Innovations In Clinical Neuroscience

CNS Summit 2016

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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[ V O L U M E 1 4 , N U M B E R 1 – 2 , J A N U A R Y – F E B R U A R Y 2 0 1 7 , S U P P L E M E N T ] Innovations in CLINICAL NEUROSCIENCE S11 The ITI-007-302 trial is ongoing, and results will be presented, if available. Conclusion: ITI-007 represents a new a pproach to the treatment of schizophrenia with unique pharmacologic properties and a differentiating clinical profile. Disclosures/funding: KEV, SJG, COG, JS, MW, SM, RED are full-time employees o f Intra-Cellular Therapies. CUC financial disclosures include Alkermes, Bristol- Myers Squibb, Forum, Gerson Lehrman Group, Intra-Cellular Therapies, Janssen/J&J, Lundbeck, Medavante, Medscape, Otsuka, Pfizer, ProPhase, Sunovion, Supernus, Takeda, and Teva. D 3 : deuterium drug development Presenters: Barag J, Laage T, Leathers T Affiliations: Premier Research, Trenton, New Jersey Objective: The objective of this review was to highlight recent developments and challenges in using deuterium atom substitution to create novel chemical entities that prolong the metabolism and therefore increase the therapeutic effect of parent compounds. Deuterium is an isotope of hydrogen having double the atomic weight (1–2) because of the addition of a neutron to the single proton in the nucleus of the most common isotope. Design: We reviewed the physiochemical (or pharmacodynamic) effects of such substitutions on the action of parent compounds (usually minimal) and the contrast with the metabolic (or pharmacokinetic) consequences of deuteration, as the strength of the covalent carbon-deuterium bond is 10 times that of the carbon-hydrogen bond (kinetic isotope effect), creating more resistance to chemical or enzymatic cleavage. If the cleavage of this bond is a metabolic, rate- determining step (often the case where oxidation or hydroxylation occurs), favorable effects of the parent compound are prolonged and deleterious effects of metabolites reduced. Intellectual property challenges involving patentability (including "art" and "obviousness") were also reviewed. Deuterated compounds currently in development (e.g., Auspex— tetrabenazine and pirfenidone; Sage— allopregnanolone; Amorsa—norketamine; Concert—dextromethorphan, ivacaftor, sodium oxybate, apremilast, ruxolitinib) and discontinued (Merck's fludalanine) were also reviewed. Conclusion: Deuteration is a powerful t echnique for developing and marketing versions of existing drugs with improved half-lives and reduced toxicity. Disclosures/funding: None reported. D rug repositioning for neurological disorders using a sustained release formulation of exenatide Presenters: Kim D 1 , 2 , Li Y 1 ,Tamargo I 1 , Kim H 2 , Tweedie D 1 , Wang Y 3 , Lee H 2 , Han B 4 , Greig N 1 Affiliations: 1 National Institute on Aging, Baltimore, Maryland; 2 Peptron Inc., Daejeon, Korea; 3 National Health Research Institutes, Taiwan; 4 KRIBB, Daejeon, Korea. Background: SmartDepot TM is Peptron's proprietary technology for the sustained release (SR) microsphere formulation of various agents to provide once weekly or longer dosing regimens. exenatide, a long- acting GLP-1 analogue that is efficacious in type 2 diabetes mellitus (T2DM), has been identified as a novel treatment strategy for neurodegenerative disorders, including chronic diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), and acute ones, such as traumatic brain injury (TBI). Consequent to its neuroprotective and neurotrophic actions, clinical trials in several of these disorders are on going. In prior preclinical research that supported these clinical studies, exenatide proved particularly efficacious when delivered continuously by a micro-osmotic pump in PD and mild TBI animal model studies. The application of the latest sustained release (SR) technology to exenatide, whereby steady- state concentrations can be effectively maintained over weeks to months, holds the potential to optimize the beneficial potential of a new drug treatment for a chronic disorder, particularly where disease-associated cognitive impairments may impact adherence. Design and results: In this study, an exenatide SR-formulation (SR-exenatide) was evaluated in a concussive mild TBI mouse model and in a PD animal model. TBI and PD animals displayed deficits in behavioral tests associated with cognitive and motor performance, respectively, whereas SR-exenatide-treated animals performed similar to sham controls when treated with a clinically translatable dose used in ongoing T2DM clinical trials of SR- exenatide. C onclusion: These behavioral data suggest a strong beneficial action of SR- exenatide in TBI and PD and are defining parameters for first human trials of SR- exenatide in these disorders. This c onvenient dosing regimen of SR- exenatide has applications for other diseases, such as AD, multiple system atrophy, and multiple sclerosis, where preclinical studies, likewise, have demonstrated promising exenatide actions. The effect of cholesterol on positive symptoms of schizophrenia Presenters: Tireman E, Templeton K, Kakar R, DeVito L, Pierre L, Pina D Affiliations: Segal Institute for Clinical Research, Ft. Lauderdale, Florida Background: Cholesterol may be a factor in the pathological development of schizophrenia, as it is an important molecular component of myelin and synapses within the brain. Currently, research has failed to investigate the effect of cholesterol on schizophrenia and instead has focused on other areas of mental illness. A relationship between cholesterol level and positive symptoms could allow physicians to increase the efficacy of antipsychotics by focusing treatment on patients with normal (neither high nor low) cholesterol. Additionally, future drug augmentation may look for agents that work on the cholesterol pathway to increase efficacy of decreasing positive symptoms. We examined positive symptoms of schizophrenia, as measured by the Brief Psychotic Rating Scale (BPRS), and fasting lipid profile to determine if lower levels of cholesterol are indicative of increased positive symptoms. Methods: Lipid profiles and BPRS scores were collected from 231 patients with schizophrenia who experienced an acute exacerbation of symptoms. Positive BRPS scores and BPRS total score at screening (i.e., items BPRS4 conceptual disorganization, BPRS10 hostility, BPRS11 suspiciousness, BPRS12 hallucinatory behavior, and BPRS15 unusual thought content) and fasting lipid profiles were analyzed to assess correlation. Results: Correlational analyses were used to examine the relationship between

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