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

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Presentation on theme: "1 A Novel Antipsychotic Drug BLE Lucette BIZIMANA Charlotte COLIN Jean-Baptiste MORISOT Nicolas."— Presentation transcript:

1 1 A Novel Antipsychotic Drug BLE Lucette BIZIMANA Charlotte COLIN Jean-Baptiste MORISOT Nicolas

2 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 2

3 Leading Causes of Years of Life Lived with Disability 3 1Unipolar depressive disorders16,40% 2Alcohol disorders5,50% 3Schizophrenia4,90% 4Iron-deficiency anemia4,90% 5Bipolar affective disorder4,70% 6Hearing loss, adult onset3,80% 7HIV/AIDS2,80% 8Chronic obstructive pulmonary disease2,40% 9Osteoarthritis2,30% 10Road traffic accidents2,30%

4 Functional Outcomes in USA 4

5 Past historic of anti-psychotics : 5

6 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 6

7 Asenapines 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 7

8 Historic November 2006 November 2007 March 2009

9 OVERVIEW OF EFFICACY

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

11 Schizophrenia program Primary efficacy endpoint Secondary efficacy endpoints 11

12 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

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

14 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

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

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

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

18 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

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

20 Primary measure of efficacy: Total Score (PANSS) ** p<0.05, asenapine versus placebo (NS) §§ p0.005, asenapine versus placebo ## p= 0.001, asenapine versus placebo 20

21 Secondary measures of efficacy: PANSS Positive Subscale Score §§ p0.005, asenapine versus placebo ## p<= 0.001, asenapine versus placebo * p<0.05, risperidone versus placebo 21

22 Negative Subscale Score ** p<0.05, asenapine versus placebo §§ p0.005, asenapine versus placebo 22

23 General Psychopathology Score ** p<0.05, asenapine versus placebo §§ p0.005, asenapine versus placebo ## p<= 0.001, asenapine versus placebo 23

24 CGI-S Score ** p<0.05, asenapine versus placebo §§ p0.005, asenapine versus placebo * p<0.05, risperidone versus placebo § p<0.01, risperidone versus placebo # P<0.005, risperidone versus placebo 24

25 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

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

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

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

29 CGI-S Score * p<0.05 versus placebo 29

30 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

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

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

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

34 CGI-S Score * p<0.05 versus placebo 34

35 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

36 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

37 General Safety Data 37

38 Adverse Reactions:Short-term Schizophrenia Trials 38 PlaceboAsenapine Preferred TermN=378 5mg BID N=274 10mg BID N=208 Insomnia13%16%15% Somnolence7%15%13% Constipation6%7%4% Vomiting5%4%7% Dizziness4%7%3%

39 Suicidality 39 Placebo All AsenapineOlanzapine Risperidone 3mg BID Haloperidol 4mg BID N=1064N=3457N=899N=120N=115 Completed Suicide 00,20%0,40%00 Suicide Attempt 0,20%0,50%0,70%0,80%0,90% Suicidal ideation 0,80%1,40%0,90%1,70%0,00%

40 Death 40 CompoundCrude Mortality Rate (%) Risperidone0,6 Olanzapine0,8 Ziprasidone0,6 Asenapine0,5 Quetiapine0,5 Aripriprazole0,5

41 Extrapyramidal Reactions 41

42 Prolactin 42 No gynecomastia, amenohrea, sexual trouble. Baseline : P=14.8µg/l A=15.8µg/l R=12.8µg/l

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

44 Long-Term Trial 44

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

46 Biological parameters 46 No cardio-vascular diseases risk

47 Asenapines pharmacologic profile Is it possible to explain everything with phamacology? Preclinical studies are not enough Clinical trials 47

48 48 Many possible reasons Lipophilic molecule mb + RE Settled way of life: unemployed, sedation… Food behavior Modification of leptine and ghreline rate. Genetic factors

49 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 49

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

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

52 Forecast sales of antipsychotics in the 7MM 52 $18,8 Billion $22,3 Billion $18,2 Billion

53 The Futur Generics : Patent expiration 53

54 54 The Antipsychotic Drugs Cost comparison

55 Important criteria 55

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

57 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 57

58 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%) 58

59 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. 59

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

61 Other mechanisms of action » Weve been looking under the lamp because thats 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. 61

62 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) 62

63 Metabotropic Glutamate Receptor LY 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) 63

64 Glutamatergic approach 64 If approved, Eli Lilly drug may be launch in 2014US/ 2015EU. Certainly high marketing potential: Current clinical trial data Lillys marketing experience Novel mechanism Possible apparition of serious adverse effect. Efficacity might be insufficient to replace 2 nd generation atypical antipsychotic in severe and acute schyzophrenia Threat for drugs like asenapine

65 Saphrisfuture… 65 Saphris Marketing Sell the molecule? Lifecycle management Improve saphris tasteObservanceLong-lasting depotExpand the indication

66 Saphrisfuture… 66 Saphris Marketing Sell the molecule? Lifecycle management Improve saphris tasteObservanceLong-lasting depotExpand the indication

67 Saphrisfuture… Marketing – Arguments: safety and efficacy 67

68 Saphrisfuture… Example of Abilify… 68

69 Saphrisfuture… Marketing – Arguments: safety and efficacy Regulatory submissions accepted in Nov07 for Schizophrenia and bipolar disorder 69

70 Votes FDA 70 EfficacySafetySafety/Efficacy YES NO Abstain SBSBSB S : Schizophrenia / B : Bipolar disorder

71 Saphrisfuture… Marketing – Arguments: safety and efficacy Regulatory submissions accepted in Nov07 for Schizophrenia and bipolar disorder Sublingual Form 71

72 Saphrisfuture… 72 Saphris Marketing Sell the molecule? Lifecycle management Improve saphris tasteObservanceLong-lasting depotExpand the indication

73 Saphrisfuture… Sell 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

74 Saphrisfuture… 74 Saphris Marketing Sell the molecule? Lifecycle management Improve saphris tasteObservance Long-lasting depot Expand the indication

75 Saphrisfuture… Lifecycle management – Improve saphris taste. – Make a once daily medication to improve observance – Develop long lasting depot – Expand the indication 75 Forum, blog: disgusting taste, fool sensation, burning taste…

76 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

77 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

78 StrenghtsWeaknesses 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 OpportunitiesThreats 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 SWOT

79 79

80 Thanks for your attention

81 81

82 Discontinuations during treatment AsenapineRisperidonePlacebo Total dicontinuations Lack of efficacy 9 (15%)16 (27%)18 (29%) Adverse events 6 (10%)4 (7%)7 (11%) Other

83


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