Human phase-1 Multiple Ascending Dose (MAD) study - safety, tolerability and pharmacokinetics of SUVN-502, a 5-HT6 receptor antagonist

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Poster Presentations P1

Wisconsin, Madison, Madison, WI, USA. Contact e-mail: wlwharto@ medicine.wisc.edu Background: Neuropsychological, clinical, observational and basic science research supports a potential cognitive benefit of soy isoflavones in older adults. While the mechanism remains unclear, mounting evidence from research examining healthy and hypertensive individuals suggests that the cognitive benefits associated with soy isoflavones could be attributed to improvements in vascular function, such as decreased blood pressure, improved lipid profiles, decreased inflammation and restoration of the vasculature. Methods: In order to clarify the potential relation between vascular factors, cognition and soy isoflavones supplements in older adults, we conducted a randomized, placebo-controlled, double-blinded pilot study in 30 men and women (age 62-89 years), using purified glycosidic isoflavones (100 mg/day), in addition to plasma levels of genistein, daidzein and equol over 6 months of treatment. Baseline assessment included blood samples for isoflavone and hormone assays, safety laboratory testing, medical evaluation and neuropsychological testing. Procedures were repeated at months 1, 3 and 6. Results: There were no differences between the groups with regard to sex, age, ApoE status, education, MMSE score or Geriatric Depression score. While similar at baseline, results showed a significant decrease in both systolic (p ¼ .05) and diastolic (p ¼ .02) blood pressure in participants treated with soy isoflavones. Improvement was not observed in measures less closely related with vascular function (temperature, pulse, respirations). Additionally, the groups differed across 6 months of treatment on 8 of 11 cognitive tests. Isoflavones-treated subjects improved on visuospatial memory (p < 0.01), construction (p ¼ 0.01), verbal fluency (p < 0.01) and speeded dexterity (p ¼ 0.04). Interestingly, there was a negative correlation between change in blood pressure and change in verbal performance in the isoflavones treated group, such that participants with the large decreases in blood pressure exhibited the most improved verbal performance (p ¼ .06 and p < .01 for systolic and diastolic, respectively). Conclusions: These data offer preliminary support for future investigations of vascular influence on cognitive function in isoflavones research. Specifically, the current study highlights vascular function as a potential mediating variable in the cognition - soy isoflavones relationship, and should be considered in future research studies. P1-251

SUVN-502: A SAFE, POTENT, SELECTIVE, BRAIN PENETRANT AND ORALLY ACTIVE 5-HT6 RECEPTOR ANTAGONIST - FIRST IN HUMAN CLINICAL PHASE-1 STUDY

Ramakrishna Nirogi, Ramasastri Kambhampati, Anil Shinde, Vishwottam Kandikere, Koteshwara Mudigonda, Gopinadh Bhyrapuneni, Pradeep Jayarajan, Renny Abraham, Mohmad Sadik Mulla, Venkat Jasti, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: nvsrk@suven. com Background: Alzheimer’s disease is a neurological condition characterized by a progressive decline in cognitive performance accompanied by behavioral and psychological syndromes. The neurochemical correlates of these clinical manifestations now appear to involve dysfunctions of multiple neurotransmitter pathways. Extensive serotonergic denervation that has been observed in the Alzheimer’s disease brain and the important role played by serotonin (5-HT) in both cognition and behavioral control, this neurotransmitter system has become a focus to identify new treatments for Alzheimer’s disease. One of the newest members of this family is the 5-HT6 receptor, a subtype localized almost exclusively in the CNS, predominating in brain regions associated with cognition and behavior. Blockade of 5-HT6 receptors leads to improvement of cognitive performance in a wide variety of learning and memory paradigms. Methods: Our effective lead generation and optimization methods have resulted in a novel and potent 5-HT6 receptor antagonist SUVN-502 with Ki of 1.71 nM and exhibited antagonist like inhibition with EC50 of 0.103 mM when tested for functional activity. SUVN-502 has more than 100 fold selectivity against the other 5-HT receptor subtypes and related GPCRs. SUVN-502 was effective in animal models of cognition. SUVN-502 has completed all regulatory safety and toxicity studies. Results: SUVN-502 reversed the age induced memory deficit in Morris water maze and novel object recognition task (NORT). SUVN-502 also reversed the spatial and work-

ing memory deficit induced by MK-801 and scopolamine in Morris water maze, NORT and radial arm maze task. The effective dose range of SUVN-502 in the these animal models was between 3 to 10 mg/kg p.o. SUVN-502 enhanced brain acetylcholine and glutamate levels in rat ventral hippocampus and frontal cortex SUVN-502 has high oral bioavailability and good brain penetration index. A double-blind, placebo-controlled, randomized, ascending single and multiple-dose study was conducted with healthy male subjects. SUVN-502 was safe and well tolerated in humans at all single and multiple doses tested. Conclusions: SUVN-502 has the potential for best in the class candidate with a favorable pharmacokinetics, safety and toxicology profile. SUVN-502 completed human Phase I clinical studies and is ready to enter clinical proof of concept studies for cognitive dysfunction associated with Schizophrenia and Alzheimer’s diseases. P1-252

SAFETY, TOLERABILITY AND PHARMACOKINETICS OF SUVN-502 - A 5-HT6 RECEPTOR ANTAGONIST, FIRST IN HUMAN PHASE-1 SINGLE ASCENDING DOSE (SAD) STUDY

Ramakrishna Nirogi, Vishwottam Kandikere, Koteshwara Mudigonda, Gopinadh Bhyrapuneni, Venkat Jasti, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: [email protected] Background: Alzheimer’s disease is a neurological condition characterized by a progressive decline in cognitive performance accompanied by behavioral and psychological syndromes. One of the newest members of serotonin family is the 5-HT6 receptor predominating in brain regions associated with cognition and behavior. The blockade of 5-HT6 receptors leads to an improvement of cognitive performance in a wide variety of learning and memory paradigms. Our effective lead generation and optimization methods have resulted in a novel, potent and selective 5-HT6 receptor antagonist SUVN502 with Ki of 1.71 nM and exhibited antagonist like inhibition with EC50 of 0.103 mM. SUVN-502 is effective in animal models of cognition. In microdialysis studies, SUVN-502 enhanced brain acetylcholine and glutamate levels in rat ventral hippocampus and frontal cortex. SUVN-502 has completed all regulatory safety and toxicity studies. The objective of the present investigation is to assess First-in-Human safety, tolerability and pharmacokinetics of ascending single oral doses of SUVN-502 in healthy subjects. Methods: A double-blind, placebo-controlled, randomized, ascending single-dose study was conducted with healthy male subjects. The safety and tolerability of single ascending doses of SUVN-502 was evaluated by assessing adverse events, physical examinations, clinical chemistry examination, hematology, ECG and urinalysis. The pharmacokinetic profile of single ascending doses of SUVN-502 was determined by estimating parent compound SUVN-502 and its active metabolite M1 of SUVN-502 in plasma samples obtained upto 72 h post dosing. Results: The tolerability of SUVN-502 upto highest dose administered was considered as very good. No serious adverse events occurred. No clinically significant changes or study medication related abnormalities were observed with respect to ECG’s and laboratory evaluations. There were no clinically significant changes of vital sign parameters. Considering the half-life of drug and active metabolite and also the overall exposure levels, SUVN-502 demonstrated a favourable pharmacokinetics with a potential for once daily dosing. Conclusions: SUVN-502 is safe and well tolerated and has a favorable pharmacokinetics profile. SUVN-502 completed human Phase I clinical studies and is ready to enter clinical proof of concept studies for cognitive dysfunction associated with Alzheimer’s disease. P1-253

HUMAN PHASE-1 MULTIPLE ASCENDING DOSE (MAD) STUDY - SAFETY, TOLERABILITY AND PHARMACOKINETICS OF SUVN-502, A 5-HT6 RECEPTOR ANTAGONIST

Ramakrishna Nirogi, Vishwottam Kandikere, Koteshwara Mudigonda, Gopinadh Bhyrapuneni, Venkat Jasti, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: [email protected] Background: Alzheimer’s disease is a neurological condition characterized by a progressive decline in cognitive performance accompanied by behavioral and psychological syndromes. One of the newest members of serotonin

Poster Presentations P1 family is the 5-HT6 receptor predominating in brain regions associated with cognition and behavior. The blockade of 5-HT6 receptors leads to an improvement of cognitive performance in a wide variety of learning and memory paradigms. Our effective lead generation and optimization methods have resulted in a novel, potent and selective 5-HT6 receptor antagonist SUVN502 with Ki of 1.71 nM and exhibited antagonist like inhibition with EC50 of 0.103 mM. SUVN-502 is effective in animal models of cognition. In microdialysis studies, SUVN-502 enhanced brain acetylcholine and glutamate levels in rat ventral hippocampus and frontal cortex. SUVN-502 has completed all regulatory safety and toxicity studies. The objective of the present investigation is to assess the safety, tolerability and pharmacokinetics of ascending multiple oral doses of SUVN-502 in healthy subjects. Methods: A double-blind, placebo-controlled, randomized, ascending multiple-dose study was conducted with healthy male subjects. Adverse events, physical examinations, clinical chemistry examination, hematology, urinalysis and ECG were measured throughout the study. The plasma concentrations of SUVN502 and its active metabolite M1 of SUVN-502 were analyzed by non-compartmental methods. Results: SUVN-502 was generally well tolerated upto highest dose administered. No serious adverse events occurred. No clinically significant changes or study medication related abnormalities were observed with respect to ECG’s and laboratory evaluations. There were no clinically significant changes of vital sign parameters. Conclusions: SUVN-502 was safe and well tolerated at multiple doses of upto highest dose. SUVN-502 has the potential for best in the class candidate with a favorable pharmacokinetics, safety and toxicology profile. SUVN-502 completed human Phase I clinical studies (both Single Ascending Dose and Multiple Ascending Dose studies) and is ready to enter clinical proof of concept studies for cognitive dysfunction associated with Schizophrenia and Alzheimer’s diseases. P1-254

A SAFETY, TOLERABILITY AND PHARMACOKINETIC STUDY OF DIMEBON IN PATIENTS WITH ALZHEIMER’S DISEASE ALREADY RECEIVING DONEPEZIL

Pierre Tariot1, Marwan Sabbagh2, Stephen Flitman3, Patricio Reyes4, Louise Taber5, Lynn Seely6, 1Banner Alzheimer’s Institute, Phoenix, AZ, USA; 2Cleo Roberts Center for Clinical Research, Sun City, AZ, USA; 3 Xenoscience, Phoenix, AZ, USA; 4Barrow Neurological Institute, Phoenix, AZ, USA; 5Pivotal Research, Peoria, AZ, USA; 6Medivation, Inc., San Francisco, CA, USA. Contact e-mail: [email protected] Background: Dimebon is a novel drug in Phase 3 development for the treatment of Alzheimer’s disease (AD). A previous study demonstrated improvement in cognition, function, and behavior in AD patients compared to placebo. The basis for its clinical effects is unknown; preclinical studies suggest dimebon may enhance mitochondrial function in the setting of cellular stress and promote neurite outgrowth. This study evaluated the safety and tolerability of dimebon in AD patients already treated with donepezil. Methods: AD patients stable on donepezil (10 mg daily) for at least 60 days and tolerating it well were randomized to dimebon (n¼15) or placebo (n¼9). The first 14 patients enrolled (9 dimebon, 5 placebo) underwent gradual within- patient dose-titration including 2.5 mg three times daily (TID) x 7 days, then 5.0 mg TID x 7 days, then 10 mg TID x 7 days, then 20 mg TID x 7 days. The next 10 patients (6 dimebon, 4 placebo) underwent more rapid dose-titration from 10 mg TID x 7 days to 20 mg TID x 7 days. Standard safety and tolerability assessments were collected, including PK of dimebon and donepezil. Results: All patients completed the treatment period except one placebo patient. No serious adverse events (AEs) or deaths occurred. 13/15 (87%) dimebon and 5/9 (56%) of placebo patients reported an AE. All dimebon AEs were mild in severity except 1 fall (moderate, without loss of consciousness) and 1 neuralgia (severe) both assessed as unrelated to study drug. AEs reported in at least 2 Dimebon patients and more frequently than in the placebo group were: fatigue (3/15, 20% vs. 0%), abdominal distension (2/15, 13% vs. 0%), dizziness (2/15, 13% vs. 1/9, 11%), fall (2/15, 13% vs. 0%), hyperkalemia (2/15, 13% vs. 1/9,11%), and nightmare (2/15,13% vs. 0%). These AEs were mild/moderate and resolved with continued treatment. Those patients who underwent the shortened titration period did not have an increased incidence of AEs as

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compared to those on the gradual titration. Co-administration of Dimebon and donepezil did not result in an increase in Cmax or AUC of either drug. Conclusions: Dimebon was well-tolerated in this study of AD patients already treated with donepezil. P1-255

THE TREATMENT COMPLIANCE WITH RIVASTIGMINE PATCH IN CLINICAL PRACTICE VERSUS TRIAL DATA: A CASE SERIES

Lucrezia Hausner, Alexander Sartorius, Lutz Froelich, Central Institute of Mental Health, Mannheim, Germany. Contact e-mail: Lucrezia.Hausner@ gmx.de Background: Treatment compliance is challenging in many disease settings, and adherence to older oral cholinesterase inhibitors has been particularly poor. Patch therapy may offer benefits over oral treatments, including improved tolerability during initial months of treatment (titration phase) and consequently enhanced compliance. Trial data suggest rivastigmine transdermal patch is well tolerated and that relatively few patients discontinue due to common adverse events such as nausea or vomiting. Our objective was to determine whether low discontinuation rates due to nausea or vomiting, or skin irritation, were also seen in everyday clinical practice. Methods: This was a case series comprising patients who were prescribed rivastigmine patch 9.5 mg/24 h at the Central Institute of Mental Health in Mannheim, Germany. Patients were included over a 4 month period. Serious adverse events (SAEs) or discontinuations were recorded, and considered in light of those seen in the large 6-month clinical trial on which rivastigmine patch approval was based (Winblad et al, 2007). Due to the exploratory nature of this investigation, no formal statistics were applied. Results: The case series comprised 45 de novo patients receiving rivastigmine patch (mean age 79 years, range 54-95 years). One patient (2%) aged 80 years reported an SAE of paroxysmal atrial fibrillation (no discontinuation). Three discontinuations in patients aged 73 to 84 were reported: one (2%) due to skin irritation and two (4%) due to diarrhea (although one case of diarrhoea was attributed to viral infection). In comparison, in the published clinical trial, 8% of patients on rivastigmine patch 9.5 mg/24 h reported SAEs, 1% withdrew due to gastrointestinal events, and 2% withdrew due to skin irritation. Conclusions: Compared with clinical trial data, our centre saw similar rates of withdrawal due to skin irritation or gastrointestinal events. SAEs were not commonly reported. Consistent with published clinical trial, we conclude that discontinuations due to tolerability problems are relatively rare with rivastigmine patch, and that this might contribute to improved treatment compliance. P1-256

ALOIS: ALZHEIMER’S AND COGNITIVE IMPROVEMENT STUDIES REGISTER, A FREE, ON-LINE REGISTER OF DEMENTIA AND COGNITIVE ENHANCEMENT TRIALS (HTTP://WWW.MEDICINE.OX.AC.UK/ALOIS/)

Reem Malouf, Anna Noel-Storr, Helen Collins, Rupert McShane, Lon S. Schneider, Oxfordshire and Buckinghamshire Mental Health Trust, Oxford, United Kingdom. Contact e-mail: [email protected] Background: Multiple publication of clinical studies makes it difficult for researchers and the public to identify unique studies from reference lists and bibliographic searches. The Cochrane Dementia and Cognitive Improvement Group’s Specialised Register has recently been extended to include reports of all trials of prevention strategies and cognitive enhancers, as well as of treatment and rehabilitation in dementia. It has also been made freely available on-line to the community of researchers and the public (http://www.medicine.ox.ac.uk/alois/). The objective of this project is to create and maintain a comprehensive, up-to-date study-based registry of all trials and to make this register freely available on-line. Methods: We developed highly sensitive search strategies for the retrieval of citations of studies of treatment, prevention, and cognitive enhancement. These were then run in major databases, trial registers and grey literature sources. Each RCT was read and data extracted. Duplicate publications were linked to the same trial record. Each record was linked to a published Cochrane review where appropriate. A user friendly, web interface for searching the database was created. Results: ALOIS contains records of 2,525 randomized