REFERENCE CODE GDHC013POA PUBLICAT ION DATE DECEM BER 2013

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1 REFERENCE CODE GDHC013POA PUBLICAT ION DATE DECEM BER 2013 ACUTE ISCHEMIC STROKE -

2 Executive Summary Acute Ischemic Stroke: Key Metrics in Six Major Pharmaceutical Markets 2012 Epidemiology Prevalent Cases 6MM 9,480,405 Incident Cases 6MM 1,250, Market Sales US 5EU Total Pipeline Assessment $376.4m $154.8m $531.2m Number of drugs in Phase III 1 Number of drugs in Phase II 10 Key Events ( ) Activase patent expiry in the US in 2015 Launch of desmoteplase in the US in 2015 Actilyse patent expiry in the EU in 2016 Launch of desmoteplase in the EU in Market Sales US 5EU Total Source: GlobalData. 6MM: US, France, Germany, Italy, Spain, UK. Level of Impact / / $945.4m $232.7m $1,178.1m Anticipated Launch of Desmoteplase Will Result in Double-Digit Sales Growth for Acute Ischemic Stroke Market The acute ischemic stroke (AIS) therapeutics market generated $531m in 2012 across the six major markets (US, France, Germany, Italy, Spain, and UK). By the end of the forecast period in 2017, the market is expected to reach $1.2 billion in sales, growing at a compound annual growth rate (CAGR) of 17.3%. The US market will continue to generate the vast majority of sales due to having the highest prevalence and incidence of ischemic stroke, and comparatively high AIS therapy prices. Major drivers of growth for the AIS therapeutics market are: The launch of desmoteplase, a novel nextgeneration thrombolytic, which has an extended therapeutic time window compared with the current standard of care, Activase/Actilyse. The increasing prominence of telemedicine, which will enhance accessibility to vital stroke care and treatment. The rapidly growing and aging population, which will result in a higher incidence of AIS as age is a major risk factor for stroke. 2

3 Executive Summary Major barriers to growth are: Stringent eligibility criteria for thrombolysis treatment, as well as a narrow therapeutic time window, which means the majority of AIS patients are currently not treated with Activase/Actilyse. Impending patent expiry to Activase/Actilyse during the forecast period (2015 and 2016 in the US and 5EU, respectively). Clinical trials attrition in the late-stage pipeline, which continues to hamper R&D efforts to bring new novel therapies to market, meaning AIS patients are still restricted to few effective treatment options. Figure below illustrates AIS therapeutics sales for the six major markets during the forecast period. Sales for Acute Ischemic Stroke by Region, % 9% 4% 2012 Total: $531.2m 29% 2012 Total: $531.2m 7% 2% 71% 71% US France Germany Italy Spain UK US 5EU 2% 5% 5% 3% 5% 2017 Total: $1.2bn 20% 2017 Total: $1.2bn 80% 80% US France Germany Italy Spain UK Source: GlobalData. US 5EU 3

4 Executive Summary The Development of New Therapies for AIS Remains Challenging There are many barriers associated with AIS clinical trials that need to be overcome in order to yield greater future trial success. A fundamental challenge with both reperfusion and neuroprotective trials design is stroke heterogeneity. Most late-stage clinical trials conducted in the US and Europe to date, including all Phase III trials of neuroprotective agents for AIS, have been negative due to unrealistic study endpoints; in fact, there is currently limited agreement on what constitutes a minimally important treatment effect in AIS trials. Other common issues in such trials, which will require more robust consideration for future studies, include testing drugs too long after stroke onset, and poor patient selection for trials; for example, the inclusion of too many severe or mild patients makes it difficult to detect any treatment effect, or the inclusion of lacunar stroke patients when there is no preclinical evidence that the drug is effective for protection of white brain matter. Desmoteplase Will Extend the Therapeutic Time Window, Addressing the Issue Regarding Low Treatment Rates Given the high rate of trial failures, the late-stage pipeline for the AIS market has changed dramatically over the last five years; in fact, desmoteplase is the only remaining Phase III candidate that can potentially achieve FDA approval within the forecast period. As a nextgeneration thrombolytic, the higher selectivity and specificity for fibrin of desmoteplase, as well as a longer half-life, allows the potential for a superior efficacy and safety profile to Activase. GlobalData expects desmoteplase to launch in 2015 and 2016 in the US and 5EU, respectively. As desmoteplase will be fulfilling a key unmet need, this novel compound is likely to be priced at a premium to Activase. Limited Availability of Treatment Options Remains the Greatest Unmet Need Despite important advances in our knowledge of stroke pathophysiology, the high attrition rate in late-stage clinical trials has resulted in Activase/Actilyse being the only pharmacological therapy approved for AIS (in 1996). However, the narrow therapeutic time window and stringent eligibility criteria mean the vast majority of AIS patients do not have access to this vital therapy. This translates to reduced clinical outcomes for many patients, and marked escalation of healthcare costs due to increased hospitalizations. 4

5 Executive Summary Several Opportunities to Remain Unmet during the Five-Year Forecast Period Given the significant unmet needs in this market, several opportunities remain for novel therapies: Thrombolytics that can be administered beyond nine hours. Although desmoteplase will have a potential extended therapeutic time window of nine hours, enabling a greater proportion of patients to be eligible for thrombolysis, there is ample opportunity for an effective and safe therapy that can be given after nine hours post-stroke onset. Effective neuroprotective therapies. AIS patients are still awaiting approval of the first effective neuroprotective therapies, and given the lack of Phase III neuroprotective agents, GlobalData does not expect any neuroprotective agents to launch within the five-year forecast period. With the absence of such a product in the AIS treatment paradigm, an approved first-in-class neuroprotective agent is likely to gain rapid patient uptake. Novel neurorestorative therapies. Although much progress has been made in the clinical management of stroke, for example in the form of next-generation thrombolytic agents such as desmoteplase, there are still limited treatment options to restore lost function once neuronal death has already occurred. What Do Physicians Think? In regards to unmet needs, one KOL indicated that the limited availability of treatment options is the most significant challenge for stroke patients: The greatest problem that we [physicians] face in the treatment of patients with ischemic stroke is that there is only one approved drug [Activase] that is effective in reversing the stroke, but this must be given within 4.5 hours. So if a patient arrives late into the clinic, there is unfortunately not really a lot we can do to help these patients. In terms of drug therapy, we can give aspirin, but this has limited benefits in reducing a stroke that has already occurred, and is only really useful in preventing further strokes. Key Opinion Leader, June 2013 While discussing the anticipated launch of desmoteplase, one KOL confirmed this novel compound is the most promising agent for AIS patients: Desmoteplase looks to be safer in comparison to t-pa [Activase], I think it would definitely make an impact if it can be given in a different time window to what we have now. Key Opinion Leader, July

6 Executive Summary While discussing future opportunities in the AIS market, a KOL confirmed there are good commercial prospects for therapeutics that can be administered after the nine-hour window: I think with desmoteplase being available up to nine hours [post-stroke] is very useful, and would mean a lot more patients will be able to receive thrombolysis. But there will still be many patients that arrive in the emergency room with stroke even after nine hours. If thrombolysis is possible for patients who arrive after 12 hours, or even 18 hours after stroke, that would be fantastic. Key Opinion Leader, July

7 List of Tables List of Figures Introduction Catalyst Related Reports Upcoming Related Reports Disease Overview Etiology and Pathophysiology Etiology Pathophysiology Prognosis Quality of Life Symptoms Epidemiology Disease Background Risk Factors and Comorbidities Atrial fibrillation increases the risk of AIS by as much as 15 times Hypertension elevates the risk of AIS by more than three times The risk of AIS is almost identical in obese men and women The risk of AIS increases with the duration of diabetes

8 4.2.5 Smoking increases the risk of AIS, which varies with the number of cigarettes smoked Age is a strong predictor of AIS in both men and women A family history of stroke, particularly a paternal history, is a strong predictor of stroke Race/ethnicity is a strong predictor of AIS, and the risk varies with the different subtypes of AIS Global and Historical Trends US France Germany Italy Spain UK Forecast Methodology Sources Used Forecast Assumptions and Methods Incident Cases of AIS Forecast Assumptions and Methods Prevalent Cases of AIS Forecast Assumptions and Methods AIS Recurrence Rate (%) Sources Not Used Epidemiological Forecast for AIS ( ) Incidence Prevalence AIS Recurrence Rate (%) Discussion

9 4.6.1 Conclusions on Epidemiology Trends Limitations of the Analysis Strengths of the Analysis Current Treatment Options Overview Product Profiles Major Brands Activase (alteplase) Additional Therapies Unmet Needs Assessment and Opportunity Analysis Overview Unmet Needs Analysis Current Lack of Effective AIS Therapies Public Awareness of Stroke Still Limited An Extended Therapeutic Time Window is Needed Safer Thrombolysis Accessibility to Acute Stroke Care Should be on Par with Myocardial Infarction Opportunity Analysis Thrombolytics That Can Be Administered Beyond Nine Hours Effective Neuroprotective Therapies Novel Neurorestorative Therapies Better Antithrombotic Agents for AIS Targeting Inflammation in AIS R&D Strategies

10 7.1 Overview Clinical Trial Design Future AIS Trial Design Pipeline Assessment Overview Promising Drugs in Clinical Development Desmoteplase Innovative Early-Stage Approaches Pipeline Valuation Analysis Clinical Benchmark of Key Pipeline Drugs Commercial Benchmark of Key Pipeline Drugs Competitive Assessment Top-Line Five-Year Forecast US EU Appendix Bibliography Abbreviations Methodology Forecasting Methodology Diagnosed AIS Patients Percent Drug-Treated Patients Drugs Included in Each Therapeutic Class

11 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 Authors Epidemiologist Global Head of Healthcare About GlobalData Disclaimer

12 1.1 List of Tables Table 1: Common Symptoms of Ischemic Stroke Table 2: TOAST Classification of Subtypes of AIS Table 3: Risk Factors and Comorbidities for AIS Table 4: Trends in the Age-Adjusted Incidence Rates of Stroke in the US (per 100,000 Population) Table 5: Trend in the Crude Mortality Rate of Stroke in the US (per 100,000 Population), Table 6: Trends in the Age-Adjusted Prevalence (%) of Stroke in the US, Ages 18 Years, Table 7: Trends in the Age-Adjusted Incidence Rates* of Stroke in France (per 100,000 Population) Table 8: Trends in the Age-Specific Prevalence of Stroke (per 100,000 Population) in France, Table 9: Trends in the Crude Annual Incidence Rates of Stroke in Germany (per 100,000 Population) Table 10: Trends in the Age-Specific Prevalence of Stroke (per 100,000 Population) in Germany, Table 11: Trends in the Total Crude Incidence Rates of Stroke in Italy (per 100,000 Population), All Ages Table 12: Trends in the Age-Specific Prevalence of Stroke (per 100,000 Population) in Italy, Table 13: Trends in the Age-Adjusted Incidence Rates of Stroke in Spain (per 100,000 Population) Table 14: Trends in the Age-Specific Prevalence of Stroke (per 100,000 Population) in Spain, Table 15: Trends in the Age-Adjusted Mortality Rate of Stroke in the UK (per 100,000 Population), Table 16: Trends in the Prevalence (%) of Stroke in the UK, Table 17: Sources of AIS Incidence Data Table 18: Sources of AIS Prevalence Data Table 19: Sources of AIS Recurrence (%) Data Table 20: Sources of AIS Subtypes (%) Data Table 21: 6MM, Incident Cases of AIS, Ages 20 Years, Both Sexes, N, Table 22: 6MM, Incident Cases of AIS, by Age, Both Sexes, N, Row (%), Table 23: 6MM, Incident Cases of AIS by Sex, Ages 20 Years, N, Row (%),

13 Table 24: 6MM, Incident Cases of AIS by Subtypes, Ages 20 Years, Both Sexes, N (Row %), Table 25: 6MM, Prevalent Cases of AIS, Ages 20 Years, Both Sexes, N, Table 26: 6MM, Prevalent Cases of AIS, by Age, Both Sexes, N, Row (%), Table 27: 6MM, Prevalent Cases of AIS, Ages 20 Years, by Sex, N, Row (%), Table 28: Criteria for Thrombolysis Using Activase/Actilyse in Patients with AIS Table 29: Leading Treatments for Acute Ischemic Stroke Table 30: Product Profile Activase Table 31: Activase/Actilyse SWOT Analysis, Table 32: Overall Unmet Needs Current Level of Attainment Table 33: STAIR Considerations for Designing Phase III AIS Trials Table 34: Acute Ischemic Stroke Late-Stage Pipeline, Table 35: Product Profile Desmoteplase Table 36: Desmoteplase SWOT Analysis, Table 37: Key Early-Stage Pipeline Products in AIS, 2013 Phase II Table 38: Key Early-Stage Pipeline Products in AIS, 2013 Phase I Table 39: Clinical Benchmark of Key Late-Stage Pipeline Drugs Table 40: Commercial Benchmark of Key Late-Stage Pipeline Drugs Table 41: Top-Line Sales Forecasts ($) for Acute Ischemic Stroke, Table 42: Key Events Impacting Sales for Acute Ischemic Stroke, Table 43: Acute Ischemic Stroke Drivers and Barriers, Table 44: Key Launch Dates Table 45: Key Patent Expiries

14 1.2 List of Figures Figure 1: The Ischemic Core and Penumbra in AIS Figure 2: The Ischemic Cascade Following Stroke Onset Figure 3: Trends in the Age-Adjusted Incidence Rates of Stroke in the US (per 100,000 Population) Figure 4: Trend in the Crude Mortality Rate of Stroke in the US, Both Sexes (per 100,000 Population), Figure 5: Trends in the Age-Adjusted Prevalence (%) of Stroke in the US, Ages 18 Years, Figure 6: Trends in the Age-Adjusted Incidence Rates* of Stroke in France (per 100,000 Population) Figure 7: Trends in the Age-Adjusted Mortality Rate of Stroke in the UK, Both Sexes (per 100,000 Population), Figure 8: Trends in the Prevalence (%) of Stroke in the UK, Figure 9: 6MM, Incident Cases of AIS, Ages 20 Years, Both Sexes, N, Figure 10: 6MM, Incident Cases of AIS, by Age, Both Sexes, N, Figure 11: 6MM, Incident Cases of AIS, by Sex, Ages 20 Years, N, Figure 12: 6MM, Age-Standardized Incidence of AIS (per 100,000 Population), Ages 20 Years, by Sex, Figure 13: 6MM, AIS Subtypes (%), Ages 20 Years, Both Sexes, Figure 14: 6MM, Incident Cases of AIS by Subtypes (N), Ages 20 Years, Both Sexes, Figure 15: 6MM, Prevalent Cases of AIS, Ages 20 Years, Both Sexes, N, Figure 16: 6MM, Prevalent Cases of AIS, by Age, Both Sexes, N, Figure 17: 6MM, Prevalent Cases of AIS, Ages 20 Years, by Sex, N, Row (%), Figure 18: 6MM, Age-Standardized Prevalence (%) of AIS, Ages 20 Years, by Sex, Figure 19: 6MM, Recurrence Rate (%) of AIS, Ages 20 Years, Both Sexes, Figure 20: Competitive Assessment of Late-Stage Pipeline Agents in AIS,

15 Figure 21: Sales for Acute Ischemic Stroke by Region,

16 Introduction 2 Introduction 2.1 Catalyst The AIS market is poised for major changes during the forecast window out to Given the impending patent expiry of Activase/Actilyse, in 2015 and 2016 in the US and 5EU respectively, the current standard of care for AIS patients is expected to lose its leading position. From 2015 onwards, Activase is expected to see declining sales; this is not only attributed to loss of patent protection, and the subsequent erosion from potential biosimilar versions, but is largely a result of the anticipated launch of Lundbeck s desmoteplase in This novel late-stage compound will increase the thrombolysis treatment rates within the AIS patient population because of the extended nine-hour therapeutic time window for acute revascularization therapy. 16

17 Appendix 10.7 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 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. 163