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1
A Novel Antipsychotic
Drug
BLE LucetteBIZIMANA CharlotteCOLIN Jean-BaptisteMORISOT 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
2
Leading Causes of Years of Life Lived with Disability
3
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%
Functional Outcomes in USA
4
Past historic of anti-psychotics :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
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)
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
17
Asenapine
Placebo
Risperidone
Placebo
Placebo
Placebo
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)
19
N=182 Randomly assigned
Asenapine 5N=60
Risperidone 3N=60
PlaceboN=62
N=59Treated
N=27 (46%)Completed trial
N=59Treated
N=25 (42%)Completed trial
N=21 (34%)Completed trial
N=62treated
DC before ttN=1
DC before ttN=1
DC N=32
DC N=34
DC N=41
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
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)
26
N=458 Randomly assigned
Asenapine 5N=114
Haloperidol 4N=115
PlaceboN=123
N=111Treated
N=70 (63%)Completed trial
N=115Treated
N=68 (60%)Completed trial
N=70 (57%)Completed trial
N=123treated
DC before ttN=4
DC N=41
DC N=47
Asenapine 10N=106
N=106Treated
N=71 (67%)Completed trial
DC N=35
DC N=53
Primary measure of efficacy:Total Score (PANSS)
* p<0.05 versus placebo
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
Phase 3 trial (41021)
31
N=417 Randomly assigned
Asenapine 5N=106
Olanzapine 15N=103
PlaceboN=106
N=104Treated
N=60 (58%)Completed trial
N=102Treated
N=58 (57%)Completed trial
N=50 (50%)Completed trial
N=100treated
DC before ttN=2
DC before ttN=1
DC N=44
DC N=44
Asenapine 10N=102
N=102Treated
N=51 (50%)Completed trial
DC N=51
DC N=50
DC N=6
Primary measure of efficacy: Total Score (PANSS)
* p<0.05, asenapine 5mg versus placebo# P<0.05, olanzapine versus placebo
32
Secondary measures of efficacy : Positive Subscale Score
* p<0.05 versus placebo
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
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
38
Placebo Asenapine
Preferred Term N=3785mg BID N=274
10mg BID N=208
Insomnia 13% 16% 15%
Somnolence 7% 15% 13%
Constipation 6% 7% 4%
Vomiting 5% 4% 7%
Dizziness 4% 7% 3%
Suicidality
39
PlaceboAll
Asenapine OlanzapineRisperidone
3mg BIDHaloperidol
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%
Death
40
Compound Crude Mortality Rate (%)Risperidone 0,6Olanzapine 0,8Ziprasidone 0,6Asenapine 0,5Quetiapine 0,5
Aripriprazole 0,5
Extrapyramidal Reactions
41
Prolactin
42No gynecomastia, amenohrea, sexual trouble.
Baseline : P=14.8µg/lA=15.8µg/lR=12.8µg/l
Asenapine And Weight GainShort-term trial
43
0
0,5
1
1,5
2
2,5
3
Placebo All Asenapine (5-10mg BID)
Olanzapine (5-20mg QD)
Risperidone (3mg BID)
Mean Change from Baseline Body Weight (Kg)
Placebo
All Asenapine (5-10mg BID)
Olanzapine (5-20mg QD)
Risperidone (3mg BID)
Baseline (kg):P=81.7A=78.5R=86.8O=78.4
Long-Term Trial
44
Long-Term TrialW
eigh
t gai
n (K
g)
45
Consequences: • PSYCHOLOGICAL: depression,solitary confinement…→ Poor compliance• SOMATIC: Sugar diabetes,obesity,dyslipidemia → CV disease
Biological parameters
46
-20
-15
-10
-5
0
5
10
15
20
25
Placebo N=503 Asenapine 5-10mg BID N=572
Olanzapine 10-20mg QD N=194
Total cholesterol (mg/dL)
HDL (mg/dL)
LDL (mg/dL)
Triglycerides fasting (mg/dL)
→ No cardio-vascular diseases risk
Asenapine’s pharmacologic profile
Is it possible to explain everything with phamacology?
Preclinical studies are not enough→ Clinical trials47
48
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
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
52
$18,8 Billion
$22,3 Billion
$18,2 Billion
The Futur Generics : Patent expiration
53
54
The Antipsychotic Drugs Cost comparison
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)
• No need to be kept refrigirated
• Zypadhera®
• Problem: PIDSS =Post Injection Delirium
Sedation Symptom(1.4%)
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
64
• 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…
65
Saphris’future…
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
70
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
Saphris’future…
• Marketing– Arguments:
• safety and efficacy
• Regulatory submissions accepted in Nov07 for Schizophrenia and bipolar disorder
• Sublingual Form
71
Saphris’future…
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…
74
Saphris’future…
• 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…
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
Strenghts WeaknessesPromising 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
SWOT
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
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