Commercial and Pipeline Insight: HRT for Menopausal Symptoms – A new class restores an old market

ABOUT DATAMONITOR HEALTHCARE 2

About the Urology and Gender-specific Health pharmaceutical analysis team 2

CHAPTER 1 EXECUTIVE SUMMARY 3

Objective of the analysis 3

Datamonitor insight into the hormone replacement therapy (HRT) market 3

Contributing experts 4

Related reports 6

Upcoming related reports 6

CHAPTER 2 MARKET DEFINITION AND OVERVIEW 8

Market definition for this report 9

ATC classes 9

ICD-10 codes 9

IMS sales data 9

Research and development 10

Strategic scoping and focus 10

Disease overview 11

Symptoms of the menopause 12

The impact of symptoms on quality of life 15

The impact of symptoms and treatment seeking 15

Premature ovarian failure 16

Surgically induced and medical menopause 16

Identifying the target population 17

Over 166 million women in the 7MM are peri- or postmenopausal 18

Approximately 115 million women in the 7MM will experience menopausal symptoms 18

Over 68 million women will seek treatment for menopausal symptoms in the 7MM 19

Premature ovarian failure affects over 1 million women in the 7MM 21

Treatment options 21

Treatment guidelines 22

US - AACE menopause guidelines 22

EU - MHRA guidelines 23

Contraindications to HRT 24

Estrogen only preparations 24

Estrogen and progestogen preparations 26

Topical sex hormones 28

CHAPTER 3 GLOBAL MARKET ASSESSMENT 30

Current market situation 31

WHI-induced market decline stabilizes at $1.5 billion in 2007 31

Despite an increase in market value from 2006-07, volume sales continued to fall 32

Small price increases lessen the impact of falling volume sales 33

US market sales account for 85% of the total 7MM revenue 34

Germany is the largest and most robust of the EU markets 35

Majority of the seven major markets show growth in 2007 36

Spanish market leads the way in recuperating losses 37

Estrogen only preparations generate highest revenue 37

Wyeth products still hold the first and second market position 38

2006-07 sales performance of the top 10 HRT brands for menopausal symptoms 39

2006-07 sales performance of the top 10 HRT brands for menopausal symptoms, by class 40

Market opportunity and threats 42

Opportunities 43

An ageing and changing population structure grows the treatable population 43

New variety in market will facilitate shift in treatment paradigms 45

Threats 47

Competition from non-hormonal treatments for menopause 47

The boom of the so-called 'bio-identical' hormone market 49

Poor dissemination of subsequent HRT research by the media 50

Unmet need in the HRT market 53

New mechanism of actions could revolutionize HRT 54

Raising the profile of HRT will expand the treatable population 56

Physician education across specialties will standardize knowledge 57

A measure of dose suitability will facilitate individualized therapy 58

CHAPTER 4 R&D PIPELINE OVERVIEW AND CLINICAL TRIAL DESIGN 61

Pipeline overview: old lifecycle management strategies give way to fundamental changes 62

Aprela's launch will begin the restoration of the market 63

Companies unwilling to invest heavily in HRT research and development 63

Bayer Schering aims to maintain its position in Women's Health 64

Brand loyalty created by commitment to market will overcome pipeline weakness 65

Short-term pipeline strategies have already been exploited 66

Products with an alternative delivery method are limited to a patient subset 66

Low-dose reformulation was an essential yet unsustainable strategy 67

Novel mechanisms of action could radically alter the HRT market 68

Head-to-head trials will help new compounds to reach their full potential 70

The first drug to market: Divigel (estradiol) 71

Forecasts to 2017 71

Divigel: capable of a competitive price point 72

Out-licensing is a key strategy for Orion 73

Patient share will depend on exact labeling approved in Japan 74

Clinical trial design in HRT research 75

FDA revised guidelines 75

Estrogen only drugs 75

Estrogen plus progestogen drugs 76

European Medicine Agency guidelines 78

Efficacy: treatment of symptoms related to estrogen deficiency 78

Safety: endometrial safety 79

Secondary safety endpoints 79

CHAPTER 5 ESTROGEN AGONISTS LATE STAGE DRUG ANALYSIS & FORECASTS 81

Overview for the estrogen agonists 82

Comparative forecasts 82

Comparative Datamonitor drug assessment summary 83

Current comparator therapy: Premarin 84

Premarin, Prempro and the WHI study 86

The damning results of the WHI - HRT linked to serious cardiovascular events and cancer 87

HRT use fell substantially as a result 87

Methodological inaccuracies in the WHI since revealed 88

Key clinical trials: the HOPE study 90

Effects on vasomotor symptoms 90

Efficacy on vulvar and vaginal atrophy 91

Effect on bone mineral density 91

Marketing and patient factors 91

Evamist (estradiol) 94

Drug overview 94

Forecasts to 2017 95

Datamonitor drug assessment 95

Patient potential 96

Marketing factors 97

Evamist will benefit from specialist manufacturers throughout development 97

Clinical trials 98

Aprela (estradiol, bazedoxifene) 99

Drug overview 99

Forecasts to 2017 99

Datamonitor drug assessment 100

Patient potential 101

SERMs and TSECs could revolutionize treatment of menopausal symptoms 101

Marketing factors 102

Large gains to be made if pathway to approval can be smoothed 102

Clinical trial data 104

Clinical trial 1 104

Clinical trial 2 105

MF-101 (estradiol) 105

Drug overview 105

Forecasts to 2017 107

Datamonitor drug assessment 108

Patient potential 108

New mechanism of action stirs excitement over potentially improved safety 108

Marketing factors 109

Bionovo's portfolio will strengthen in the long term 109

Clinical trial data 110

232802 111

Drug overview 111

Marketing and patient factors 111

GSK branches into Women's Health 111

Clinical trial data 112

Phase II trial methodology 112

CHAPTER 6 ESTROGEN AND PROGESTOGEN AGONISTS LATE STAGE DRUG ANALYSIS & FORECASTS 114

Overview for the estrogen and progestogen agonists 115

Comparative forecasts 115

Comparative Datamonitor drug assessment summary 116

Definition of current comparator therapy: Prempro 116

Prempro's key clinical trials 119

The WHI findings 119

Key clinical trials: the HOPE study 120

Effects on vasomotor symptoms 120

Effects on vulvar and vaginal atrophy 120

Effects on the endometrium 120

Effects on bone mineral density 121

Marketing and patient factors 122

Angeliq low-low (ethinyl estradiol, drospirenone) 122

Drug overview 122

Forecasts to 2017 122

Datamonitor drug assessment 123

Patient potential 124

Marketing factors 125

Strong marketing support cannot help if patients are refractory to treatment 125

CHAPTER 7 FORECAST ANALYSIS 126

Key events 126

New product launches in the 7MM 127

Evamist: chosen launch market has most latent potential 128

Angeliq low-low: useful strategy to combat Angeliq generics 128

Aprela: strong uptake in time 129

MF-101: battling Aprela in the US 130

Patent expiries in the 7MM 130

FemHRT (ethinyl estradiol, norethindrone acetate) 132

Activelle (estradiol, norethindrone acetate) 132

Estalis (estradiol, norethisterone acetate) 133

Prempro (CEE, medroxyprogesterone acetate) 133

Angeliq (estradiol, drospirenone) 134

Prices and pricing assumptions 134

Product positioning 135

Datamonitor's pipeline drug assessment model 135

BIBLIOGRAPHY 137

Journal papers 137

Websites 140

APPENDIX 145

Contributing experts 145

Report methodology 145

Datamonitor's drug assessment summary 145

Data definitions, limitations and assumptions 147

Standard Units 147

Estimated 2007 sales revenue 147

HRT for menopause specific sales calculations 147

Derivation of sales forecasts and pricing trends 148

Estimation of launch dates 148

Forecasts 148

Japanese Market Data 148

About Datamonitor 149

About Datamonitor Healthcare 149

About the Gender-specific Health analysis team 150

Disclaimer 151

List of Tables

Table 1: Frequency of menopausal symptoms in a sample of women aged 40-55 years old, by menopausal transition phase 14

Table 2: The potential treatable population for menopausal symptoms, in the 7MM, 2008? 18

Table 3: The number of women who experience menopausal symptoms in the menopausal transition period, in the 7MM, 2008 19

Table 4: The number of women seeking treatment for menopausal symptoms, in the 7MM, 2008 20

Table 5: Number of women in the 7MM with POF, 2008 21

Table 6: The top 10 products, by 2007 sales, in the 7MM HRT market 22

Table 7: Sales of estrogen only preparations used for the treatment of menopausal symptoms in the 7MM, 2007 26

Table 8: Sales of estrogen and progestogen preparations of HRT used for the treatment of menopausal symptoms in the 7MM, 2007 28

Table 9: Sales of topical sex hormones used for the treatment of menopausal symptoms in the 7MM, 2007 29

Table 10: Summary of key opportunities and threats in the HRT market across the 7MM, 2007 43

Table 11: Novel non-hormonal agents in development for the potential treatment of menopausal symptoms, 2008 48

Table 12: Pipeline products in development as HRT for menopausal symptoms, 2008 62

Table 13: Bayer Schering's brand revenue from the HRT market for menopausal symptoms (excluding osteoporosis), 2007 65

Table 14: Key estrogen agonist products in late-stage R&D pipeline for the treatment of menopausal symptoms, 2008 82

Table 15: Premarin: key facts 86

Table 16: Key estrogen and progestogen agonist products in late-stage R&D pipeline for the treatment of menopausal symptoms, 2008 115

Table 17: Prempro: key facts 119

Table 18: Datamonitor's launch dates for HRT products in the US, 5EU and Japanese market, 2008-2017 127

Table 19: Expiry dates for HRT products in the US, 5EU and Japanese market, 2008-2017 131

Table 20: Datamonitor's prices per standard unit and pricing assumptions of the forecast pipeline products, 2008 135

Table 21: Datamonitor's 'research and clinical' drug assessment parameters 146

Table 22: Datamonitor's 'commerical drug assessment parameters 146

Table 23: Estimation of launch dates by phase of development 148

List of Figures

Figure 1: The menopausal transition 12

Figure 2: Frequency of menopausal symptoms in a sample of women aged 40-55 years old 13

Figure 3: Number of women in the 7MM menopausal symptoms treatment pathway, 2008 17

Figure 4: Value of the HRT for menopausal symptoms market in the 7MM, 2003-07 31

Figure 5: Volume sales of HRT products by class in the 7MM combined, 2003-07 32

Figure 6: Value sales of HRT products, by class, in the 7MM combined, 2003-07 34

Figure 7: Value of the HRT for menopausal symptoms market in the 5EU and Japan, 2003-07f 35

Figure 8: Year-on-year growth for HRT for menopausal symptoms in the 7MM, 2003-07f for 36

Figure 9: Market share and market growth of the HRT markets in the 7MM, 2006-07 37

Figure 10: Sales of HRT products for menopausal symptoms by class in the 7MM, 2007 38

Figure 11: Sales performance of the top 10 HRT brands for menopausal symptoms in the 7MM, 2006--07 39

Figure 12: Sales performance of key estrogen only (G3E) HRT brands in the 7MM, 2006-07 40

Figure 13: Sales performance of key estrogen and progestogen (G3F) HRT brands in the 7MM, 2006--07 41

Figure 14: Sales performance of key topical sex hormone (G2F) HRT brands in the 7MM, 2006--07 42

Figure 15: Number of women (million) aged 45 years and above in the 7MM, 2007 and 2017 44

Figure 16: The potential threat of new mechanisms of action on the existing HRT market 49

Figure 17: Google trend analysis of media coverage of 'WHI' from 2005-08. 51

Figure 18: Unmet need in the HRT market according to opinion leaders, 2008 54

Figure 19: Drugs in the HRT development pipeline by stage, 2008 63

Figure 20: Drugs in the HRT development pipeline by mechanism of action, 2008 69

Figure 21: Datamonitor's forecast of sales for Divigel in Japan 2007f-2017 72

Figure 22: Datamonitor's sales forecast for estrogen agonists for the treatment of menopausal symptoms across the 7MM, 2007-2017 83

Figure 23: Datamonitor's competitive positioning analysis for Premarin, Aprela, MF-101 and Evamist in the 7MM, 2008-2017 84

Figure 24: The Wyeth Prem Range, 2008 92

Figure 25: Total promotional spend for the Prem range in the US, 1999-2006 93

Figure 26: Datamonitor's sales forecast of Evamist across the 7MM($m), 2007-2017 95

Figure 27: Datamonitor's competitive positioning analysis for Evamist, relative to Premarin in the 7MM, 2008-2017 96

Figure 28: Datamonitor's forecast of sales for Aprela across the 7MM 7MM($m), 2007-2017 100

Figure 29: Datamonitor's competitive positioning analysis for Aprela, relative to Premarin in the 7MM, 2008-2017 101

Figure 30: Datamonitor's forecast of sales for MF-101 across the 7MM ($m), 2007-2017 107

Figure 31: Datamonitor's competitive positioning analysis for MF-101, relative to Premarin in the 7MM7MM, 2008-2017 108

Figure 32: Datamonitor's comparative forecast of sales for the estrogen and progestogen agonists for the treatment of menopausal symptoms across the 7MM ($m), 2007-2017 115

Figure 33: Datamonitor's competitive positioning analysis for Prempro, and Angeliq low-low in the 7MM, 2008-2017 116

Figure 34: Volume and values sales of Prempro in the 7MM, 2003-07 118

Figure 35: Datamonitor's forecast of sales for Angeliq low-low across the 7MM ($m), 2007-2017 123

Figure 36: Datamonitor's competitive positioning analysis for Angeliq low-low, relative to Prempro, in the seven major markets, 2008-2017 124

Figure 37: Impact of key events on the HRT market for menopausal symptoms, 2008-2017 126

Figure 38: Datamonitor's pipeline assessment model for forecast products in the HRT for menopausal symptoms market, 2008 136

</p>>!!