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Terminology Drug Development 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 Nascholing Psychosen 14-15 maart 2013 1 P. de Boer 20-3-2013 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 Nascholing Psychosen 14-15 maart 2013 2 P. de Boer 20-3-2013 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 <p<0.1, after adjusting for multiplicity, as appropriate tangles (1) Subscales A+B+C+D *: p<0.05 (2) Subscales A+B **: p<0.01 (3) Subscales C+D ***: p<0.001 3/8/2013 14 -:173/8/2013 Not significant at 5% level Psychosis Cluster Psychosis Cluster 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 Nascholing Psychosen 14-15 maart 2013 3 P. de Boer 20-3-2013 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 Nascholing Psychosen 14-15 maart 2013 4 P. de Boer 20-3-2013 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.
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