CHAPTER 1 EXECUTIVE SUMMARY

3

Scope of the analysis

3

Datamonitor insight into the depression market

5

Summary

5

Key metrics

6

Datamonitor Pipeline Assessment Summary

7

CHAPTER 2 PIPELINE OVERVIEW AND DYNAMICS

23

Pipeline overview

24

Pipeline drugs in pre-registration and registration

25

Pipeline drugs in Phase III clinical development

26

Pipeline drugs in Phase II clinical development

27

Discontinued and suspended projects

28

CP-316311 and CP-122721

28

Aprepitant and L-759274

28

Dilopetine

28

MN-305

28

OPC-14523

29

Radafaxine

29

Key companies involved in the depression pipeline

29

GSK

29

Paxil

30

Wellbutrin

30

GSK will hope that pipeline drugs fill the gap left by Paxil's decline

31

Sanofi-Aventis

32

Key R&D company strategies

33

Reformulation strategies

33

Drug delivery reformulations

33

Chemical reformulation

35

Secondary indications

36

Datamonitor's gold standard MDD drug

37

Paxil chosen due to its frequent incorporation into clinical trial designs

37

CHAPTER 3 DEPRESSION - MARKET POTENTIAL

39

Definition of depression

40

DSM-IV

40

ICD-10

41

Segmentation of MDD

42

Elderly MDD

42

Child and adolescent MDD

43

Epidemiology of depression

45

MDD prevalence in the major markets

45

12-month prevalence rate of 6.6% in the US

45

12-month prevalence rate of 6.7% across Europe

46

Substantially lower prevalence rate in Japan than in the US or Europe

46

Age group variance in MDD prevalence rate

46

Diagnosis and treatment

46

Current classes used in depression treatment

47

MAOIs and TCAs-effective but side effects and safety are a concern

47

SSRIs retain the efficacy of MAOIs and TCAs but with more favorable side-effect and safety profiles

49

SNRIs have added to the treatment options, but are generally not used first-line

50

Treatment algorithms for MDD

51

Co-morbid disorders

52

More than half of MDD sufferers also suffer from anxiety

52

Unmet needs in depression

54

Faster onset of action

55

Side effects

56

Patient compliance

57

Efficacy

57

Efficacy may be low for first monotherapy, but improves at second-line

57

Efficacy similar between currently available antidepressants

58

Better combinations

59

CHAPTER 4 R&D APPROACH

60

Classification of pipeline products

61

Datamonitor's classification of pipeline products

61

SNRIs

61

Triple reuptake inhibitors

61

NK receptor antagonists

61

Serotonin receptor ligands

62

Other therapies

63

Clinical trial design in depression

63

Patient population

63

Placebo effect

63

Clinical trial endpoints in depression

64

Hamilton Rating Scale for Depression

64

Hamilton Rating Scale for Anxiety

65

Montgomery-Asberg Depression Rating Scale

65

Clinical Global Impression Scale

65

The Beck Depression Rating Scale

66

The Zung Self-Rating Depression Scale

66

Brief Psychiatric Rating Scale

66

CHAPTER 5 SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS LATE-STAGE DRUG ANALYSIS AND FORECASTS

67

Overview for SNRIs

68

Pipeline summary

68

Definition of current comparator therapy

68

Effexor XR (venlafaxine extended release)

68

Desvenlafaxine (Pristiq)

70

Profile

70

Drug overview: metabolite of the blockbuster Effexor

70

Clinical trial data

71

Efficacy and safety of Pristiq in the treatment of MDD

71

Randomized, double-blind, placebo-controlled study of desvenlafaxine succinate in MDD

72

Adverse events in the two desvenlafaxine Phase III studies

73

Double-blind, placebo- and moxifloxacin-controlled crossover study of the effects of desvenlafaxine succinate on QT interval in healthy adult female subjects

73

Ongoing clinical trials investigating the efficacy of desvenlafaxine as a treatment of MDD

74

Preclinical

74

Patient potential

75

Marketing factors

78

Satisfaction of unmet needs

80

Forecasts to 2016

81

Generic Effexor XR launch

82

Switching from Effexor XR to Pristiq in the estimated two years before the launch of generics

83

Datamonitor drug assessment summary

84

CHAPTER 6 TRIPLE REUPTAKE INHIBITORS (SEROTONIN/NOREPINEPHRINE/DOPAMINE) LATE-STAGE DRUG ANALYSIS AND FORECASTS

85

Overview for triple reuptake inhibitors

86

Pipeline summary

86

Triple reuptake inhibitors are designed to inhibit the reuptake of serotonin, norepinephrine and dopamine

86

Studies investigating triple reuptake inhibition with two separate compounds

87

Definition of current comparator therapy

88

Effexor XR

88

DOV-216 303

88

Profile

88

Drug overview : DOV-216,303 has a complicated licensing history

88

Clinical trial data

88

Phase II clinical trial

89

Phase 1b clinical trial

89

Phase 1a clinical trial

90

Preclinical studies

91

Datamonitor comments

91

NS-2359 (GSK372475)

94

Profile

94

Drug overview: triple reuptake inhibitor under development by GSK

94

Ongoing clinical trials

95

Datamonitor comments

95

CHAPTER 7 NK RECEPTOR ANTAGONISTS LATE-STAGE DRUG ANALYSIS AND FORECASTS

96

Overview for NK receptor antagonists

97

Pipeline summary

97

Lack of efficacy of the NK1 receptor antagonist aprepitant in the treatment of MDD

97

Definition of current comparator therapy

99

Saredutant

99

Profile

99

Drug overview: NK2 receptor antagonist

99

Clinical trials data

99

Phase IIb clinical trial data

99

Preclinical data

100

Ongoing clinical trial program for saredutant in MDD

101

Patient potential

102

Room for an alternative mode of action in the depression market

102

Possible indication expansion into anxiety and pain

102

Marketing factors

103

Sanofi-Aventis has a broad experience of marketing drugs to psychiatrists

103

Satisfaction of unmet needs

104

Speed of onset of action

104

Side effects

104

Patient compliance

105

Better combinations

105

Forecasts to 2016

106

Saredutant could gain market share from current third-line therapies

107

Datamonitor drug assessment summary

108

Other NK receptor modulators in development

109

Casopitant

109

Vestipitant + paroxetine

109

CHAPTER 8 SEROTONIN RECEPTOR LIGANDS LATE-STAGE DRUG ANALYSIS AND FORECASTS

110

Overview for serotonin receptor ligands

111

Pipeline summary

111

Definition of current comparator therapy

111

Gepirone ER

111

Profile

111

Drug overview: resubmission likely six years following original submission

111

Regulatory submissions

112

Clinical trial data

113

Relapse prevention with gepirone ER in outpatients with MDD

113

Retrospective subgroup analysis in patients with MDD

114

Sustained efficacy of gepirone-IR in MDD: a double-blind placebo substitution trial

115

Relapse prevention with gepirone ER in outpatients with MDD

116

Effect of gepirone ER on sexual function in patients with MDD

117

Gepirone ER in patients with anxious depression

118

Effects of gepirone ER on depression with anxiety symptoms: a double-blind, placebo-controlled study

118

Gepirone ER: new evidence for efficacy in the treatment of MDD

119

Phase II relapse prevention during long-term gepirone IR therapy for MDD: a double-blind substitution trial

120

Patient potential

121

Marketing factors

122

Satisfaction of unmet needs

123

Faster onset of action

123

Side effects

123

Patient compliance

124

Efficacy

124

Better combinations

124

Forecasts to 2016

125

Gepirone ER will gain market share from third-line therapies in the US and EU

126

Datamonitor drug assessment summary

128

Quetiapine (Seroquel SR)

129

Profile

129

Drug overview: atypical antipsychotic

129

Clinical trial data

130

BOLDER I-A randomized, double-blind, placebo-controlled trial of Seroquel (quetiapine) in the treatment of bipolar I or II depression.

130

BOLDER II-Efficacy of Seroquel (quetiapine) monotherapy in bipolar depression: A confirmatory double-blind, placebo-controlled study

131

Ongoing clinical trial program for Seroquel SR in MDD

132

Current state of development

132

Vilazodone

134

Profile

134

Drug overview: targeting niche sub-population of MDD sufferers

134

Genetically guided antidepressant

135

Clinical trial data

135

Phase III program

135

Preclinical

135

Ongoing clinical trial program

136

Current state of development

136

Other Serotonin receptor ligands

137

Elzasonan

137

F-2695

137

CHAPTER 9 OTHER THERAPIES LATE-STAGE DRUG ANALYSIS AND FORECASTS

138

Overview for other therapies

139

Pipeline summary

139

Definition of current comparator therapy

140

Agomelatine

140

Profile

140

Drug overview: the first melatonergic antidepressant

140

Failed European submission by Servier

140

US filing by Novartis

141

Clinical trial data

141

Placebo-controlled trial of agomelatine in the treatment of MDD presented at the 13th Congress of the Association of European Psychiatrists (April 2005).

141

Placebo-controlled trial of agomelatine in the treatment of MDD

142

Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with Paxil: a randomized, double-blind, placebo-controlled discontinuation study.

143

Double-blind pilot study comparing the therapeutic effect of two doses of agomelatine in the treatment of MDD

144

Determination of the dose of agomelatine, a melatonergic agonist and selective 5-HT2C antagonist, in the treatment of MDD: a placebo-controlled dose range study.

145

Melatonin and agomelatine increase REM sleep and wake-up propensity without modifying NREM sleep homeostasis.

146

Ongoing clinical trials

146

Patient potential

147

Marketing factors

149

Satisfaction of unmet needs

149

Faster onset of action

149

Side effects

150

Patient compliance

150

Efficacy

150

Better combinations

150

Forecasts to 2016

151

Significant market share gained from hypnotics currently prescribed for depression

152

Datamonitor drug assessment summary

153

Nemifitide

154

Profile

154

Clinical trial data

154

Double-blind, placebo-controlled study of nemifitide in the treatment of outpatients with MDD

154

Phase IIc open-label extension study

155

Phase IIa - A double-blind, placebo-controlled, efficacy, safety, and pharmacokinetic study of nemifitide, a novel antidepressant peptide, in the treatment of major depression

156

Clinical pharmacokinetic studies with INN 00835 (nemifitide), a novel pentapeptide antidepressant

157

Preclinical

158

Patient potential

159

Marketing factors

160

Satisfaction of unmet needs

161

Faster onset of action

161

Side effects

161

Patients compliance

161

Efficacy

161

Better combinations

162

Forecasts to 2016

162

Uptake is slow and market share gain limited due to route of administration

163

Datamonitor drug assessment summary

164

Corlux (mifepristone)

165

Profile

165

Drug overview: specifically targeting psychotic depression

165

Clinical trial data

166

Corcept 09

166

Corcept 07

166

Corcept 03 - Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression

167

Corcept 02 - Clinical and biological effects of mifepristone treatment for psychotic depression

168

An eight-week open-label trial of a six-day course of mifepristone for the treatment of psychotic depression

168

An open-label trial of C-1073 (mifepristone) for psychotic major depression

169

Rapid reversal of psychotic depression using mifepristone

170

Ongoing clinical trial program for mifepristone in MDD

170

Amibegron

172

Profile

172

Drug overview: beta-3 adrenergic receptor agonist

172

Clinical trial data

172

Phase III European study in patients with a recurrent major depressive episode (EFC 5374)

172

EFC 5379 - Non-conclusive result from North American study

174

Ongoing clinical trial program for amibegron in MDD

174

Other novel therapies in clinical development

176

Miraxion (LAX-101)

176

BMS-562086

176

TRIDMAC

177

Clinical trial data

177

Org 24448

178

Org 34517

179

Ongoing clinical trials

180

SSR149415

180

Ongoing clinical trials

181

YKP10A

181

Phase II study

181

Phase I

182

CHAPTER 10 INNOVATIVE EARLY-STAGE PROJECTS

183

Key Phase I and preclinical compounds in MDD

184

Key Phase I compounds in depression

185

TC-2216

185

How are NNRs and depression linked?

185

Preclinical and clinical development of TC-2216

186

SEP-225289

187

BIBLIOGRAPHY

189

Journals

189

Websites

197

APPENDIX A

201

Methodology

201

Datamonitor forecast methodology

201

ICD-10 codes used to define current depression market

201

Estimated 2006 sales revenue

202

MDD specific sales calculations

202

Product forecasts

202

Definition of a standard unit

202

Japanese market data

203

Datamonitor drug assessment summary

203

Report methodology

203

APPENDIX B

204

About Datamonitor

204

About Datamonitor Healthcare

204

Datamonitor Healthcare's therapy area capabilities

205

Disclaimer

206

List of Tables

Table 1: Datamonitor's forecast MDD revenues of key pipeline drugs and the total MDD market across the seven major markets ($m), 2008-2016

6

Table 2: Key pipeline drugs in registration and pre-registration for MDD in the seven major markets, 2007

25

Table 3: Key pipeline drugs in Phase III development for MDD in the seven major markets, 2007

26

Table 4: Key pipeline drugs in Phase II development for MDD, 2007

27

Table 5: Prevalence rate and population size for MDD across the seven major markets, 2007

45

Figure 6: Non-cost related unmet needs in MDD, 2007

54

Table 6: Key SNRI class drugs in the late-stage MDD R&D pipeline, 2007

68

Table 7: Estimated key events, approvals and launch dates impacting Pristiq's revenue forecast, 2006-2016

82

Table 8: Key triple reuptake inhibitor class drugs in the late-stage MDD R&D pipeline, 2007

86

Table 9: Key NK receptor antagonist class drugs in the late-stage MDD R&D pipeline, 2007

97

Table 10: Estimated key events, approvals and launch dates impacting saredutant's revenue forecast, 2006-2016

107

Table 11: Key serotonin receptor ligands class drugs in the late-stage MDD R&D pipeline, 2007

111

Table 12: Estimated key events, approvals and launch dates impacting gepirone ER's revenue forecast, 2006-2016

126

Table 13: Key other therapies class drugs in the late-stage MDD R&D pipeline, 2007

139

Table 14: Estimated key events, approvals and launch dates impacting agomelatine's revenue forecast, 2006-2016

152

Table 15: Estimated key events, approvals and launch dates impacting nemifitide's revenue forecast, 2006-2016

163

Table 16: Key pipeline drugs in Phase I development for MDD, 2007

184

Table 17: Key pipeline drugs in preclinical development for MDD, 2007

185

Table 18: Possible roles of neuronal nicotinic receptors

187

Table 19: ICD-10 and DSM-IV codes for MDD

201

List of Figures

Figure 1: Datamonitor's MDD drug assessment summary

7

Figure 2: Drugs in development at each stage of development for MDD, 2007

24

Figure 3: $1.8 billion decrease in GSK's global depression portfolio between 2003 and 2006.

31

Figure 4: Company reported, all-indication global sales revenue for Prozac, 2000-05

34

Figure 5: STAR*D treatment algorithm for depression

52

Figure 7: Effexor (venlafaxine) versus SSRIs

69

Figure 8: Datamonitor's forecast of MDD specific sales for Pristiq across the seven major markets ($m), 2006-2016

81

Figure 9: Datamonitor's competitive positioning analysis for Pristiq in MDD

84

Figure 10: Datamonitor's forecast of MDD specific sales for saredutant across the seven major markets ($m), 2006-2016

106

Figure 11: Datamonitor's competitive positioning analysis for saredutant in MDD

108

Figure 12: Datamonitor's forecast of MDD specific sales for gepirone ER across the seven major markets ($m), 2006-2016

125

Figure 13: Datamonitor's competitive positioning analysis for gepirone in MDD

128

Figure 14: Dose adjustment of Seroquel for different indications.

130

Figure 15: Datamonitor's forecast of MDD specific sales for agomelatine across the seven major markets ($m), 2006-2016

151

Figure 16: Datamonitor's competitive positioning analysis for agomelatine in MDD

153

Figure 17: Datamonitor's forecast of MDD specific sales for nemifitide across the seven major markets ($m), 2006-2016

162

Figure 18: Datamonitor's competitive positioning analysis for nemifitide in MDD

164

Figure 19: Clinical trial path for amibegron MDD trial (EFC5374)

173