Contents:

ABOUT US 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 Aprelas 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 Womens 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 Bionovos 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 Womens 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 Prempros 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 Our pipeline drug assessment model 135 BIBLIOGRAPHY 137 Journal papers 137 Websites 140 APPENDIX 145 Contributing experts 145 Report methodology 145 Our 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 Scherings 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: Datamonitors 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: Datamonitors prices per standard unit and pricing assumptions of the forecast pipeline products, 2008 135 Table 21: Datamonitors research and clinical drug assessment parameters 146 Table 22: Datamonitors 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: Datamonitors forecast of sales for Divigel in Japan 2007f-2017 72 Figure 22: Datamonitors sales forecast for estrogen agonists for the treatment of menopausal symptoms across the 7MM, 2007-2017 83 Figure 23: Datamonitors 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: Datamonitors sales forecast of Evamist across the 7MM($m), 2007-2017 95 Figure 27: Datamonitors competitive positioning analysis for Evamist, relative to Premarin in the 7MM, 2008-2017 96 Figure 28: Datamonitors forecast of sales for Aprela across the 7MM 7MM($m), 2007-2017 100 Figure 29: Datamonitors competitive positioning analysis for Aprela, relative to Premarin in the 7MM, 2008-2017 101 Figure 30: Datamonitors forecast of sales for MF-101 across the 7MM ($m), 2007-2017 107 Figure 31: Datamonitors competitive positioning analysis for MF-101, relative to Premarin in the 7MM7MM, 2008-2017 108 Figure 32: Datamonitors comparative forecast of sales for the estrogen and progestogen agonists for the treatment of menopausal symptoms across the 7MM ($m), 2007-2017 115 Figure 33: Datamonitors competitive positioning analysis for Prempro, and Angeliq low-low in the 7MM, 2008-2017 116 Figure 34: Volume and values sales of Prempro in the 7MM, 2003-07 118 Figure 35: Datamonitors forecast of sales for Angeliq low-low across the 7MM ($m), 2007-2017 123 Figure 36: Datamonitors 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: Datamonitors pipeline assessment model for forecast products in the HRT for menopausal symptoms market, 2008 136