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Blind, Placebo-Controlled Study of NSI-189 Phosphate, a Neurogenic A Phase 1B, Randomized, Double- Blind, Placebo-Controlled Study of NSI-189 Phosphate, a Neurogenic Compound, in Patients with Major Depressive Disorder (MDD) Maurizio Fava, MD Director, Clinical Research Program Executive Vice Chair, Department of Psychiatry Executive Director, MGH Psychiatry CTNI Massachusetts General Hospital (MGH) Slater Family Professor of Psychiatry, Harvard Medical School Disclosures (lifetime): Maurizio Fava, MD Type Company Advisory Board/ Abbott Laboratories; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; Auspex Consultant Pharmaceuticals; Avanir Pharmaceuticals; AXSOME Therapeutics; Bayer AG; Best Practice Project Management, Inc.; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; BrainCells Inc; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon, Inc.; Cerecor; CNS Response, Inc.; Compellis Pharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Dinippon Sumitomo Pharma Co. Inc.; Dov Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai Inc.; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; ePharmaSolutions; EPIX Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Forum Pharmaceuticals; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; i3 Innovus/Ingenis; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson & Johnson Pharmaceutical Research & Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Nestle Health Sciences; Neuralstem, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG;Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Otsuka Pharmaceuticals; Pamlab, LLC.; Pfizer Inc.; PharmaStar; Pharmavite® LLC.; PharmoRx Therapeutics; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; PPD; Puretech Ventures; PsychoGenics; Psylin Neurosciences, Inc.; RCT Logic, LLC ( formerly Clinical Trials Solutions, LLC); Rexahn Pharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; Sanofi-Aventis US LLC.; Sepracor Inc.; Servier Laboratories; Schering-Plough Corporation; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex Pharmaceuticals, Inc.; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Vanda Pharmaceuticals, Inc. Speaking/ Adamed, Co; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; Publishing AstraZeneca; Belvoir Media Group; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Cephalon, Inc.; CME Institute/Physicians Postgraduate Press, Inc.; Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer Inc.; PharmaStar; United BioSource,Corp.; Wyeth-Ayerst Laboratories. Research Support Abbot Laboratories; Alkermes, Inc.; American Cyanamid;Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Clintara, LLC; Covance; Covidien; Eli Lilly and Company;EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante; Methylation Sciences Inc; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates., Inc.; Pharmavite® LLC;PharmoRx Therapeutics; Photothera; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Stanley Medical Research Institute (SMRI); Synthelabo; Wyeth-Ayerst Laboratories Stock/Other Equity Holdings: Compellis; PsyBrain, Inc. Financial Options Royalty/patent, other income: Patents for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development, LLC (PPD); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven. Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte.Ltd. Stress and Neurogenesis • Recent data suggest neurogenesis occurs in key brain areas (eg, hippocampus1) • BDNF is associated with production of new neurons and their growth and development2 • Neurogenesis and BDNF production shuts down with stress2 • Antidepressants reverse alterations in brain structure and BDNF BDNF=brain-derived neurotrophic factor. 1. Gould E. Neuropsychopharmacology. 1999;21(2 suppl):46S-51S. 2. Duman RS, et al. Arch Gen Psychiatry. 1997;54(7):597-606. The Effect of Stress and CRF on Neurogenesis Stress Adrenal steroids Stellate NMDAr cell Median raphe Mature granule 5-HT TGFα ● neuron Precursor cell Entorhinal cortex Dividing cell Derived from: Gould E. Neuropsychopharmacology. 1999;21(2 suppl):46S-51S. Actions of Stress and Antidepressant Treatment on Hippocampal Neurons Hippocampus CA1 sc Dentate gyrus Granule CA3 cell mf pathway Stress Antidepressant Stress Antidepressant treatment treatment é Glucocorticoid é NE and 5-HT é Glucocorticoid é NE and 5-HT ê BDNF é BDNF Increased Atrophy or Increased survival Decreased death neurogenesis neurogenesis and growth Increased vulnerability as a result of environmental and genetic factors Derived from: Duman RS et al. Biol Psychiatry. 1999;46:1811–1191. Preclinical Studies on the Role of Adult Hippocampal Neurogenesis (AHN) in Depression • Rodents – Diverse rodent models of depression and anxiety impair AHN • Non-human primates – Social stress impairs AHN • Rodents – Ablation of AHN does not increase baseline depression-like behaviors in most studies, but it may potentiate these behaviors after acute stress – Ablation of AHN impairs pattern separation and cognitive flexibility: cognitive functions relevant to depression • Rodents – Electroconvulsive shock and diverse antidepressants boost AHN in stressed animals • Non-human primates – Electroconvulsive shock and fluoxetine boost AHN in stressed animals Miller and Hen, Current Opinion in Neurobiology 2015, 30:51–58 NS-189 • Stimulates neurogenesis of human hippocampus derived neural stem cells in vitro and stimulates neurogenesis in mouse hippocampus in vivo • Increases neurogenesis in the dentate gyrus and significantly increases hippocampal volume • Hypothesized to have a highly specific effect in the hippocampus and subventricular zone, two well-known neurogenic regions in adults Phase 1B Study of NSI-189 Phosphate in the Treatment of MDD • Primary Objective: To assess the safety and tolerability of escalating daily doses of monotherapy with NSI-189 Phosphate for 28 consecutive days in patients with depression • Exploratory Objective: To obtain preliminary data on efficacy in the treatment of MDD Overview Phase I Study: Double-blind, randomized, placebo-controlled, multiple-dose study with three ascending cohorts (N=24) Cohort 1 N=8 (6 drug, 2 40 mg QD placebo) Cohort 2 N=8 (6 drug, 2 40 mg BID placebo) Cohort 3 N=8 (6 drug, 2 40 mg TID placebo) Acute treatment: 28 Follow up: Days 35, 42, 49, days 70, 84 (End-of-study) Participants • Male or female, 18 to 60 years of age, diagnosed with MDD, recurrent, as per DSM- IV-TR confirmed by SCID-CT • Patients at screening could be taking an antidepressant medication(s), or have a history of taking antidepressant medication(s) in the past for their depressive disorder • At least two prior depressive episodes (including current episode) Outcome Measures Items Symptoms of Depression Questionnaire (SDQ) 43 items Montgomery-Asberg Depression Rating Scale 10 items (MADRS) Clinical Global Impressions – Improvement (CGI-I) 1 item Cognitive and Physical Functioning Questionnaire 7 items (CPFQ) Strategy to Enhance Signal Detection • Independent review of appropriateness of subject inclusion by remote rater: – SAFER Clinical Interview • State vs. Trait, Assessability, Face validity, Ecological validity, Rule of the Three Ps (pervasive, persistent, pathological) – MGH ATRQ (Antidepressant Treatment Resistance Questionnaire) – MADRS Results Preliminary Efficacy Data Analytic Strategy • Analysis of covariance (ANCOVA) – DVs: CGI-I, MADRS, SDQ, and CPFQ observed at • Day 28 (end of treatment) • Day 84 (end of follow-up) – Covariate: baseline values to adjust for initial differences • For CGI-I, day 7 as covariate • Note: – Placebo (n=6) and Tx (n=18) groups collapsed – Excluding n=2 early termination patients (replaced) – Incomplete follow-up (i.e., missing
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