P. de Boer 20-3-2013

Drug Development

1. Drug development is for a well-accepted and New Developments in the demarcated indication that will become part Pharmacological Therapy of of the product label (rather than for a symptom – family of symptoms); Schizophrenia 2. Symptoms may overlap between disease Peter de Boer, PhD categories. It is acceptable to develop Senior Director Experimental Medicine multiple indications but it is generally not Janssen Research and Development acceptable to develop symptom-specific therapies.

3/8/2013 Psychosis Cluster 4

This presentation may contain off-label information or data on investigational compounds. Please always refer to the full product information before prescribing any medicine. Section 1 Views and opinions expressed in this presentation represent those of the presenter and are not necessarily the company. WHY CATEGORIES RATHER THAN DIMENSIONS?

3/8/2013 Psychosis Cluster 2 3/8/2013 Psychosis Cluster 5

Schizophrenia as a disorder of Terminology Frequency cognition (1) Category: An ICD-10/DSM-IV diagnosis (e.g., • Schizophrenia Normal schizophrenia, schizoaffective disorder, Morbid schizotypal personality disorder); Premorbid • Dimension: A symptom or symptom cluster that occurs throughout the population and that, if of sufficient intensity, may lead to a categorical diagnosis (e.g., aberrant sensory experiences); • Symptom: A characteristic sign (e.g., a delusion, IQ Test Score avolition); Impaired Normal High Functioning • Target: A biological process affected by a drug.

3/8/2013 Psychosis Cluster 3 3/8/2013 Psychosis Cluster 6

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Schizophrenia as a disorder of Psychosis: Dimension/Category (2) Frequency cognition (2) Intensity Schizophrenia Psychotic Experiences Schizophrenia Normal 1%

Schizotypical Tx A 10% C

Normal 1% Test Score 40% 49%

Impaired B Normal High Functioning Not strictly continuous variables?

3/8/2013 Psychosis Cluster 7 3/8/2013 Psychosis Cluster 10

Schizophrenia as a disorder of Psychosis in dementia cognition - issues 1. Cognition is a non-specific term; impaired cognitive performance may have diverse causes (= pseudo continuous); 2. Although schizophrenia may be within the family of ‘cognitive disorders’ this does not help with identifying it as a diagnostic entity; 3. Issues may exist in identifying the right target population to treat.

Sultzer et al., 2008 Am J Psychiatry 165: 844 – 854

3/8/2013 Psychosis Cluster 8 3/8/2013 Psychosis Cluster 11

Psychosis: Dimension/Category (1) No dopaminergic dysfunction in AD Intensity Schizophrenia Control Parkinson’s Psychotic Experiences 1%

Schizotypical 10%

Alzheimer’s Dementia /Lewy Normal 40% 49%

Not strictly continuous variables?

3/8/2013 Psychosis Cluster 3/8/2013 Psychosis Cluster 12 9

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But psychosis in AD may be related to Implication? neocortical density of neurofibrillary tangles Efficacy of D 2 Neurofibrillary tangle density densities in individuals with antagonists versus without psychosis by brain region (density ± SD [No / Hypothesis: mm2]) DA with w/o Brain region P hyperactivity psychosis psychosis Therapy: A AD in AD? Middle frontal cortex 7.9 (9.7) 2.8 (5.5) .01 Yes Superior temporal Therapy: B 11.9 (15.2) 5.2 (7.9) .008 cortex AD / LBD Therapy Inferior parietal cortex 7.4 (10.0) 4.0 (7.4) .006 No Therapy: C Improved D2R AD / vascular Hippocampus 36.0 (32.6) 26.7 (28.7) .5 modulators

Entorhinal cortex 19.3 (18.0) 14.1 (10.1) .3 Observation; Multiple pathological Farber et al. Arch Gen Psychiatry. 2000;57(12):1165-1173. processes

3/8/2013 Psychosis Cluster 13 3/8/2013 16 Psychosis Cluster

Risperidone in neuropsychiatric symptom A drug development paradigm based on ‘understanding’ pathophysiological drivers for clusters in dementia psychosis: BPSD population PAD pop. Efficacy Variables RIS-USA-63 RIS-INT-24 RIS-AUS-5 RIS-USA-232 Efficacy of D 2 antagonists 1 mg 2 mg Ris Hal

Hypothesis: Behave-AD DA Psychotic Agitation (1) *** *** - ** *** - hyperactivity Psychosis (2) ** * - + ** - Assumption: in AD? Yes Agitation (3) *** *** * *** *** - ‘Classic’ but very localized AD pathology causes NPS Therapy: CMAI Anti-tau No Total Aggression *** *** ** + *** NA Improved D2R Total Non-Aggression * ** - - ** NA modulators Observation: Total *** *** + - *** NA Psychosis BEHAVE-AD: Behavioral Pathology in Alzheimer’s Disease CMAI: Cohen Mansfield Agitation Inventory related to +: 0.05

A clinical phenotype of dementia may result from multiple co-existing pathological processes Psychosis: Dimension or Category - conclusions 1. Psychosis as a phenomenon is common in the general population; 2. However, the underlying causes of psychotic experiences are diverse (see example dementia); 3. Hence, the efficacy of a drug against a symptom / symptom cluster in a specific diagnostic category cannot be extrapolated to another diagnostic category without proof.

Sweet et al 2004 Neuropsychopharmacology 29 2242 – 2250

3/8/2013 15 3/8/2013 Psychosis Cluster 18 Psychosis Cluster

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Preclinical 5955 Correlation D2 occupancy / inhibition of Correlation D2 occupancy / inhibition of apomorphine-induced stereotypy amphetamine-induced hyperlocomotion 100 100 slope: 0.96 ± 0.06 slope: 0.53 ± 0.13 2 2 r : 0.98 clozapine r : 0.76 10 10 clozapine quetiapine quetiapine aripiprazole aripiprazole 1 1 ziprasidone ziprasidone risperidone risperidone 0.1 olanzapine 0.1 olanzapine

ED50 Apo. inhibition ED50 haloperidol

haloperidol Amph. inhibition ED50 0.01 0.01 0.01 0.1 1 10 100 0.01 0.1 1 10 100 ED50 D2 occupancy ED50 D2 occupancy Correlation D2 occupancy / inhibition of Correlation D2 occupancy / inhibition of Section 3 PCP-induced hyperlocomotion conditioned avoidance response 100 100 slope: 0.61 ± 0.11 r2: 0.87 clozapine clozapine REVIEW OF PROJECTS 10 10 quetiapine quetiapine aripiprazole aripiprazole 1 ziprasidone 1 ziprasidone risperidone risperidone 0.1 olanzapine 0.1 olanzapine slope: 0.76 ± 0.23 haloperidol

ED50 PCP inhibition ED50 haloperidol ED50 CAR inhibition ED50 r2: 0.69 0.01 Apo = Apomorphine 0.01 3/8/2013 Psychosis Cluster 19 0.01 0.1 1 10 100 PCP = Phencyclidine 0.01 0.1 1 10 100 ED50 D2 occupancy ED50 = Effective Dose for 50% of maximal effect ED50 D2 occupancy Data on file

Clinical

At efficacious dose levels

Olanzapine blocks 65 - 75% D 2 receptors

3/8/2013 Psychosis Cluster 20 3/8/2013 Psychosis Cluster Data on file 23

Compound Characterization 5955

DA-related – some beliefs. Correlation D2 occupancy / inhibition of Correlation D2 occupancy / inhibition of apomorphine-induced stereotypy amphetamine-induced hyperlocomotion 100 100 slope: 0.96 ± 0.06 681 slope: 0.52 ± 0.15 681 r2: 0.98 646 r2: 0.76 646 1. All currently used antipsychotic medications are 10 10

dopamine D 2 antagonists / weak partial 1 1

agonists; 0.1 0.1 ED50 Apo.inhibition ED50 ED50 Amph. inhibition ED50 0.01 0.01 2. Dopamine systems are well characterized and > 0.01 0.1 1 10 100 0.01 0.1 1 10 100 ED50 D2 occupancy ED50 D2 occupancy 50 years of model development is available to Correlation D2 occupancy / inhibition of Correlation D2 occupancy / inhibition of PCP-induced hyperlocomotion conditioned avoidance response support drug development; 100 100 slope: 0.61 ± 0.11 681 681 r2: 0.87 646 646 3. Hence, demonstration of efficacy of a novel drug 10 10

in a model of dopamine hyperactivity has strong 1 1

predictive validity for clinical efficacy. 0.1 0.1 slope: 0.76 ± 0.23 ED50 PCP inhibition ED50 ED50 CAR ED50 inhibition r2: 0.69 0.01 Apo = Apomorphine 0.01 3/8/2013 Psychosis Cluster 21 3/8/20130.01 0.1 1 10 100 PCP = PhencyclidinePsychosis Cluster 0.01 0.1 1 10 100 24 ED50 D2 occupancy ED50 = Effective Dose for 50% of maximal effect ED50 D2 occupancy Data on file

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Clinical pharmacology PDE10 inhibitor In striatum:

70 D1 agonist D2 antagonist 60 10mg JNJ-37822681 bid (Day 14)

[JNJ-37822681] 50 plasma 80 calculated striatal D 2 occupancy 80 "conventional" antipsychotic threshold 40 70 70

30 60

60 20 50 OC 50 = 27.1 ng/mL C raclopride displacement 40 50 1 1 10 % 30 0 40 C raclopride dispalcement C raclopride [JNJ-37822681]ng/mL

20 11

0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 30 % 10

log 10 [JNJ-37822681] 0 20 0 2 4 6 8 10 12 14 time after dose administration (hours) Nishi et al., 2011

3/8/2013 Psychosis Cluster 25 3/8/2013 Psychosis Cluster 28

5955 Number of subjects included in each treatment group, In vivo , PDE10 inhibitors have a (somewhat) different completers and striatal receptor occupancy throughout the dosing interval as measured with 11 C raclopride PET. behavioral profile compared to a D 2 antagonist Test (acute) PDE10 inhibitor D antagonist Treatment (n) Completers (%) Minimum D Maximum D 2 2 2 Target occupancy ED 1.4 mg/kg po (ex vivo ) ED 0.39 mg/kg sc (in vivo ) bid occupancy (%) occupancy (%) 50 50 (rat striatum) (662 ng/mL plasma) and 6.26 mg/kg sc (ex vivo ) Placebo (24) 100 - - ↓ 1mg/kg APO-stereotypy ED 50 1.3 mg/kg po ED 50 0.194 mg/kg po 10mg JNJ-37822681 (16) 100 43.1 ± 11.2 64.1 ± 11.8 (rat)

20mg JNJ-37822681 (16) 62.5 67.9 ± 6.4 80.7 ± 4.7 ↓ 5mg/kg AMPH-stereotypy ED 50 0.67 mg/kg sc ED 50 0.294 mg/kg sc (rat) 30mg JNJ-37822681 (8) 62.5 71.2 ± 3.0 86.7 ± 2.42 ↓ 1.25 mg/kg AMPH- ED 50 8.2 mg/kg sc ED 50 1.02 mg/kg sc hyperlocomotion (rat) 0.25 4.6 ↓ 1.25 mg/kg PCP- ED 50 2.04 mg/kg sc ED 50 4.7 mg/kg sc The 20 mg bid dose was predicted to provide optimal D2 occupancy in time hyperlocomotion for an antipsychotic effect while the 10 and 30 mg bid doses are too low and high, DA cell firing SN No effect on # neurons/tract Haloperidol: respectively. ↑ spike frequency ↓ # neurons/tract

Ro-4-1284-induced Reversal: ED 50 = 2.69 mg/kg sc No reversal hypolocomotion [stimulant activity @ 3.1]

Haloperidol-induced catalepsy Reversal: ED 50 = 8.2 mg/kg sc Not done

3/8/2013 Psychosis Cluster Data on file 26 3/8/2013 Psychosis Cluster 29

Similarly, in sub-chronic drug safety studies Clinical improvement over time different behavioral profiles are observed

Species Dose PDE10 inhibitor D2 antagonist Rat – 4wk L --- GLP M NOAEL ↓ general activity, narrowing palpebral fissure (sedation) H No behavioral toxicities See above but more intense Dog – 2wk ↓ general activity, ataxia, Not done Non GLP tremors, catalepsy, yelping, biting Monkey – L (< IC50) NOAEL Sleepiness 5wk M (IC50- ↓ activity, hunched Excessive sleepiness, decrease in GLP 2x IC50) appearance, lethargy, staring, movement, trance-like state, staring, aggression, self-biting , tremors abnormal posture, tremors H (10x See above + self-mutilation See above but more intense IC50) (1M)

3/8/2013 Psychosis Cluster Data on file 27 3/8/2013 Psychosis Cluster 30

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Clinical Effect mGlu2/3 Agonist (Acute Primary Efficacy Results Schizophrenia) Efficacy on the change from baseline on the PANSS total score was significantly greater for RIS vs. placebo, but not for either PF-02545920 group 0

-5

PF 15 mg -10

Placebo -15

PF 5 mg -28) Day (Day PANSS -20

-25 placebo LY05 LY20 LY40 LY80 Olanzapine Risperidone Treatment Group Kinon et al., 2011

Patil et al., 2007

3/8/2013 Psychosis Cluster 31 3/8/2013 Psychosis Cluster 34

mGlu2: Target and Mechanism of Action Biology of mGlu2 Receptor Positive allosteric modulation

GLUTAMATE PAM

mGLU2 Receptor A Positive Allosteric Modulator (PAM) enhances the effect of glutamate at the receptor but has no, or very The ‘net’ effect of mGlu2R stimulation is limited, activity at the hypothesized to be a normalization of hyper- receptor on its own glutamatergic transmission 3/8/2013 Psychosis Cluster 32

mGlu2/3 agonists – positive allosteric 4011813SCH2001 – Overall Design modulators Part B Week 1 – 4(-5) Week 5(-6) – 12(-13) Residual JNJ-40411813 Placebo POSITIVE (max 150mg bid)*

JNJ-40411813 JNJ-40411813 Residual (50 mg bid) (max 150mg bid) NEGATIVE

JNJ-40411813 JNJ-40411813 (max 150mg bid) (max 150mg bid) Clozapine, partial responders Note: The initial 18 subjects in Part B will only receive JNJ-813 50 mg BID or PBO for the first 4 weeks. Once safety confirmed in this cohort, higher dose can be used

* In this group: 10(-11) weeks on active Part A

JNJ-40411813 (Sub)acute (max 150mg bid)

Wolley et al., 2011 3/8/2013 Psychosis Cluster 33 3/8/2013 Psychosis Cluster 36

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Clinical Effect mGlu2 PAM Do we know what to look for?

3/8/2013 Psychosis Cluster 37 3/8/2013Keshavan et al., 2011 Psychosis Cluster 40

Elevated Glutamate and Glutamine in Early Course Schizophrenia

Section 3 SOME COMMENTS ABOUT DRUG DEVELOPMENT

Marsman A et al. Schizophr Bull 2011 3/8/2013 Psychosis Cluster 38 3/8/2013 Psychosis Cluster 41

Conclusions Drug development: the historical model

1. Despite contrary perceptions, there still is significant (Serendipitous) investment in drug development for schizophrenia; Clinical 2. Although clinical efficacy can be reasonably well Observations predicted for a dopamine D2 antagonist, recent experience with e.g. PDE10i and mGlu2R stimulation Mechanistic Sensitive Animal CLOSED LOOP: suggests that models do not easily translate to novel Understanding / Models Incremental improvements MoAs; Disease Modeling 3. Rather than a primary focus on ‘predictive models’, anomalies need explanation; 4. New drug development for schizophrenia ultimately Novel Chemical relies on experiments in patients. Structures

3/8/2013 Psychosis Cluster 39 3/8/2013 Psychosis Cluster 42

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Selected Challenges for Novel Drug Brain networks supporting different functions Development. use identical biochemistry (2). 1. Understanding of symptoms, biological processes and Software ‘Behavioral’ effects of interventions are interactional; Behavior Therapies 2. Reciprocal interactions exist between biochemistry and behavior; different psychological processes may Psychology have the same biological substrates;

3. Biological understanding is imperfect hence resulting Neural Network in biased target selection and evaluation; 4. Animal models generally allow for the study of exaggerated normal behavior (i.e. are dimensional). Biology

Biochemistry Drugs Hardware

3/8/2013 Psychosis Cluster 43 3/8/2013 Psychosis Cluster 46

The acquisition of knowledge to support drug Biological Understanding (3) development is a non-linear process (1).

Current Possible Knowledge Symptom 1 Biology Intervention Knowledge Possible Drug Targets Disease (Category) Symptom 1 Reciprocal relations Possible Endpoints Possible Models Selected Endpoints Symptom 1 Selection of “Relevant” Selection of “Relevant” Models Targets

3/8/2013 Psychosis Cluster 44 3/8/2013 Psychosis Cluster 47

Reciprocal relations between biochemistry and Animal Models (4) behavior (2). Symptoms Clinical ‘Behavioral’ Observations Behavior Therapies

Predictive Animal Biology New Target Therapy Models

Biochemistry Drugs Mode of Action

Chemical Processes 3/8/2013 Psychosis Cluster 45 3/8/2013 Psychosis Cluster 48

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What to Do with Animal Models?

2 Philosophies: 1. Drug effects in animal models provide relevant information guiding the direction of the clinical indication selection (i.e. animal models have predictive validity for human disease / are translational ⇒ “predictive animal models” ); 2. Drug effects in animal models provide information about the relationship between plasma concentration Section 4 and effect (PK/PD relationship) but only in a very broad sense guide indication selection (i.e. animal DECONSTRUCTING SCHIZOPHRENIA models have no or limited predictive validity for human disease ⇒ “supportive animal models” ).

3/8/2013 Psychosis Cluster 49 3/8/2013 Psychosis Cluster 52

“Predictive” Animal Models Deconstructing Schizophrenia

1. Recapitulates (part of) human pathological DSM IV TR: condition in a biologically plausible manner; A. Characteristic symptoms: (1) delusions, (2) hallucinations, (3) disorganized speech, (4) grossly 2. Is sensitive to currently available therapy whilst disorganized or catatonic behavior, (5) negative also allowing to investigate the effect of an NME symptoms (affective flattening, alogia, avolition); B. Social/occupational dysfunction; as add-on/adjunct therapy; C. Continuous signs of disturbance persist for at least 6 3. (Drug) target expression comparable to humans. months; D. ≠ Schizoaffective- or mood disorder;
Rarely used in drug development (labor-intense, E. ≠ Consequence of substance abuse or medical marginally validated, difficult to reproduce) condition; F. [relation to pervasive development disorders].

3/8/2013 Psychosis Cluster 50 3/8/2013 Psychosis Cluster 53

“Supportive” Animal Models Deconstructing Schizophrenia Delusions Ψ • Express drug target and target engagement Hallucinations yields a measurable effect (“whatever”); POS Disorganized Speech • Effects are gradual allowing study of dose- / Dis concentration effect relations; Disorganized Behavior Social & Occupational Dysfunction • Formation of potentially active metabolites Affective Flattening

compares to (anticipated) human situation; Alogia NEG

• Preferably, “tox-compatible” species. Avolition
Most frequently used in support of clinical

dosing. COG

3/8/2013 Psychosis Cluster 51 3/8/2013 Psychosis Cluster 54

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Deconstructing Schizophrenia Too much dopamine?

Perception Hallucinations Delusions [Salience Attribution]

Disorganized Avolition Speech Cognition [Cognitive Control] Disorganized Alogia Behavior

Emotions [ …] Affective Flattening

Laruelle et al. PNAS 1996

3/8/2013 Psychosis Cluster 55 3/8/2013 Psychosis Cluster 58

Salience Attribution: Cortex, Striatum, and Dopamine Cognitive Control: Frontal Cortex

Martin-Soelch et al., 2001 Arnsten et al., 2012 3/8/2013 Psychosis Cluster 56 3/8/2013 Psychosis Cluster 59

Potential Targets to Improve Frontal How to understand D antagonists? 2 Cortex Function

1. Dopamine alerts the brain to unexpected 1. Dopamine D 1 agonists (psychostimulants); events; 2. Enhancement of NMDA receptor function 2. D2 receptor antagonists reduce the (GlyT1, mGlu5, …); importance (salience) of stimuli; 3. Nicotinic α agonists; 3. In agreement, patients report a reduction in 7 the attention to (aberrant stimuli); 4. Ampakines;

4. Rather than anti-schizophrenic, a D 2 5. GABA α5 negative allosteric modulators; antagonist affects a specific cognitive process GABA α2/3 positive allosteric modulators. that is excessively abnormal in schizophrenia.

3/8/2013 Psychosis Cluster 57 3/8/2013 Psychosis Cluster 60

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Negative/Cognitive Symptoms in Schizophrenia Emotion Estimated Launch Timeline •TC-5619 A (α7 agonist; Targacept)

•Bitopertin (RG1678/RO-4917838) •CYR 101 M (Mitsubishi, 5HT2A/sigma2 antag) •AMG-747 A (Amgen, GlyT1 A (Roche; GlyT1 inhib.) •EVP-6124 A (Bayer/EnVivo, α7 agonist) inhibitor) (2019) •Lisdexamfetamine A (Shire, Amphetamine)

Negative

2013 2014 2015 2016 2017 2018 2019 2020 +

Cognitive •TC-5619 A (α7 agonist; NEW BIOCHEMISTRY Targacept) •NBI 98854 * A (Neurocrine •CYP 1020/BL1020 M •Neboglamine ? (Rottapharm, Biosciences; VMAT2 inhibitor) (BLRX/Cypress Bio, DA antag/GABA agonist) NMDA-R Gly site PAM; NET inhibitor)

•EVP-6124 A (Bayer/EnVivo, α7 agonist) •AQW051 A (Novartis, α7 agonist) ? •CYR 101 M (Mitsubishi, 5HT2A/sigma2 antag) •Eltoprazine A (PsychoGenics, 5HT1B partial •AVN-211 A (Avineuro, 5HT6 antagonist) agonist) •ABT-288 A (Abbott, H3 antag.) •Tiprolisant A (BF2.649) (Bioprojet, H3 inverse •ABT-126 A (Abbott, α7 agonist) agonist)

Legend: A: Add-on M: Monotherapy

Source: GBI Analysis (Feb 2013), Pipeline, Company Press Releases and websites, Analyst Reports, BI reports Ph2 = 2 yrs; Ph3 to filing = 3.5 yrs; Approval: 12 months. Note: Compounds currently in phase I or preclinical development not included in timeline TIP: View in SLIDESHOW mode for active links to drug records;(*) = New to timeline

3/8/2013 Psychosis Cluster 61 3/8/2013 Psychosis Cluster 64

Beyond the classic schizophrenia The Price to Pay: Polypharmacy clusters D2-selective D2-selective Positive Symptoms Antipsychotic Antipsychotic D2/5HT2A-acting Negative Symptoms GlyT1 Inhibitor Antipsychotic ‘Clozapine-like’ / mood D2/5HT2A-acting Disorganization stabilizer Antipsychotic

Cognitive Symptoms Nicotine α7 agonist

Mood Antidepressant Antidepressant

Anxiety Benzodiazepines Benzodiazepines, mGlu2

e.g. statins, e.g. statins, Somatic Tollefson and Sanger, 1999 (Eli Lilly & Co) antihypertensives … antihypertensives … 3/8/2013 Psychosis Cluster 62 3/8/2013 Psychosis Cluster 65

Schizophrenia Estimated Launch Timeline

•Adasuve A (agitation) (AZ-004) (Alexza; •Bitopertin (RG1678/RO-4917838 ) A (Roche; GlyT1 D2 antag) inhib.) •Aripiprazole depot M (Otsuka/LUN; D2 •Zicronapine M (LU 31130) (LUN/Otsuka; partial agonist) (US) 5HT2A/5HT2C/D2 antagonist) •Cariprazine M (Gedeon Richter/Forest, •CYP1020/BL1020 M (BLRX/Cypress Bio; DA D3/D2 antagonist) antag/GABA agonist) •Clozapine (oral susp) * M (Jazz •Brexpiprazole M (OPC34712) (Otsuka/Lundbeck; Pharma; D4 antagonist) D2 partial agonist) •Aripiprazole lauroxil (ALKS9070) M (Alkermes; D2 partial agonist)

2013 2014 2015 2016 2017 2018 2019 2020+

•Aripiprazole depot M (Otsuka/LUN; D2 •PF-2545920 M (PFE, PDE10 inhibitor) •JNJ40411813/ADX711 partial agonist) (EU) •CYR 101 M (Mitsubishi; 5HT2A/sigma2 antag) 49 M/A (Addex/J&J; •ITI-007 M (Intracellular Therapies; 5HT2A antag/DA mGlu2 PAM phosphoprotein modulator/SSRI) Section 5 •RP-5063 M (Reviva Pharma; partial D2/5HT1A agonist, D3/D4 antagonist) A DIFFERENT MODEL?

Legend: Key Patent Expirations A: Add-on Abilify (US 4Q14; EU, JP 2015) Geodon (EU 2013) Saphris (US 2015) M: Monotherapy Fanapt (US 2016) Latuda (US 2018) Seroquel XR (US 2016)

Source: GBI Analysis (Feb 2013), Pipeline, Company Press Releases and websites, Analyst Reports, Decision Resources/Pharmaview, BI reports Ph2 = 2 yrs; Ph3 to filing = 3.5 yrs; Approval: 12 months. Note: Compounds currently in phase I or preclinical development not included in timeline TIP: View in SLIDESHOW mode for active links to drug records; ( *) = New to timeline

3/8/2013 Psychosis Cluster 63 3/8/2013 Psychosis Cluster 66

Nascholing Psychosen 14-15 maart 2013 11 P. de Boer 20-3-2013

Encephalitis and NR1 – NR2 antibodies

Lieberman et al 2001 3/8/2013 Psychosis Cluster 67 3/8/2013 Psychosis Cluster 70

The schizophrenias? Encephalitis and NR1 – NR2 antibodies

Prodromal Phase: Unresponsive Phase: DA hyperactivity Fever, malaise, inability to Not able to follow oral subtype concentrate, nausea, commands, appear mute diarhea, vomiting, and akinetic. Catatonic NMDA receptor headache. features. hypofunction subtype 0 2 weeks 4 6 Positive Inflammatory Psychotic/Seizure Phase: Hyperkinetic Phase: Subtype (viral?) Negative Emotional/behavioral disturbances (apathy, fear, Autonomic instability, depression, psychosis, dyskinesias . Early Life Trauma / Cognitive decline cognitions), ataxia, Stress Subtype choreiform movements, seizures.

3/8/2013 Psychosis Cluster 68 3/8/2013 Psychosis Cluster 71

The Schizophrenia: NMDA Receptor High occurrence in acute schizophrenia Hypofunction

1. Non-competitive NMDA receptor antagonists (ketamine, PCP) precipitate schizophrenia-like behaviors in healthy subjects; 2. Similarly, in patients with 9.9% Schizophrenia schizophrenia, symptoms 2.8% MDD 0% BLPD are exacerbated; 0.4% control

3/8/2013 Psychosis Cluster 69 3/8/2013 Psychosis Cluster 72

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Potential for Drug Development?

Other Tx Anti-NR1a/Nr2b (IgM/IgA)? NO Neuropsychiatric Diagnostic Test Symptoms YES • Anti alpha 4 integrin Anti-NMDA (e.g. Nataluzimab); Antibody Tx • Anti B-cell (e.g. Rituximab); • Copaxone-like • Plasmapheresis; • … 3/8/2013 Psychosis Cluster 73

Conclusions

1. Psychiatric symptoms, similar in expression, may have different biological triggers; 2. Hence, the dominant effect of a single drug may differ across populations; 3. The reductionist approach to ‘dissect’ schizophrenia has not (yet) yielded new treatment approaches. Also, it may lead to polypharmacy; 4. Likely, multiple schizophrenias exist. A better understanding of the diversity of schizophrenia biology may lead to a more individualized treatment approach. However, this promise still needs to materialize.

3/8/2013 Psychosis Cluster 74

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