Robert K. Hofbauer

Magnetic resonance imaging and neuropsychological results from a trial of memantine in Alzheimer's disease.

This study was designed to assess changes in brain volume and cognitive abilities in memantine‐treated patients with Alzheimers disease (AD) by using an exploratory, single‐arm, delayed‐start design.

Cumulative, additive benefits of memantine-donepezil combination over component monotherapies in moderate to severe Alzheimer’s dementia: a pooled area under the curve analysis

IntroductionTreatment in moderate or severe Alzheimer’s disease (AD) often involves adding memantine to a cholinesterase-inhibitor (ChEI: donepezil, galantamine, rivastigmine). Evidence from six-month randomized trials and long-term observational studies supports superiority of memantine-ChEI combination to ChEI monotherapy. We utilized area-under-the-curve (AUC) analysis to assess six-month cumulative treatment efficacy of memantine-donepezil combination versus component monotherapies on individual clinical domains and on a composite index.MethodsData were pooled from 1,408 individuals with moderate to severe AD from four six-month randomized trials of memantine monotherapy (n = 570) or add-on therapy (donepezil-only subset: n = 847). AUC changes from baseline on measures of cognition (SIB), function (ADCS-ADL19), behavior (NPI), global status (CIBIC-Plus), and a composite index (4D-CI: equally weighted composite of four domain measures) were calculated using the trapezoidal rule and evaluated via analysis of covariance (ANCOVA) (2-sided-α = 0.05). AUC results were contrasted with visit-by-visit changes from baseline (“snapshot analysis”), performed using a mixed-effects model with repeated measures (MMRM).ResultsOver the entire six-month period, placebo-only treatment was associated with significant cumulative worsening on all outcomes. Memantine-donepezil combination showed significantly greater AUC improvements (point x week) on the SIB, NPI, and CIBIC-Plus than placebo-donepezil (SIB: 68.4 versus 32.0, P = 0.019; NPI: −74.3 versus −28.2, P = 0.003; CIBIC-Plus: −2.5 versus 1.4, P = 0.006) and memantine-only monotherapies (SIB: 68.4 versus 12.0, P <0.001; NPI: −74.3 versus −7.4, P <0.001; CIBIC-Plus: −2.5 versus 2.7, P <0.001), whereas these comparisons were not significant for the ADCS-ADL19 (memantine-donepezil (1.4) versus placebo-donepezil (−0.9), P = 0.407; versus memantine-only (−12.2), P = 0.310). Composite index analysis demonstrated significant cumulative advantages of memantine-donepezil combination (630.0) over placebo-donepezil (344.7, P <0.001) and memantine-only (152.1, P <0.001) treatments. Combining memantine and donepezil had an additive effect. Compared with AUC analysis, baseline-to-endpoint change-score analysis underestimated effects of combination therapy, monotherapies, or both.ConclusionsThis large pooled area-under-the-curve analysis of randomized-trial data in moderate to severe AD provides ecologically valid support that adding memantine to stable donepezil results in overall clinical benefits that are additive compared with individual monotherapies, continue to accumulate through six-month treatment, and are at least 50% greater than those of monotherapies.

Memantine and Functional Communication in Alzheimer's Disease: Results of a 12-Week, International, Randomized Clinical Trial

Post hoc analyses suggest that memantine treatment may provide communication-related benefits in patients with Alzheimers disease (AD). In this 12-week, international, randomized, double-blind, placebo-controlled trial of memantine (10 mg bid), the functional communication abilities of patients with AD (MMSE range: 10-19) were assessed using the Functional Linguistic Communication Inventory (FLCI; primary measure). Two combined subscales (Social Communication and Communication of Basic Needs) from the American Speech-Language-Hearing Association Functional Assessment of Communication Skills for Adults (ASHA FACS; secondary measure) were administered to caregivers. Treatment-emergent adverse events were also recorded. After 12 weeks, memantine-treated patients (n = 133) demonstrated a non-significant improvement on the FLCI (placebo: -0.6; memantine: 0.7; p = 0.070, LOCF) and a significant improvement on the ASHA FACS (placebo: -5.3; memantine: 0.5; p = 0.022), compared with placebo-treated patients (n = 124). Memantine had a low incidence of adverse events. In patients with moderate AD, memantine treatment improved functional communication, as recognized by caregivers.

Effects of memantine treatment on language abilities and functional communication: A review of data

Background: Impairment in language abilities occurs in a number of neurological conditions, including Alzheimers disease (AD) and other dementias, primary progressive aphasia, multiple sclerosis and stroke. Currently, no pharmacotherapy is approved for aphasia of any aetiology. Memantine, an antagonist of N-methyl-D-aspartate glutamate receptors that is approved for the treatment of moderate-to-severe AD, has shown promising results on several measures of language and communication in clinical trials. Aims: This review summarises the knowledge gathered from prospective studies and post hoc analyses involving patients with AD and other neurological conditions in whom the effects of memantine treatment on language or communication have been examined. Main Contribution: PubMed searches yielded a total of four prospective studies and three post hoc analyses that assessed the effects of memantine on language and communication in AD (one additional post hoc analysis was published as a conference proceeding only), together with seven prospective studies in other conditions (Parkinsons disease, frontotemporal lobe degeneration, chronic post-stroke aphasia, primary progressive aphasia, multiple sclerosis, risk of dementia). Available data suggest that memantine provides modest language and communication benefits in patients with moderate-to-severe AD; potential benefits in Parkinsons disease and post-stroke aphasia were also observed. Conclusions: Memantine may provide clinical benefits in language and communication in AD and other neurological conditions. Since communication problems create a significant burden for patients and their caregivers, larger prospective trials, conducted to provide more precise estimates of benefits in that domain, are merited.

AREA UNDER THE CURVE (AUC) POOLED ANALYSIS OF FOUR RANDOMIZED CLINICAL TRIALS SHOWS CUMULATIVE BENEFITS OF MEMANTINE-DONEPEZIL COMBINATION OVER COMPONENT MONOTHERAPIES ACROSS CLINICAL DOMAINS IN ALZHEIMER'S DEMENTIA

Background: Synapse loss and dysfunction characteristic of Alzheimer’s disease (AD) have been linked to the degeneration of neuronal membranes and increased breakdown of membrane phospholipids. Recent studies have demonstrated lower plasma levels of several phospholipid species in AD and/or mild cognitive impairment (MCI) subjects compared with those in healthy individuals. Most interestingly, Mapstone (2014, Nat Med) validated a prognostic biomarker panel of 10 plasma lipids that could predict conversion to MCI/AD within 2-3 years with >90% accuracy. The lower levels of these lipids, particularly phosphatidylcholine species, could reflect altered phospholipid metabolism in the brain and periphery. Methods: We tested in drug-na€ıve patients with very mild to mild AD, a nutritional intervention (Souvenaid , 125mL, taken once daily) containing a specific nutrient combination in a 24-week, randomized, controlled, double-blind, parallel-group, multi-country trial. Baseline and 24-week plasma samples of patients taking either the investigational or control product were analyzed for lipid profiles at the Kansas Lipidomics Research Center using ESI-MS/ MS.Results: Five of the 7 measured phosphatidylcholine species described by Mapstone, were significantly increased following the 24-week treatment with the nutrient combination. Plasma concentration (mM; mean (s.d.)) among patients taking the investigational product increased as follows: phosphatidylcholine diacyl (PCaa)-C36:6: +0.66 (0.79); PCaa-C38:0: +1.42 (2.00); PCaa-C38:6: +81.14 (36.74); PCaa-C40:6: +33.58 (16.95); phosphatidylcholine acyl-alkyl (PCae)-C40:6: +3.27 (1.88); (all P<0.001, change from baseline using paired t-test; and all P<0.0001, investigational vs. control product using ANCOVA). Conclusions: These results indicate that a biomarker profile reflecting disturbed phospholipid metabolism and perhaps indicative of early neurodegeneration can be modified in AD by providing nutrients which rate-limit phospholipid biosynthesis. These nutrients are substrates in the Kennedy pathway which synthesizes the phospholipids present in synaptic membranes and could thus ameliorate synaptic degeneration in AD. Previous observations from the same study indicate that this nutritional intervention improves memory performance (Scheltens, 2012, JAD), and preserves brain network organization in AD patients (de Waal, 2014, PLoS One), which both may result from enhanced formation of synaptic membranes. Our findings suggest that the nutritional intervention may also be useful in asymptomatic subjects with a plasma lipid profile prognostic of AD. Souvenaid is a registered trademark of N.V. Nutricia.

Effects of memantine on functional communication in patients with moderate AD: Results of a 12-week placebo-controlled trial

Background: EHT 0202 is a GABAA receptor modulator and a PDE4 inhibitor developed for the treatment of Alzheimer’s disease (AD). EHT 0202 is novel because it stimulates a-secretases, increasing the production of procognitive and neurotrophic sAPPa fragment of APP. Preclinical studies have shown that EHT 0202 1 ) protects cortical neurons against Ab42 and associated stresses and neuroprotection is associated with sAPPa induction, 2 ) demonstrates procognitive properties in various preclinical models: age-related memory impairment and scopolamine-induced amnesia and 3 ) chronic oral administrations of EHT 0202 reduce Ab42 levels in brain and CSF in rat and guinea pigs. These data suggest that EHT 0202 is able to reduce Ab burden by redirecting APP processing towards the a-secretase pathway and have favorable effects on neuron viability and cognition. Methods: Phase I studies demonstrated good tolerability of EHT 0202 in healthy young volunteers. No sedative effects or emesis were observed clinically and no alteration of attention and cognition on test battery were detected. Further, repeated doses in aged volunteers (60-75 years old) indicated that overall tolerability of EHT 0202 was good after a 10-day repeated administration up to 160 mg BID. Based on phase I results, a phase 2, parallel group, placebo-controlled, study of EHT 0202 (40 and 80 mg bid) was initiated. This randomized, doubleblind, multicentre study was designed to explore the clinical safety/tolerability and exploratory efficacy of EHT 0202 as adjunctive therapy to acetylcholinesterase inhibitor in ambulatory patients suffering from mild to moderate AD. Results: 135 patients are randomized to receive either 40 or 80 mg EHT 0202 bid or placebo bid. Patients are being followed over a 3-month period to determine the safety of EHT 0202 as well as its efficacy as measured by cognitive measures (ADAS-Cog, NTB, MMSE), global patient’s assessment (CDR-SB, CGI-C), behavior (NPI), activities of daily living (ADCS-ADL) and caregiver’s burden (Zarit’s scale). In addition, EHT 0202’s efficiency will be monitored using ExonHit’s recently developed companion diagnostic that allows quantitation of sAPPa in blood and patients’ transcriptomic profile will be determined using ExonHit’s SpliceArray platform. Conclusions: Trial status and information concerning EHT 0202 development program will be presented.

BENEFITS OF EARLY VERSUS DELAYED MEMANTINE ADDITION TO DONEPEZIL MONOTHERAPY IN PATIENTS WITH MODERATE TO SEVERE ALZHEIMER'S DISEASE: A POOLED ANALYSIS OF TWO RANDOMIZED TRIALS

P4-356 BENEFITS OF EARLY VERSUS DELAYED MEMANTINE ADDITION TO DONEPEZIL MONOTHERAPY IN PATIENTS WITH MODERATE TO SEVERE ALZHEIMER’S DISEASE: A POOLED ANALYSIS OF TWO RANDOMIZED TRIALS Stephen M. Graham, Suzanne Hendrix, Vojislav Pejovic, Robert K. Hofbauer, Victor B. Otcheretko, Forest Research Institute, Jersey City, New Jersey, United States; Pentara Corporation, Salt Lake City, Utah, United States; Prescott Medical Communications Group, Chicago, Illinois, United States. Contact e-mail: shendrix@pentaracorp. com

Memantine and prevention of worsening across multiple domains: Post hoc analysis of a randomized, placebo-controlled trial in patients with moderate Alzheimer's disease

Background: Preclinical research as well as preliminary human studies suggest that blocking of 5 hydroxytrypamine [5 HT6] receptors has an effect on cognitive function by stimulating the release of the two neurotransmitters acetylcholine and glutamate. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized, in part, by a number of deficits in the the function of these neurotransmitters. To date, direct modification of these systems alone leads to only small improvements in the symptoms associated with the disease. Efforts are now underway to evaluate 5 HT6 antagonism as a mechanism for modulating multiple neurotransmitter systems in order to mediate events associated with synpatic plasticity and impact cognition. Methods: Ascending single oral doses of SAM-760 will be administered to healthy young adult and elderly subjects in a placebo controlled, inpatient, 8-12 sequential dose group fashion with 8 subjects per group (6 receiving SAM-760 and 2 receiving matching placebo). Additional cohorts will include a food effect (high fat meal) and drug-drug interaction (ketoconazole, N 1⁄4 12-16) evaluation. Full safety evaluations will be administered at baseline (pretreatment), ongoing during the treatment period and posttreatment to assure appropriate study entry, continuous safety monitoring and final follow up (for any continuing events). Results: Safety and tolerability will be evaluated and presented from adverse events, summaries of physical examinations, supine and orthostatic vital sign measurements, cardiac rhythm monitoring, 12-lead digital ECGs, neurological evaluations, clinical laboratory test results. Preliminary SAM-760 and metabolite (in a limited cohort) pharmacokinetics will also be presented. Conclusions: An initial phase 1 study was designed to assess the safety, tolerability, preliminary pharmacokinetic and CNS effects of SAM-760, a 5 HT6 receptor antagonist, as a potential symptomatic treatment for reducing the cognitive deficits in patients with mild to moderate AD. A drug of similar mechanism of action to that of SAM 760 (i.e., SAM531) is currently in phase 2 development and shows potential as such a treatment: the current compound has been proposed as a promising backup for the this lead compound.

Discontinuation of Memantine Therapy in Nursing Home Residents With Alzheimer’s Disease is Associated With Increased Utilization of Psychotropic Medications and Decreased Body Weight

Introduction/Objective: This analysis examined the effect of discontinuation of memantine treatment on the utilization of psychotropic medications and change in body weight in nursing home residents with Alzheimer’s disease (AD). Design/Methodology: Data from medical charts of subjects with AD, / 50 years of age, and residing in nursing homes for / 90 days, were collected from 113 US nursing home sites. Residents who took memantine continuously for 90-120 days were compared to those who took memantine for 30 days, then discontinued the treatment for 60-90 days. Logistic regression models were used to estimate the odds of change in psychotropic drug utilization, controlling for age, gender, baseline weight, comorbidities, and an indicator of overall baseline psychotropic use. In addition, separate models were run for drug classes of antipsychotics, antidepressants, anticonvulsants, anxiolytics, and sedative hypnotics, controlling for baseline resident characteristics and baseline use of each drug class. Weight change from baseline was assessed using an analysis of covariance model, adjusted for baseline demographics and comorbidities. Results: The data were collected from 248 residents who discontinued memantine treatment and 273 residents who took memantine continuously. Overall, those who discontinued memantine therapy had a significantly higher rate of psychotropic use (32.3% vs 16.5%; OR 2.49; p 0.001), and significantly higher adjusted odds of utilizing antipsychotics (OR 2.48; p 0.005), anxiolytics (OR 2.46; p 0.01), antidepressants (OR 3.51; p 0.001), and anticonvulsants (OR 6.63; p 0.003). The effect was not significant for sedative hypnotics (OR 1.45; p 0.60). Residents who discontinued memantine treatment experienced an adjusted mean ( SD) weight loss of 1.48 5.0 kg, compared to a weight gain of 0.19 4.9 kg in residents who were treated continuously (p 0.001). Conclusion/Discussion: In nursing home residents with AD, memantine discontinuation was associated with higher odds of increased psychotropic use (including antipsychotics, anxiolytics, antidepressants, and anticonvulsants) and with significant weight loss, compared to continuous treatment. Disclosures: Constantine Lyketsos, MD received grant support (research or CME) from NIMH, NIA, Associated Jewish Federation of Baltimore, Forest Pharmaceuticals, Inc, GlaxoSmithKline, Eisai Inc., Pfizer Inc., AstraZeneca, Eli Lilly and Company, Ortho-McNeil, Inc., Bristol-Myers Squibb, and Novartis. He is a consultant/advisor for AstraZeneca, GlaxoSmithKline, Eisai Inc., Forest Pharmaceuticals, Inc, Novartis, Supernus, Adlyfe, Takeda Pharmaceutical Company, and Wyeth Pharmaceuticals and received honoraria or travel support from Pfizer Inc., GlaxoSmithKline, and Health Monitor. Howard Fillit, MD received speaker honoraria from Eisai Inc., Pfizer Inc., Sanofi Aventis, Neurochem Inc., Forest Pharmaceuticals, Inc., and Johnson & Johnson. Product(s) made by these companies related to this topic: Aricept, Memantine, Razadyne, and Exelon. Moshe Fridman, PhD received a consulting fee from Forest Laboratories, Inc. Product(s) made by this company related to this topic: Memantine. Haim Erder, PhD, Juliana Setyawan, PharmD, MS, and Stavros Tourkodimitris, PhD are salaried employees of Forest Laboratories, Inc. and has stock options. Product(s) made by this company related to this topic: Lexapro, Namenda, and acamprostate. Malca Resnick, PhD and Robert K. Hofbauer, PhD are salaried employees of Forest Research Institute. Product(s) made by this company related to this topic: Memantine.