Innovations In Clinical Neuroscience

Summit 2017

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

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drug screening data were collected four m onths after the initiation of the cohort study. Results: Due to a large spread of data points, each patient was given a score for illicit opioid use based on urine drug t est results for every two weeks using their available data (a block analysis similar to the Treatment Effectiveness Score). The blocks were averaged across patients for each cohort (MedicaSafe vs. control). Results show that those patients on the dispenser had less opioid presence in urine than those in the control group. Subjects in the control group had an illicit opioid presence in urine of 33.3% at Weeks 8 to 16 of the study, and of 21.4% at Qeeks 16 to 24. Those in the MedicaSafe group had zero percent illicit opioid presence in those same weeks. Conclusion: Use the MedicaSafe dispenser among patients in medication- assisted, opioid addiction treatment programs correlated with decreased presence of illicit opioids. Scientific rationale and clinical development of AXS-05 for neuropsychiatric disorders Presenters: O'Gorman C 1 , Jones A 1 , Kennon K 1 , Niecestro R 1 , and Tabuteau H 1 Affiliations: 1 Axsome Therapeutics, Inc. New York, New York, USA. Background/Objective: AXS-05 is a novel, oral, investigational, fixed-dose combination of bupropion and dextromethorphan in clinical development for treatment-resistant depression (TRD) and agitation associated with dementia of the Alzheimer's disease type. Bupropion serves to increase the bioavailability of dextromethorphan by inhibiting its metabolism through CYP2D6. Combined mechanisms of action of AXS-05 include NMDA-receptor antagonism, sigma-1 receptor agonism, and reuptake inhibition of norepinephrine, serotonin, and dopamine. The potential for pharmacokinetic and pharmacodynamic synergies with the combination exists. Design: Phase I studies examined the pharmacokinetics of dextromethorphan after AXS-05 dosing. The efficacy and safety of AXS-05 is being evaluated in a Phase III, randomized, double-blind, a ctive-controlled, 12-week study of subjects with TRD. This study consists of a six-week open-label, bupropion lead-in period, and a six-week, double- blind treatment period. The primary o utcome measure is the Montgomery- Åsberg Depression Rating Scale (MADRS). The efficacy and safety of AXS-05 for the treatment of agitation in patients with Alzheimer's disease is being evaluated in a Phase II/III randomized, double-blind, placebo- controlled, five-week study. The primary outcome measure is the Cohen- Mansfield Agitation Inventory (CMAI) score. Results: In Phase I trials, co- administration of bupropion and dextromethorphan resulted in substantial increases in dextromethorphan plasma concentrations. AXS-05 was well tolerated. The TRD study (STRIDE-1) is expected to enroll approximately 350 subjects. The Alzheimer's agitation study (ADVANCE) is expected to enroll approximately 435 subjects. Conclusion: AXS-05 is a fixed-dose combination of dextromethorphan and bupropion. Increased dextromethorphan bioavailability has been demonstrated. Ongoing trials are evaluating AXS-05 in patients with TRD and in patients with agitation associated with Alzheimer's disease. Disclosures/funding: All authors are full-time employees of Axsome Therapeutics, Inc. Tolperisone shows no evidence of sedation compared to cyclobenzaprine and placebo in a driving simulation study Presenters: Caron J 1 , Kay G 2 , Rosenberg R 3 , Walling D 4 , Horonovich S 2 , and Hochadel T 2 Affiliations: 1 Neurana Pharmaceuticals, 2 Cognitive Research Corporation, 3 NeuroTrials Research, 4 Collaborative Neuroscience Network Background/Objective: Tolperisone is a centrally acting muscle relaxant being developed in the United States for treatment of occupational/sports-related muscle spasms. Tolperisone previously demonstrated muscle relaxant and analgesic effects without sedation. The p resent study explores the impact of tolperisone on driving, self-reported sleepiness, and cognition compared to placebo and cyclobenzaprine, an active comparator. D esign: This three-way, randomized, blinded, crossover study assessed the safety and effects on cognition of tolperisone in 36 healthy volunteers. Treatment groups included 450mg tolperisone administered three times a day (150mg TID), 30mg cyclobenzaprine (10mg TID), and placebo (TID). Participants spent three days a week for three weeks in the clinic. Dosing occurred on the morning of Days 1, 2, and 3, and in the afternoon (PM) and at bedtime on Days 1 and 2. Subjects completed 100km (60 minutes) of simulated driving on Day 1 one hour after their PM dose (i.e., at drug T max) , and again the morning of Day 2 (pre- dosing) to assess next day residual effects, and the morning of Day 3 (post- dose) to assess the effects of drug accumulation seen at steady-state. Subjects returned on Days 7 and 14 to repeat procedures. Results: For the primary endpoint of standard deviation of lateral position (SDLP) over 100km of driving, tolperisone was no different than placebo (p=0.9); cyclobenzaprine, however, showed significant impairment (p=<0.001). Additional measures of driving, self-reported sleepiness, cognition, and safety indicated no impairment for tolperisone versus placebo. Conclusion: Tolperisone was found equivalent to placebo on measures of driving, self-reported sleepiness, and cognition, whereas cyclobenzaprine demonstrated significant impairment on SDLP, an objective measure highly correlated to blood alcohol levels. Disclosures/funding: Judy Caron is an employee of Neurana Pharmaceuticals, the sponsor of this study; Russell Rosenberg is participating in a study funded by Neurana Pharmaceuticals; David Walling is participating in a study funded by Neurana Pharmaceuticals; Gary Kay and Thomas Hochadel are employees of Cognitive Research Corporation. ICNS Innovations in Clinical Neuroscience • November–December 2017 • Volume 14 • Number 11–12 • Supplement S9

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