- Email: [email protected]
SUVN-D4010: A POTENT AND SELECTIVE 5-HT4 RECEPTOR PARTIAL AGONIST— ASSESSMENT OF SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HEALTHY HUMAN VOLUNTEERS
Poster Presentations: Sunday, July 16, 2017
of the depositions, 6E10-positive depositions were observed torus-like shapes with having relatively strongly immunoreactive cores, and m6H4-positive depositions existed inhomogeneous granular shapes. Conclusions: Ab oligomer depositions possibly grow according to the increase of Ab depositions, but its immunoreactivity was different from those of senile plaques. References: 1. Saito T, et al. Nat Neurosci 2014; 17(5): 661–3. 2. Takamura A, et al. Mol Neurodegener 2011;6(1):20.
P1-460
SUVN-D4010: A POTENT AND SELECTIVE 5-HT4 RECEPTOR PARTIAL AGONIST— ASSESSMENT OF SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HEALTHY HUMAN VOLUNTEERS
Gopinadh Bhyrapuneni, Koteshwara Mudigonda, Veera Raghava Chowdary Palacharla, Pradeep Jayarajan, 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: [email protected] Background: SUVN-D4010 is a potent, selective and orally
bioavailable 5-HT4 receptor partial agonist being developed for the treatment of Alzheimer’s disease (AD). SUVN-D4010 has shown to improve the memory in preclinical animal models. SUVN-D4010 also produced significant increase in the brain acetylcholine levels and cortical sAPPa with simultaneous decrease in amyloid-b protein levels. Methods: SUVN-D4010 was studied in a single-center, multi-faceted, phase 1 clinical trial (US IND) to evaluate its safety, tolerability, and pharmacokinetics after single or multiple ascending doses in healthy male subjects. For single dose evaluation, subjects were dosed with 5 mg, 15 mg, 30 mg or 45 mg of SUVN-D4010 tablets, once. For multiple ascending dose evaluation, the once daily doses of 10, 25 and 40 mg SUVN-D4010 were administered for 14 days. SUVN-D4010 was administered at a dose of 25 mg for evaluation of food, gender and age effect. Effect of food on SUVND4010 pharmacokinetics was evaluated under fed and fasted conditions in healthy adult male subjects. For evaluation of gender and age effect, SUVN-D4010 was administered under fasted conditions in healthy female and elderly subjects. SUVN-D4010 was quantified in plasma using a validated LCMS/MS method. Safety and tolerability was assessed by incidence and severity of AEs, abnormalities in vital signs, ECG and laboratory assessments. Results: SUVN-D4010 was well tolerated up to the highest tested dose of 45 mg single dose or 40 mg/day multiple doses in healthy male subjects. There were no clinically relevant or serious adverse events reported. During single ascending dose studies, the absorption of SUVN-D4010 was rapid and exposures (Cmax and AUC) were dose proportional. During multiple ascending dose studies, SUVN-D4010 achieved steady state on day 3 in the tested population. Conclusions: SUVN-D4010 has excellent safety and pharmacokinetic profile following single or multiple dose administration for 14 days in healthy male subjects. Projected efficacy concentrations of SUVN-D4010 achieved during multiple ascending dose studies. SUVN-D4010 is currently being evaluated for long term safety in animal models.
P1-461
P463
CSF Ab1-42 AS THE PATHOLOGICAL AD BIOMARKER IN TYPE 2 DIABETES MELLITUS PATIENTS
Wei Li1, Shannon L. Risacher2,3, Sujuan Gao2,3, Andrew J. Saykin2,3,4, 1Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA; 2Indiana Alzheimer Disease Center, Indianapolis, IN, USA; 3Indiana University School of Medicine, Indianapolis, IN, USA; 4Indiana University Network Science Institute, Bloomington, IN, USA. Contact e-mail: wl23@ iu.edu Background: Type 2 diabetes mellitus (T2DM) is a risk factor for
Alzheimer’s disease (AD), and amyloid b1-42 (Ab1-42) is a classic pathological AD biomarker. However, it is largely unknown how the Ab1-42 in cerebrospinal fluid (CSF) functions as a pathological biomarker in T2DM patients. Methods: Data from the Alzheimer’s Disease Neuroimaging Initiative was used. Participants with T2DM were separated from those without T2DM by keywords from their medical history database. A two-way analysis of covariance (ANCOVA) model was used to analyze how T2DM and baseline diagnosis affects the CSF Ab1-42. Relation between the CSF Ab1-42 and cortical amyloid burden assessed by florbetapir F 18 PET were also reported. Then cortical amyloid burden and its distribution among cortical sub-regions were compared between the T2DM and non-diabetic groups. Results: The CSF Ab1-42 for the T2DM group is 204.35 6 9.40 pg/ml (95% CI: 185.89-222.80 pg/ ml, n ¼ 76), which is higher than the same measure in the non-diabetic group of 168.58 6 4.49 pg/ml (95% CI: 159.76-177.40 pg/ml, n ¼ 731, p ¼ 0.001). The CSF Ab1-42 is negatively correlated with the cortical florbetapir 18F standardized uptake value ratio (SUVR) for the b amyloid (r ¼ -0.701, n ¼ 812, p<0.005). The mean cortical florbetapir 18F SUVR for the T2DM group is 1.11 6 0.05 (95% CI: 1.02-1.20, n ¼ 77), which is lower than the same measure in the nondiabetic group of 1.23 6 0.02 (95% CI: 1.18-1.27, n ¼ 735, p ¼ 0.02). The lower corticla amyloid is seen in all the examined cortical subregions. Conclusions: A higher CSF Ab1-42 and a lower cortical amyloid burden in participants with T2DM than those without T2DM suggest that T2DM-related cognitive impairment might have a different mechanism than AD.
P1-462
[11C]PK11195 PET IMAGING REVEALS NEUROINFLAMMATION IN DEMENTIA WITH LEWY BODIES IS NEGATIVELY ASSOCIATED WITH DISEASE SEVERITY: NIMROD STUDY
Ajenthan Surendranathan, Li Su, Luca Passamonti, Young T. Hong, William Richard Bevan-Jones, Robert Arnold, Patricia Vazquez Rodriguez, Elijah Mak, Tim D. Fryer, Franklin I. Aigbirhio, James B. Rowe, John T. O’Brien, University of Cambridge, Cambridge, United Kingdom. Contact e-mail: [email protected] Background: Recent PET studies show microglial activation in vivo
in Parkinson’s disease dementia that negatively correlates with cognitive ability [1]. However, it is unclear whether similar changes occur in dementia with Lewy bodies (DLB), though alpha-synuclein is known to activate microglia and pathology studies suggest neuroinflammation in the pathogenesis of DLB [2]. We aimed to determine if subjects with DLB have increased microglial
of the depositions, 6E10-positive depositions were observed torus-like shapes with having relatively strongly immunoreactive cores, and m6H4-positive depositions existed inhomogeneous granular shapes. Conclusions: Ab oligomer depositions possibly grow according to the increase of Ab depositions, but its immunoreactivity was different from those of senile plaques. References: 1. Saito T, et al. Nat Neurosci 2014; 17(5): 661–3. 2. Takamura A, et al. Mol Neurodegener 2011;6(1):20.
P1-460
SUVN-D4010: A POTENT AND SELECTIVE 5-HT4 RECEPTOR PARTIAL AGONIST— ASSESSMENT OF SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HEALTHY HUMAN VOLUNTEERS
Gopinadh Bhyrapuneni, Koteshwara Mudigonda, Veera Raghava Chowdary Palacharla, Pradeep Jayarajan, 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: [email protected] Background: SUVN-D4010 is a potent, selective and orally
bioavailable 5-HT4 receptor partial agonist being developed for the treatment of Alzheimer’s disease (AD). SUVN-D4010 has shown to improve the memory in preclinical animal models. SUVN-D4010 also produced significant increase in the brain acetylcholine levels and cortical sAPPa with simultaneous decrease in amyloid-b protein levels. Methods: SUVN-D4010 was studied in a single-center, multi-faceted, phase 1 clinical trial (US IND) to evaluate its safety, tolerability, and pharmacokinetics after single or multiple ascending doses in healthy male subjects. For single dose evaluation, subjects were dosed with 5 mg, 15 mg, 30 mg or 45 mg of SUVN-D4010 tablets, once. For multiple ascending dose evaluation, the once daily doses of 10, 25 and 40 mg SUVN-D4010 were administered for 14 days. SUVN-D4010 was administered at a dose of 25 mg for evaluation of food, gender and age effect. Effect of food on SUVND4010 pharmacokinetics was evaluated under fed and fasted conditions in healthy adult male subjects. For evaluation of gender and age effect, SUVN-D4010 was administered under fasted conditions in healthy female and elderly subjects. SUVN-D4010 was quantified in plasma using a validated LCMS/MS method. Safety and tolerability was assessed by incidence and severity of AEs, abnormalities in vital signs, ECG and laboratory assessments. Results: SUVN-D4010 was well tolerated up to the highest tested dose of 45 mg single dose or 40 mg/day multiple doses in healthy male subjects. There were no clinically relevant or serious adverse events reported. During single ascending dose studies, the absorption of SUVN-D4010 was rapid and exposures (Cmax and AUC) were dose proportional. During multiple ascending dose studies, SUVN-D4010 achieved steady state on day 3 in the tested population. Conclusions: SUVN-D4010 has excellent safety and pharmacokinetic profile following single or multiple dose administration for 14 days in healthy male subjects. Projected efficacy concentrations of SUVN-D4010 achieved during multiple ascending dose studies. SUVN-D4010 is currently being evaluated for long term safety in animal models.
P1-461
P463
CSF Ab1-42 AS THE PATHOLOGICAL AD BIOMARKER IN TYPE 2 DIABETES MELLITUS PATIENTS
Wei Li1, Shannon L. Risacher2,3, Sujuan Gao2,3, Andrew J. Saykin2,3,4, 1Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA; 2Indiana Alzheimer Disease Center, Indianapolis, IN, USA; 3Indiana University School of Medicine, Indianapolis, IN, USA; 4Indiana University Network Science Institute, Bloomington, IN, USA. Contact e-mail: wl23@ iu.edu Background: Type 2 diabetes mellitus (T2DM) is a risk factor for
Alzheimer’s disease (AD), and amyloid b1-42 (Ab1-42) is a classic pathological AD biomarker. However, it is largely unknown how the Ab1-42 in cerebrospinal fluid (CSF) functions as a pathological biomarker in T2DM patients. Methods: Data from the Alzheimer’s Disease Neuroimaging Initiative was used. Participants with T2DM were separated from those without T2DM by keywords from their medical history database. A two-way analysis of covariance (ANCOVA) model was used to analyze how T2DM and baseline diagnosis affects the CSF Ab1-42. Relation between the CSF Ab1-42 and cortical amyloid burden assessed by florbetapir F 18 PET were also reported. Then cortical amyloid burden and its distribution among cortical sub-regions were compared between the T2DM and non-diabetic groups. Results: The CSF Ab1-42 for the T2DM group is 204.35 6 9.40 pg/ml (95% CI: 185.89-222.80 pg/ ml, n ¼ 76), which is higher than the same measure in the non-diabetic group of 168.58 6 4.49 pg/ml (95% CI: 159.76-177.40 pg/ml, n ¼ 731, p ¼ 0.001). The CSF Ab1-42 is negatively correlated with the cortical florbetapir 18F standardized uptake value ratio (SUVR) for the b amyloid (r ¼ -0.701, n ¼ 812, p<0.005). The mean cortical florbetapir 18F SUVR for the T2DM group is 1.11 6 0.05 (95% CI: 1.02-1.20, n ¼ 77), which is lower than the same measure in the nondiabetic group of 1.23 6 0.02 (95% CI: 1.18-1.27, n ¼ 735, p ¼ 0.02). The lower corticla amyloid is seen in all the examined cortical subregions. Conclusions: A higher CSF Ab1-42 and a lower cortical amyloid burden in participants with T2DM than those without T2DM suggest that T2DM-related cognitive impairment might have a different mechanism than AD.
P1-462
[11C]PK11195 PET IMAGING REVEALS NEUROINFLAMMATION IN DEMENTIA WITH LEWY BODIES IS NEGATIVELY ASSOCIATED WITH DISEASE SEVERITY: NIMROD STUDY
Ajenthan Surendranathan, Li Su, Luca Passamonti, Young T. Hong, William Richard Bevan-Jones, Robert Arnold, Patricia Vazquez Rodriguez, Elijah Mak, Tim D. Fryer, Franklin I. Aigbirhio, James B. Rowe, John T. O’Brien, University of Cambridge, Cambridge, United Kingdom. Contact e-mail: [email protected] Background: Recent PET studies show microglial activation in vivo
in Parkinson’s disease dementia that negatively correlates with cognitive ability [1]. However, it is unclear whether similar changes occur in dementia with Lewy bodies (DLB), though alpha-synuclein is known to activate microglia and pathology studies suggest neuroinflammation in the pathogenesis of DLB [2]. We aimed to determine if subjects with DLB have increased microglial