A Novel Antipsychotic Drug BLE Lucette BIZIMANA Charlotte COLIN Jean-Baptiste MORISOT Nicolas

Introduction Antipsychotics remain the current standard of care for mental disorders including schizophrenia and bipolar mania. Schizophrenia is a young people disease Appearance between 18 and 25 years, before 45 years Symptoms domains Positive symptoms : hallucination Negative symptoms : lack of motivation Cognitive disturbances : memory disorders General symptoms : depressive or anxiety symptoms

Leading Causes of Years of Life Lived with Disability 1 Unipolar depressive disorders 16,40% 2 Alcohol disorders 5,50% 3 Schizophrenia 4,90% 4 Iron-deficiency anemia 5 Bipolar affective disorder 4,70% 6 Hearing loss, adult onset 3,80% 7 HIV/AIDS 2,80% 8 Chronic obstructive pulmonary disease 2,40% 9 Osteoarthritis 2,30% 10 Road traffic accidents 2,30%

Functional Outcomes in USA

Past historic of anti-psychotics :

Schizophrenia and Bipolar I Disorder : Limitations with Current Treatment Effective only in a subset of patients Prediction of individual treatment response not possible Are associated with safety and tolerability issues Extrapyramidal symptoms and akathisia (Haloperidol) Prolactin increases (Risperidone) Metabolic changes (Olanzapine) Weight gain (Olanzapine/Risperidone) Cardiovascular risk factors (QTc prolongation) (Quetiapine) Clinical practice: a high rate of switching due to limited efficacy and/ or tolerability

Asenapine’s Profile Asenapine is an important new treatment option for patients with schizophrenia and bipolar I disorder Asenapine has its predominant pharmacological effect due to serotonin (5HT2A) and dopamine (D2) antagonism. Pharmaceutical form: Sublingual tablet Strength: 5 and 10 mg Twice daily

Historic November 2006 November 2007 March 2009

OVERVIEW OF EFFICACY

Short-term trials in schizophrenia Asenapine 5 Risperidone 3 Placebo Phase 2 trial (41004) Asenapine 5 Asenapine 10 Haloperidol 4 Placebo Phase 3 trial (41023) Asenapine 5 Asenapine 10 Olanzapine 15 Placebo Phase 3 trial (41021)

Schizophrenia program Primary efficacy endpoint Secondary efficacy endpoints PANSS Total Score Positive , negative and general psychopathological subscales scores CGI-S score 11 11

PANSS Score Evaluation of the psychopathological symptoms 3 dimensions:  positive symptoms  negative symptoms  general psychopathology 30 items, scored from 1 (absent) to 7 (extreme) 12

Positive subscale items P1: delusion P2: conceptual disorganisation P3: hallucinatory behaviour P4: excitement P5: grandiosity P6: suspiciousness/persecution P7: hostility 13

Inclusion criteria age >18 years DSM-IV diagnosis of schizophrenia: disorganized,paranoid,catatonic or undifferentiated subtypes acute exacerbation: CGI-S Score > 4 and PANSS > 60

Exclusion criteria actively suicidal state DMS-IV diagnosis of residual schizophrenia, schizo-affective disorder primary psychiatric diagnosis other than schizophrenia

Trials design patients randomly assigned 3 (phase 2) or 4 (phases 3) arms double-blind double-dummy

Double-dummy when two medications are different in appearance in order to maintain blinding and avoid ascertainment bias arm 1 arm 2 arm 3 Risperidone Asenapine Placebo 17 Placebo Placebo Placebo 17

Trials design patients randomly assigned 3 (phase 2) or 4 (phase 3) arms double-blind double-dummy measure of adherence: - before the trial - during the trial

Phase 2 trial (41004) N=182 Randomly assigned Asenapine 5 N=60 Risperidone 3 N=60 Placebo N=62 DC before tt N=1 DC before tt N=1 N=62 treated N=59 Treated N=59 Treated DC N=32 DC N=34 DC N=41 N=27 (46%) Completed trial N=25 (42%) Completed trial N=21 (34%) Completed trial 19 19

Primary measure of efficacy: Total Score (PANSS) ** p<0.05, asenapine versus placebo (NS) §§ p≤0.005, asenapine versus placebo ## p= 0.001, asenapine versus placebo 20 20

Secondary measures of efficacy: PANSS Positive Subscale Score §§ p≤0.005, asenapine versus placebo ## p<= 0.001, asenapine versus placebo * p<0.05, risperidone versus placebo 21 21

Negative Subscale Score ** p<0.05, asenapine versus placebo §§ p≤0.005, asenapine versus placebo 22 22

General Psychopathology Score ** p<0.05, asenapine versus placebo §§ p≤0.005, asenapine versus placebo ## p<= 0.001, asenapine versus placebo 23 23

CGI-S Score ** p<0.05, asenapine versus placebo * p<0.05, risperidone versus placebo § p<0.01, risperidone versus placebo # P<0.005, risperidone versus placebo 24 24

Conclusions of the phase 2 trial Asenapine 5mg BID was effective in patients with acute schizophrenia Asenapine may provide a new option for control of negative symtoms 25 25

Phase 3 trial (41023) N=458 Randomly assigned Asenapine 10 N=106 Haloperidol 4 N=115 Placebo N=123 Asenapine 5 N=114 DC before tt N=4 N=115 Treated N=111 Treated N=106 Treated N=123 treated DC N=41 DC N=35 DC N=47 DC N=53 N=70 (63%) Completed trial N=68 (60%) Completed trial N=71 (67%) Completed trial N=70 (57%) Completed trial 26 26

Primary measure of efficacy: Total Score (PANSS) * p<0.05 versus placebo 27 27

Secondary measures of efficacy : Positive Subscale Score * p<0.05 versus placebo 28

CGI-S Score * p<0.05 versus placebo 29

Conclusion of the phase 3 trial Asenapine at the 5 mg twice daily dose level was effective in the treatment of subjects with schizophrenia 30 30

Phase 3 trial (41021) N=417 Randomly assigned Asenapine 10 N=102 Olanzapine 15 N=103 Placebo N=106 Asenapine 5 N=106 DC before tt N=1 DC before tt N=2 DC N=6 N=102 Treated N=104 Treated N=102 Treated N=100 treated DC N=44 DC N=51 DC N=44 DC N=50 N=60 (58%) Completed trial N=58 (57%) Completed trial N=51 (50%) Completed trial N=50 (50%) Completed trial 31 31

Primary measure of efficacy: Total Score (PANSS) * p<0.05, asenapine 5mg versus placebo # P<0.05, olanzapine versus placebo 32 32

Secondary measures of efficacy : Positive Subscale Score * p<0.05 versus placebo 33 33

CGI-S Score * p<0.05 versus placebo 34

Conclusions of the phase 3 trial Asenapine at the 5 mg twice daily and 10 mg twice daily dose levels did not achieve statistical significance on the primary endpoint  negative study! 35 35

Summary of efficacy Asenapine 5mg twice daily efficacious in the acute treatment of schizophrenia in two adequate and well-controled short-term trials Very interesting results concerning negative symptoms 36

General Safety Data

Adverse Reactions:Short-term Schizophrenia Trials   Placebo Asenapine Preferred Term N=378 5mg BID N=274 10mg BID N=208 Insomnia 13% 16% 15% Somnolence 7% Constipation 6% 4% Vomiting 5% Dizziness 3%

Suicidality Placebo All Asenapine Olanzapine Risperidone 3mg BID   Placebo All Asenapine Olanzapine Risperidone 3mg BID Haloperidol 4mg BID N=1064 N=3457 N=899 N=120 N=115 Completed Suicide 0,20% 0,40% Suicide Attempt 0,50% 0,70% 0,80% 0,90% Suicidal ideation 1,40% 1,70% 0,00%

Crude Mortality Rate (%) Death Compound Crude Mortality Rate (%) Risperidone 0,6 Olanzapine 0,8 Ziprasidone Asenapine 0,5 Quetiapine Aripriprazole

Extrapyramidal Reactions

Prolactin No gynecomastia, amenohrea, sexual trouble. Baseline : P=14.8µg/l A=15.8µg/l R=12.8µg/l No gynecomastia, amenohrea, sexual trouble.

Asenapine And Weight Gain Short-term trial Baseline (kg): P=81.7 A=78.5 R=86.8 O=78.4 43

Long-Term Trial 44

Long-Term Trial Weight gain (Kg) Consequences: • PSYCHOLOGICAL: depression,solitary confinement…→ Poor compliance • SOMATIC: Sugar diabetes,obesity,dyslipidemia → CV disease 45

Biological parameters → No cardio-vascular diseases risk 46 46

Asenapine’s pharmacologic profile Is it possible to explain everything with phamacology? Preclinical studies are not enough→ Clinical trials

Many possible reasons Lipophilic molecule → mb + RE Settled way of life: unemployed, sedation… Food behavior Modification of leptine and ghreline rate. Genetic factors

Safety Conclusions : Asenapine is safe and well tolerated EPS profile comparable to other SGAs No new or unexpected AEs compared to other atypical antipsychotics Minimal impact on metabolic parameters Weight gain Lipids Prolactin

Threat for Asenapine Threat with price : Threat with rival molecules Genericization of the market Threat with rival molecules Long-acting injection could increase patient compliance and also demand price premium New approaches 50

Threat for Asenapine Threat with price : Threat with rival molecules Genericization of the market Threat with rival molecules Long-acting injection could increase patient compliance and also demand price premium New approaches 51

Forecast sales of antipsychotics in the 7MM $18,8 Billion $22,3 Billion $18,2 Billion

The Futur Generics : Patent expiration 53

The Antipsychotic Drugs Cost comparison 54

Important criteria Efficacy : Side effects ratio Cost Patient Profile (medication history, disease stage, age) Efficacy : Side effects ratio Delivery system (formulation, onset of action) Patient request Cost 55

Threat for Asenapine Threat with price : Threat with rival molecules Genericization of the market Threat with rival molecules Long-acting injection could increase patient compliance and also demand price premium New approaches 56

Improvement of compliance : Invega sustenna®(Paliperidone palmitate) : Zypadhera® (Olanzapine) Both approved by FDA and EMEA Long acting IM depot( every 4 weeks) Launch in 2009 US; 2010 Eu

Comparison Invega sustenna ® Switch from Risperdal® Consta® to Paliperidone Palmitate.(Same molecule) No need to be kept refrigirated Zypadhera® Problem: PIDSS =Post Injection Delirium Sedation Symptom(1.4%)

Conclusion Invega sustenna ®has a side effect profile advantage over Zypadhera® .( PIDSS) Doctors see their patient every month → Better medical supervision (efficacy, side effect) Powerfull marketing experience of these two companies concerning CNS.

Threat for Asenapine Threat with price : Threat with rival molecules Genericization of the market Threat with rival molecules Long-acting injection could increase patient compliance and also demand price premium New approaches 60

Other mechanisms of action   »We’ve been looking under the lamp because that’s where the light shines… » We do really need : much research to understand the underlying pathophysiology of the disease. Tools to improve stratification of patient. Develop better animal models Future: polypharmacy treating multiple symptom domains of schizophrenia.

Glutamatergic approach Since 1950 we know NMDA glutamate R antagonism (ketamine) produces schizophrenia-like symptoms. Multiple potential sites to target for enhancing NMDA receptor activity: Glutamate binding site (direct agonists → neurotoxicity). Glycine binding site (inhibits glycine transporter)

Metabotropic Glutamate Receptor LY 2140023 by mgluR2/3 agonist Possible target concerning positive symptoms and cognitive deficit. Phase II development in Europe drug showed: → slihtly weaker efficacity compared to Zyprexa® (olanzapine). → Better side effect profile(weight increase; EPS; prolactin) → Refractory patient?? Cognitive symptom?? (Need more clinical trial)

Glutamatergic approach If approved, Eli Lilly drug may be launch in 2014US/ 2015EU. Certainly high marketing potential: Current clinical trial data Lilly’s marketing experience Novel mechanism Possible apparition of serious adverse effect. Efficacity might be insufficient to replace 2nd generation atypical antipsychotic in severe and acute schyzophrenia Threat for drugs like asenapine

Saphris’future… Saphris Marketing Sell the molecule? Lifecycle management Improve saphris taste Observance Long-lasting depot Expand the indication 65

Saphris’future… Saphris Marketing Sell the molecule? Lifecycle management Improve saphris taste Observance Long-lasting depot Expand the indication 66

Saphris’future… Marketing Arguments: safety and efficacy 67

Saphris’future… Example of Abilify… 68 68

Saphris’future… Marketing Arguments: safety and efficacy Regulatory submissions accepted in Nov07 for Schizophrenia and bipolar disorder 69

Votes FDA Efficacy Safety Safety/Efficacy YES 10 12 9 NO 2 1 Abstain S   Efficacy Safety Safety/Efficacy YES 10 12 9 NO 2 1 Abstain S B S : Schizophrenia / B : Bipolar disorder

Saphris’future… Marketing Arguments: safety and efficacy Regulatory submissions accepted in Nov07 for Schizophrenia and bipolar disorder Sublingual Form 71

Saphris’future… Saphris Marketing Sell the molecule? Lifecycle management Improve saphris taste Observance Long-lasting depot Expand the indication 72

Saphris’future… Sell Saphris? Keep Saphris Why? No marketing experience in CNS To whom? J&J or Lilly Keep Saphris Patent cliff : (Cozaar/Hyzaar) in february:$ 3.4 to 3.7 millions /year Introduce theirselves in CNS market Life cycle management 73

Saphris’future… Saphris Marketing Sell the molecule? Lifecycle management Improve saphris taste Observance Long-lasting depot Expand the indication 74

Saphris’future… Lifecycle management Improve saphris taste. Make a once daily medication to improve observance Develop long lasting depot Expand the indication Forum, blog: disgusting taste, fool sensation, burning taste…

Targeted population: children and adolescents study SATIETY: cardiometabolic risk of second generation antipsychotics during first time use results: significant gain weight in each medication - olanzapine: 8,3 kg - quetiapine: 6,1 kg - risperidone: 5,3 kg - aripiprazole: 4,4 kg - asenapine: ???? 76 76

Targeted population: the ederly people increased risk of cerebral vascular accident with antipsychotics for elderly people associated cardiovascular diseases in this population risk of sudden cardiac stroke with antipsychotics (increasing QTc) asenapine = good solution for this population 77 77

SWOT Strenghts Weaknesses Promising safety and efficacy against placebo and Risperdal Will be a late-entrant into a crowded market Sublingual, fast-dissolving formulation under investigation Mechanism of action is undifferented from other launched atypicals Regulatory submissions accepted in Nov07 for Schizophrenia and bipolar disorder. Limited clinical information available   Opportunities Threats Patient switching due to an accumulation of comparative trial data demonstrating efficacy, safety and/or tolerability advantages. Existing, well-established competitor antipsychotics with similar profile Limit threat from generic risperidone competition by showing clear Generic risperidone may become available prior to asenapine launch Results from phase I of the CATIE study have reinforced the need for improved antipsychotic agents Other potential news comers paliperidone and bifeprunox

Thanks for your attention

Discontinuations during treatment Asenapine Risperidone Placebo Total dicontinuations 32 34 41 Lack of efficacy 9 (15%) 16 (27%) 18 (29%) Adverse events 6 (10%) 4 (7%) 7 (11%) Other 17 14 16