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Negative Symptoms of Schizophrenia NEGATIVE SYMPTOMS OF SCHIZOPHRENIA March 22, 2018 Confidential & Proprietary Forward-Looking Statement Safe-Harbor This presentation contains forward-looking statements about Minerva Neurosciences which are subject to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts, reflect management’s expectations as of the date of this presentation, and involve certain risks and uncertainties. Forward-looking statements include, but are not limited to: the benefits, efficacy and safety of our new formulations; the potential of the diagnosis and treatment of negative symptoms of schizophrenia; statements regarding our ability to successfully develop and commercialize our therapeutic products; our ability to expand our long-term business opportunities; our expectations regarding approval for our products by the U.S. Food and Drug Administration or equivalent foreign regulatory agencies; estimates regarding the market potential for our products; and future performance. All of such statements are subject to certain risks and uncertainties, many of which are difficult to predict and generally beyond the control of the Company, that could cause actual results to differ materially from those expressed in, or implied or projected by, the forward-looking statements. These forward-looking statements are based on our current expectations and may differ materially from actual results due to a variety of factors including, without limitation, whether any of our therapeutic products will advance further in the clinical trials process and whether and when, if at all, they will receive final approval from the U.S. Food and Drug Administration or equivalent foreign regulatory agencies and for which indications; whether the results of future clinical trials of roluperidone (MIN-101) will be consistent with the results of past clinical trials; whether roluperidone will be successfully marketed if approved; whether our therapeutic product discovery and development efforts will be successful; our ability to achieve the results contemplated by our co-development agreements; the strength and enforceability of our intellectual property rights; our ability to raise additional capital to fund our operations on terms acceptable to us; and general economic conditions. These and other potential risks and uncertainties that could cause actual results to differ from the results predicted are more fully detailed under the caption “Risk Factors” in our filings with the Securities and Exchange Commission, including our Annual Report on Form 10-K for the year ended December 31, 2017, filed with the Securities and Exchange Commission on March 12, 2018. Copies of reports filed with the SEC are posted on our website at www.minervaneurosciences.com. Our audience is cautioned not to place undue reliance on these forward-looking statements that speak only as of the date hereof, and we disclaim any obligation to update any forward-looking statements, except as required by law. 2 All trademarks, trade names and service marks appearing in this presentation are the property of their respective owners. Understanding the Neurobiology of Schizophrenia: From Receptors to Real Life Ofer Agid, M.D. Schizophrenia Program Centre for Addiction and Mental Health (CAMH) Associate Professor of Psychiatry Department of Psychiatry, University of Toronto Confidential & Proprietary Frontal Lobotomy 4 Egas Moniz (1874-1955) Won the Nobel Prize in Physiology & Medicine 1949 for his discovery of the therapeutic value of frontal lobotomy in psychoses 5 First Report of Antipsychotic Treatment “…Within 3 days chlorpromazine alleviated hallucinations and stopped internal voices…” Delay J, Deniker P, Harl JM. Ann Med Psychol (Paris) 1952 6 Nobel Prize in Physiology & Medicine 2000 Arvid Carlsson – Arvid Carlsson overturned conventional wisdom by showing that the chemical dopamine is an important neurotransmitter in the brain. – Before, dopamine was presumed to be merely a precursor to a more important neurotransmitter, noradrenaline (norepinephrine). 7 Dopaminergic Pathways in the Brain 8 Dopaminergic Pathways in the Brain DLPFC a Mesolimbic Striatum Thalamus NAc b Mesocortical c a Substantia b nigra Hypothalamus VMPFC c Nigrostriatal d d Tuberoinfundibular Pituitary Tegmentum DLPFC=dorsolateral prefrontal cortex; NAc=nucleus accumbens; VMPFC=ventromedial prefrontal cortex Stahl. Stahl’s Essential Psychopharmacology. 4th edition, 2013, Cambridge University Press 9 The Mesolimbic Dopamine Hypothesis of Positive Symptoms of Schizophrenia Positive symptoms HIGH Mesolimbic hyperactivity = excessive dopamine Stahl. Stahl’s Essential Psychopharmacology. 4th edition, 2013, Cambridge University Press 10 The Mesocortical Dopamine Hypothesis of Cognitive, Negative and Affective Symptoms of Schizophrenia Cognitive symptoms Negative symptoms LOW Affective symptoms Mesocortical hypoactivity = low dopamine Stahl. Stahl’s Essential Psychopharmacology. 4th edition, 2013, Cambridge University Press 11 Schizophrenia as a Heterogeneous Group of Disorders with DifferentLocalization Onsets, Presentations, of symptom Treatment domains Response, in schizophrenia Trajectories and Outcomes Stahl. Stahl’s Essential Psychopharmacology. 4th edition, 2013, Cambridge University Press 12 The Negative Symptom Domain in Schizophrenia Mueser et al. 1994; Sayers et al. 1996; Kelley et al. 1999; Peralta & Cuesta 1999; Kimhy et al. 2006; Foussias & Remington 2010; Messinger et al. 2011; Liemburg et al. 2013; Strauss et al. 2013; Fervaha et al. 2014. 13 Relationship Between Striatal Dopamine Blockade and Total Score on the Subject Well-being Under Neuroleptics (SWN) Scale 130 Received benztropine 110 90 70 Total score on SWN Total SWN scale total score was significantly 50 associated with striatal occupancy (r -0.66, p=0.01) 40 50 60 70 80 90 100 Striatal occupancy (%) SWN=Subjective Well-Being Under Neuroleptics Scale Patients with recent-onset psychosis (N=12) were randomly assigned to olanzapine (2.5 or 15 mg/day) or risperidone (1 or 4 mg/day). 11 Subjective experiences, and striatal dopamine D2 receptors (determined with ([ C]raclopride PET scans) were evaluated after 2 weeks of continuous antipsychotic treatment Mizrahi et al. Am J Psychiatry 2007;164(4):630–637 14 Tight-binding Agents and Their Influence on Emotional Experience Positive affect Negative affect • There was a significant effect for D2 receptor binding estimates on 2 χ 5.2 3.3 positive affect ( 2=6.42, p=0.04). There was a clear 5.0 2.8 decrease in positive affect in the 4.8 middle occupancy group (range 68%–81%) and an even larger 4.6 2.3 decrease in the group with the highest D2 receptor occupancy 4.4 1.8 (>81%) 4.2 • Additionally, D2 occupancy was assessment Likert score assessment Likert score 1.3 - 4.0 - significantly related to negative affect (χ2 =29.48, p=0.0001), Self Self 2 3.8 0.8 with a significant increase in <68% 68%–81% >81% <68% 68%–81% >81% negative affect in the highest D2 D2 occupancy (tertiles) D2 occupancy (tertiles) receptor occupancy Lataster et al. J Clin Psychiatry 2011;72(10):1397–1404 15 Too Little Dopamine, or Too Much? Mesocortical hypoactivity Mesolimbic hyperactivity LOW HIGH Cognitive Negative Affective Onset of positive symptoms symptoms symptoms symptoms Remington et al. Expert Rev Neurother 2011;11(4):589–607; Stahl. Stahl’s Essential Psychopharmacology. 4th edition, 2013, Cambridge University Press 16 Group Placebo Response Trajectories in One-Year Trial: PANSS Total Score Potkin, Agid et al. SCZ Res. 2011: 32(2-3):108-13. 17 Our Treatment Goals in Schizophrenia Have Changed1, but How Successful are We Today? ~13.5%2 Recovery ~303,4 Remission Stabilisation 1. Remington et al. CNS Drugs 2010;24(1):9–20; 2. Jääskelainen et al. Schizophr Bull 2013;39(6):1296–1306; 3. Meesters et al. Schizophr Res 2011;126(1–3):237–244; 4. Boter et al. Schizophr Res 2009;115(2–3):97–103 18 Summary • Schizophrenia is a complex, multi-domain and perhaps the most devastating disorder of mankind. • While treated as one illness, it is probably a heterogeneous group of disorders differentiating in etiology, course, response to treatment and outcome. • There is no current treatment for schizophrenia; the only available medications are antipsychotics. • The dopamine hypothesis presents the complexity of treating schizophrenia and the double edge sword of dopamine blockade. • While recovery and functioning are the ultimate goals of treatment, more than sixty years of antipsychotic treatment have not brought us closer to achieving these goals. • There is a lack of efficacy of all current treatment options for negative symptoms with minimal effect size across pharmacological and behavioral interventions. 19 Regulatory Perspective on the Development of Drug Therapies for Residual Symptoms in Schizophrenia Thomas Laughren, M.D. Director, Laughren Psychopharm Consulting, LLC Confidential & Proprietary Topics for Discussion . A shifting focus from schizophrenia as a broad target of drug development to phases of the illness and specific symptom constructs within phases – Early vs late schizophrenia – Prodromal, acute, residual schizophrenia – Positive symptoms, negative symptoms, cognitive impairment, depression, aggression, etc. Alternative models for treating schizophrenia . Alternative designs for studying potential treatments for schizophrenia 21 Conventional Thinking About Schizophrenia . Chronic, essentially life-long condition . Prodromal Phase:
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