- Email: [email protected]
Safety and pharmacokinetics of PF-04447943, a PDEA inhibitor, in single and multiple dose Phase 1 studies in healthy volunteers
Oral O3-05: Developing Treatments for Alzheimer’s and Other Dementias reduction in CSF total tau seen with AN1792 immunotherapy. These observations suggest that bapineuzumab treatment may alter neurodegenerative processes downstream from effects on Ab. Confirmation in ongoing phase 3 studies is necessary.
O3-05-02
ALLOSTERIC ACTIVATION OF M1 AND M5 PROVIDE EFFICACY IN ALZHEIMER MODELS
Craig W. Lindsley, Vanderbilt, Nashville, TN, USA. Contact e-mail: craig. [email protected] Background: Muscarinic acetylcholine receptor agonists have shown efficacy in preclinical AD models and in AD patients; however, these orthosteric agonists, due to poor mAChR selectivity, have serious GI side effects which precluded their development. M1 and/or M5 are the relevant mAChR subtypes of intetest as targets for AD, and highly selective M1 and M5 activators are needed. Methods: Employing functional screening, we identified M1 positive allosteric modulators (PAMs), M1 allosteric agonists and M5 PAMs. Results: M1 and M5 HTS leads were optimized to provide highly selective, centrally penetrant M1 PAMs, M1 allosteric agonists as well as M5 PAMs. In vitro molecular pharamacological characterization confirmed that these highly M1 or M5 ligands were indeed allosteric ligands, with >100-fold selectivity versus other mAChRs and devois of other ancillary pharmacology. Novel allosteric binding sites were identified for these ligands through mutagenesis studies which also supported the development of mAChR homology models. Different chemotypes of allosteric M1 activators were found to differential effects on downstream receptor signaling; thus, all M1 activation is not equivalent. In vivo electrophysiology and in vivo cognition studies, in both wild type and APP mice, showed robust improvement in cognitive performance. In vitro studies showed a significant decrease in Ab40-42 and a shift in APP processign towards the non-amyloidogeneic pathway. While both were efficacious, M1 allosteric agonists outperformed M1 PAMs. M5 PAMs showed similar, but lessened effects, perhaps due to lower receptor expression or a smaller contribution relative to M1. Conclusions: Data from in vivo electrophysiology, rodent cognition models and transgenic rodent models suggest that selective activation of M1 has both a palliative cognitive benefit as well as disease modification potential in AD. M5 while efficacious, plays a minor role as compared to M1. Thus, M1 allosteric agonists represent a novel therapeutic approach for the treatment of Alzheimer’s disease.
O3-05-03
GLUCAGON-LIKE PEPTIDE-1 MIMETIC PEPTIDE EXENDIN 4 PRESERVES MEMORY FUNCTION AND ATTENUATES NEUROPATHOLOGY IN APP/PS1 DOUBLE TRANSGENIC MICE
Ling Li, Dongfeng Cao, Hailin Lu, Terry Lewis, Robert Mans, University of Alabama at Birmingham, Birmingham, AL, USA. Contact e-mail: lili@uab. edu Background: To date there is no effective therapy to prevent or treat Alzheimer’s disease (AD). Emerging evidence shows that type 2 diabetes mellitus (T2DM) is a risk factor for AD and that anti-diabetes strategies are potentially effective to curtail AD. Incretin-based therapies are among the newly developed treatments for T2DM. Incretins are intestinal postprandial peptide hormones that stimulate insulin release from the pancreas, one of which being glucagon-like peptide-1 (GLP-1). However, GLP-1 has a very short half-life and is degraded mainly by the enzyme dipeptidyl peptidase IV (DPP-IV). Therefore, GLP-1 mimetic peptides and DPP-IV inhibitors have been developed to overcome these limitations. Exendin 4 (Ex4) isolated from the saliva of the Gila monster, a peptide with about 50% sequence homology to GLP-1, is a full agonist for the GLP-1 receptor and is resistant to DPP-IV. Synthetic Ex4 (exenatide) has been approved for the treatment of T2DM. In addition to peripheral effects, incretins have been shown to exert effects on the central nervous system and may affect the development of AD. Objective: The present study was designed to investigate the effect of Ex4 treatment on glucose homeostasis, spatial learning and memory, and amyloid-beta (Abeta) neuropathology in APP/PS1 double transgenic (Mo/
S135
HuAPPswe-PS1dE9) mice, an established mouse model of AD. Methods: A group of male APP/PS1 mice at 4 months old, an age at which amyloid plaques start to form in the brain, were treated with Ex4 by daily intra-peritoneal injections of 100 ng Ex4 in 100 ml PBS. After 2 months of drug treatment, the mice were subjected to behavioral, metabolic, pathologic, and biochemical analysis. Littermates injected with PBS without Ex4 served as controls. Results: We found that Ex4 treatment improved glucose homeostasis, preserved memory function, and reduced Abeta deposition in APP/PS1 mice. Biochemical analysis showed that Ex4 modulated levels of signaling molecules pertinent to neuroprotection and memory formation. Conclusions: Our findings suggest that incretin-based therapies could be a double-edged sword against the two devastating disorders, T2DM and AD.
O3-05-04
SAFETY AND PHARMACOKINETICS OF PF04447943, A PDEA INHIBITOR, IN SINGLE AND MULTIPLE DOSE PHASE 1 STUDIES IN HEALTHY VOLUNTEERS
Rebecca M. Evans, Timothy Nicholas, Vu Le, Ruolun Qiu, William Martin, David Martin, Scott Styren, Terence Fullerton, Elias Schwam, Pfizer, Groton, CT, USA. Contact e-mail: [email protected] Background: cGMP plays a key role in synaptic plasticity and PDE9A inhibition affects hippocampal structure and function (Kleiman, ICAD 2010; van der Staay, 2008). PF-04447943 is a potent and selective PDE9A inhibitor that increases cGMP levels in brain and CSF of animals, and CSF of healthy volunteers (Nicholas, ICAD, 2009). Methods: Studies B0401001 and B0401009 evaluated safety, tolerability, PK and pharmacodynamics of PF-04447943. B0401001 was a three-period, subject and investigator blinded, randomized, single dose, crossover study. Each subject received two doses and placebo. Healthy adult (HA) subjects (mean age 36, n ¼ 18) received single oral doses ranging from 1 to 150 mg; healthy elderly (HE) (mean age 66, n ¼ 4) received doses from 30 to 120mg. A CSF cohort received a single dose of 40 mg or placebo (n ¼ 5:2). B0401009 was a subject and investigator blinded, randomized, ascending multiple dose study in HE subjects (mean age 72.7). Three cohorts each received 5, 15, and 35 mg bid for 7 days. A 4th cohort received 35 mg bid for 14 days. All cohorts were randomized 6:2 (active: placebo). Results: In B0401001, HA had 8 mild adverse events (AEs); HE had 10 AEs (8 mild). Treatment-related AEs included nausea and abdominal distension. CSF cohort AEs were generally attributed to the lumbar puncture; 3 AEs were severe. In B0401009, all AEs were mild except one headache. The most common AEs were diarrhea and headache. In both studies, no deaths, serious AEs, discontinuations from AEs, or clinically significant changes in neurological exams, vital signs, safety labs, or ECG parameters, including QTc occurred. PF-04447943 was rapidly absorbed with Cmax at 0.5 - 2 hr post dose, with linear PK. At the 150 mg SD dose, the geometric mean Cmax was 1198 ng/mL; the geometric mean AUC (ng*hr/mL) was 10420 ng*h/mL. Steady state was reached within 3 days. Exposure increased 30% at day 3. PF-04447943 elimination was bi-phasic, with estimated terminal tˇ1/2 of 19-31 hours. Conclusions: PF-04447943 was well tolerated in these studies. Drug-related AEs were generally mild; the most common were diarrhea, headache and nausea. It is currently in a phase 2 study for the treatment of Alzheimer’s disease. O3-05-05
CD45 DEFICENCY PROMOTES NEURODEGENERATION IN PSAPP MICE
Jun Tan1, Yuyan Zhu1, Huayan Hou1, JingJi Jin1, Takashi Mori2, Carmelina Gemma3, Demian Obregon1, Natasa Dragicevic4, Patrick Bradshaw4, Paula Bickford3, Terrence Town5, Brian Giunta1, 1Department of Pscychiatry, University of South Florida, Tampa, FL, USA; 2 Departments of Medical Science and Pathology, Saitama Medical Center/Saitama Medical University, Kawagoe/Saitama, Japan; 3Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL, USA; 4Department of Biology, University of South Florida, Tampa, FL, USA; 5Departments of Neurosurgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Contact e-mail: [email protected]
O3-05-02
ALLOSTERIC ACTIVATION OF M1 AND M5 PROVIDE EFFICACY IN ALZHEIMER MODELS
Craig W. Lindsley, Vanderbilt, Nashville, TN, USA. Contact e-mail: craig. [email protected] Background: Muscarinic acetylcholine receptor agonists have shown efficacy in preclinical AD models and in AD patients; however, these orthosteric agonists, due to poor mAChR selectivity, have serious GI side effects which precluded their development. M1 and/or M5 are the relevant mAChR subtypes of intetest as targets for AD, and highly selective M1 and M5 activators are needed. Methods: Employing functional screening, we identified M1 positive allosteric modulators (PAMs), M1 allosteric agonists and M5 PAMs. Results: M1 and M5 HTS leads were optimized to provide highly selective, centrally penetrant M1 PAMs, M1 allosteric agonists as well as M5 PAMs. In vitro molecular pharamacological characterization confirmed that these highly M1 or M5 ligands were indeed allosteric ligands, with >100-fold selectivity versus other mAChRs and devois of other ancillary pharmacology. Novel allosteric binding sites were identified for these ligands through mutagenesis studies which also supported the development of mAChR homology models. Different chemotypes of allosteric M1 activators were found to differential effects on downstream receptor signaling; thus, all M1 activation is not equivalent. In vivo electrophysiology and in vivo cognition studies, in both wild type and APP mice, showed robust improvement in cognitive performance. In vitro studies showed a significant decrease in Ab40-42 and a shift in APP processign towards the non-amyloidogeneic pathway. While both were efficacious, M1 allosteric agonists outperformed M1 PAMs. M5 PAMs showed similar, but lessened effects, perhaps due to lower receptor expression or a smaller contribution relative to M1. Conclusions: Data from in vivo electrophysiology, rodent cognition models and transgenic rodent models suggest that selective activation of M1 has both a palliative cognitive benefit as well as disease modification potential in AD. M5 while efficacious, plays a minor role as compared to M1. Thus, M1 allosteric agonists represent a novel therapeutic approach for the treatment of Alzheimer’s disease.
O3-05-03
GLUCAGON-LIKE PEPTIDE-1 MIMETIC PEPTIDE EXENDIN 4 PRESERVES MEMORY FUNCTION AND ATTENUATES NEUROPATHOLOGY IN APP/PS1 DOUBLE TRANSGENIC MICE
Ling Li, Dongfeng Cao, Hailin Lu, Terry Lewis, Robert Mans, University of Alabama at Birmingham, Birmingham, AL, USA. Contact e-mail: lili@uab. edu Background: To date there is no effective therapy to prevent or treat Alzheimer’s disease (AD). Emerging evidence shows that type 2 diabetes mellitus (T2DM) is a risk factor for AD and that anti-diabetes strategies are potentially effective to curtail AD. Incretin-based therapies are among the newly developed treatments for T2DM. Incretins are intestinal postprandial peptide hormones that stimulate insulin release from the pancreas, one of which being glucagon-like peptide-1 (GLP-1). However, GLP-1 has a very short half-life and is degraded mainly by the enzyme dipeptidyl peptidase IV (DPP-IV). Therefore, GLP-1 mimetic peptides and DPP-IV inhibitors have been developed to overcome these limitations. Exendin 4 (Ex4) isolated from the saliva of the Gila monster, a peptide with about 50% sequence homology to GLP-1, is a full agonist for the GLP-1 receptor and is resistant to DPP-IV. Synthetic Ex4 (exenatide) has been approved for the treatment of T2DM. In addition to peripheral effects, incretins have been shown to exert effects on the central nervous system and may affect the development of AD. Objective: The present study was designed to investigate the effect of Ex4 treatment on glucose homeostasis, spatial learning and memory, and amyloid-beta (Abeta) neuropathology in APP/PS1 double transgenic (Mo/
S135
HuAPPswe-PS1dE9) mice, an established mouse model of AD. Methods: A group of male APP/PS1 mice at 4 months old, an age at which amyloid plaques start to form in the brain, were treated with Ex4 by daily intra-peritoneal injections of 100 ng Ex4 in 100 ml PBS. After 2 months of drug treatment, the mice were subjected to behavioral, metabolic, pathologic, and biochemical analysis. Littermates injected with PBS without Ex4 served as controls. Results: We found that Ex4 treatment improved glucose homeostasis, preserved memory function, and reduced Abeta deposition in APP/PS1 mice. Biochemical analysis showed that Ex4 modulated levels of signaling molecules pertinent to neuroprotection and memory formation. Conclusions: Our findings suggest that incretin-based therapies could be a double-edged sword against the two devastating disorders, T2DM and AD.
O3-05-04
SAFETY AND PHARMACOKINETICS OF PF04447943, A PDEA INHIBITOR, IN SINGLE AND MULTIPLE DOSE PHASE 1 STUDIES IN HEALTHY VOLUNTEERS
Rebecca M. Evans, Timothy Nicholas, Vu Le, Ruolun Qiu, William Martin, David Martin, Scott Styren, Terence Fullerton, Elias Schwam, Pfizer, Groton, CT, USA. Contact e-mail: [email protected] Background: cGMP plays a key role in synaptic plasticity and PDE9A inhibition affects hippocampal structure and function (Kleiman, ICAD 2010; van der Staay, 2008). PF-04447943 is a potent and selective PDE9A inhibitor that increases cGMP levels in brain and CSF of animals, and CSF of healthy volunteers (Nicholas, ICAD, 2009). Methods: Studies B0401001 and B0401009 evaluated safety, tolerability, PK and pharmacodynamics of PF-04447943. B0401001 was a three-period, subject and investigator blinded, randomized, single dose, crossover study. Each subject received two doses and placebo. Healthy adult (HA) subjects (mean age 36, n ¼ 18) received single oral doses ranging from 1 to 150 mg; healthy elderly (HE) (mean age 66, n ¼ 4) received doses from 30 to 120mg. A CSF cohort received a single dose of 40 mg or placebo (n ¼ 5:2). B0401009 was a subject and investigator blinded, randomized, ascending multiple dose study in HE subjects (mean age 72.7). Three cohorts each received 5, 15, and 35 mg bid for 7 days. A 4th cohort received 35 mg bid for 14 days. All cohorts were randomized 6:2 (active: placebo). Results: In B0401001, HA had 8 mild adverse events (AEs); HE had 10 AEs (8 mild). Treatment-related AEs included nausea and abdominal distension. CSF cohort AEs were generally attributed to the lumbar puncture; 3 AEs were severe. In B0401009, all AEs were mild except one headache. The most common AEs were diarrhea and headache. In both studies, no deaths, serious AEs, discontinuations from AEs, or clinically significant changes in neurological exams, vital signs, safety labs, or ECG parameters, including QTc occurred. PF-04447943 was rapidly absorbed with Cmax at 0.5 - 2 hr post dose, with linear PK. At the 150 mg SD dose, the geometric mean Cmax was 1198 ng/mL; the geometric mean AUC (ng*hr/mL) was 10420 ng*h/mL. Steady state was reached within 3 days. Exposure increased 30% at day 3. PF-04447943 elimination was bi-phasic, with estimated terminal tˇ1/2 of 19-31 hours. Conclusions: PF-04447943 was well tolerated in these studies. Drug-related AEs were generally mild; the most common were diarrhea, headache and nausea. It is currently in a phase 2 study for the treatment of Alzheimer’s disease. O3-05-05
CD45 DEFICENCY PROMOTES NEURODEGENERATION IN PSAPP MICE
Jun Tan1, Yuyan Zhu1, Huayan Hou1, JingJi Jin1, Takashi Mori2, Carmelina Gemma3, Demian Obregon1, Natasa Dragicevic4, Patrick Bradshaw4, Paula Bickford3, Terrence Town5, Brian Giunta1, 1Department of Pscychiatry, University of South Florida, Tampa, FL, USA; 2 Departments of Medical Science and Pathology, Saitama Medical Center/Saitama Medical University, Kawagoe/Saitama, Japan; 3Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL, USA; 4Department of Biology, University of South Florida, Tampa, FL, USA; 5Departments of Neurosurgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Contact e-mail: [email protected]