Chronic Myeloid Leukemia (CML)

Chronic Myeloid Leukemia (CML) Japan Drug Forecast and Market Analysis to 2022 GDHC1088CFR / Published April 2013

Executive Summary Sales for CML in Japan The Japan CML therapeutics market in the 7MM is forecasted to grow from $488.7m in 2012 to $564.7m in 2022 at a CAGR of 1.5%. Drivers of growth in the CML therapeutics market in Japan will include: Sales for CML Therapeutics in Japan by Brand, 2012 2022 23.6% 2012 Total: $488.7m 47.9% An increasing prevalence of CML, which will result in greater number of drug-treated patients 28.5% Increased uptake of higher-priced second-generation TKIs in newly diagnosed patients, and thirdgeneration TKIs in later lines of therapy The major barriers to growth in the CML therapeutics market in Japan will include: Gleevec Sprycel Tasigna Bosulif Iclusig 3.3% 10.3% 28.8% 2022 Total: $564.7m Delayed launch of Bosulif and Iclusig compared with the other major markets 32.6% Biennial cuts to pharmaceutical prices Generic erosion of Gleevec and Sprycel sales The following figure shows the breakdown of sales of CML therapeutics market by brand in Japan from 2012 to 2022. 25.1% Gleevec Sprycel Tasigna Bosulif Iclusig Source: GlobalData What Do the Physicians Think? Our experts believe that the most promising new market entrant is Ariad s Iclusig (ponatinib). Although it is highly efficacious, they expect its use to be limited to later lines of therapy as a result of its premium price and associated toxicities. Page 2 GDHC1088CFR / Published APR 2013

Executive Summary Ponatinib is a really good drug and I think that it s the one that has a chance to really move up. Because I think a lot of [physicians], they are thinking about it for people who have T315I mutations but it works on almost all the mutations. So I think there is going to be a move to kind of use that as a salvage therapy, especially for people who have started on dasatinib and nilotinib and don t do well. They will go to ponatinib. US Key Opinion Leader, February 2013 Ponatinib is a very active drug against all mutations, and it has a very, very good chance for third-line, of course, but also [for] second-line treatment. The study for firstline treatment is ongoing, that means I expect some more [use] in first-line as well. But then, having four drugs available for first-line treatment it really depends on the economics. 5EU Key Opinion Leader, February 2013 Key opinion leaders in the 7MM believe that the safety and cost will be the most critical factors influencing future prescribing patterns. In the next five years, the most important factors will be the side effects and the cost [of a drug] more than the efficacy, because all these drugs are very effective. 5EU Key Opinion Leader, January 2013 Physicians are eager for the launch of generic imatinib. They believe that although other therapies are stronger, the cost savings associated with generic imatinib will make it the drug of choice for low- to intermediate-risk newly diagnosed CP-CML patients. In many markets, particularly in the 5EU, they expect the use of generic imatinib to be mandated by payers. I think that when you calculate the prevalence of CML in the world, I think that [using generic imatinib in newly diagnosed CML patients] is the right decision. You can help more patients when you use the cheaper drug, in total. But of course, the individual patient would benefit from the more expensive and efficacious drug; but the worldwide population of CML patients will benefit from the cheaper drug because more patients can be treated with the cheaper drug. That s the responsibility we all have. 5EU Key Opinion Leader, February 2013 The discontinuation of TKI therapy is the future of CML, and something highly desired by patients. The target for the 21st century must be to stop a tyrosine kinase inhibitor in a way that a person doesn t need to take it for the rest of their life. So all attention focuses on a) how you can increase the proportion of patients who achieve a complete, durable, molecular response and b) what additional measures you can take to ensure that eventually a TKI can be stopped. 5EU Key Opinion Leader, January 2013 Currently, there is no best sequence of TKIs to prescribe for CML patients. More long-term follow-up data is needed to justify routinely prescribing second- or third-generation TKIs for newly diagnosed CP-CML patients rather than Gleevec. There is still not enough data for us to recommend any specific treatment other than just tyrosine kinase inhibitors for upfront therapy for CML. Especially regarding an increase in survival. US Key Opinion Leader, February 2013 Page 3 GDHC1088CFR / Published APR 2013

Table of Contents 1 Table of Contents 1 Table of Contents... 4 1.1 List of Tables... 8 1.2 List of Figures... 9 2 Introduction... 10 2.1 Catalyst... 10 2.2 Related Reports... 10 2.3 Upcoming Related Reports... 11 3 Disease Overview... 12 3.1 Etiology and Pathophysiology... 12 3.1.1 Etiology... 12 3.1.2 Pathophysiology... 13 3.1.3 Clinical Staging... 15 3.1.4 Prognosis... 16 3.1.5 Quality of Life... 17 3.2 Symptoms... 17 4 Disease Management... 19 4.1 Global Trends... 19 4.1.1 Treatment Overview... 19 4.1.2 Diagnostic Tests... 21 4.1.3 Genetic Testing... 22 4.1.4 Monitoring Patient Response to Treatment... 24 4.1.5 Future Directions: Discontinuation Therapy... 27 4.2 Japan... 28 4.2.1 Diagnosis and Monitoring... 28 4.2.2 Clinical Treatment... 28 4.2.3 Genetic Testing... 29 5 Competitive Assessment... 30 Page 4 GDHC1088CFR / Published APR 2013

Table of Contents 5.1 Overview... 30 5.2 Strategic Competitor Assessment... 30 5.3 Product Profiles- Major Brands... 33 5.3.1 Gleevec (imatinib)... 33 5.3.2 Sprycel (dasatinib)... 37 5.3.3 Tasigna (nilotinib)... 43 5.3.4 Bosulif (bosutinib)... 48 5.3.5 Iclusig (ponatinib)... 53 5.3.6 Minor Therapeutic Classes... 57 6 Opportunity and Unmet Need... 59 6.1 Overview... 59 6.2 Unmet Need: A Drug that Can Cure CML... 60 6.3 Unmet Need: Lower Annual Cost of Therapy... 61 6.4 Unmet Need: Treatments for Patients Who Have Primary Resistance to or are Refractory to TKIs... 62 6.5 Unmet Need: More Efficacious Treatments for AP and BP CML... 62 6.6 Unmet Need: Therapies with Fewer Chronic Side Effects... 63 6.7 Unmet Need: Better Compliance from Patients on Long-Term Oral Therapy... 63 6.8 Unmet Need: Methods of Determining the Optimal Therapy for a Patient... 64 6.9 Opportunity: Exploration into Discontinuation Therapy... 64 6.10 Opportunity: Companion Devices to Enhance Patient Adherence to Oral Therapy... 65 6.11 Opportunity: Therapies with BCR-ABL Independent MOAs... 65 6.12 Opportunity: Extended-Release Formulations of TKIs... 66 6.13 Opportunity: Biomarkers to Identify the Optimal Therapy for a Given Patient... 66 7 Pipeline Assessment... 67 7.1 Overview... 67 7.2 Innovative Early-Stage Approaches... 67 7.2.1 Project 1: The Wnt Signaling Pathway... 69 7.2.2 Project 2: Jak2 Inhibitors... 70 Page 5 GDHC1088CFR / Published APR 2013

Table of Contents 7.2.3 Project 3: Grb-2... 71 7.2.4 Case Study: Smoothened Inhibitors... 71 8 Market Outlook... 73 8.1 Japan... 73 8.1.1 Forecast... 74 8.1.2 Key Events... 75 8.1.3 Drivers and Barriers... 76 9 Appendix... 79 9.1 Bibliography... 79 9.2 Abbreviations... 85 9.3 Methodology... 88 9.4 Forecasting Methodology... 88 9.4.1 Diagnosed CML patients... 88 9.4.2 Drug-treated Patients on X Line of Therapy... 89 9.4.3 Drugs Included in Each Therapeutic Class... 89 9.4.4 Launch and Patent Expiry Dates... 89 9.4.5 General Pricing Assumptions... 90 9.4.6 Compliance Assumptions for Oral TKIs... 91 9.4.7 Individual Drug Assumptions... 91 9.4.8 Generic Erosion... 93 9.4.9 Pricing of New Market Entrants... 93 9.5 Physicians and Specialists Included in this Study... 94 9.6 Survey of High Prescribing Physicians... 95 9.7 About the Authors... 96 9.7.1 Authors... 96 9.7.2 Epidemiologists... 97 9.7.3 Global Director of Epidemiology and Clinical Trials Analysis... 98 9.7.4 Global Head of Healthcare... 99 Page 6 GDHC1088CFR / Published APR 2013

Table of Contents 9.8 About GlobalData... 100 9.9 Contact Us... 100 9.10 Disclaimer... 100 Page 7 GDHC1088CFR / Published APR 2013

Table of Contents 1.1 List of Tables Table 1: The Staging of CML as Defined by Commonly Used Staging Systems... 15 Table 2: Prognostic Scoring Systems for CML... 16 Table 3: Common Symptoms of CML by Disease Phase... 18 Table 4: Most Commonly Followed Treatment Guidelines for CML... 20 Table 5: Most Prescribed First-Line Therapies for CP, AP and BP CML in the Global Markets, 2013... 21 Table 6: Suggested Treatments for CML Patients with Selected BCR-ABL Kinase Domain Mutations... 24 Table 7: CML Response Types, Criteria, and Corresponding Tests... 25 Table 8: Leading Treatments for Chronic Myeloid Leukemia, 2013... 32 Table 9: Product Profile Gleevec... 34 Table 10: Hematologic and Cytogenetic Reponses to Gleevec in Newly Diagnosed CML Patients... 35 Table 11: Gleevec SWOT Analysis, 2013... 37 Table 12: Product Profile Sprycel... 39 Table 13: Hematologic and Cytogenetic Reponses to Sprycel in Imatinib Resistant or Intolerant Advanced Phase CML... 40 Table 14: Sprycel SWOT Analysis, 2013... 42 Table 15: Product Profile Tasigna... 44 Table 16: Molecular and Cytogenetic Responses of Tasigna Compared with Gleevec in Newly Diagnosed Ph+ CML in CP... 45 Table 17: Tasigna SWOT Analysis, 2013... 47 Table 18: Product Profile Bosulif... 49 Table 19: Bosulif SWOT Analysis, 2013... 52 Table 20: Product Profile Iclusig... 54 Table 21: Iclusig SWOT Analysis, 2013... 57 Table 22: Summary of Minor Therapeutic Classes, 2013... 58 Table 23: Overall Unmet Needs Current Level of Attainment... 60 Table 24: Early-stage Pipeline Projects in CML... 69 Page 8 GDHC1088CFR / Published APR 2013

Table of Contents Table 25: Sales Forecasts ($m) for CML Therapeutics in Japan, 2012 2022... 74 Table 26: Key Events Impacting Sales of CML Therapeutics in Japan, 2013... 75 Table 27: CML Market in Japan Drivers and Barriers, 2013... 76 Table 28: Key Launch Dates... 89 Table 29: Key Patent Expiries... 89 Table 30: Physicians Surveyed, by Country... 95 1.2 List of Figures Figure 1: Translocation of Chromosomes 9 and 22... 13 Figure 2: Comparison of Normal and Leukemia Blood Cells... 14 Figure 3: Sales for CML Therapeutics in Japan by Brand, 2012 2022... 75 Page 9 GDHC1088CFR / Published APR 2013

Introduction 2 Introduction 2.1 Catalyst The launch of Novartis BCR-ABL inhibitor Gleevec (imatinib) in 2001 forever changed the treatment of chronic myeloid leukemia (CML). With Gleevec, and later the second-generation TKIs, BMS Sprycel (dasatinib) and Novartis Tasigna (nilotinib), CML has become less of a death sentence and more of a chronic, manageable condition. The CML market has grown as a result of this steadily increasing disease prevalence, and the high cost of branded TKIs places a heavy financial burden on patients and global healthcare systems. The effects of this burden will have a major impact on the future CML market. The sustained and escalating costs of branded TKI therapy have left payers, physicians and patients anxiously awaiting the launch of generic imatinib. Swift erosion of Gleevec sales will follow, and physicians will be left with the question of whether to prescribe second-generation TKIs for newly diagnosed patients, or the more cost-effective generic Gleevec. Ultimately, the launch and uptake of generic imatinib will be the primary driver of the decreasing size of the global CML market. New entrants Pfizer s Bosulif (bosutinib) and Ariad s Iclusig (ponatinib) will be welcome treatment options for patients who are refractory to or intolerant of Gleevec, Sprycel and Tasigna. In light of the aforementioned fiscal constraints, these drugs will be predominantly prescribed in later lines of therapy, restricting their ability to compensate for the market s loss of Gleevec sales. 2.2 Related Reports GlobalData (2013). Chronic Myeloid Leukemia - United States Drug Forecast and Market Analysis to 2022. GDHC1082CFR GlobalData (2013). Chronic Myeloid Leukemia - United Kingdom Drug Forecast and Market Analysis to 2022. GDHC1087CFR GlobalData (2013). Chronic Myeloid Leukemia - France Drug Forecast and Market Analysis to 2022. GDHC1083CFR GlobalData (2013). Chronic Myeloid Leukemia - Germany Drug Forecast and Market Analysis to 2022. GDHC1084CFR GlobalData (2013). Chronic Myeloid Leukemia - Italy Drug Forecast and Market Analysis to 2022. GDHC1085CFR Page 10 GDHC1088CFR / Published APR 2013

Introduction GlobalData (2013). Chronic Myeloid Leukemia - Spain Drug Forecast and Market Analysis to 2022. GDHC1086CFR GlobalData (2013). Gleevec (Chronic Myeloid Leukemia) - Forecast and Market Analysis to 2022. GDHC1136DFR GlobalData (2013). Sprycel (Chronic Myeloid Leukemia) - Forecast and Market Analysis to 2022. GDHC1137DFR GlobalData (2013). Tasigna (Chronic Myeloid Leukemia) - Forecast and Market Analysis to 2022. GDHC1138DFR GlobalData (2013). Bosulif (Chronic Myeloid Leukemia) - Forecast and Market Analysis to 2022. GDHC1139DFR GlobalData (2013). Iclusig (Chronic Myeloid Leukemia) - Forecast and Market Analysis to 2022. GDHC11340FR GlobalData (2013). Synribo (Chronic Myeloid Leukemia) - Forecast and Market Analysis to 2022. GDHC1141DFR GlobalData (2013). Chronic Myeloid Leukemia - Current and Future Players. GDHC1011FPR Page 11 GDHC1088CFR / Published APR 2013

Appendix 9.8 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. 9.10 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. Page 100 GDHC1088CFR / Published APR 2013