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

3. Leading Causes of Years of Life Lived with Disability1
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%

4. Functional Outcomes in USA

5. Past historic of anti-psychotics :

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

7. 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

8. Historic
November 2006
November 2007
March 2009

9. OVERVIEW OF EFFICACY

10. 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)

11. Schizophrenia program
Primary efficacy endpoint Secondary efficacy endpoints
PANSS Total Score
Positive , negative and general psychopathological subscales scores
CGI-S score 11 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 arm arm 3
Risperidone
Asenapine
Placebo 17
Placebo
Placebo
Placebo 17

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) 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

20. 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

21. 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

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

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

24. 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

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 25

26. 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

27. Primary measure of efficacy: Total Score (PANSS)
* p<0.05 versus placebo 27 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 30

31. 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

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

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

38. 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%

39. 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%

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

41. Extrapyramidal Reactions

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

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

44. Long-Term Trial 44

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

46. Biological parameters
→ No cardio-vascular diseases risk 46 46

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

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

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 50

51. 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

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

53. The Futur Generics : Patent expiration53

54. The Antipsychotic Drugs Cost comparison54

55. 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

56. 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

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

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%)

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.

60. 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

61. 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.

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)

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)

64. 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

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

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

67. Saphris’future…
Marketing
Arguments:
safety and efficacy 67

68. Saphris’future…
Example of Abilify… 68 68

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

70. 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

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

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

73. 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

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

75. 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…

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 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 77

78. 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

80. Thanks for your attention

82. 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