#CHAIR2015

September 24 – 26, 2015 | JW Marriott Miami | Miami, Florida

Sponsored by Emerging Agents in the Management of

Jeffrey A. Lieberman, MD Columbia University College of Physicians and Surgeons New York, NY

Jeffrey A. Lieberman, MD Disclosures

● Research/Grants: Alkermes; BioMarin Pharmaceutical Inc.; EnVivo Pharmaceuticals, Inc./FORUM Pharmaceuticals Inc.; Novartis Corporation; Sunovion Pharmaceuticals Inc. ● Consultant: Clintara; Intracellular Therapies, Inc.; Pear Therapeutics Learning Objective

Describe the emerging therapies for the treatment of schizophrenia Schizophrenia Treatment Update

● Conventional mechanism treatments ● New targets and novel treatments ● Genetically targeted treatments – personalized medicine Schizophrenia Treatment Update

● Conventional mechanism treatments ● New targets and novel treatments ● Genetically targeted treatments – personalized medicine FDA Approved Antipsychotics

● Chlorpromazine - 1957 ● - 1989 ● Perphenazine - 1957 ● * - 1993 ● Trifluoperazine - 1959 ● * - 1996 ● Fluphenazine* - 1960 ● Quetiapine - 1997 ● Thioridazine - 1962 ● Ziprasidone - 2001 ● Haloperidol* - 1967 ● * - 2002 ● Thiothixene - 1967 ● Paliperidone* - 2006 ● Molindone - 1974 ● Iloperidone - 2009 ● Loxapine - 1975 ● Asenapine - 2009 ● Pimozide - 1984 ● Lurasidone - 2010 ● Brexpiprazole - 2015 ● Cariprazine - 2015 * Long Acting Injectable Formulation Comparison of APDs MOAs

● How do different classes of antipsychotic drugs (APD) work ? – Sustained full D-2 antagonism – Intermittent D-2 antagonism – Sustained D-2/3 partial agonism Brexpiprazole Otsuka, Lundbeck • Atypical antipsychotic with partial agonist activity at 5-HT1A and DA–D2 receptors and antagonist activity at 5-HT2A receptors. • Second generation version of aripiprazole, and with slightly different activity at 5-HT and DA receptors • Could mean an improved clinical profile with fewer side effects such as restlessness • Approved for schizophrenia and depression • Taken once daily with or without food • Started at lower dose and then gradually increased to target dosage. • Side effects include weight gain and akathisia

PI for brexpiprazole.Drugs@FDA Website. hp://www.accessdata.fda.gov/drugsada_docs/label/ 2015/205422s000lbl.pdf Cariprazine (Allergan)

● High affinity dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors ● US FDA approved for schizophrenia and bipolar disorder ● Major side effects – EPS – Did not increase prolactin levels – Minimal effects on weight gain and metabolic parameters – No QT prolongation

PI for cariprazine.Drugs@FDA Website. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204370lbl.pdf ITI-007 for the Treatment of Schizophrenia: A 4-week Randomized, Double-Blind, Controlled Trial Jeffrey A. Lieberman, Robert E. Davis, Christoph U. Correll, Donald C. Goff, John M. Kane, Carol A. Tamminga, Sharon Mates, Kimberly E. Vanover

● Pharmacology – 5-HT2A Receptor Antagonist – Dopamine Phosphoprotein Modulator (DPPM)

– Phosphoprotein Modulator (D1/GluN2B) – Serotonin Reuptake Inhibitor ● Efficacy – Improves sleep quality – Enhances antipsychotic and antidepressant activity – Antipsychotic efficacy for ‘positive’ symptoms; reduced agitation – negative symptoms and positive’ symptoms – Improved cognition and improved affect – Antidepressant efficacy – Pro-social function ● Side Effects – sedation

Lieberman, JA, et al. Biol Psychiatry. 2015. Epub. . /www.biologicalpsychiatryjournal.com/article/S0006-3223(15)00694-0/abstract ITI-007 (60 mg) Improves Negative Symptoms in Subgroup with Prominent Negative Symptoms at Baseline

● ITI-007 (60 mg): PANSS Negative Symptom Subscale Patient Subgroup Exhibiting Prominent Negative Symptoms at Baseline – Improved negative Score of 4 or higher on at least 3 negative symptoms at Baseline symptoms, especially in a subgroup of patients with N=29 N=33 N=25 N=33 prominent negative 0 symptoms at baseline – Significantly improved -2 certain items on the PANSS subscales -4 consistent with improved social function Effect Size = 0.34 -0.04 -0.02 – Significantly improved -6

other prosocial measures, thru D28 Completing Patients in such as reduced Baseline from (SEM) Change Mean Placebo depression 60 mg ITI-007 120 mg ITI-007 4 mg Risperidone PANSS Subscale Scores for Negative Symptoms Subscale in a subgroup of patients exhibiting prominent negative symptoms at baseline; Change from Baseline to Day 28 (Completer Analysis)

Lieberman, JA, et al. Biol Psychiatry. 2015. Epub. . /www.biologicalpsychiatryjournal.com/article/S0006-3223(15)00694-0/abstract ITI-007 Did Not Increase Metabolic Parameters

ITI-007 Did Not Increase ITI-007 Did Not Increase Insulin (pmol/L) Glucose (mmol/L) 100 0.8

0.6 50 0.4

0 0.2

0.0 -50 Placebo 60 mg 120 mg RISP Placebo 60 mg 120 mg RISP Change from Baseline to 28 Day Baseline from Change Change from Baseline to 28 Day Baseline from Change ITI-007 ITI-007 Figure 6 ITI-007 Did Not Increase ITI-007 Did Not Increase ITI-007 Did Not Increase Total Cholesterol (mmol/L) LDL Cholesterol (mmol/L) Prolactin (mcIU/mL) 0.4 0.4 1000

0.2 0.2 500 0.0 0.0

-0.2 -0.2 0

-0.4 -0.4 Placebo 60 mg 120 mg RISP Placebo 60 mg 120 mg RISP -500 Placebo 60 mg 120 mg RISP Change from Baseline to 28 Day Baseline from Change Change from Baseline to 28 Day Baseline from Change ITI-007 ITI-007 to 28 Day Baseline from Change ITI-007

Lieberman, JA, et al. Biological Psychiatry. Website 1 http://www.biologicalpsychiatryjournal.com/article/S0006-3223(15)00694-0/abstract/. August 31, 2015 3 Schizophrenia Treatment Update

● Conventional mechanism treatments ● New targets and novel treatments ● Genetically targeted treatments – personalized medicine Targets for Novel Drug Development

● Alpha-7 nicotinic receptor: partial agonists ● D1 receptor: partial agonists ● Glutamate – NMDA receptor allosteric modulators (glycine, sarcosine) – AMPA receptor agonists – Metabotropic receptor partial agonists () ● M1 muscarinic receptor agonists ● GABA-A R subtype selective agonists ● Nona Peptides (Oxytocin) ● Cannabinoid receptors (CB-1) (Cannabadiol) ● Immunologic – Anti-inflammatory drugs Evidence that Optimal WM Requires Optimal D1 Stimulation

Arnsten and Goldman-Rakic. 1986; Arnsten et al. 1994; Murphy et al. 1994, 1996 a,b., 1997; Williams and Goldman-Rakic. 1995; Verma and Moghaddam. 1996, Goldman Rakic et al, 2000, Brain Res Rev

Seamans et al, J Neuro, 2001. May 15;21(10):3628-38. DAR-0100 (Dihydrexidine) a Potent Selective D1 Agonist Tested in Schizophrenia and Parkinson’s Disease Patients ● 4 individuals with Parkinson’s Disease ● 2 mg to 70 mg of DAR-0100 ● SC over 15 to 120 minutes ● Flushing, hypotension, tachycardia observed in all cases Blanchet et al., Clinical Neuropharmacology 1999

•

George MS, et al. Schizophr Res. 2007 Jul;93(1-3):42-50. Study Design

● Randomized clinical trial ● Stable schizophrenia outpatients on stable doses of aripiprazole, haloperidol, risperidone, lurasidone, paliperidone ● Add-on: DAR-0100A – (0.5mg, 15mg) or placebo IV over 30 min – 5 day course of Rx repeated X 2 with 1 week separation ● fMRI (Baseline and Day 5): WM tasks (SOT and N Back) ● Battery (MATRICS, PANSS, SANS, N Back, CDRS, Cogstate, Trails b)

New York Psychiatric Institute. ClinicalTrials.gov Identifier: NCT01519557. First received: January 13, 2012. Last updated: March 3, 2015 Results

● No treatment effects: – fMRI hemodynamic response – PANSS – CDRS – SANS ● Cognitive assessments – MATRICS – Cog State

New York Psychiatric Institute. ClinicalTrials.gov Identifier: NCT01519557. First received: January 13, 2012. Last updated: March 3, 2015 D1 Receptor Occupancy by DAR-0100A in NHP Using [11C]NNC112 in Striatum

New York Psychiatric Institute. ClinicalTrials.gov Identifier: NCT01519557. First received: January 13, 2012. Last updated: March 3, 2015 Glutamate Based Treatments

Rationale ● NMDA allosteric modulators: Glycine, D-Serine, GlyT inhibitors ● Glutamate modulators: Pomaglumetad, Gabapentin, Pregabalin, NAC, Benzoate ● mGluR-5 modulators ● AMPA potentiators

- Metabotropic Glutamate Receptors (mGluR2) Stimulation RedUces Glutaamate Hyperactivity

mGluR2 NMDA!

Glutamate AMPA!

mGluR!

mGluR2 agonists reduce glutamate release and synaptic concentrations Moghaddam & Adams. Science. 1999. Krystal J, et al. Psychopharm. 2005. Patil PANSS Total in Patients with Schizophrenia of Effects ST, et al.

Nature Med Nature Change in PANSS total score -25 -20 -15 -10 -5 *** ** Pomaglumetad

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Placebo Placebo Olanzapine LY2140023 0.001 0 , 2007;13:1102-7. PMID: 17767166. 1 ** ** Week 2 (40 mg (40 BID) on *** *** 3 *** *** 4 *** ***

Kinon PANSS Negative and = Positive LY = Replicate Replicate AP Study HBBM Efficacy Follow Up Studies Failto HBBD to Pomaglumetad et al. Presented at 14th ICOSR, New Drug Session, Session, at ICOSR,Drug 14th et New al. Presented 2013. April Change in PANSS Total Score

(LS Mean +/- SE) -15 -10 -25 -20

-5 0 5 0 * ; PBO = placebo; RIS = risperidone; ITT; RIS PBO= risperidone; = placebo; = intent-to-treat; LS = least-square;

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(n = 124) (n = 124)

(n = 253) (n = 253) (n = 229) (n = 229) (n = 251) Ketamine Effects on Resting State fMRI in Healthy Volunteers

Kinon et al. Presented at 14th ICOSR, New Drug Session, April 2013.

Inflammatory Targets

Targets: Elevations in cytokines, especially TNF-α (trait) and Interleukin-6 (state), are robust and replicated findings in schizophrenia Miller BJ, et al. Biol Psychiatry. 2011 Oct 1;70(7):663-671. PMID: 21641581. Potential Inflammatory Agents

● Nonspecific anti-inflammatory agents: – Celecoxib – Aspirin ● DMARDs: – zTNF, IL-1, IL-6, T Cell, B Cell, JAK-STAT inhibitors ● Schizophrenia Treatment Update

● Conventional mechanism treatments ● New targets and novel treatments ● Genetically targeted treatments – personalized medicine Personalized Medicine

Clinical research Biomarkers

Personalized Animal models medicine Genetic mutation

Disease mechanism Stem cell research Personalized Medicine

● The success of personalized medicine depends on having accurate, reproducible and clinically useful companion diagnostic tests to identify subgroup of patients who can benefit from targeted therapies ● Companion Diagnostics are those tests that provide information that is essential for the safe and effective use of a corresponding drug or biological product. Drug Development Trend in Cancer Rx

● Dramatic increase in biomarker-targeted drug development programs – In the early 1990’s, 5%V of new drug approvals were for targeted therapies – In 2013, 45% were for targeted therapies N of One Studies

The actress Glenn Close has been open about the fact that there is serious mental illness her family. Her sister, Jessie, and nephew, Calen, have psychotic disorders. They were in a research study at McLean. The research team found that Calen and Jessie shared a rare genomic copy number variant resulting in extra copies of the gene for glycine decarboxylase. This gene encodes the enzyme that degrades glycine, a key modulator of the NMDA receptor, which has been implicated in psychosis. When Calen and Jessie were given glycine the response was like giving insulin to a person with diabetes—their psychiatric symptoms largely resolved. When the drug was stopped, their symptoms returned. When they received glycine again under non-blind conditions, the same improvements were observed. One Current Example…

● Large number of intragenic mutations in CNTNAP2 in Old Order Amish. Affected individuals manifest psychosis and autistic features. ● Transgenic animal model: – Identification of disease mechanism (mTOR overactivation) – Extensive phenotypic characterization – Rescue of disease phenotypes with a specific drug (mTOR kinase inhibitor) that targets disease mechanism Personalized Medicine Clinical Trial

● First trial in psychiatry where we will select patients by genotype ● Characterize patients on symptom domains that extend beyond diagnostic assumptions and which correlate with functional impairment ● Utilize specific targets of the signaling pathway on PET imaging as biomarkers ● By targeting disease mechanism, can we potentially reverse or prevent mental illness…? The Glass is Half Full, Not Empty!

Thank you for your attention ! Questions & Answers