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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

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Leading Causes of Years of Life Lived with Disability

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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

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Past historic of anti-psychotics :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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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

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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

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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 >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

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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)

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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

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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

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Negative Subscale Score

** p<0.05, asenapine versus placebo §§ p≤0.005, asenapine versus placebo

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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

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Phase 3 trial (41023)

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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

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Secondary measures of efficacy : Positive Subscale Score

* p<0.05 versus placebo

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CGI-S Score

* p<0.05 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)

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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

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Secondary measures of efficacy : Positive Subscale Score

* p<0.05 versus placebo

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CGI-S Score

* p<0.05 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 Reactions:Short-term Schizophrenia Trials

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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

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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

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

Aripriprazole 0,5

Extrapyramidal Reactions

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Prolactin

42No gynecomastia, amenohrea, sexual trouble.

Baseline : P=14.8µg/lA=15.8µg/lR=12.8µg/l

Asenapine And Weight GainShort-term trial

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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

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Long-Term TrialW

eigh

t gai

n (K

g)

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Consequences: • PSYCHOLOGICAL: depression,solitary confinement…→ Poor compliance• SOMATIC: Sugar diabetes,obesity,dyslipidemia → CV disease

Biological parameters

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-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

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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

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

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$18,8 Billion

$22,3 Billion

$18,2 Billion

The Futur Generics : Patent expiration

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The Antipsychotic Drugs Cost comparison

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

• »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.

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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) 63

Glutamatergic approach

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• 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…

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Saphris’future…

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Saphris’future…

• Marketing– Arguments:

• safety and efficacy

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Saphris’future…

• Example of Abilify…

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Saphris’future…

• Marketing– Arguments:

• safety and efficacy

• Regulatory submissions accepted in Nov07 for Schizophrenia and bipolar disorder

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Votes FDA

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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

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Saphris’future…

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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

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Saphris’future…

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Saphris’future…

• Lifecycle management– Improve saphris taste.– Make a once daily medication to improve

observance – Develop long lasting depot– Expand the indication

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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: ????

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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

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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

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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