Contents:

ABOUT US HEALTHCARE 2 About the Womens Health pharmaceutical analysis team 2 CHAPTER 1 EXECUTIVE SUMMARY 3 Scope of the analysis 3 Contributing experts 3 Our insight into the Endometriosis market 4 Related reports 5 CHAPTER 2 MARKET DYNAMICS 7 Endometriosis market definition 8 Limitations in sizing the endometriosis market with IMS data 9 Current market overview 9 Market size has yet to recover from 2006 fall 9 US market changes have contributed to 7MM market shrink 11 Political changes have boosted sales in Spain 12 POCs are the most common treatment option for endometriosis 13 Lupron remains the most popular GnRH agonist treatment 15 CHAPTER 3 DISEASE OVERVIEW 18 Definition of endometriosis 19 Classification of endometriosis: Re-AFS 20 Etiology of endometriosis: still not well understood 22 Retrograde menstruation and implantation 23 Lymphatic/vascular dissemination 23 Developmental coelomic metaplasia 24 Genetic predisposition 24 Environmental factors 25 Immunological susceptibility 25 Dynamic progression of endometriosis 26 Recurrence in endometriosis 27 Symptoms of endometriosis 27 Epidemiology of endometriosis 29 Socio-demographic contributors to endometriosis prevalence 29 Limitations of endometriosis epidemiology analysis 30 Factors specific to endometriosis: 30 Factors generalized to all epidemiology analysis: 32 The gold standard endometriosis epidemiology study 32 Prevalence estimates: the general versus gynecologic population 33 Prevalence of endometriosis in the general population is assumed to be 10% 35 Prevalence of endometriosis in the gynecologic population may be more representational 35 Unmet need in endometriosis 42 Understanding the etiology of endometriosis will aid the development of prophylactic and specific treatments 43 Non-invasive diagnostic procedures will lower morbidity 45 Physician education will quicken time to diagnosis 46 Patient education promotes treatment seeking 47 Better pain management concepts will help women cope 47 CHAPTER 4 TREATMENT TRENDS 49 Endometriosis patient diagnosis and referral algorithm 50 Under-diagnosed and over treated 50 Treatment of endometriosis 51 Combined oral contraceptives: first-line therapy 53 Short term efficacy is similar to that of GnRH agonists 53 Progestogen treatments are most commonly used therapy 55 Antiprogestogen use is limited to gestrinone 56 Androgens: Danazol-first treatment indicated for endometriosis 57 Efficacious for pain relief 58 Side effects limit usefulness of product 59 Danazol remains useful for niche patients 60 GnRH agonists: short-term efficacy at the expense of side effects 61 Characteristics of successfully marketed GnRH agonists 62 Lupron: the gold standard 64 Lupron with add-back makes side effects more manageable 66 Surgery for severe and non-responsive endometriosis 68 Laparoscopic surgery: a range of techniques can reduce pain 68 Hysterectomy: the last treatment option 69 Patient treatment goals 69 Pain reduction 70 Pregnancy 71 CHAPTER 5 RESEARCH AND DEVELOPMENT 73 The ideal drug for the treatment of endometriosis 74 Efficacy must prevent recurrence 74 Safety essential in a young patient population 75 Side-effects profile must be improve compliance 75 Cost must be kept low for long-term use 76 Pipeline overview 77 Considerable variety in mechanism, delivery mode, and manufacturer 77 Large pipeline is beginning to mature 79 New methods of drug delivery attempt to fulfill unmet need 80 Nasal administration may be hindered by unwelcome irritation 81 Vaginal route unpopular in conservative patient population 81 Late-stage products offer some hope to patients 82 Visanne progestogen could benefit from specific endometriosis label 82 Balance will need marketing partner to realize Libras full potential 84 FP-1096 benefits from a novel drug delivery technique 85 Mechanisms of action of pipeline products 86 Aromatase inhibitors may offer long-term remission 88 Chemokine receptor antagonists center on inflammatory and immune response 88 Immunomodulators are still regarded warily 89 Combination products will not radically alter treatment 89 Promising estrogen receptor beta agonists require more research 90 GnRH antagonists have important advantages over agonists 91 Progestogen agonists are as effective as marketed therapies 93 Selective progestogen receptor modulators 94 Clinical trial design in endometriosis 95 Difficulties inherent in clinical trials of endometriosis therapies 95 Patient recruitment must be carefully considered 97 Endpoints in clinical trial design 98 Arguably pain is the endpoint of most relevance to the patient 98 That lesion size should be a secondary endpoint is a contentious issue 99 Quality of life scale expands on the endpoint of pain 100 CHAPTER 6 CURRENT MARKET ISSUES 102 Raising the profile of endometriosis 103 Breaking the taboo 103 Raising awareness: lessons from other disease areas 104 The EEA takes the lead in lobbying in Europe 105 Current issues in diagnosis of endometriosis 107 Biomolecular and genetic diagnostics are desirable but not trusted 108 Current research 108 CA-125 testing has had a mixed response 109 Imaging diagnostics currently offer the most promise 111 The endometriosis indication 112 Physicians find specific labeling increasingly useful 114 The potential of endometriosis as a secondary indication 114 Uterine fibroids 115 Menorrhagia (excessive bleeding) 116 BIBLIOGRAPHY 117 Journal papers 117 Websites 127 APPENDIX 130 IMS data 130 Medical sales data caveats 130 Medical sales data methodology 130 Contributing experts 131 About Our 131 About Our Healthcare 131 Our Healthcares therapy area capabilities 132 About the Disease analysis team 133 Disclaimer 134 List of Tables Table 1: ICD-10 codes used to define the endometriosis market 8 Table 2: Frequency and location of endometriosis implants in the pelvis 20 Table 3: Frequency of symptoms among surgically diagnosed endometriosis patients, 2007 28 Table 4: Common symptoms of endometriosis and other conditions 29 Table 5: Epidemiology overview of endometriosis, 2007 34 Table 6: Endometriosis prevalence in the 7MM general population, 2007 35 Table 7: Endometriosis prevalence in the CPP (gynecological) population, 2007 37 Table 8: Endometriosis prevalence in the infertile (gynecologic) population across the seven major markets, 2007 41 Table 9: Summary of endometriosis treatment with danazol 58 Table 10: Endometriosis-specific sales of GnRH agonists in the seven major markets combined, by molecule, 2006-07 62 Table 11: Cost of select GnRH agonists in the UK, 2007 63 Table 12: Lupron product range, 2007 64 Table 13: Overview of the endometriosis pipeline, 2007 77 Table 14: Mechanism of action of the drugs in the endometriosis pipeline, 2007 87 Table 15: Action taken by the European Endometriosis Alliance in H1, 2007 106 List of Figures Figure 1: The seven major endometriosis markets by country, 2003-07 10 Figure 2: The five major European (EU) endometriosis markets. 2003-07. 11 Figure 3: Seven major endometriosis market size, split by region, 2003--07 12 Figure 4: Volume sales of products within endometriosis treatment types in the seven major markets combined, 2007 14 Figure 5: Market share and market growth of key GnRH agonists in the seven major endometriosis markets, 2006-07 16 Figure 6: Prevalence of CPP and endometriosis in the female population and prevalence of endometriosis in the CPP population (000s), 2007 38 Figure 7: Causes of infertility for US couples undergoing assisted reproductive technology using fresh, non-donor eggs or embryos, 2004 40 Figure 8: Prevalence of infertility and endometriosis in the female population and prevalence of endometriosis in the infertile population (000s), 2007 42 Figure 9: Unmet needs in endometriosis as identified by key opinion leaders, 2007 43 Figure 10: Patient diagnosis referral pathway in endometriosis, according to key opinion leaders, 2007 51 Figure 11: Side-effect versus efficacy profile of key treatments on the endometriosis market according to interviewed EU and US opinion leaders, 2007 52 Figure 12: An endometriosis patient treatment pathway dependent on treatment goal 70 Figure 13: Frequency of products in the pipeline, by development stage, 2007 79 Figure 14: Breakdown of pipeline products by delivery method, where known, in 2007 80

Companies Mentioned

Abbott Laboratories AEA Technology plc. Aftermarket Technology Corp. Alliance Imaging Inc Ameriana Bancorp AstraZeneca PLC CDC SPA Columbia Laboratories Inc Community Banks Incorporation Cramer Systems Ltd Davis Service Group PLC, The GraceKennedy Ltd IMS Health Insight Communications Company, Inc. Ipsen Merck & Co., Inc. Mochida Pharmaceutical Co., Ltd. Pfizer Inc Repros Therapeutics Inc. Sanofi-Aventis TAP Pharmaceutical Products, Inc. Wyeth