional outcome data from Alzheimer's disease (AD) clinical trials and to better evaluate the effect of donepezil treatment on function in patients with AD. METHODS: Based on pre-specified criteria, six studies were selected from among all donepezil clinical trials in AD. Individual items from nine ADL scales used in these trials were mapped to a standardized functional scale comprising 12 domains (six basic, six instrumental); scores were transformed to a 0-100 scale. External validation of this scale yielded a concordance rate of 90.8%. For each domain, mean change from baseline to 24 weeks in the placebo and donepezil groups was compared for the total population and for subgroups stratified by baseline disease severity. Study settings included outpatient, assisted living, and skilled nursing facilities. Participants comprised 2183 patients (donepezil, 1261; placebo; 922) with baseline Mini-mental State Examination (MMSE) scores 5-26. RESULTS: Significant treatment differences favoring donepezil were observed for five items (two instrumental and three basic). Patients with moderate AD at baseline (MMSE 10-17) demonstrated the greatest treatment effect. CONCLUSION: Functional data were successfully pooled using standardizing methodology. A beneficial effect of donepezil treatment on function was demonstrated using this standardized functional scale. Similar analyses from studies with other anti-dementia drugs may help to determine the generalizability of these findings and potentially encourage use of functional assessment as a clinical tool.

Cognition and function in Alzheimer's disease: identifying the transitions from moderate to severe disease.

BACKGROUND/AIMS: Cognitive and functional decline define the transition from moderate to severe Alzheimer's disease (AD); however, specific relationships between deteriorating cognition and functional abilities are less well characterized. Such relationships are important in care planning and understanding patient needs. Objectives of this post hoc analysis of data from a multicenter randomized double-blind placebo-controlled study were to describe changes in Severe Impairment Battery (SIB) scores over 6 months in patients with moderate to severe AD (MSAD), including an assessment of donepezil treatment on SIB scores, and to potentially identify a cognitive transition point associated with predicted functional disability. METHODS: The study comprised 290 patients with MSAD (standardized Mini-Mental State Examination score, 5-17) treated with donepezil 5-10 mg/day or matching placebo. Measurements were SIB, Functional Rating Scale, and Disability Assessment for Dementia. RESULTS: The largest decline in ability to perform basic activities of daily living (bADLs) occurred in placebo-treated patients with a baseline SIB score of approximately 70. Changes were reduced in the donepezil-treated group. CONCLUSIONS: This post hoc exploratory analysis suggests that a transition point between moderate and severe AD exists at a SIB score of approximately 70 and is associated with predictably declining bADLs.

Effectiveness of donepezil in reducing clinical worsening in patients with mild-to-moderate alzheimer's disease.

BACKGROUND: Therapeutic endpoints based on reduced clinical worsening represent clinically relevant and realistic goals for patients suffering from progressive neurodegenerative disorders such as Alzheimer's disease (AD). METHODS: Data from 906 patients (388 receiving placebo; 518 receiving donepezil) with mild-to-moderate AD [Mini-Mental State Examination (MMSE) score 10-27] were pooled from 3 randomized, double-blind placebo-controlled studies. Clinical worsening was defined as decline in (1) cognition (MMSE), (2) cognition and global ratings (Clinician's Interview-Based Impression of Change plus Caregiver Input/Gottfries-Bråne-Steen scale) or (3) cognition, global ratings and function (various functional measures). RESULTS: At week 24, lower percentages of donepezil-treated patients than placebo patients met the criteria for clinical worsening, regardless of the definition. The odds of declining were significantly reduced for donepezil-treated versus placebo patients (p < 0.0001; all definitions). Among patients meeting criteria for clinical worsening, mean declines in MMSE scores were greater for placebo than donepezil-treated patients. CONCLUSION: In this population, donepezil treatment was associated with reduced odds of clinical worsening of AD symptoms. Moreover, patients worsening on donepezil were likely to experience less cognitive decline than expected if left untreated. This suggests that AD patients showing clinical worsening on donepezil may still derive benefits compared with placebo/untreated patients.

Donepezil treatment in severe Alzheimer's disease: a pooled analysis of three clinical trials.

OBJECTIVE: Individual clinical trials have demonstrated benefits of donepezil in patients with severe Alzheimer's disease (AD). Data were pooled from three randomized, placebo-controlled trials of donepezil for severe AD to further evaluate treatment effects and overall tolerability/safety. METHODS: Total scores and sub-scores were analyzed for measures of cognition, global function, function, and behavior. Additional analyses were performed to investigate (1) relationships between cognitive, functional, and behavioral changes, and (2) patterns of combined domain response. RESULTS: Using pooled total scores, significant treatment differences at endpoint in favor of donepezil were observed for cognition, global function (both p < 0.0001), and function (p = 0.03), with an effect size (Cohen's d) of 0.51, 0.26, and 0.17, respectively. There was no significant treatment difference for behavior. However, donepezil-treated patients with stabilized/improved cognition tended to show significant improvements in function and behavior over placebo-treated patients. Patients treated with donepezil were 2-3 times more likely to achieve a combined domain response than placebo-treated patients (p < 0.0001). Adverse events were as expected for cholinergic therapy, and mortality rates were similar between the treatment groups. CONCLUSIONS: These findings suggest measurable donepezil-mediated symptomatic benefits in cognition, global function, and daily living activities in patients with severe AD. The treatment effects support the importance of cholinesterase inhibition as a clinically relevant therapeutic option across the spectrum of AD.

Rates of cognitive change in Alzheimer disease: observations across a decade of placebo-controlled clinical trials with donepezil.

Treatment success in Alzheimer disease (AD) trials is generally based on benefits over placebo-treated controls. Consequently, variation in rates of decline among placebo-treated patients could impact outcomes from AD trials. In the present analyses, individual patient data [baseline Mini-Mental State Examination (MMSE): 10 to 26] were pooled from randomized, placebo-controlled studies of donepezil for AD conducted during the 1990s, and grouped by initiation year-group 1: 1990 to 1994; group 2: 1996 to 1999. Changes in MMSE and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) were compared between groups 1 and 2 for placebo, and then between donepezil and placebo. Data were available from 3403 patients in 13 trials. Group 2 (post-1995) included patients with lower baseline MMSE scores, older patients, fewer males, more comorbidity, and more concomitant medications. MMSE decline by week 24 was significantly greater among group 1 (pre-1995) placebo patients versus group 2; a similar trend was observed with the ADAS-cog. Nevertheless, donepezil-mediated treatment effects were consistent over the decade of enrollment. These analyses suggest that patients are showing slower rates of cognitive decline in more recent trials compared with older trials, although having more comorbidities. This finding may have important potential implications for future clinical trial design.

Defining treatment response to donepezil in Alzheimer's disease: responder analysis of patient-level data from randomized, placebo-controlled studies.

BACKGROUND: Defining treatment success in progressive diseases, such as Alzheimer's disease (AD), can be challenging. OBJECTIVE: To explore the impact of employing different criteria to define a treatment 'responder' using analyses of patient-level data from randomized, placebo-controlled studies of donepezil in AD. METHODS: Trials were included in the analysis if they met several criteria, including the following: randomized, placebo-controlled trial of donepezil 10 mg/day in mild-to-moderate AD; cognition measured by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) or Mini-Mental State Examination (MMSE); and a 24-week endpoint and outcomes that included global assessments. Definitions of response were: improvements in cognition plus one other domain; improvement in cognition only; improvement or improvement/no change in global response; and improvement/stabilization/less than expected decline by < or = 2 or < or = 4 or < or = 6 points on the ADAS-cog. RESULTS: Five studies identified from the literature search met the specified criteria for inclusion. The response to donepezil measured by ADAS-cog varied from 26% to 63% and that of placebo from 14% to 47%, depending on the definition of improvement used. For definitions that included a less than expected decline on ADAS-cog, the more modest the effect defined, the less the drug versus placebo difference and the higher the percentage of patients meeting this definition. CONCLUSIONS: The definition of treatment 'response' in a progressive neurodegenerative disease can encompass a variety of outcomes, including short-term improvement, longer-term stabilization and a slowed decline in one or more clinically relevant symptoms or symptom domains. The ability to identify groups of people who respond to donepezil underscores the clinical utility of the medication and may contribute to more focused assessments of the cost effectiveness of cholinesterase inhibitors.

Effectiveness of open-label donepezil treatment in patients with Alzheimer's disease discontinuing memantine monotherapy.

OBJECTIVE: To evaluate the efficacy and safety of donepezil in patients with Alzheimer's disease (AD) who discontinue memantine due to a lack of efficacy or not being well tolerated. METHODS: This study enrolled patients with moderate-to-severe AD (Mini-Mental State Examination [MMSE] score 5-17) who had a history of treatment with memantine monotherapy (10 mg/BID) for > or = 3 months prior to screening and maintained until study baseline. For inclusion in this study, the patient's memantine treatment had to have been judged as lacking efficacy or not well tolerated at the screening visit. Information on previous memantine use was also obtained with regard to dose and duration of treatment. At the baseline visit, patients were switched to open-label donepezil 5 mg/day for 4 weeks, and 10 mg/day thereafter. The primary efficacy measure was a change in MMSE at week 12 using a last observation carried forward (LOCF) analysis. Secondary measures included Physician and Caregiver Satisfaction Questionnaires (PSQ, CSQ), the Clinical Global Impression-Improvement (CGI-I), Neuropsychiatric Inventory (NPI), and a Caregiver Diary (CD). RESULTS: At week 12-LOCF, MMSE scores increased by a mean of 1.55 points from baseline (p < 0.0001). At end point, the PSQ and CSQ indicated consistent improvements in satisfaction/ease of use with donepezil; 60.2% of patients improved on the CGI-I; and 44.4-55.6% improved on each of three components of the CD. Improvements on the MMSE, CSQ, and CGI-I were apparent, irrespective of previous cholinesterase (ChE) inhibitor use. No significant effects were seen for the total score on the NPI. Withdrawal rates (8.7% due to adverse events [AEs]) and AEs were consistent with the known donepezil safety profile. CONCLUSION: Donepezil was effective and well tolerated in moderate-to-severe AD patients who discontinued memantine monotherapy, including those with previous exposure to ChE inhibitors.

Health economics and the value of therapy in Alzheimer's disease.

In increasingly aging societies throughout the developed and developing world, Alzheimer's disease and related dementias are fast becoming a critical public health issue, exacting an enormous toll on individuals and healthcare systems. Over the past 10 years, five drugs have been developed and approved for the symptomatic treatment of Alzheimer's dementia, and several disease-modifying drugs are in various stages of clinical development. While symptomatic medications were consistently shown to have clinical benefit in numerous efficacy studies, the cost effectiveness of antidementia therapies and their value to healthcare systems remain unclear. The pharmacoeconomics of antidementia therapies is an evolving field, with several unanswered questions. This poses many challenges for biopharmaceutical companies developing these therapies, regulatory agencies responsible for their approval, and payers responsible for ensuring their availability to patients. The challenge partly relates to the unique nature of dementia as a disease of impaired cognition, behavior, and function. Thus, the selection of appropriate outcome measures that directly relate to healthcare utilization, quality of life, caregiver burden, and pharmacoeconomic analysis has been difficult. The development of meaningful and widely acceptable outcome measures, as well as novel clinical-study designs, is needed to better evaluate cost effectiveness and to demonstrate the value of therapeutics for Alzheimer's disease. Providing the decision-makers in healthcare systems with a body of evidence that demonstrates a positive relationship between clinical outcomes and the economic and humanistic benefits of antidementia therapeutics will improve patient access to novel drugs as they become available.

Efficacy and safety of donepezil in patients with more severe Alzheimer's disease: a subgroup analysis from a randomized, placebo-controlled trial.

BACKGROUND: There have been very limited investigations of cholinesterase inhibitor therapy in more advanced stages of Alzheimer's disease (AD). The efficacy and safety of donepezil were evaluated in post hoc analyses of a subgroup of patients with more severe AD (standardized Mini-Mental State Examination [sMMSE] score 5-12) within a randomized, placebo-controlled trial in moderate to severe AD (MSAD study). Additional analyses examined whether donepezil's treatment effects were consistent across the full range of baseline AD severity studied (sMMSE score 5-17). METHODS: Patients with moderate to severe AD (n = 290) who were living in the community or in assisted living facilities received donepezil or placebo for 24 weeks; n = 145 in the more severe AD subgroup. The primary outcome measure was the Clinician's Interview-Based Impression of Change (CIBIC-plus) with secondary outcomes including the sMMSE, Severe Impairment Battery, Neuropsychiatric Inventory, and Disability Assessment for Dementia. Analysis of Variance and Analysis of Covariance models tested for treatment x disease severity interaction in the full MSAD study sample. RESULTS: CIBIC-plus scores for donepezil patients were significantly improved compared with placebo for each time-point, with a 0.70 mean treatment difference at Week 24 last observation carried forward (LOCF; p = 0.0002). Significant differences favoring donepezil were noted at Week 24 LOCF for all secondary measures. There were no treatment x severity interactions for any of the efficacy measures. CONCLUSIONS: In this analysis, donepezil had significant benefits over placebo on global, cognitive, functional, and behavioral measures in a subgroup of patients with more severe AD. Furthermore, the treatment effects of donepezil were not driven by a particular stratum within the moderate to severe dementia range.

Cholinesterase inhibitors used in the treatment of Alzheimer's disease: the relationship between pharmacological effects and clinical efficacy.

The deficiency in cholinergic neurotransmission in Alzheimer's disease has led to the development of cholinesterase inhibitors as the first-line treatment for symptoms of this disease. The clinical benefits of these agents include improvements, stabilisation or less than expected decline in cognition, function and behaviour. The common mechanism of action underlying this class of agents is an increase in available acetylcholine through inhibition of the catabolic enzyme, acetylcholinesterase. There is substantial evidence that the cholinesterase inhibitors, including donepezil, galantamine and rivastigmine, decrease acetylcholinesterase activity in a number of brain regions in patients with Alzheimer's disease. There is also a significant correlation between acetylcholinesterase inhibition and observed cognitive improvement. However, the cholinesterase inhibitors are reported to have additional pharmacological actions. Rivastigmine inhibits butyrylcholinesterase with a similar affinity to acetylcholinesterase, although it is not clear whether the inhibition of butyrylcholinesterase contributes to the therapeutic effect of rivastigmine. Based on data from preclinical studies, it has been proposed that galantamine also potentiates the action of acetylcholine on nicotinic receptors via allosteric modulation; however, the effects appear to be highly dependent on the concentrations of agonist and galantamine. It is not yet clear whether these concentrations are related to those achieved in the brain of patients with Alzheimer's disease within therapeutic dose ranges. Preclinical studies have shown that donepezil and galantamine also significantly increase nicotinic receptor density, and increased receptor density may be associated with enhanced synaptic strengthening through long-term potentiation, which is related to cognitive function. Despite these differences in pharmacology, a review of clinical data, including head-to-head studies, has not demonstrated differences in efficacy, although they may have an impact on tolerability. It seems clear that whatever the subsidiary modes of action, clinical evidence supporting acetylcholinesterase inhibition as the mechanism by which cholinesterase inhibitors treat the symptoms of Alzheimer's disease is accumulating. Certainly, as a class, the currently approved cholinesterase inhibitors (donepezil, galantamine, rivastigmine and tacrine) provide important benefits in patients with Alzheimer's disease and these drugs offer a significant advance in the management of dementia.