Pipeline Insight: Antipsychotics - Novel Antipsychotics Driving Market Evolution

Table of Contents

CHAPTER 1 EXECUTIVE SUMMARY 3

1.1 Scope of the analysis 3

1.2 Datamonitor insight into the antipsychotics pipeline 3

Following safety concerns with key late stage products, namely Novartis�EZomaril (iloperidone) and Lundbeck's Serdolect (sertindole), Datamonitor believes that the antipsychotic pipeline is unlikely to provide a blockbuster drug over the forecast period, 2003�E011. Datamonitor believes out-licensing is the best option for Novartis and Lundbeck, although finding a buyer will prove difficult. 4

The remaining Phase III drugs include Lundbeck/Solvay's bifeprunox, Dainippon's Lonasen, and Organon/Pfizer's asenapine, all of which are MNRAs. Datamonitor believes that bifeprunox has the greatest market potential, based upon the drugs superior efficacy and side effect profile; although the recent collaboration of Organon and Pfizer over the development of asenapine, indicates that the drug has strong therapeutic and commercial capabilities. 5

The majority of antipsychotics in Phase II development and below demonstrate a paradigm shift from the traditional D2 dopamine and 5-HT2 serotonin receptor antagonism to alternative dopaminergic and serotonergic receptor targeting, in addition to a plethora of novel neurotransmitter receptors. Datamonitor believes that although this demonstrates a transition towards the potential future treatment strategy of polytherapy, a number of hurdles have to be approached first. 7

Summary 9

1.3 Key metrics 10

CHAPTER 2 PATIENT POTENTIAL 12

2.1 Introduction: antipsychotic indications 13

2.2 Schizophrenia 14

Disease definition 14

Epidemiology 16

Comorbid disorders 17

Segmentation of schizophrenia 20

Diagnosis, treatment and compliance 22

2.3 Bipolar disorder 24

Disease definition 24

Epidemiology 25

Comorbidity disorders 28

Segmentation of bipolar disorder 30

Diagnosis, treatment and compliance 30

2.4 Future prevalence trends of schizophrenia and bipolar disorder 31

2.5 Unmet needs 33

2.6 Efficacy 33

Compliance 34

Onset of action 35

Side-effect profile 35

Refractory patients 35

CHAPTER 3 R&D APPROACH 37

3.1 Classification of pipeline products 38

Dopamine antagonists 38

Mixed neurotransmitter receptor antipsychotics 39

Novel antipsychotics 39

3.2 Clinical trial assessment tools 40

Positive and Negative Syndrome Assessment 40

Brief Psychiatric Rating Scale 41

Other tests 41

3.3 Side effects of antipsychotics 41

Extrapyramidal symptoms 42

Prolactin serum levels 42

Sexual dysfunction 42

Weight gain 42

Diabetes 43

QTc prolongation 44

Agranulocytosis 44

3.4 Clinical trial design in psychosis 45

Randomization 45

Double blind and placebo controlled 45

Placebo effect in clinical trials 46

Comparator drugs: equivalence and non-inferiority trials 47

Comparator drugs: doses 48

CHAPTER 4 ANTIPSYCHOTIC PIPELINE ANALYSIS 49

4.1 Pipeline overview 50

Registered and Phase III overview 50

Phase II overview 51

Phase I overview 53

Preclinical overview 54

4.2 Key companies involved in the antipsychotic pipeline 60

4.3 Organon and Cortex 61

4.4 Sanofi-Synthélabo 63

Collaboration between Sanofi and Organon? 67

4.5 Strategies for success 67

Antipsychotic delivery systems 67

Polytherapy 71

CHAPTER 5 MIXED NEUROTRANSMITTER RECEPTOR ANTAGONISTS 74

5.1 Pipeline overview 75

5.2 Definition of current gold standard for MNRA class 75

Zyprexa (olanzapine) 76

5.3 Zomaril (iloperidone) 78

Profile 78

Forecast to 2011 83

5.4 Serdolect (sertindole) 84

Profile 84

Forecast to 2011 89

5.5 Bifeprunox (DU127090) 91

Profile 91

Forecast to 2011 94

5.6 Lonasen (blonanserin) 96

Profile 96

Forecast to 2011 100

5.7 Other MNRA drugs in late-stage development 101

Asenapine (ORG-5222) 101

SM-13496 103

SLV 310/313 104

5.8 Comparison of mixed neurotransmitter receptor antagonists 104

Efficacy 105

Compliance 105

Side-effect profile 105

Marketing strength 106

MNRA market forecast to 2011 107

5.9 Recently discontinued MNRAs 107

Eplivanserin 108

CHAPTER 6 DOPAMINERGIC ANTIPSYCHOTICS 109

6.1 Pipeline overview 110

6.2 Definition of gold standard 110

6.3 Abilify (aripiprazole) 111

6.4 Drug analysis 112

PNU-170413 112

CHAPTER 7 NOVEL LATE-STAGE ANTIPSYCHOTICS 114

7.1 Pipeline overview 115

7.2 Definition of gold standard 115

7.3 Clozaril (clozapine) 115

7.4 CX-516 116

Profile 116

7.5 LAX-101 120

Profile 120

7.6 ORG-24448 122

7.7 ABT-089 123

7.8 Osanetant 123

Profile 123

7.9 Talnetant (SB-223412) 124

7.10 Recently discontinued novel antipsychotics 124

7.11 E-5826 125

Profile 125

CHAPTER 8 INNOVATIVE EARLY-STAGE PROJECTS 126

8.1 Current research strategies 127

Niacin skin test 127

Susceptibility genes for schizophrenia 128

Bipolar and schizophrenia genetic link 129

8.2 Key antipsychotics in Phase I and preclinical development 130

5-HT receptor targeting: ACP-103 130

Dopamine receptor targeting 132

Novel receptor targets 134

8.3 Contributing experts 136

8.4 List of tables 137

8.5 List of figures 137

8.6 Bibliography 137

Patient potential 137

R&D approach 140

Clinical trial data 141

Websites 146

Other sources 147

8.7 R&D research methodology 147

8.8 About Datamonitor 148

About Datamonitor Healthcare 148

Datamonitor Healthcare's research and analysis methodologies 149

8.9 Datamonitor Healthcare's therapy area capabilities 149

About CNS analysis team 150

Datamonitor Healthcare's Consulting expertise 151

Key therapy team members 152

Disclaimer 153

List of Tables

Table 1: Key parameters of psychosis, 2003-2011 10

Table 2: Forecast key pipeline products in psychosis to 2011 ($m) 10

Table 3: Range of 12-month prevalence between regions, 2003 16

Table 4: Adult schizophrenia patient potential in the seven major markets, 2003 17

Table 5: Prevalence of BD between countries, 2003 25

Table 6: Adult prevalence rates of BDI and BDII in the seven major markets, 2003 27

Table 7: Adult prevalence rates of BDI and BDII in the seven major markets using the MDQ prevalence rate, 2003 27

Table 8: Trends in the combined adult prevalence of schizophrenia and BD, 2003-2011 (000s) 32

Table 9: Registered antipsychotics, 2003 50

Table 10: Phase III antipsychotics pipeline, 2003 50

Table 11: Phase II antipsychotics pipeline, 2003 52

Table 12: Phase I antipsychotic pipeline, 2003 53

Table 13: Preclinical MNRA pipeline, 2003 55

Table 14: Preclinical serotonergic antipsychotic pipeline, 2003 56

Table 15: Preclinical dopaminergic antipsychotic pipeline, 2003 57

Table 16: Preclinical novel antipsychotics pipeline, 2003 (originators A-M) 58

Table 17: Preclinical novel antipsychotics pipeline, 2003 (originators N-U) 59

Table 18: Sanofi's marketed CNS portfolio 64

Table 19: Sanofi's antipsychotic pipeline, 2003 65

Table 20: Reformulations of antipsychotic brands, 2003 68

Table 21: MNRAs in late-stage R&D antipsychotic pipeline 75

Table 22: Marketed antipsychotics considered for MNRA gold standard, 2003 75

Table 23: Global sales forecasts for Serdolect, 2003�E1 89

Table 24: Impacting factors on the sales of Serdolect, 2004�E1 90

Table 25: Global sales forecasts for bifeprunox, 2003�E1 94

Table 26: Impacting factors on the sales of bifeprunox, 2005�E1 94

Table 27: Global sales forecasts for Lonasen, 2003�E1 100

Table 28: Impacting factors on the sales of Lonasen, 2004�E1 100

Table 29: Global sales forecasts for MNRAs, 2003�E011 ($m) 107

Table 30: Recently discontinued MNRAs, 2003 107

Table 31: Late-stage dopamine antagonists, 2003 110

Table 32: Marketed antipsychotics considered for dopaminergic gold standard, 2003 110

Table 33: Late-stage R&D pipeline antipsychotics, 2003 115

Table 34: Recently discontinued MNRAs, 2003 124

Table 35: Candidate susceptibility genes for schizophrenia 128

List of Figures

Figure 1: Summary of major antipsychotic market events, 2003-2011 9

Figure 2: Unmet needs in the treatment of psychosis, 2003 33

Figure 3: Zomaril's satisfaction of unmet needs, 2003 82

Figure 4: Serdolect's satisfaction of unmet needs, 2003 88

Figure 5: Bifeprunox's satisfaction of unmet needs, 2003 93

Figure 6: Lonasen's satisfaction of unmet needs, 2003 99

Figure 7: Satisfaction of unmet needs of MNRAs in late-stage development, 2003 104

Figure 8: Datamonitor's Healthcare Consultancy 151

Figure 9: Datamonitor Healthcare's Therapeutic Consulting capabilities 152