Effect of masupirdine (SUVN-502) on cognition in patients with moderate Alzheimer's disease: A randomized, double-blind, phase 2, proof-of-concept study.

Introduction: This study explored the efficacy and safety of a serotonin-6 receptor antagonist, masupirdine, as adjunct treatment in patients with moderate Alzheimer's disease (AD) concomitantly treated with donepezil and memantine. Methods: The effects of masupirdine were evaluated in patients with moderate AD dementia on background treatment with donepezil and memantine. Five hundred thirty-seven patients were expected to be randomized in a 1:1:1 ratio, using permuted blocked randomization. After a 2- to 4-week screening period, the study consisted of a 26-week double-blind treatment period, and a 4-week washout period. The primary efficacy measure was the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog 11). Secondary efficacy measures were Clinical Dementia Rating Scale-Sum of Boxes, Mini-Mental State Examination, 23-item Alzheimer's Disease Co-operative Study Activities of Daily Living, and 12-item Neuropsychiatric Inventory. Changes from baseline were analyzed using a mixed effects model for repeated measures (MMRM). A total of 564 patients were randomized to receive either daily masupirdine 50 mg (190 patients), masupirdine 100 mg (185 patients), or placebo (189 patients). The study is registered at ClinicalTrials.gov (NCT02580305). Results: The MMRM results showed statistically non-significant treatment differences in change from baseline in ADAS-Cog 11 scores at week 26, comparing each masupirdine dose arm to the placebo arm. No significant treatment effects were observed in the secondary evaluations. Discussion: Masupirdine was generally safe and well tolerated. Possible reasons for the observed trial results are discussed. Highlights: Masupirdine was evaluated in moderate Alzheimer's disease patients.First trial in class with background treatment of donepezil and memantine.Masupirdine was generally safe and well tolerated.Possible reasons for the observed trial results are discussed.

Safety and tolerability of donepezil at doses up to 20 mg/day: results from a pilot study in patients with Alzheimer's disease.

BACKGROUND: Donepezil is licensed for the treatment of mild-to-moderate Alzheimer's disease (AD) at doses of 5-10 mg/day and has recently been approved in the US for severe AD. Multiple studies have suggested that donepezil 10 mg/day provides additional cognitive and functional benefits over the 5 mg/day dose. Higher doses of donepezil, if safe and well tolerated, might provide further benefits for patients with AD. OBJECTIVE: To evaluate the safety and tolerability of donepezil at doses of 15 and 20 mg/day. METHOD: A 24-week, randomized, double-blind, placebo-controlled, pilot study conducted at two investigational sites in the US. Enrolled patients (male and female; aged 50-86 years) had a diagnosis of probable AD at the mild-to-moderate stage (Mini-Mental State Examination [MMSE] score 10-26). All patients had been treated with donepezil 10 mg/day for 12-30 months prior to enrolment. Patients (n = 31) were randomized 1 : 1 to receive either a standard dose of donepezil (donepezil 10 mg/day plus placebo 5 mg/day for weeks 1-12; donepezil 10 mg/day plus placebo 10 mg/day for weeks 13-24) or a higher dose of donepezil (donepezil 15 mg/day for weeks 1-12; donepezil 20 mg/day for weeks 13-24). Primary outcome measures were tolerability (as determined by monitoring of discontinuations, dose modifications and adverse events) and safety (as determined by adverse event monitoring, physical examinations, clinical laboratory tests and ECGs). Psychometric measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-cog], MMSE and Clinician's Interview-Based Impression of Change with caregiver information [CIBIC+]) and pharmacokinetic/pharmacodynamic parameters were secondary outcomes. RESULTS: No patients withdrew from the study and there were no serious adverse events or deaths. By week 24, 15 of 16 patients in the higher-dose group tolerated the maximum 20 mg/day dose; one patient had a permanent dose reduction to donepezil 15 mg/day. In the standard-dose group, 14 of 15 patients tolerated donepezil 10 mg/day plus placebo 10 mg/day by the end of the study; one patient had a permanent dose reduction to donepezil 10 mg/day plus placebo 5 mg/day. Temporary dose reductions occurred in two patients (one from each group). Adverse events reported were as expected for donepezil and were all mild to moderate in intensity. Adverse events considered to be possibly or probably related to treatment were reported for three patients in the standard-dose group and six patients in the higher-dose group. One patient in the higher-dose group had weight loss reported as possibly or probably treatment related. Mean changes on ECGs were not clinically significant in either group, and the incidence of bradycardia was comparable. No treatment difference on any of the psychometric measures was observed between the groups. Pharmacokinetic analyses showed that an increased donepezil dose was associated with an increase in donepezil plasma concentrations from baseline. CONCLUSION: In this small pilot study of patients with mild-to-moderate AD already stabilized on donepezil 10 mg/day, doses of 15 and 20 mg/day of donepezil appeared safe and well tolerated. These results justify initiation of larger clinical trials designed to investigate the efficacy and safety of doses of donepezil higher than 10 mg/day in patients with AD.

Antiamnesic and neuroprotective effects of donepezil against learning impairments induced in mice by exposure to carbon monoxide gas.

Donepezil is a potent acetylcholinesterase inhibitor that also interacts with the sigma1 receptor, an intracellular neuromodulatory protein. In the present study, we analyzed the antiamnesic and neuroprotective activities of donepezil in a mouse hypoxia model induced by repetitive CO exposure, comparing donepezil's pharmacological profile with other cholinesterase inhibitors tacrine, rivastigmine, and galanthamine, and the reference sigma1 agonist igmesine. CO exposure induced, after 7 days, hippocampal neurodegeneration, analyzed by Cresyl violet staining, and behavioral alterations, measured using spontaneous alternation and passive avoidance responses. When injected 20 min before the behavioral tests, i.e., 7 to 8 days after CO, all drugs showed antiamnesic properties. Preadministration of the sigma1 receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047) blocked only the igmesine and donepezil effects. The neuroprotective activity of the drugs was tested by injection 20 min before the first CO exposure (preinsult protection) or by injection 1 h after the last CO exposure (postinsult protection). All drugs alleviated the hypoxia-induced neurodegeneration and behavioral impairments when injected before CO exposure. Preadministration of BD1047 blocked both the igmesine and donepezil effects. However, when injected after CO exposure, only igmesine and donepezil induced effective neuroprotection, and the morphological and behavioral effects were BD1047-sensitive. These results showed that donepezil is a potent antiamnesic and neuroprotective compound against the neurodegeneration induced by excitotoxic insult, and its pharmacological actions as both an acetylcholinesterase inhibitor and sigma1 receptor agonist contribute to its marked efficacy. In particular, the drug is a more potent postinsult protecting agent compared with more selective cholinesterase inhibitors.

Interaction with sigma(1) protein, but not N-methyl-D-aspartate receptor, is involved in the pharmacological activity of donepezil.

In the present study, we examined the interaction of (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-1H-inden-1-one hydrochloride (donepezil), a potent cholinesterase inhibitor, with two additional therapeutically relevant targets, N-methyl-d-aspartate (NMDA) and sigma(1) receptors. Donepezil blocked the responses of recombinant NMDA receptors expressed in Xenopus oocytes. The blockade was voltage-dependent, suggesting a channel blocker mechanism of action, and was not competitive at either the l-glutamate or glycine binding sites. The low potency of donepezil (IC(50) = 0.7-3 mM) suggests that NMDA receptor blockade does not contribute to the therapeutic actions of donepezil. Of potential therapeutic relevance, donepezil binds to the sigma(1) receptor with high affinity (K(i) = 14.6 nM) in an in vitro preparation (Neurosci Lett 260:5-8, 1999). Thus, we sought to determine whether an interaction with the sigma(1) receptor may occur in vivo under physiologically relevant conditions by evaluating the sigma(1) receptor dependence effects of donepezil in behavioral tasks. Donepezil showed antidepressant-like activity in the mouse-forced swimming test as did the sigma(1) receptor agonist igmesine. This effect was not displayed by the other cholinesterase inhibitors, rivastigmine and tacrine. The donepezil and igmesine effects were blocked by preadministration of the sigma(1) receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine (BD1047) and an in vivo antisense probe treatment. The memory-enhancing effect of donepezil was also investigated. All cholinesterase inhibitors attenuated dizocilpine-induced learning impairments. However, only the donepezil and igmesine effects were blocked by BD1047 or the antisense treatment. Therefore, donepezil behaved as an effective sigma(1) receptor agonist on these behavioral responses, and an interaction of the drug with the sigma(1) receptor must be considered in its pharmacological actions.

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.

Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy of donepezil in patients with early-stage Alzheimer disease. DESIGN: Multicenter, randomized, double-blind, 24-week, placebo-controlled study that enrolled patients with early-stage Alzheimer disease. Patients were randomized in an approximately 2:1 ratio to donepezil, 5 mg/d, for the first 6 weeks, with a forced escalation to 10 mg/d thereafter (n = 96), or placebo (n = 57). The primary efficacy measure was the modified Alzheimer Disease Assessment Scale-cognitive subscale. Secondary efficacy measures included the Mini-Mental State Examination, the Computerized Memory Battery Test, the Clinical Dementia Rating Scale-Sum of the Boxes, the Patient Global Assessment Scale, and the Apathy Scale. RESULTS: Improvements favoring donepezil on the Alzheimer Disease Assessment Scale-cognitive subscale were found at weeks 12 and 24 and at the end point (last observation carried forward); treatment differences were 1.9 (P = .03), 2.3 (P = .008), and 2.3 (P = .001) points, respectively. Improvements favoring donepezil on the Mini-Mental State Examination were found at weeks 6, 12, and 24 and at the end point (last observation carried forward); treatment differences were 1.4 (P = .02), 1.2 (P = .04), 1.4 (P = .03), and 1.8 (P = .002) points, respectively. Donepezil-treated patients showed greater mean improvement compared with placebo-treated patients on the following Computerized Memory Battery Test subscales: facial recognition (P = .007 in the intent-to-treat population and P = .04 in the fully evaluable population), first and last name total acquisition (P = .02), and name-face association delayed recall (P = .04). Donepezil was safe and well tolerated in this population; serious adverse events occurred in similar numbers of donepezil- and placebo-treated patients. CONCLUSION: These data suggest significant treatment benefits of donepezil in early-stage Alzheimer disease, supporting the initiation of therapy early in the disease course to improve daily cognitive functioning.

Randomized, placebo-controlled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer's disease.

OBJECTIVE: The authors examined the effect of the acetylcholinesterase inhibitor donepezil on magnetic resonance markers of neurodegeneration in Alzheimer's disease. METHOD: In this randomized, double-blind, placebo-controlled pilot study, 67 patients with mild to moderate Alzheimer's disease received 24 weeks of treatment with donepezil (5 mg/day for the first 28 days and 10 mg/day thereafter) or placebo. Patients were reevaluated at 6-week intervals to measure change from baseline in several outcome measures, including right, left, and total hippocampal volumes, measured with magnetic resonance imaging; brain concentrations of N-acetylaspartate, measured with proton magnetic resonance spectroscopy; and cognition, assessed with the Alzheimer's Disease Assessment Scale cognitive subscale. RESULTS: At some interim assessments, mean normalized measures of N-acetylaspartate concentration tended to be higher in the donepezil-treated patients than in the patients who received placebo, but these differences were not significant at endpoint. At endpoint, the donepezil-treated patients had significantly smaller mean decreases in total and right hippocampal volumes and a smaller, nearly significant mean decrease in left hippocampal volume, compared with the placebo-treated patients. Mean Alzheimer's Disease Assessment Scale cognitive subscale scores were improved after treatment with donepezil, relative to placebo, at weeks 6, 12, 18, and 24. CONCLUSIONS: These preliminary results suggest that donepezil may have a potentially protective effect in Alzheimer's disease. Larger, longer-term confirmatory studies of the medication's effects are warranted.

Donepezil is associated with delayed nursing home placement in patients with Alzheimer's disease.

OBJECTIVES: To assess the relationship between donepezil treatment and time to nursing home placement (NHP) for patients with Alzheimer's disease (AD). DESIGN: Observational follow-up of patient NHP and vital status. SETTING: Community. PARTICIPANTS: Patients previously enrolled in one of three randomized, double-blind, placebo-controlled clinical trials of donepezil and two subsequent open-label studies (total N = 1,115); 671 patients provided complete data for analysis. MEASUREMENTS: Data were obtained through follow-up interviews with caregivers and chart reviews of patients with AD. Comparison groups were defined by whether patients received an effective dose of donepezil (>/=5 mg/d; >/=80% compliance) for specific numbers of weeks during the double-blind or open-label trial phase, in both phases, or in neither. Cox proportional hazards models were used to estimate risk ratios for NHP and survival curves from which median times to NHP were estimated for first dementia-related placement of longer than 2 weeks and permanent placement. The models were adjusted for age, sex, baseline Mini-Mental State Examination score, whether the caregiver was a spouse, caregiver continuity, and use of other cholinesterase inhibitors after the clinical trials. RESULTS: Use of donepezil of 5 mg/d or more was associated with significant delays in NHP. A cumulative dose-response relationship was observed between longer-term sustained donepezil use and delay of NHP. When donepezil was taken at an effective dose for at least 9 to 12 months, conservative estimates of the time gained before NHP were 21.4 months for first dementia-related NHP and 17.5 months for permanent NHP. CONCLUSION: Use of donepezil by AD patients resulted in significant delays in NHP. Long-term use of donepezil may help AD patients live longer in community settings, with consequent personal, social, and economic benefits.

Donepezil HCl (E2020) maintains functional brain activity in patients with Alzheimer disease: results of a 24-week, double-blind, placebo-controlled study.

OBJECTIVE: The authors evaluated the effects of donepezil (10 mg/day) versus placebo on brain glucose metabolism. METHODS: This was a randomized, double-blind, parallel-group, 24-week pilot study in 28 patients with mild-to-moderate Alzheimer disease (AD). Functional brain activity was quantified by measuring average glucose metabolism in an axial brain slice and regional brain glucose metabolism using positron emission tomography. RESULTS: At Week 24, relative to the pons metabolic rate, mean brain glucose metabolism in an axial slice at the level of the striatum was maintained within 0.5% of mean baseline levels for donepezil-treated patients, whereas it declined by an average of 10.4% in placebo-treated patients. This observation was confirmed by an analysis of differences in the mean slopes of glucose metabolism in the striatal slice in donepezil- and placebo-treated patients during the 24-week period. Significant treatment differences at Week 24 favoring donepezil for the mean percentage change from baseline in regional brain glucose metabolism were observed in four predefined regions of interest: the right parietal lobe 1, left temporal lobe 2, right frontal lobe 2, and left frontal lobe 2. CONCLUSION: Placebo-treated patients with AD show a decline in functional brain activity, relative to the pons, in several regions, and treatment with donepezil may slow this decline.

PET Studies of the Effect of the Antidepressant Drugs Nefazodone or Paroxetine on [11C]Raclopride Binding in Human Brain.

Serotonin modulates dopamine release in the striatum. In this study we set out to determine whether nefazodone and paroxetine, two antidepressant drugs that interact with the brain serotonin system, produce detectable changes in synaptic dopamine in vivo in the human brain using positron emission tomography (PET) and [11C]raclopride, a dopamine D-2 receptor specific radiotracer that is sensitive to changes in synaptic dopamine. Three normal healthy human volunteers had 4 PET/[11C]raclopride scans each in 2 sessions. In the first session, subjects had a baseline [11C]raclopride scan and a second scan 1 hour following the oral administration of either nefazodone (200 mg PO) or paroxetine (20 mg PO). Four to 6 weeks later, in a second PET/[11C]raclopride session, the same subjects received the other drug for comparison. Neither nefazodone nor paroxetine produced significant changes in [11C]raclopride binding. This and other reports in the literature indicate that different drugs that affect the serotonin system do not produce consistent and predictable changes in [11C]raclopride binding and that a full understanding of their actions on serotonin and the associated changes in dopamine requires further investigation.