A Novel Antipsychotic Drug

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• A Novel Antipsychotic Drug

BLE Lucette BIZIMANA Charlotte COLIN
Jean-Baptiste MORISOT Nicolas
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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

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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
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Functional Outcomes in USA
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Past historic of anti-psychotics
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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

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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

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Historic
November 2006
November 2007
March 2009
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OVERVIEW OF EFFICACY
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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)
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Schizophrenia program

• Primary efficacy endpoint
• Secondary efficacy endpoints

PANSS Total Score
Positive , negative and general
psychopathological subscales scores
CGI-S score
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PANSS Score

• Evaluation of the psychopathological symptoms
• 3 dimensions
• ? positive symptoms
• ? negative symptoms
• ? general
  psychopathology
• 30 items, scored from 1 (absent) to 7 (extreme)

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Positive subscale items

• P1 delusion
• P2 conceptual disorganisation
• P3 hallucinatory behaviour
• P4 excitement
• P5 grandiosity
• P6 suspiciousness/persecution
• P7 hostility

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Inclusion criteria

• age gt18 years
• DSM-IV diagnosis of schizophrenia
  disorganized,paranoid,catatonic or
  undifferentiated subtypes
• acute exacerbation
• CGI-S Score gt 4 and PANSS gt 60

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Exclusion criteria

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

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Trials design

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

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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
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Placebo
Placebo
Placebo
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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
  

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Phase 2 trial (41004)
N182 Randomly assigned
Asenapine 5 N60
Risperidone 3 N60
Placebo N62
DC before tt N1
DC before tt N1
N62 treated
N59 Treated
N59 Treated
DC N32
DC N34
DC N41
N27 (46) Completed trial
N25 (42) Completed trial
N21 (34) Completed trial
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Primary measure of efficacy Total Score (PANSS)
plt0.05, asenapine versus placebo (NS)
p0.005, asenapine versus placebo p 0.001,
asenapine versus placebo
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Secondary measures of efficacy PANSS Positive
Subscale Score
p0.005, asenapine versus placebo plt
0.001, asenapine versus placebo plt0.05,
risperidone versus placebo
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Negative Subscale Score
plt0.05, asenapine versus placebo p0.005,
asenapine versus placebo
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General Psychopathology Score
plt0.05, asenapine versus placebo p0.005,
asenapine versus placebo plt 0.001, asenapine
versus placebo
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CGI-S Score
plt0.05, asenapine versus placebo p0.005,
asenapine versus placebo plt0.05, risperidone
versus placebo plt0.01, risperidone versus
placebo Plt0.005, risperidone versus placebo
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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

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Phase 3 trial (41023)
N458 Randomly assigned
Haloperidol 4 N115
Placebo N123
Asenapine 10 N106
Asenapine 5 N114
DC before tt N4
N115 Treated
N111 Treated
N123 treated
N106 Treated
DC N41
DC N47
DC N35
DC N53
N70 (63) Completed trial
N68 (60) Completed trial
N70 (57) Completed trial
N71 (67) Completed trial
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Primary measure of efficacyTotal Score (PANSS)
plt0.05 versus placebo
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Secondary measures of efficacy Positive
Subscale Score
plt0.05 versus placebo
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CGI-S Score
plt0.05 versus placebo
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Conclusion of the phase 3 trial

• Asenapine at the 5 mg twice
  daily dose level was effective in the
  treatment of subjects with schizophrenia

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Phase 3 trial (41021)
N417 Randomly assigned
Olanzapine 15 N103
Placebo N106
Asenapine 10 N102
Asenapine 5 N106
DC before tt N1
DC before tt N2
DC N6
N102 Treated
N104 Treated
N100 treated
N102 Treated
DC N44
DC N44
DC N51
DC N50
N60 (58) Completed trial
N58 (57) Completed trial
N50 (50) Completed trial
N51 (50) Completed trial
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Primary measure of efficacy Total Score (PANSS)

• plt0.05, asenapine 5mg versus placebo
• Plt0.05, olanzapine versus placebo

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Secondary measures of efficacy Positive
Subscale Score
plt0.05 versus placebo
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CGI-S Score
plt0.05 versus placebo
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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!

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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

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General Safety Data
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Adverse ReactionsShort-term Schizophrenia Trials
  Placebo Asenapine Asenapine
Preferred Term N378 5mg BID N274 10mg BID N208  
Insomnia 13 16 15  
Somnolence 7 15 13  
Constipation 6 7 4  
Vomiting 5 4 7  
Dizziness 4 7 3  
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Suicidality
  Placebo All Asenapine Olanzapine Risperidone 3mg BID Haloperidol 4mg BID
  N1064 N3457 N899 N120 N115
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
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Death

Compound Crude Mortality Rate ()
Risperidone 0,6
Olanzapine 0,8
Ziprasidone 0,6
Asenapine 0,5
Quetiapine 0,5
Aripriprazole 0,5
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Extrapyramidal Reactions
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Prolactin
Baseline P14.8µg/l A15.8µg/l R12.8µg/l
No gynecomastia, amenohrea, sexual trouble.
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Asenapine And Weight GainShort-term trial
Baseline (kg) P81.7 A78.5 R86.8 O78.4
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Long-Term Trial
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Long-Term Trial
Weight gain (Kg)
Consequences PSYCHOLOGICAL
depression,solitary confinement? Poor
compliance SOMATIC Sugar diabetes,obesity,dysli
pidemia ? CV disease
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Biological parameters
? No cardio-vascular diseases risk
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Asenapines pharmacologic profile
Is it possible to explain everything with
phamacology? Preclinical studies are not enough?
Clinical trials
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Many possible reasons

• Lipophilic molecule ? mb RE
• Settled way of life unemployed, sedation
• Food behavior
• Modification of leptine and ghreline rate.
• Genetic factors

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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

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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

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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

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Forecast sales of antipsychotics in the 7MM
18,8 Billion
22,3 Billion
18,2 Billion
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The Futur Generics Patent expiration
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The Antipsychotic Drugs Cost comparison
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Important criteria
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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

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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

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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)

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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.

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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

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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.

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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)

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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)

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Glutamatergic approach

• 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 2nd
  generation atypical antipsychotic in severe and
  acute schyzophrenia
• Threat for drugs like asenapine

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Saphrisfuture
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Saphrisfuture
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Saphrisfuture

• Marketing
• Arguments
• safety and efficacy

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Saphrisfuture

• Example of Abilify

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Saphrisfuture

• Marketing
• Arguments
• safety and efficacy
• Regulatory submissions accepted in Nov07 for
  Schizophrenia and bipolar disorder

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Votes FDA
  Efficacy Efficacy Safety Safety Safety/Efficacy 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
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Saphrisfuture

• Marketing
• Arguments
• safety and efficacy
• Regulatory submissions accepted in Nov07 for
  Schizophrenia and bipolar disorder
• Sublingual Form

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Saphrisfuture
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Saphrisfuture

• Sell Saphris?
• Why? No marketing experience in CNS
• To whom? JJ 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

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Saphrisfuture
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Saphrisfuture

• 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
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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 ????

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Targeted populationthe 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

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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
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Thanks for your attention
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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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