REFERENCE CODE GDHC015POA PUBLICAT ION DATE DECEM BER 2013

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1 REFERENCE CODE GDHC015POA PUBLICAT ION DATE DECEM BER 2013 ENDOMETRIOSIS -

2 Executive Summary The table below presents the key metrics for endometriosis therapeutics in the six major pharmaceutical markets covered in this report (US, France, Germany, Italy, Spain, and UK) during the forecast period from For the purposes of this report, the endometriosis market consists of drugs commonly prescribed to patients with a diagnosis of endometriosis confirmed by laparoscopy. While certain classes of drugs commonly used off label namely, combined oral contraceptives (COCs) which contain both an estrogen and a progestin are included in this forecast, others are not. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) and other analgesics are deliberately omitted from this analysis. Endometriosis Therapeutics: Key Metrics in Six Major Markets (6MM), Patient Population 6MM Prevalent population (ages Years) Prevalent population (ages Years) Treated population* 2012 Market Sales US 5EU Total Key Events ( ) Lupron (leuprolide acetate) patent expiry in the US and EU 2014 Elagolix launch in the US and EU Market Sales US 5EU Total Source: GlobalData 5.8 million 8.3 million 1.64 billion 71.1 million 1.71 billion Level of Impact *Excludes patients managed only via NSAIDs or surgery alone. 6MM = US and 5EU (France, Germany, Italy, Spain, and UK) $1.67 billion $68.48 million $1.74 billion Global Endometriosis Therapeutics Market Expected to Decrease at a Compound Annual Growth Rate of 0.19% During GlobalData estimates that the global endometriosis therapeutics market in the 6MM was valued at $1.88 billion in The market was largely dominated by the US, with sales of $1.1 billion. Combined sales in the 5EU were estimated at $137.6m. By 2017, GlobalData forecasts that global sales of endometriosis therapeutics will decrease slowly to $1.66 billion at a Compound Annual Growth Rate (CAGR) of 0.19%. By the end of the forecast period in 2017, GlobalData foresees that market growth will remain driven by the US, with marginal changes in the 5EU share by The patent expiry of Lupron (leuprolide acetate) in 2014 is expected to have a negative effect on this market. However, since it is a sterile injectable drug, GlobalData has tempered the potential effect of this event, as manufacturers may face barriers when attempting to create generic equivalents. The figure below illustrates the global sales for endometriosis therapeutics by region during the forecast period. 2

3 Executive Summary Global Sales for Endometriosis Therapeutics by Region, Source: GlobalData 4% 4% 96% 96% 2012 Total:$1.71bn US 5EU 2017 Total:$1.75bn US 5EU Nonetheless, this waning market will regain momentum upon the expected launch of elagolix, a first-in-class oral gonadotropin-releasing hormone (GnRH) antagonist, in the US and 5EU in Since price is a primary attribute driving therapy choice in this market, new entrants such as elagolix will have little potential to steal share from low-cost therapies such as OCs, NSAIDs, and progestins. Endometriosis Market Plagued by High Unmet Need Patients with endometriosis have significant unmet needs due to the lack of approved treatment options that have both continuous efficacy and a favorable long-term safety profiles. Laparoscopic surgery, either alone or in combination with hormone therapy (HT), is typically the first treatment choice for physicians. However, the methods of treating the condition, have been largely haphazard. As a result, women often undergo numerous rounds of surgery and try several medical approaches before finding relief. Even after finding a suitable solution, patients can expect a high rate of recurrence. The current approved treatment options for endometriosis include GnRH agonists, progestins, and androgens, each of which has its own safety and efficacy limitations. Although the use of GnRH agonists has increased in the past decade, the duration of therapy is typically limited to six months due to hypoestrogenic side effects, such as hot flashes, and significant bone mineral density (BMD) loss. Moreover, these drugs come with hefty price tags, which further stifles their appeal for long-term use. NSAIDs and COCs are commonly prescribed off label for confirmed and suspected cases of endometriosis, although their efficacy in this indication has not been validated via randomized clinical trials. Because of the intrinsic limitations of the currently available therapies, innovative drugs with novel mechanisms of action are required in order to address the unmet needs of endometriosis patients. 3

4 Executive Summary GnRH Antagonists will Replace GnRH Agonists, but Their High Price Will Limit Further Adoption GnRH antagonists dominate the late-stage pipeline for endometriosis therapeutics, with three agents being in Phase II or Phase III (Abott s elagolix, Takeda s relugolix, and Astellas ASP-1707). Elagolix, which is in Phase III, promises to be the first oral GnRH antagonist approved for endometriosis. This class of therapies has several key advantages over the currently marketed GnRH agonists. In terms of safety and tolerability, elagolix avoids the detrimental hypoestrogenic side effects seen with GnRH agonists such as Lupron and Zoladex (goserelin acetate). According to key opinion leaders (KOLs) interviewed by GlobalData, an oral formulation will be a welcome addition to the field because it provides doctors with increased control over dosing and allows for the immediate cessation of therapy, if necessary. Therefore, GlobalData believes that GnRH antagonists will rapidly replace the GnRH agonist market segment. Based on their improved efficacy and safety profile, GnRH antagonists like elagolix are likely to be priced at a premium over GnRH agonists such as Lupron. Due to the low cost of progestins, COC s, and NSAIDs, GlobalData believes that the GnRH antagonists are unlikely to take substantial market share away from these drugs. Like GnRH agonists, GnRH antagonists can only be administered for a short period of time, which will restrict their use to late-line therapy and sicker patients. Until more long-term safety data are gathered, and there is evidence that GnRH agonists can be used safely for a longer treatment duration, GlobalData believes that GnRH antagonists will only serve as follow-up drugs to GnRH agonists. The figure below provides a competitive assessment of the marketed and late-stage pipeline agents in endometriosis therapeutics during the forecast period. Competitive Assessment of Marketed and Late- Stage Pipeline Agents in Endometriosis Therapeutics, Commercial Score 4 2 Lupron ASP-1707 Depo Sub-Q Provera Elagolix TAK-385 COC's 2 Clinical Score 4 Source: GlobalData Opportunity Remains High for Innovative Therapies Since none of the late-stage drug candidates are meant to address the high unmet need in the endometriosis therapeutics market, the management of the disease is not likely to evolve during the forecast period, and opportunities in the market will remain particularly high. Whether it is for safer drugs or drugs that demonstrate efficacy in mild or severe patients through robust clinical trials, the market is crying for new therapies. Ultimately, since all of the marketed, off-label, and pipeline drugs have little impact in curbing the disease progression, a high rate of recurrence is 4

5 Executive Summary expected upon cessation of therapy. Therefore, large opportunities will remain for safe, efficacious therapies that target the root cause of the condition. Non-hormonal strategies, in particular, are promising, including immune modulators, peroxisome proliferator-activated receptor (PPAR) agonists, tumor necrosis factor-alpha (TNF-alpha) inhibitors, and antiangiogenic agents. In conclusion, a much better understanding of the underlying pathology of this condition will be required in order for a novel therapy to achieve considerable success in the endometriosis market. What Do Physicians Think? The consensus among the KOLs interviewed for this report is that endometriosis patients have significant unmet needs due to the lack of safe, efficacious, long-term therapies. Furthermore, significant gaps in the current understanding of the underlying disease pathology were flagged as a hurdle plaguing endometriosis therapy development. Although the KOLs are optimistic about the potential approval of first-in-class therapy, elagolix, they still foresee that unmet needs will persist. One common concern about GnRH antagonist therapy is that it continues to approach the treatment of endometriosis via hormonal pathways. A key limitation is that these drugs do not target the underlying cause of the disease, which means that recurrence is expected to occur once a woman stops therapy. Since endometriosis starts as early as adolescence and can be expected to persist until menopause, any drug that only addresses the symptoms of endometriosis will translate into decades of disease management, rather than resolution of the condition. One key weakness of the hormonal regimens used to treat endometriosis is that they prevent conception. Given the fact that the majority of women who suffer from endometriosis are of childbearing age, there is a considerable unmet need for a novel therapy that allows for continuation of the normal menstrual cycle and provides for the possibility of pregnancy during treatment. Given the estrogen-dependent nature of endometriosis, the current therapies target the condition by disrupting hormonal pathways which play a key role in fertility. Although some novel therapeutic classes that are under development have shown promising efficacy data, many of these approaches have side effects that would contraindicate their use in women looking to conceive. I am sure that GnRH antagonists will be effective. The problem is that women will have recurrences [of endometriosis] once they will discontinue the drug. EU KOL, October 2013 Approaching the disease from an inflammatory standpoint would be an innovative approach that I would be interested in seeing. EU KOL, October

6 Executive Summary We don t know very much about the real mechanism underlying the generation of pain in endometriosis. US KOL, October 2013 The oral formulation of GnRH antagonists will certainly provide advantages over the injectable GnRH agonists. US KOL, October 2013 I believe GnRH antagonists will be yet another class [of drugs] that would be useful in the management of endometriosis. US KOL, October

7 Table of Contents 1 Table of Contents 1 Table of Contents List of Tables List of Figures Introduction Catalyst Related Reports Disease Overview Etiology and Pathophysiology Etiology Pathophysiology Clinical Prognosis Quality of Life Symptoms and Diagnosis Epidemiology Risk Factors and Comorbidities Family history is a strong predictor for the risk of endometriosis Late age at menarche protects women from developing endometriosis Higher parity decreases the risk for endometriosis Global Trends US EU Forecast Methodology Sources Used Sources Not Used Forecast Assumptions and Methods Epidemiological Forecast for Endometriosis ( )

8 Table of Contents Diagnosed Prevalent Cases of Endometriosis Age-Specific Prevalent Cases of Endometriosis Age-Standardized Diagnosed Prevalence of Endometriosis Diagnosed Prevalent Cases of Endometriosis by Stage Discussion Epidemiological Forecast Insight Limitations of the Analysis Strengths of the Analysis Current Treatment Options Overview Product Profiles Major Brands Zoladex (goserelin acetate) Lupron (leuprolide acetate depot) Synarel (nafarelin nasal spray) Visanne (dienogest) Depo-SubQ Provera 104 (medroxyprogesterone injection) Danazol (Danocrine) Off-Label Treatment: Combined Oral Contraceptives, Progestins, and NSAIDs Unmet Needs Assessment and Opportunity Analysis Overview Unmet Needs Analysis Unmet Need: Non-Invasive Diagnostics Unmet Need: Non-Hormonal Therapies Unmet Need: Better Pain Management Unmet Need: Better Understanding of the Disease Pathology to Prevent Recurrence Unmet Need: Identification of Biomarkers Unmet Need: Transparency in Clinical Trials

9 Table of Contents 6.3 Opportunity Analysis Opportunity: Biomarkers Identification Opportunity: Treatment Options for Adolescents Opportunity: Drugs Targeting Pain Pathways Opportunity: Novel Targets Opportunity: Efficacious Treatments Suitable for Long-Term Use Research and Development Strategies Overview The Race for the Development of GnRH Antagonists Alliances and In-Licensing Strategies Maximizing Return-on-Investment by Targeting Secondary indications Clinical Trial Design Overview Defining Efficacy in Endometriosis Clinical Trials Future Trends in Endometriosis Clinical Trial Design Pipeline Assessment Overview Promising Drugs in Development Elagolix (ABT-602) Relugolix (TAK-385) ASP Innovative Early-Stage Approaches Overview Anti-Inflammatory Approaches Cellular Adhesion Angiogenesis Endometriotic Implants Selective Progesterone Receptor Modulators

10 Table of Contents Aromatase Inhibitors Pipeline Valuation Analysis Overview Clinical Benchmarking of Key Pipeline Drugs Commercial Benchmarking of Key Pipeline Drugs Competitive Assessment Top-Line, Five-Year Forecasts Overview US EU Appendix Bibliography Abbreviations Methodology Forecasting Methodology Diagnosed Endometriosis Patients Percent Drug Treated Patients Drugs Included in Each Therapeutic Class Launch and Patent Expiry Dates General Pricing Assumptions Individual Drug Assumptions Generic Erosion Pricing of Pipeline Agents Physicians and Specialists Included in This Study About the Authors Author Epidemiologist

11 Table of Contents Global Director of Epidemiology and Health Policy Global Head of Healthcare About GlobalData Disclaimer

12 Table of Contents 1.1 List of Tables Table 1: ICD-9-CM Codes for Endometriosis and Pelvic Pain Table 2: Stages of Endometriosis Table 3: Symptoms of Endometriosis Table 4: Risk Factors for Endometriosis Table 5: Epidemiological Sources for the Diagnosed Prevalence and Stages of Endometriosis Table 6: 6MM, Diagnosed Prevalent Cases of Endometriosis, Ages Years, N, Table 7: 6MM, Diagnosed Prevalent Cases of Endometriosis, by Age, N, Row (%), Table 8: Leading Branded Treatments for Endometriosis Table 9: Product Profile Zoladex Table 10: SWOT Analysis Zoladex Table 11: Product Profile Lupron Table 12: SWOT Analysis Lupron Table 13: Product Profile Synarel Table 14: SWOT Analysis Synarel Table 15: Product Profile Visanne Table 16: SWOT Analysis Visanne Table 17: Product Profile Depo-SubQ Provera Table 18: SWOT Analysis Depo-SubQ Provera Table 19: Product Profile Danazol Table 20: SWOT Analysis Danazol Table 21: Branded Hormonal Contraceptives Commonly Used Off Label for Endometriosis Table 22: Progestins Commonly Used Off Label for Endometriosis Table 23: Overall Unmet Needs Current Level of Attainment

13 Table of Contents Table 24: Common Primary and Secondary Outcome Measures in Endometriosis Clinical Trials Table 25: Design of the Most Relevant Current Phase II and III Clinical Trials in Endometriosis Table 26: Endometriosis Late-Stage Pipeline, Table 27: Product Profile Elagolix Table 28: SWOT Analysis Elagolix Table 29: Product Profile Relugolix Table 30: SWOT Analysis Relugolix Table 31: Product Profile ASP Table 32: SWOT Analysis ASP Table 33: Early-Stage Pipeline Products for Endometriosis Table 34: Clinical Benchmarking of Key Pipeline Drugs for Endometriosis Table 35: Commercial Benchmarking of Key Pipeline Drugs for Endometriosis Table 36: Top Line Sales Forecasts ($) for Endometriosis, Table 37: Endometriosis Therapeutics Market Drivers and Barriers, Table 38: Key Events Influencing Sales for Endometriosis, Table 39: Key Launch Dates Table 40: Key Patent Expiries

14 Table of Contents 1.2 List of Figures Figure 1: 6MM, Diagnosed Prevalent Cases of Endometriosis, Ages Years, N, Figure 2: 6MM, Diagnosed Prevalent Cases of Endometriosis, by Age, N, Figure 3: 6MM, Age-Standardized Diagnosed Prevalence (%) of Endometriosis, Ages Years, Figure 4: 6MM, Diagnosed Prevalent Cases of Endometriosis by Stage, Ages Years, Figure 5: Endometriosis Pipeline by Phase, Figure 6: Advantages of GnRH Antagonists Over GnRH Agonists Figure 7: Competitive Assessment of Late-Stage Pipeline Agents in Endometriosis Therapeutics, Figure 8: Global Sales for Endometriosis Therapeutics by Region,

15 Introduction 2 Introduction 2.1 Catalyst The endometriosis therapeutics market has been in need of innovative therapies for quite a while. Competition in this market has historically been weak due to the lack of approved products. Hormonal therapies have dominated this market, yet the currently approved drugs leave much to be desired in terms of their risk-benefit profiles and long-term efficacy. The endometriosis therapeutics market is expected to experience a flurry of changes over the next five years. Although the market-leading gonadotropin-releasing hormone (GnRH) agonist, Lupron (leuprolide acetate), will lose patent protection in 2014, this change will be offset by the launch of AbbVie and Neurocrine s first-in-class oral GnRH antagonist, elagolix. The entry of elagolix will provide a muchneeded jolt to this market. In fact, this product will be the first major innovation in this indication in many years. Being orally active is a major benefit of elagolix, which will potentially offer several advantages over the incumbent injectable GnRH agonists. The GnRH antagonist mechanism of action allows for the rapid onset of estrogen suppression, without the hormonal flare effect seen with the GnRH agonists. Furthermore, the deleterious BMD loss seen with the injectable GnRH agonists is not seen with the GnRH antagonists. Ultimately, elagolix s oral route of administration will be a welcome addition to the therapeutic paradigm that will give doctors more control over dosing and will allow for the titration of circulating estrogen levels. By allowing for modulation of the level of ovarian suppression, elagolix will be a customizable solution, with increased safety over the currently approved drugs. Elagolix s major commercial attribute will be its potential to tap into a larger patient pool than drugs such as the GnRH agonists, Lupron and Zoladex (gosarelin acetate). 2.2 Related Reports GlobalData (2013). EpiCast Report: Endometriosis Epidemiology Forecast to 2022, PHARMAEPIA

16 Appendix Global Director of Epidemiology and Health Policy Franka des Vignes, PhD, currently serves as the Global Director of Epidemiology and Health Policy at GlobalData in New York City, where her primary responsibilities include managing the production and quality of the epidemiology reports and forecast models, improving the epidemiology database, liaising with clients to identify their satisfaction with the existing epidemiology offerings, prioritizing critical unmet needs, and supporting GlobalData teams with consulting opportunities. Prior to joining GlobalData, Franka worked for several years in the public sector to implement and manage several large projects leading to successful disease surveillance programs in the United States. Her experience includes analyzing epidemiological trends, assessing clinical trials, and performing pharmaceutical market forecasting in the private sector. In the nonprofit sector, she served as the Deputy Director of a Washington DC-based organization focused on health policy regarding HIV/AIDS. In the international arena, she has advised national Ministries of Health and has worked for international health organizations such as CAREC/PAHO/WHO to provide technical assistance to governments with health systems strengthening, patient population databases, and the assessment of surveillance systems in more than 20 countries in the Caribbean and Latin America. Franka holds a Master of Science in Microbiology and a PhD in Epidemiology and Public Health from Yale University Global Head of Healthcare Bonnie Bain, PhD, is Global Head of Healthcare for GlobalData in Boston, managing the Medical and Pharmaceutical arms of the business. Prior to this role, she was Vice President and Global Research & Analysis Director for Informa, where she oversaw the global strategy and operations for Datamonitor Healthcare s syndicated business. Bonnie has over 15 years of experience in the healthcare sector and a proven track record of developing innovative solutions on both the client and vendor sides of the business. Prior to joining Informa, she was Director of Product Development at Wood Mackenzie, where she oversaw the development and management of two product lines. Bonnie also worked for several years at Decision Resources as an Analyst and Project Manager. On the client side of the industry, she worked for several years as a Senior Manager in Marketing Strategy and Analytics at Boston Scientific, where her work contributed to the successful commercialization of the first-ever Access and Visualization Platform at the company. She has a PhD in Biochemistry and Molecular Biology from Purdue University, and was a postdoctoral fellow in molecular pharmacology at the University of Miami School of Medicine. 137

17 Appendix 9.7 About GlobalData GlobalData is a leading global provider of business intelligence in the healthcare industry. GlobalData provides its clients with up-to-date information and analysis on the latest developments in drug research, disease analysis, and clinical research and development. Our integrated business intelligence solutions include a range of interactive online databases, analytical tools, reports, and forecasts. Our analysis is supported by a 24/7 client support and analyst team. GlobalData has offices in New York, Boston, London, India, and Singapore. 9.8 Disclaimer All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher, GlobalData. 138