A Novel Antipsychotic
Drug
BLE Lucette
BIZIMANA Charlotte
COLIN Jean-Baptiste
MORISOT Nicolas
1
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
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
4,90%
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%
3
Functional Outcomes in USA
90%
80%
70%
60%
50%
80%
40%
30%
20%
20%
10%
0%
Unemployed
Married or Equivalent
4
Past historic of anti-psychotics :
5
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
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
7
Historic
November
2006
November 2007
March 2009
OVERVIEW OF EFFICACY
Short-term trials in schizophrenia
Asenapine 5
Phase 2 trial
(41004)
Risperidone 3
Placebo
Asenapine 5
Phase 3 trial
(41023)
Asenapine 10
Haloperidol 4
Placebo
Asenapine 5
Phase 3 trial
(41021)
Asenapine 10
Olanzapine 15
Placebo
Schizophrenia program
Primary efficacy endpoint
Secondary efficacy endpoints
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
Asenapine
Placebo
Risperidone
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
DC before tt
N=1
N=59
Treated
DC before tt
N=1
N=62
treated
N=59
Treated
DC
N=32
N=27 (46%)
Completed trial
Placebo
N=62
DC
N=34
N=25 (42%)
Completed trial
DC
N=41
N=21 (34%)
Completed trial
19
Primary measure of efficacy:
Total Score (PANSS)
0
week 0
week 1
week 2
week 3
week 4
week 5
week 6
-2
-4
-6
-8
ASENAPINE (baseline value: 96.48)
-10
PLACEBO (baseline value: 92.43)
RISPERIDONE ( baseline value: 92.18)
-12
**
-14
-16
§§
##
-18
§§
##
-20
** p<0.05, asenapine versus placebo (NS)
§§ p≤0.005, asenapine versus placebo
## p= 0.001, asenapine versus placebo
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
Negative Subscale Score
** p<0.05, asenapine versus placebo
§§ p≤0.005, asenapine versus placebo
22
General Psychopathology Score
** p<0.05, asenapine versus placebo
§§ p≤0.005, asenapine versus placebo
## p<= 0.001, asenapine versus placebo
23
CGI-S Score
** p<0.05, asenapine versus placebo
§§ p≤0.005, asenapine versus placebo
* p<0.05, risperidone versus placebo
§ p<0.01, risperidone versus placebo
# P<0.005, risperidone versus placebo
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
Phase 3 trial (41023)
N=458 Randomly assigned
Asenapine 10
N=106
Asenapine 5
N=114
Haloperidol 4
N=115
Placebo
N=123
N=115
Treated
N=123
treated
DC before tt
N=4
N=111
Treated
N=106
Treated
DC
N=41
N=70 (63%)
Completed trial
DC
N=35
N=71 (67%)
Completed trial
DC
N=47
N=68 (60%)
Completed trial
DC
N=53
N=70 (57%)
Completed trial
26
Primary measure of efficacy:
Total Score (PANSS)
0
week 0
week 1
week 2
week 3
week 4
week 5
week 6
-2
-4
-6
placebo (baseline: 89)
-8
asenapine 5 (baseline: 88,9)
asenapine 10 (baseline: 89,4)
-10
haloperidol (baseline: 88,5)
-12
*
*
-14
*
*
*
*
-16
*
*
-18
* p<0.05 versus placebo
27
Secondary measures of efficacy :
Positive Subscale Score
0
-1
week 0 week 1 week 2 week 3 week 4 week 5 week 6
-2
-3
-4
*
-5
*
-6
*
*
*
*
*
*
-7
* p<0.05 versus placebo
28
CGI-S Score
0
week 0 week 1 week 2 week 3 week 4 week 5 week 6
-0.2
-0.4
-0.6
*
*
-0.8
-1
*
*
*
*
*
*
* 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
Phase 3 trial (41021)
N=417 Randomly assigned
Asenapine 10
N=102
Asenapine 5
N=106
Olanzapine 15
N=103
DC before tt
N=1
DC before tt
N=2
N=104
Treated
N=102
Treated
N=102
Treated
DC
N=44
N=60 (58%)
Completed trial
Placebo
N=106
DC
N=51
N=51 (50%)
Completed trial
N=100
treated
DC
N=44
N=58 (57%)
Completed trial
DC
N=6
DC
N=50
N=50 (50%)
Completed trial
31
Primary measure of efficacy:
Total Score (PANSS)
0
week 0
week 1
week 2
week 3
week 4
week 5
week 6
-2
-4
-6
placebo (baseline: 93,7)
-8
asenapine 5 (baseline: 90,8)
asenapine 10 (baseline: 93,2)
-10
olanzapine (baseline: 92,6)
-12
-14
*
-16
#
#
-18
* p<0.05, asenapine 5mg versus placebo
# P<0.05, olanzapine versus placebo
32
Secondary measures of efficacy :
Positive Subscale Score
0
week0 week1 week2 week3 week4 week5 week6
-1
-2
-3
-4
*
*
-5
*
-6
*
*
*
*
*
*
* p<0.05 versus placebo
33
CGI-S Score
0
-0.1
week0 week1 week2 week3 week4 week5 week6
-0.2
-0.3
-0.4
-0.5
-0.6
-0.7
-0.8
-0.9
*
-1
*
* 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
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
37
Adverse Reactions:Short-term
Schizophrenia Trials
Placebo
Asenapine
5mg BID
10mg BID
N=274
N=208
Preferred Term
N=378
Insomnia
13%
16%
15%
Somnolence
7%
15%
13%
Constipation
6%
7%
4%
Vomiting
5%
4%
7%
Dizziness
4%
7%
3%
38
Suicidality
All
Risperidone Haloperidol
Placebo Asenapine Olanzapine 3mg BID
4mg BID
N=1064
N=3457
N=899
N=120
N=115
Completed
Suicide
0
0,20%
0,40%
0
0
Suicide
Attempt
0,20%
0,50%
0,70%
0,80%
0,90%
Suicidal
ideation
0,80%
1,40%
0,90%
1,70%
0,00%
39
Death
Compound
Risperidone
Olanzapine
Ziprasidone
Asenapine
Quetiapine
Aripriprazole
Crude Mortality Rate (%)
0,6
0,8
0,6
0,5
0,5
0,5
40
Dyskinesia
Haloperidol
Parkinsonism
41
olanzapine
Asenapine
Placebo
Risperidone
Akathisia
Haloperidol
Risperidone
olanzapine
Asenapine
Placebo
Haloperidol
Risperidone
olanzapine
Asenapine
Placebo
Extrapyramidal Reactions
Patient Percentage (%)
30
25
20
15
10
5
0
Prolactin
change from baseline(µg/L)
25
20
15
10
5
0
Placebo N=706
-5
Asenapine 5-10mg BID Risperidone 3mg BID
N=1953
N=120
No gynecomastia, amenohrea, sexual trouble.
Baseline :
P=14.8µg/l
A=15.8µg/l
R=12.8µg/l
42
Asenapine And Weight Gain
Short-term trial
Mean Change from Baseline Body Weight (Kg)
3
2,5
2
Placebo
All Asenapine (5-10mg BID)
1,5
Olanzapine (5-20mg QD)
1
Risperidone (3mg BID)
0,5
0
Placebo
All Asenapine (5- Olanzapine (5-20mg Risperidone (3mg
10mg BID)
QD)
BID)
Baseline (kg):
P=81.7
A=78.5
R=86.8
O=78.4
43
Long-Term Trial
Mean Change From Baseline Body
Weight (Kg)
6
Olanzapine 10-20mg n=177
Asenapine 5-10mg n=341
5
4
3
2
1
0
0
1
2
3
4
6
8
12 16 20 24 28 32 36 40 44 48 52
44
Weight gain (Kg)
Long-Term Trial
8
7
6
5
4
3
2
1
0
Asenapine Olanzapine Asenapine Olanzapine Asenapine Olanzapine
BMI< 23
23<BMI<27
BMI>27
Consequences:
• PSYCHOLOGICAL: depression,solitary confinement…→ Poor compliance
• SOMATIC: Sugar diabetes,obesity,dyslipidemia → CV disease
45
Biological parameters
25
20
15
10
Total cholesterol (mg/dL)
5
HDL (mg/dL)
0
LDL (mg/dL)
-5
Placebo N=503
Asenapine 5-10mg BID Olanzapine 10-20mg QD
N=572
N=194
Triglycerides fasting (mg/dL)
-10
-15
-20
→ No cardio-vascular diseases risk
46
Asenapine’s pharmacologic profile
Is it possible to explain everything with phamacology?
Preclinical studies are not enough→ Clinical trials
47
Many possible reasons
• Lipophilic molecule → mb + RE
• Settled way of life: unemployed, sedation…
• Food behavior
• Modification of leptine and ghreline rate.
• Genetic factors
48
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
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
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
Forecast sales of antipsychotics in the
7MM
$18,8 Billion
Years
2018
2017
2016
2015
2014
2013
2012
$22,3 Billion
Branded (non-depot)
Generics
2011
Branded (depots)
Pipeline (oral)
2010
2009
$18,2 Billion
2008
Sales ($m)
0
5000
10000
15000
20000
52
The Futur Generics :
Patent expiration
53
The Antipsychotic Drugs
Cost comparison
54
Important criteria
55
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
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
Comparison
• Invega sustenna ®
• Switch from Risperdal®
Consta® to Paliperidone
Palmitate.(Same molecule)
• Zypadhera®
• Problem: PIDSS
=Post Injection Delirium
Sedation Symptom(1.4%)
• No need to be kept
refrigirated
58
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
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
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.
61
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
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)
63
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
64
Saphris’future…
Marketing
Saphris
Sell the
molecule?
Improve saphris taste
Observance
Lifecycle
management
Long-lasting depot
Expand the indication
65
Saphris’future…
Marketing
Saphris
Sell the
molecule?
Improve saphris taste
Observance
Lifecycle
management
Long-lasting depot
Expand the indication
66
Saphris’future…
• Marketing
– Arguments:
• safety and efficacy
67
Saphris’future…
• Example of Abilify…
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
12
12
9
12
NO
2
0
0
0
1
0
Abstain
0
0
0
0
2
0
S
B
S
B
S
B
S : Schizophrenia / B : Bipolar disorder
70
Saphris’future…
• Marketing
– Arguments:
• safety and efficacy
• Regulatory submissions accepted in Nov07 for
Schizophrenia and bipolar disorder
• Sublingual Form
71
Saphris’future…
Marketing
Saphris
Sell the
molecule?
Improve saphris taste
Observance
Lifecycle
management
Long-lasting depot
Expand the indication
72
Saphris’future…
• 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
Saphris’future…
Marketing
Saphris
Sell the
molecule?
Improve saphris taste
Observance
Lifecycle
management
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…
75
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
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
SWOT
Strenghts
Promising safety and efficacy against
placebo and Risperdal
Weaknesses
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
Patient switching due to an accumulation
of comparative trial data demonstrating
efficacy, safety and/or tolerability
advantages.
Limit threat from generic risperidone
competition by showing clear
Results from phase I of the CATIE study
have reinforced the need for improved
antipsychotic agents
Threats
Existing, well-established competitor
antipsychotics with similar profile
Generic risperidone may become available
prior to asenapine launch
Other potential news comers paliperidone
and bifeprunox
79
Thanks for your attention
81
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