- Email: [email protected]
SUVN-D4010, A POTENT AND SELECTIVE 5-HT4 RECEPTOR PARTIAL AGONIST: SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HUMANS
Poster Presentations: Tuesday, July 26, 2016
biogenesis include erythropoietin and pioglitazone. Erythropoietin activates eNOS, causing production of nitric oxide (NO), which then triggers transcription of genes involved in mitochondrial biogenesis (3). Thiazolidinediones, e.g., pioglitazone, induce mitochondrial biogenesis by increasing expression of PPAR-1a-coactivator, the principle regulator of mitochondrial biogenesis. (4). Treatment using concurrent combinations having different targets is more effective than sequentially using single agents. A clinical trial would test the hypothesis that a combination of lithium, erythropoietin, and pioglitazone, might impede the progression of MCI to AD, or of early to more advanced AD. Conclusions: Dysfunctional mitochondria underlie AD and may be disposed, by combining lithium, erythropoietin, and pioglitazone to enhance mitophagy, which then stimulates production of new organelles by enhancing mitochondrial biogenesis. 1. Nixon, J Cell Sci 2007;120:4081-4091. 2. Sarkar, J Cell Biol 2011;101:514-519. 3. Burger, Cardiovasc Res 2006;72:51-59. 4. Gosh, Mol Pharmacol 2007;71:1695-1702.
P3-014
EFFECT OF FOOD ON THE PHARMACOKINETICS OF RVT-101 IN HEALTHY ADULT SUBJECTS
Stephen C. Piscitelli1, Lori Jones1, Brendan Johnson1, Ilise Lombardo2, Lawrence Friedhoff2, 1Roivant Sciences, Inc., New York, NY, USA; 2Axovant Sciences, Inc., New York, NY, USA. Contact e-mail: [email protected] Background: RVT-101 is an oral, potent antagonist of the 5-hy-
droxytryptamine 6 (5-HT6) serotonin receptor currently being evaluated in a pivotal phase 3 study for the treatment of Alzheimer’s disease. RVT-101 promotes the release of acetylcholine, glutamate, and other neurotransmitters providing a complementary mechanism of action with cholinesterase inhibitors. The effect of a high fat meal on the pharmacokinetics of the phase 3 tablet formulation was evaluated. Methods: This was an open-label, randomized, single dose, two-period, balanced crossover study to assess the effect of food on the pharmacokinetics of RVT-101 in healthy adult subjects. Subjects were randomized to receive a 35 mg oral dose in two separate dosing periods. In one period, the dose was administered after an overnight fast. In the other period, the dose was administered within 30 minutes after the start of a meal with fat comprising approximately 53% of total caloric content (approximately 870 calories). A wash out period of at least 10 days was required between each dose. Safety assessments were performed throughout each period and serial PK samples were collected for 168 hours following each dose of study drug. Results: Twelve subjects (10 males, 2 females) with ages ranging from 20 to 50 years were enrolled and completed the study. RVT-101 was well tolerated. There were no Grade 2-4 adverse events and no withdrawals due to adverse events. The presence of food did not affect the pharmacokinetics of RVT-101. The AUC(0-N) was 3645 ng*h/ml fasted and 3769 ng*h/ml with food (ratio 0.97, 90% confidence interval 0.76-1.24). Cmax was 105 ng/ml and 104 ng/ml fasted and fed, respectively (ratio 1.01, 90% confidence interval 0.77-1.33). Conclusions: RVT-101 can be given without regard to meals and easily added to existing medication schedules providing a convenient once daily dosing regimen for patients and caregivers.
P3-015
RESEARCH PARTICIPATION AND PERCEPTIONS AMONG COMMUNITY MEMBERS WHO REPORT A HISTORY OF DEMENTIA
Sadaf Milani, Linda B. Cottler, Catherine Striley, University of Florida, Gainesville, FL, USA. Contact e-mail: [email protected]
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Background: The prevalence of dementia in individuals aged 60 or older around the world ranges from 5-7%. As the population ages, the prevalence of dementia will increase. More research is needed, however, low research participation rates, especially among minorities, hinder progress. Methods: Data were acquired from HealthStreet, a community engagement program at University of Florida which relies on Community Health Workers to assess health conditions and concerns of community residents in North East and North Central Florida. Participants who completed an intake from November 2011 to January 2016 were included in this cross sectional analysis (n¼7,034). Likelihood to participate in different types of health research studies, trust in research and trust in researchers was assessed. Since participants reporting dementia were judged as competent to consent, their dementia was likely mild. Results: Of the 7,034 respondents, 1.4% reported a lifetime history of dementia. Community members reporting dementia were more likely to report previous participation in a health research study (22.8%) compared to all other HealthStreet participants (17.6%). Among those reporting dementia, 73.3% said that they were definitely interested in participating in a research study compared to only 51.0% of total HealthStreet participants; they were also more willing to participate in a study without compensation (89.1%) compared to all HealthStreet participants (77.7%). Over half of those reporting dementia were female (53.5%) and their mean age was 53.0. Approximately half of these individuals were African American (49.5%), followed by Caucasian (45.5%) and other (5.0%). Conclusions: Community members reporting dementia were consistently more likely to have participated in and to desire future participation in health research compared to all other HealthStreet participants. This high interest in health research among those with dementia should lead to requests to participate. Community dwelling populations are very likely willing to participate, but they need to be invited to do so; Coordinators and PIs should do so. HealthStreet provides a model program that recruits older populations into health research. While this analysis shows that interest in research participation among this population is high, barriers to their research participation need to be identified.
P3-016
SUVN-D4010, A POTENT AND SELECTIVE 5-HT4 RECEPTOR PARTIAL AGONIST: SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HUMANS
Pradeep Jayarajan, Gopinadh Bhyrapuneni, Koteshwara Mudigonda, Kiran Kumar Penta, NageswaraRao Muddana, Veera Raghava Chowdary Palacharla, Vijay Benade, Renny Abraham, Ramkumar Subramanian, Vinod Kumar Goyal, Santosh Kumar Pandey, Rajesh Kumar Boggavarapu, Devender Reddy Ajjala, Mohammed Abdul Rasheed, Ramakrishna Nirogi, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: pradeep@ suven.com Background: SUVN-D4010 is a potent, selective and orally
bioavailable 5-HT4receptor partial agonist. Efficacy of SUVND4010 has been proved in preclinical models of cognition where it improved the episodic, working and emotional memory in rats as well as increased brain acetylcholine levels. A significant increase in cortical sAPPa and decrease in amyloid-b protein levels was also seen. SUVN-D4010 is being developed for the treatment of cognitive deficits associated with Alzheimer’s disease (AD). Methods: SUVN-D4010 was studied in a single-center, multifaceted, phase 1 clinical trial (US IND) to evaluate its safety, tolerability, and pharmacokinetics after single and multiple ascending doses in healthy adult male subjects. For evaluation after single
P824
Poster Presentations: Tuesday, July 26, 2016
dose, subjects were dosed with 5, 15, 30 and 45 mg of SUVND4010 tablets. For multiple ascending dose evaluation, the once daily doses of SUVN-D4010 tablets were administered for 14 days. SUVN-D4010 was quantified in plasma and urine using a validated LC-MS/MS method. Safety was evaluated based on assessments of adverse events, physical examinations, laboratory tests, vital signs, orthostatic vital signs, 12-lead ECGs and continuous telemetry. Results: SUVN-D4010 was well tolerated in healthy male subjects and there were no clinically relevant or serious adverse events reported. During single ascending dose studies, the absorption of SUVN-D4010 is rapid and exposures (Cmaxand AUC) were dose proportional at the tested doses. During multiple ascending dose studies, SUVN-D4010 has shown a favorable pharmacokinetic profile. SUVN-D4010 achieved the projected efficacy concentrations and attained steady state on day 3 in the tested population. Conclusions: SUVN-D4010 has favorable safety and pharmacokinetic profile following single and multiple administration for 14 days in healthy male subjects. SUVN-D4010 exposures were dose proportional following single or multiple oral administrations. SUVN-D4010 achieved the projected efficacy concentrations and attained steady state on day 3 upon multiple administrations. SUVN-D4010 is well tolerated with adequate plasma exposure for efficacy and favorable pharmacokinetics suitable for once a day oral administration. Long term non-clinical safety studies are in progress and Phase II proof-of-concept studies is being planned. P3-017
THE IMPACT OF CENTRAL RATING REVIEW PROGRAMS ON ADAS-COG ERROR VARIANCE
Magdalena Perez1, Judith Montero1, Michael Ward2, Robert Paul2, William Cho2, Kristina Bertzos1, Christine Bougard1, Heather R. Romero1, Daniel Conroy3, 1inVentiv Health, Cary, NC, USA; 2Genentech, Inc, South San Francisco, CA, USA; 3inVentiv Health, Burlington, MA, USA. Contact e-mail: [email protected] Background: Rater administration and scoring errors on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADASCog) may be masking positive drug effects in Alzheimer disease (AD) clinical trials (Kobak, 2010; Schafer et al., 2011). Such errors can contribute to larger error variance, higher sample sizes, and reduced power to detect a treatment effect. Despite rigorous rater training and clinical review programs, raters continue to make at least one error per in-study assessment throughout the life of a clinical trial (Bertzos et al., 2013; Perez et al., 2013). Few studies have examined the impact these errors could have on ADAS-Cog outcome data if left uncorrected. This study examines how ADAS-Cog errors impact overall error variance of the ADAS-Cog total scores. Methods: ADAS-Cog data from a clinical trial using 436 mild to moderate AD subjects, randomized to two different treatment cohorts were analyzed. A total of 1940 assessments administered by 117 raters across five study visits were centrally reviewed by clinicians. Errors identified were addressed and corrected by the raters. ADAS-Cog scores were calculated for each visit using both corrected and uncorrected scores. The standard deviations and standard errors of the mean between the corrected and uncorrected ADAS-Cog total scores will be compared at each visit for each treatment cohort. Results: It is hypothesized that the clinical review process will decrease the error variance within each of the five visits as well as across time for each treatment cohort. Conclusions: The impact of central review programs on ADAS-Cog error variance, across the life of a trial, will be discussed to determine whether these programs improve the quality of the data. In addition, the impact that central rating review programs have on estimated sample sizes will be explored.
P3-018
AN EVALUATION OF THE SAFETY OF NELOTANSERIN, A HIGHLY POTENT AND SELECTIVE 5-HT2A INVERSE AGONIST THAT IS BEING DEVELOPED AS A TREATMENT FOR VISUAL HALLUCINATIONS AND REM BEHAVIOR DISORDER IN LEWY BODY DEMENTIA
Warren Wen1, Shankar Ramaswamy1, Stephen C. Piscitelli2, Sherri Cicero1, Shau Yu Lynch1, Lawrence Friedhoff1,2, 1Axovant Sciences, Inc., New York, NY, USA; 2Roivant Sciences, Inc., New York, NY, USA. Contact e-mail: [email protected] Background: Lewy bodies Dementia (LBD) is a progressive neurodegenerative disease, affecting approximately 1.4 million elderly in the US. It includes two related disorders: dementia with Lewy bodies (DLB) and Parkinson’s disease dementia. While cognitive dysfunction is a core component of LBD, approximately 80% of the patients also exhibit behavioral disturbances early in the disease, including visual hallucinations (VH) and REM sleep behavior disorders (RBD). The mechanisms underlying these behavioral disturbances are poorly understood; an imbalance between cholinergic and monoaminergic (ie, serotonin) neurotransmitters may be involved, and excessive 5-HT2a receptor activity has been implicated. As VH have been shown to coincide with REM sleep, RBD may be linked to VH in LBD patients. Nelotanserin is an oral, potent and selective 5-HT2a inverse agonist. In earlier studies, nelotanserin has been shown to reduce awakenings and arousals, sleep stage shifts, and Stage 1 and 2 sleep, and increase slow wave sleep and Stage 3 and 4 sleep. Currently, nelotanserin is being developed for the treatment of VH in LBD and RBD in DLB. This analysis evaluated the safety of nelotanserin in completed studies. Methods: The results from seven studies were evaluated. Safety analysis included adverse events (AEs), clinical laboratory evaluations, vital signs, and ECGs. Results: A total of 792 subjects (male and female, ages 18 to 65) were treated with nelotanserin: 113 received single doses of up to 160 mg; 679 received repeated doses of up to 80 mg for up to 14 days. Results from clinical laboratory evaluations, vital signs, ECGs were generally unremarkable. The most common treatment-emergent AEs include headache, somnolence, and dizziness; no dose response relationship was observed for these AEs. There were no deaths. One subject who received a single dose of nelotanserin 20 mg experienced a serious AE of diverticulitis; this event was deemed by the investigator to be unrelated to nelotanserin. Less than 2% of subjects experienced AEs that led to treatment discontinuation. There was no evidence of QTc prolongation. Conclusions: Nelotanserin was generally safe and well tolerated. Studies evaluating the safety and efficacy of nelotanserin in LBD are ongoing. P3-019
DECREASED BEHAVIORAL ABNORMALITIES AFTER TREATMENT OF COMBINED DONEPEZIL AND YOKUKANSANKACHIMPIHANGE IN ALZHEIMER’S DISEASE: THE OSAKI-TAJIRI PROJECT
Kenichi Meguro1, Keiichi Kumai2, Keiko Chida1, Yuriko Kato1, Junko Takada1, Satoshi Yamaguchi3, 1Tohoku University CYRIC, Sendai, Japan; 2Tohoku University, Sendai, Japan; 3Osaki-Tajiri SKIP Center, Osaki, Japan. Contact e-mail: [email protected] Background: Traditionally, yokukansankachimpihange (YKH) has
been used for the treatment of neurasthenia, hysteria, insomnia, menopausal neurosis, and pediatric epilepsy. Recently there were several reports on the effectiveness on behavioral abnormalities such as delusion or aggressiveness of patients with Alzheimer’s disease (AD). Methods: We retrospectively evaluated the clinical
biogenesis include erythropoietin and pioglitazone. Erythropoietin activates eNOS, causing production of nitric oxide (NO), which then triggers transcription of genes involved in mitochondrial biogenesis (3). Thiazolidinediones, e.g., pioglitazone, induce mitochondrial biogenesis by increasing expression of PPAR-1a-coactivator, the principle regulator of mitochondrial biogenesis. (4). Treatment using concurrent combinations having different targets is more effective than sequentially using single agents. A clinical trial would test the hypothesis that a combination of lithium, erythropoietin, and pioglitazone, might impede the progression of MCI to AD, or of early to more advanced AD. Conclusions: Dysfunctional mitochondria underlie AD and may be disposed, by combining lithium, erythropoietin, and pioglitazone to enhance mitophagy, which then stimulates production of new organelles by enhancing mitochondrial biogenesis. 1. Nixon, J Cell Sci 2007;120:4081-4091. 2. Sarkar, J Cell Biol 2011;101:514-519. 3. Burger, Cardiovasc Res 2006;72:51-59. 4. Gosh, Mol Pharmacol 2007;71:1695-1702.
P3-014
EFFECT OF FOOD ON THE PHARMACOKINETICS OF RVT-101 IN HEALTHY ADULT SUBJECTS
Stephen C. Piscitelli1, Lori Jones1, Brendan Johnson1, Ilise Lombardo2, Lawrence Friedhoff2, 1Roivant Sciences, Inc., New York, NY, USA; 2Axovant Sciences, Inc., New York, NY, USA. Contact e-mail: [email protected] Background: RVT-101 is an oral, potent antagonist of the 5-hy-
droxytryptamine 6 (5-HT6) serotonin receptor currently being evaluated in a pivotal phase 3 study for the treatment of Alzheimer’s disease. RVT-101 promotes the release of acetylcholine, glutamate, and other neurotransmitters providing a complementary mechanism of action with cholinesterase inhibitors. The effect of a high fat meal on the pharmacokinetics of the phase 3 tablet formulation was evaluated. Methods: This was an open-label, randomized, single dose, two-period, balanced crossover study to assess the effect of food on the pharmacokinetics of RVT-101 in healthy adult subjects. Subjects were randomized to receive a 35 mg oral dose in two separate dosing periods. In one period, the dose was administered after an overnight fast. In the other period, the dose was administered within 30 minutes after the start of a meal with fat comprising approximately 53% of total caloric content (approximately 870 calories). A wash out period of at least 10 days was required between each dose. Safety assessments were performed throughout each period and serial PK samples were collected for 168 hours following each dose of study drug. Results: Twelve subjects (10 males, 2 females) with ages ranging from 20 to 50 years were enrolled and completed the study. RVT-101 was well tolerated. There were no Grade 2-4 adverse events and no withdrawals due to adverse events. The presence of food did not affect the pharmacokinetics of RVT-101. The AUC(0-N) was 3645 ng*h/ml fasted and 3769 ng*h/ml with food (ratio 0.97, 90% confidence interval 0.76-1.24). Cmax was 105 ng/ml and 104 ng/ml fasted and fed, respectively (ratio 1.01, 90% confidence interval 0.77-1.33). Conclusions: RVT-101 can be given without regard to meals and easily added to existing medication schedules providing a convenient once daily dosing regimen for patients and caregivers.
P3-015
RESEARCH PARTICIPATION AND PERCEPTIONS AMONG COMMUNITY MEMBERS WHO REPORT A HISTORY OF DEMENTIA
Sadaf Milani, Linda B. Cottler, Catherine Striley, University of Florida, Gainesville, FL, USA. Contact e-mail: [email protected]
P823
Background: The prevalence of dementia in individuals aged 60 or older around the world ranges from 5-7%. As the population ages, the prevalence of dementia will increase. More research is needed, however, low research participation rates, especially among minorities, hinder progress. Methods: Data were acquired from HealthStreet, a community engagement program at University of Florida which relies on Community Health Workers to assess health conditions and concerns of community residents in North East and North Central Florida. Participants who completed an intake from November 2011 to January 2016 were included in this cross sectional analysis (n¼7,034). Likelihood to participate in different types of health research studies, trust in research and trust in researchers was assessed. Since participants reporting dementia were judged as competent to consent, their dementia was likely mild. Results: Of the 7,034 respondents, 1.4% reported a lifetime history of dementia. Community members reporting dementia were more likely to report previous participation in a health research study (22.8%) compared to all other HealthStreet participants (17.6%). Among those reporting dementia, 73.3% said that they were definitely interested in participating in a research study compared to only 51.0% of total HealthStreet participants; they were also more willing to participate in a study without compensation (89.1%) compared to all HealthStreet participants (77.7%). Over half of those reporting dementia were female (53.5%) and their mean age was 53.0. Approximately half of these individuals were African American (49.5%), followed by Caucasian (45.5%) and other (5.0%). Conclusions: Community members reporting dementia were consistently more likely to have participated in and to desire future participation in health research compared to all other HealthStreet participants. This high interest in health research among those with dementia should lead to requests to participate. Community dwelling populations are very likely willing to participate, but they need to be invited to do so; Coordinators and PIs should do so. HealthStreet provides a model program that recruits older populations into health research. While this analysis shows that interest in research participation among this population is high, barriers to their research participation need to be identified.
P3-016
SUVN-D4010, A POTENT AND SELECTIVE 5-HT4 RECEPTOR PARTIAL AGONIST: SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HUMANS
Pradeep Jayarajan, Gopinadh Bhyrapuneni, Koteshwara Mudigonda, Kiran Kumar Penta, NageswaraRao Muddana, Veera Raghava Chowdary Palacharla, Vijay Benade, Renny Abraham, Ramkumar Subramanian, Vinod Kumar Goyal, Santosh Kumar Pandey, Rajesh Kumar Boggavarapu, Devender Reddy Ajjala, Mohammed Abdul Rasheed, Ramakrishna Nirogi, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: pradeep@ suven.com Background: SUVN-D4010 is a potent, selective and orally
bioavailable 5-HT4receptor partial agonist. Efficacy of SUVND4010 has been proved in preclinical models of cognition where it improved the episodic, working and emotional memory in rats as well as increased brain acetylcholine levels. A significant increase in cortical sAPPa and decrease in amyloid-b protein levels was also seen. SUVN-D4010 is being developed for the treatment of cognitive deficits associated with Alzheimer’s disease (AD). Methods: SUVN-D4010 was studied in a single-center, multifaceted, phase 1 clinical trial (US IND) to evaluate its safety, tolerability, and pharmacokinetics after single and multiple ascending doses in healthy adult male subjects. For evaluation after single
P824
Poster Presentations: Tuesday, July 26, 2016
dose, subjects were dosed with 5, 15, 30 and 45 mg of SUVND4010 tablets. For multiple ascending dose evaluation, the once daily doses of SUVN-D4010 tablets were administered for 14 days. SUVN-D4010 was quantified in plasma and urine using a validated LC-MS/MS method. Safety was evaluated based on assessments of adverse events, physical examinations, laboratory tests, vital signs, orthostatic vital signs, 12-lead ECGs and continuous telemetry. Results: SUVN-D4010 was well tolerated in healthy male subjects and there were no clinically relevant or serious adverse events reported. During single ascending dose studies, the absorption of SUVN-D4010 is rapid and exposures (Cmaxand AUC) were dose proportional at the tested doses. During multiple ascending dose studies, SUVN-D4010 has shown a favorable pharmacokinetic profile. SUVN-D4010 achieved the projected efficacy concentrations and attained steady state on day 3 in the tested population. Conclusions: SUVN-D4010 has favorable safety and pharmacokinetic profile following single and multiple administration for 14 days in healthy male subjects. SUVN-D4010 exposures were dose proportional following single or multiple oral administrations. SUVN-D4010 achieved the projected efficacy concentrations and attained steady state on day 3 upon multiple administrations. SUVN-D4010 is well tolerated with adequate plasma exposure for efficacy and favorable pharmacokinetics suitable for once a day oral administration. Long term non-clinical safety studies are in progress and Phase II proof-of-concept studies is being planned. P3-017
THE IMPACT OF CENTRAL RATING REVIEW PROGRAMS ON ADAS-COG ERROR VARIANCE
Magdalena Perez1, Judith Montero1, Michael Ward2, Robert Paul2, William Cho2, Kristina Bertzos1, Christine Bougard1, Heather R. Romero1, Daniel Conroy3, 1inVentiv Health, Cary, NC, USA; 2Genentech, Inc, South San Francisco, CA, USA; 3inVentiv Health, Burlington, MA, USA. Contact e-mail: [email protected] Background: Rater administration and scoring errors on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADASCog) may be masking positive drug effects in Alzheimer disease (AD) clinical trials (Kobak, 2010; Schafer et al., 2011). Such errors can contribute to larger error variance, higher sample sizes, and reduced power to detect a treatment effect. Despite rigorous rater training and clinical review programs, raters continue to make at least one error per in-study assessment throughout the life of a clinical trial (Bertzos et al., 2013; Perez et al., 2013). Few studies have examined the impact these errors could have on ADAS-Cog outcome data if left uncorrected. This study examines how ADAS-Cog errors impact overall error variance of the ADAS-Cog total scores. Methods: ADAS-Cog data from a clinical trial using 436 mild to moderate AD subjects, randomized to two different treatment cohorts were analyzed. A total of 1940 assessments administered by 117 raters across five study visits were centrally reviewed by clinicians. Errors identified were addressed and corrected by the raters. ADAS-Cog scores were calculated for each visit using both corrected and uncorrected scores. The standard deviations and standard errors of the mean between the corrected and uncorrected ADAS-Cog total scores will be compared at each visit for each treatment cohort. Results: It is hypothesized that the clinical review process will decrease the error variance within each of the five visits as well as across time for each treatment cohort. Conclusions: The impact of central review programs on ADAS-Cog error variance, across the life of a trial, will be discussed to determine whether these programs improve the quality of the data. In addition, the impact that central rating review programs have on estimated sample sizes will be explored.
P3-018
AN EVALUATION OF THE SAFETY OF NELOTANSERIN, A HIGHLY POTENT AND SELECTIVE 5-HT2A INVERSE AGONIST THAT IS BEING DEVELOPED AS A TREATMENT FOR VISUAL HALLUCINATIONS AND REM BEHAVIOR DISORDER IN LEWY BODY DEMENTIA
Warren Wen1, Shankar Ramaswamy1, Stephen C. Piscitelli2, Sherri Cicero1, Shau Yu Lynch1, Lawrence Friedhoff1,2, 1Axovant Sciences, Inc., New York, NY, USA; 2Roivant Sciences, Inc., New York, NY, USA. Contact e-mail: [email protected] Background: Lewy bodies Dementia (LBD) is a progressive neurodegenerative disease, affecting approximately 1.4 million elderly in the US. It includes two related disorders: dementia with Lewy bodies (DLB) and Parkinson’s disease dementia. While cognitive dysfunction is a core component of LBD, approximately 80% of the patients also exhibit behavioral disturbances early in the disease, including visual hallucinations (VH) and REM sleep behavior disorders (RBD). The mechanisms underlying these behavioral disturbances are poorly understood; an imbalance between cholinergic and monoaminergic (ie, serotonin) neurotransmitters may be involved, and excessive 5-HT2a receptor activity has been implicated. As VH have been shown to coincide with REM sleep, RBD may be linked to VH in LBD patients. Nelotanserin is an oral, potent and selective 5-HT2a inverse agonist. In earlier studies, nelotanserin has been shown to reduce awakenings and arousals, sleep stage shifts, and Stage 1 and 2 sleep, and increase slow wave sleep and Stage 3 and 4 sleep. Currently, nelotanserin is being developed for the treatment of VH in LBD and RBD in DLB. This analysis evaluated the safety of nelotanserin in completed studies. Methods: The results from seven studies were evaluated. Safety analysis included adverse events (AEs), clinical laboratory evaluations, vital signs, and ECGs. Results: A total of 792 subjects (male and female, ages 18 to 65) were treated with nelotanserin: 113 received single doses of up to 160 mg; 679 received repeated doses of up to 80 mg for up to 14 days. Results from clinical laboratory evaluations, vital signs, ECGs were generally unremarkable. The most common treatment-emergent AEs include headache, somnolence, and dizziness; no dose response relationship was observed for these AEs. There were no deaths. One subject who received a single dose of nelotanserin 20 mg experienced a serious AE of diverticulitis; this event was deemed by the investigator to be unrelated to nelotanserin. Less than 2% of subjects experienced AEs that led to treatment discontinuation. There was no evidence of QTc prolongation. Conclusions: Nelotanserin was generally safe and well tolerated. Studies evaluating the safety and efficacy of nelotanserin in LBD are ongoing. P3-019
DECREASED BEHAVIORAL ABNORMALITIES AFTER TREATMENT OF COMBINED DONEPEZIL AND YOKUKANSANKACHIMPIHANGE IN ALZHEIMER’S DISEASE: THE OSAKI-TAJIRI PROJECT
Kenichi Meguro1, Keiichi Kumai2, Keiko Chida1, Yuriko Kato1, Junko Takada1, Satoshi Yamaguchi3, 1Tohoku University CYRIC, Sendai, Japan; 2Tohoku University, Sendai, Japan; 3Osaki-Tajiri SKIP Center, Osaki, Japan. Contact e-mail: [email protected] Background: Traditionally, yokukansankachimpihange (YKH) has
been used for the treatment of neurasthenia, hysteria, insomnia, menopausal neurosis, and pediatric epilepsy. Recently there were several reports on the effectiveness on behavioral abnormalities such as delusion or aggressiveness of patients with Alzheimer’s disease (AD). Methods: We retrospectively evaluated the clinical