Gastrointestinal Therapeutics in Asia-Pacific Markets to 2019 Strong Potential for Pipeline Biologics on Account of High Regional Unmet Need

GBI Research Report Guidance

GBI Research Report Guidance  The second chapter provides an introduction to the GI therapeutic indications of IBS, UC and CD, including epidemiology, symptoms, etiology, pathophysiology, diagnosis, disease classification and determination of disease severity, and treatment.  The third chapter provides an overview of the product profiles for six key marketed products for the treatment of IBS, UC, and CD.  The fourth chapter analyses the IBS, UC, and CD pipeline, providing details of, among other parameters, drug distribution by phase, molecule type, and mechanism of action. The chapter also profiles three promising drug candidates in the pipeline.  The fifth chapter provides a market forecast to 2019 for the APAC markets of Australia, India, China, and Japan, and includes prevalence population, Annual Cost of Therapy (ACoT) and market size forecast, along with details of drivers and barriers affecting the GI market.  Chapter six provides a strategic consolidation analysis, including details of major co-development and licensing deals.

Executive Summary

The gastrointestinal market Executive Summary is expected to grow in Asia- Gastrointestinal Therapeutics Market in Asia-Pacific to Grow by XX% to Reach $XX Billion in 2019 Pacific region due to new product launches The Gastrointestinal (GI) therapeutics market for Irritable Bowel Syndrome (IBS), Ulcerative Colitis (UC), and Crohn’s Disease (CD) in the Asia-Pacific (APAC) region, comprising Australia, India, China, and Japan, had an estimated value of $XXm in 2012, which is expected to increase at a Compound Annual Growth Rate (CAGR) of XX% during the forecast period to reach $XXm in 2019. India registers the fastest growth rate at a CAGR of XX%, followed by China, which is expected to register growth at a CAGR of XX%. Japan is the market leader in the APAC region, accounting for $XXm in 2012, equivalent to almost XX% of the total GI market in the region. The market is expected to grow due to new product launches and substantial growth in the size of the diseased population during the forecast period.

Gastrointestinal Therapeutics Market, Asia-Pacific, Market Size ($m), 2012–2019 Revenue Revenue ($m)

2012 2019

Australia India China Japan

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

Table of Contents

1 Table of Contents 1 Table of Contents ...... 6 1.1 List of Tables ...... 9 1.2 List of Figures...... 10 2 Gastrointestinal Therapeutics in Asia-Pacific Market – Introduction ...... 11 2.1 Irritable Bowel Syndrome ...... 11 2.1.1 Classification ...... 11 2.1.2 Symptoms ...... 11 2.1.3 Etiology ...... 11 2.1.4 Pathophysiology...... 12 2.1.5 Diagnosis ...... 12 2.1.6 Epidemiology ...... 14 2.1.7 Prognosis ...... 14 2.1.8 Treatment Options ...... 14 2.2 Ulcerative Colitis ...... 15 2.2.1 Classification ...... 15 2.2.2 Symptoms ...... 17 2.2.3 Etiology ...... 17 2.2.4 Pathophysiology...... 17 2.2.5 Diagnosis ...... 18 2.2.6 Epidemiology ...... 19 2.2.7 Prognosis ...... 19 2.2.8 Treatment Options ...... 19 2.3 Crohn’s Disease ...... 21 2.3.1 Classification ...... 21 2.3.2 Symptoms ...... 22 2.3.3 Etiology ...... 22 2.3.4 Pathophysiology...... 23 2.3.5 Diagnosis ...... 23 2.3.6 Epidemiology ...... 24 2.3.7 Prognosis ...... 24 2.3.8 Treatment Options ...... 25 3 Gastrointestinal Therapeutics in Asia-Pacific Market – Marketed Products (Global) ...... 26 3.1 Irritable Bowel Syndrome ...... 26 3.2 Ulcerative Colitis ...... 26 3.3 Crohn’s Disease ...... 26 3.4 Key Marketed Products ...... 27 3.4.1 Amitiza ...... 27 3.4.2 Humira ...... 28 3.4.3 Remicade ...... 29 3.4.4 Simponi ...... 30 3.4.5 Cimzia...... 31 3.4.6 Tysabri ...... 32 4 Gastrointestinal Therapeutics in Asia-Pacific Market – Pipeline Analysis ...... 34 4.1 Irritable Bowel Syndrome ...... 34 4.1.1 Overall Pipeline ...... 34 4.1.2 Pipeline Analysis by Molecule Type ...... 36 4.1.3 Pipeline Analysis by Mechanism of Action ...... 37 4.2 Ulcerative Colitis Pipeline ...... 39 4.2.1 Overall Pipeline ...... 39 4.2.2 Pipeline Analysis by Molecule Type ...... 41

Table of Contents

4.2.3 Pipeline Analysis by Mechanism of Action ...... 42 4.3 Crohn’s Disease Pipeline ...... 44 4.3.1 Overall Pipeline ...... 44 4.3.2 Pipeline Analysis by Molecule Type ...... 46 4.3.3 Pipeline Analysis by Mechanism of Action ...... 47 4.4 Promising Drug Candidates in the Pipeline ...... 49 4.4.1 GSK-1605786 ...... 49 4.4.2 MLN0002 ...... 49 4.4.3 EMD-61753 ...... 49 5 Gastrointestinal Therapeutics in Asia-Pacific Market – Market Forecast to 2019 ...... 50 5.1 Asia-Pacific Markets ...... 50 5.1.1 Treatment Usage Patterns...... 50 5.1.2 Annual Cost of Therapy ...... 50 5.1.3 Market Size ...... 50 5.2 Australia ...... 52 5.2.1 Treatment Usage Patterns...... 52 5.2.2 Annual Cost of Therapy ...... 52 5.2.3 Market Size ...... 52 5.3 India ...... 54 5.3.1 Treatment Usage Patterns...... 54 5.3.2 Annual Cost of Therapy ...... 54 5.3.3 Market Size ...... 54 5.4 China ...... 56 5.4.1 Treatment Usage Patterns...... 56 5.4.2 Annual Cost of Therapy ...... 56 5.4.3 Market Size ...... 56 5.5 Japan ...... 58 5.5.1 Treatment Usage Patterns...... 58 5.5.2 Annual Cost of Therapy ...... 58 5.5.3 Market Size ...... 58 5.6 Drivers and Barriers ...... 60 5.6.1 Drivers ...... 60 5.6.2 Barriers ...... 60 6 Gastrointestinal Therapeutics in Asia-Pacific Market – Deals and Strategic Consolidations (Global) ...... 61 6.1 Deals Analysis ...... 61 6.2 Major Co-Development Deals...... 63 6.2.1 AstraZeneca Enters into Co-Development Agreement with Ironwood Pharma for Linaclotide ...... 64 6.2.2 Amgen Enters into Co-development Agreement with AstraZeneca for Five Monoclonal Antibodies...... 64 6.2.3 Galapagos and AbbVie Extend GLPG0634 Development Agreement to Include Crohn's Disease ...... 64 6.3 Major Licensing Deals ...... 65 6.3.1 AstraZeneca Enters into Licensing Agreement with Ardelyx for NHE3 Inhibitor Program .....66 6.3.2 Sanofi-Aventis Enters into Licensing Agreement with Kyowa Hakko Kirin ...... 66 6.3.3 GlaxoSmithKline Enters into Licensing Agreement with ChemoCentryx ...... 66 7 Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix ...... 67 7.1 Market Definitions ...... 67 7.2 Abbreviations ...... 67 7.3 Sources...... 69 7.4 All Pipeline Drugs by Phase ...... 71 7.4.1 Discovery ...... 71

Table of Contents

7.4.2 Preclinical ...... 71 7.4.3 IND/CTA-filed ...... 72 7.4.4 Phase I ...... 73 7.4.5 Phase II ...... 74 7.4.6 Phase III ...... 76 7.4.7 Pre-Registration ...... 76 7.4.8 Undisclosed...... 77 7.5 Market Forecasts to 2019 ...... 77 7.5.1 Asia-Pacific Markets ...... 77 7.5.2 Australia ...... 78 7.5.3 India ...... 79 7.5.4 China ...... 80 7.5.5 Japan ...... 81 7.6 Research Methodology ...... 82 7.6.1 Coverage ...... 82 7.6.2 Secondary Research ...... 82 7.6.3 Primary Research ...... 82 7.6.4 Therapeutic Landscape ...... 83 7.6.5 Geographical Landscape ...... 85 7.6.6 Pipeline Analysis...... 86 7.7 Expert Panel Validation ...... 86 7.8 Contact Us ...... 86 7.9 Disclaimer...... 86

Table of Contents

1.1 List of Tables Table 1: Gastrointestinal Therapeutics Market, Irritable Bowel Syndrome, Classification, 2009 ...... 11 Table 2: Gastrointestinal Therapeutics Market, Treatment Recommendations for Irritable Bowel Syndrome, 2009 ...... 15 Table 3: Gastrointestinal Therapeutics Market, Classification of Ulcerative Colitis, 2004 ...... 15 Table 4: Gastrointestinal Therapeutics Market, Diagnosis of Ulcerative Colitis, 2007...... 18 Table 5: Gastrointestinal Therapeutics Market, Difference Between Ulcerative Colitis and Crohn’s Disease, 2007...... 18 Table 6: Gastrointestinal Therapeutics Market, Treatment Options of Ulcerative Colitis, 2011 ...... 21 Table 7: Gastrointestinal Therapeutics Market, Classification of Crohn’s Disease, 2013 ...... 21 Table 8: Gastrointestinal Therapeutics Market, Percentage of Patients Affected by Symptoms of Crohn’s Disease (%), 2012 ...... 22 Table 9: Gastrointestinal Therapeutics Market, Treatment Options for Crohn’s Disease, 2009 ...... 25 Table 10: Gastrointestinal Therapeutics Market, Global, Pipeline (Discovery), 2013 ...... 71 Table 11: Gastrointestinal Therapeutics Market, Global, Pipeline (Preclinical), 2013 ...... 71 Table 12: Gastrointestinal Therapeutics Market, Global, Pipeline (IND/CTA-filed), 2013...... 72 Table 13: Gastrointestinal Therapeutics Market, Global, Pipeline (Phase I), 2013 ...... 73 Table 14: Gastrointestinal Therapeutics Market, Global, Pipeline (Phase II), 2013 ...... 74 Table 15: Gastrointestinal Therapeutics Market, Global, Pipeline (Phase III), 2013 ...... 76 Table 16: Gastrointestinal Therapeutics Market, Global, Pipeline (Pre-Registration), 2013 ...... 76 Table 17: Gastrointestinal Therapeutics Market, Global, Pipeline (Undisclosed), 2012 ...... 77 Table 18: Gastrointestinal Therapeutics Asia-Pacific Markets, Irritable Bowel Syndrome, Market Forecast, 2012–2019 ...... 77 Table 19: Gastrointestinal Therapeutics Market, Asia-Pacific Markets, Ulcerative Colitis, Market Forecast, 2012–2019 ...... 78 Table 20: Gastrointestinal Therapeutics Market, Asia-Pacific Markets, Crohn’s Disease, Market Forecast, 2012–2019 ...... 78 Table 21: Gastrointestinal Therapeutics Market, Australia, Irritable Bowel Syndrome, Market Forecast, 2012–2019 ...... 78 Table 22: Gastrointestinal Therapeutics Market, Australia, Ulcerative Colitis, Market Forecast, 2012–2019 ...... 79 Table 23: Gastrointestinal Therapeutics Market, Australia, Crohn’s Disease, Market Forecast, 2012–2019 ...... 79 Table 24: Gastrointestinal Therapeutics Market, India, Irritable Bowel Syndrome, Market Forecast, 2012– 2019 ...... 79 Table 25: Gastrointestinal Therapeutics Market, India, Ulcerative Colitis, Market Forecast, 2012–2019 ...79 Table 26: Gastrointestinal Therapeutics Market, India, Crohn’s Disease, Market Forecast, 2012–2019 .....80 Table 27: Gastrointestinal Therapeutics Market, China, Irritable Bowel Syndrome, Market Forecast, 2012– 2019 ...... 80 Table 28: Gastrointestinal Therapeutics Market, China, Ulcerative Colitis, Market Forecast, 2012–2019 ..80 Table 29: Gastrointestinal Therapeutics Market, China, Crohn’s Disease, Market Forecast, 2012–2019 ....80 Table 30: Gastrointestinal Therapeutics Market, Japan, Irritable Bowel Syndrome, Market Forecast, 2012– 2019 ...... 81 Table 31: Gastrointestinal Therapeutics Market, Japan, Ulcerative Colitis, Market Forecast, 2012–2019 ..81 Table 32: Gastrointestinal Therapeutics Market, Japan, Crohn’s Disease, Market Forecast, 2012–2019 ....81

Table of Contents

1.2 List of Figures Figure 1: Gastrointestinal Therapeutics Market, Treatment Algorithm of Ulcerative Colitis, 2007 ...... 20 Figure 2: Gastrointestinal Therapeutics Market, Global, Sales of Amitiza ($m), 2006–2012 ...... 27 Figure 3: Gastrointestinal Therapeutics Market, Global, Sales of Humira ($bn), 2006–2012 ...... 28 Figure 4: Gastrointestinal Therapeutics Market, Global, Sales of Remicade ($bn), 2006–2012 ...... 29 Figure 5: Gastrointestinal Therapeutics Market, Global, Sales of Simponi ($m), 2009–2012 ...... 30 Figure 6: Gastrointestinal Therapeutics Market, Global, Sales of Cimzia ($m), 2008–2012 ...... 31 Figure 7: Gastrointestinal Therapeutics Market, Global, Sales of Tysabri ($m), 2006–2012 ...... 32 Figure 8: Gastrointestinal Therapeutics Market, Global, Irritable Bowel Syndrome, Pipeline, (%), 2013 ...35 Figure 9: Gastrointestinal Therapeutics Market, Global, Irritable Bowel Syndrome, Pipeline by Molecule Type, 2013 ...... 36 Figure 10: Gastrointestinal Therapeutics Market, Global, Irritable Bowel Syndrome, Pipeline by Mechanism of Action, 2012 ...... 38 Figure 11: Gastrointestinal Therapeutics Market, Global, Ulcerative Colitis, Pipeline, (%) 2013 ...... 40 Figure 12: Gastrointestinal Therapeutics Market, Global, Ulcerative Colitis, Pipeline by Molecule Type, 2013 ...... 41 Figure 13: Gastrointestinal Therapeutics Market, Global, Ulcerative Colitis, Pipeline by Mechanism of Action, 2013 ...... 43 Figure 14: Gastrointestinal Therapeutics Market, Global, Crohn’s Disease, Pipeline, (%), 2013 ...... 45 Figure 15: Gastrointestinal Therapeutics Market, Global, Crohn’s Disease, Pipeline by Molecule Type, 2013 ...... 46 Figure 16: Gastrointestinal Therapeutics Market, Global, Crohn’s Disease, Pipeline by Mechanism of Action, 2013 ...... 48 Figure 17: Gastrointestinal Therapeutics Market, Asia-Pacific, Market Size, 2012–2019 ...... 51 Figure 18: Gastrointestinal Therapeutics Market, Australia, Market Size, 2012–2019 ...... 53 Figure 19: Gastrointestinal Therapeutics Market, India, Market Size, 2012–2019 ...... 55 Figure 20: Gastrointestinal Therapeutics Market, China, Market Size, 2012–2019 ...... 57 Figure 21: Gastrointestinal Therapeutics Market, Japan, Market Size, 2012–2019...... 59 Figure 22: Gastrointestinal Therapeutics Market, Global, Deals, 2006–2013 ...... 62 Figure 23: Gastrointestinal Therapeutics Market, Global, Co-Development Deals, 2006–2013 ...... 63 Figure 24: Gastrointestinal Therapeutics Market, Global, Licensing Deals, 2006–2013 ...... 65 Figure 25: GBI Research Market Forecasting Model ...... 85

Gastrointestinal Therapeutics in Asia-Pacific Market – Introduction

2 Gastrointestinal Therapeutics in Asia-Pacific Market – Introduction 2.1 Irritable Bowel Syndrome 2.1.1 Classification In terms of severity level, Irritable Bowel Syndrome (IBS) can be mild, moderate or severe. Mild symptoms, which occur infrequently, sometimes interfere with normal daily functioning. Moderate symptoms are more intense, occur more frequently, and often interfere with daily activities, whereas severe symptoms chronically interfere with daily functioning. Classification is based on Rome III criteria along with patient stool characteristics, as outlined in the following table.

Table 1: Gastrointestinal Therapeutics Market, Irritable Bowel Syndrome, Classification, 2009 IBS-D IBS-C IBS-M Loose stools >25% of the time and Hard stools >25% of the time and Both hard and soft stools >25% of the hard stools <25% of the time loose stools <25% of the time time Both hard and soft stools >25% of the Up to one third of cases Up to one third of cases time Between one third and one half of More common in men Up to one third of cases cases

Source: WGO, 2009a IBS-D: Irritable Bowel Syndrome Diarrhea IBS-C: Irritable Bowel Syndrome Constipation IBS-M: Irritable Bowel Syndrome Mixed

2.1.2 Symptoms The symptoms of IBS include abdominal pain or discomfort, changes in bowel habits, the passing of mucus along with stool, abdominal bloating or distension and a feeling of incomplete defecation. For IBS to be diagnosed, all of these symptoms should occur at least three times a month. Bowel movements usually occur more or less often than normal and with stool that appears looser and more watery, or harder and more lumpy than usual. The symptoms are usually long-term, which may occur in episodes, may be meal- related, and sometimes may even lead to severe intestine infection. Sometimes, IBS symptoms may also be confused or overlapped with gastroesophageal reflux disease or dyspepsia. 2.1.3 Etiology IBS is a multifactorial functional disorder related to the following genetic, environmental and psychological factors. Diet Lactose intolerance, as well as intolerance to sorbitol or fructose, has been implicated in IBS. The hypersensitive guts of patients with IBS show exaggerated responses to the gaseous and fluid distention caused by incomplete absorption of carbohydrate. Psychological factors Intense emotional states, such as stress and anxiety, can trigger chemical changes that interfere with the normal functioning of the digestive system. Anger is closely associated with enhanced contractile activity in the sigmoid-rectum area, whereas reduced motility is documented in cases of fear. Anxiety can induce rapid small bowel transit and enhanced stool frequency. Depression is associated with delayed small bowel and colonic transit. Common characteristics of IBS patients are the pathologic gradation of visceral perception, endogenous pain facilitation, and a reduced threshold for pain.

Gastrointestinal Therapeutics in Asia-Pacific Market – Marketed Products (Global)

3.4.4 Simponi

Figure 5: Gastrointestinal Therapeutics Market, Global, Sales of Simponi ($m), 2009–2012

Revenue Revenue ($m) 2013: FDA approval for UC in US

2009: FDA approval in 2009 for RA, psoriatic arthritis, and ankylosing spondilytis in US, Canada and Europe

2009 2010 2011 2012

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

Simponi (golimumab), a monoclonal antibody, is an immunosuppressive drug that binds to both soluble and transmembrane bioactive forms of human TNF-α and does not allow TNF-α to bind to its receptor, working as a TNF-α inhibitor. Simponi does not lyse human monocytes expressing transmembrane TNF in the presence of complement or effector cells. TNF-α is an important mediator of articular inflammation, which is characteristic of inflammatory diseases. Simponi can be administered subcutaneously once a month and is available in the form of injections of different strengths; a XXmg/ml pen injector, XXmg/ml syringe, XXmg/XXml Smartject pen injection, or XXmg/4ml vial. Simponi received initial FDA approval in 2009 for the treatment of RA, psoriatic arthritis, and ankylosing spondylitis. On May 15, 2013, the FDA approved Simponi for the treatment of UC. On June 19, 2013, Simponi Aria (golimumab) received FDA approval for the treatment of moderate to severe active RA. Golimumab was developed by Centocor (Johnson & Johnson) and is marketed in Europe by Merck & Co, Inc. The efficacy and safety of Simponi were evaluated in two randomized, double-blind, placebo-controlled clinical trials. Clinical response was noted after 54 weeks of treatment. XX% of placebo and XX% of Simponi treated subjects have shown clinical response. Simponi has shown adverse events such as hepatic enzyme elevation, autoimmune disorders, injection site reactions, and immunogenicity.

Gastrointestinal Therapeutics in Asia-Pacific Market – Pipeline Analysis

A substantial proportion of 4 Gastrointestinal Therapeutics in Asia-Pacific Market – Pipeline Analysis pipeline products in the 4.1 Irritable Bowel Syndrome clinical stages of development are small 4.1.1 Overall Pipeline molecules The current developmental pipeline for IBS drugs is moderate in terms of number of molecules, with a total of XX drug candidates in various stages of clinical development. Of these, XX% are in Phase I, XX% in Phase II, XX% are in Phase III and 20% are in the preclinical stage (Figure 8, Panel A). A significant proportion – XX% – of pipeline products in the clinical stages of development are novel, whereas only XX% of molecules are generic (Figure 8, Panel B). The route of administration for the majority of pipeline drugs is oral (XX%), followed by intravenous (XX%) and intradermal/subcutaneous (XX%). The shares of all other routes of administration are displayed in Figure 8, Panel C. A substantial proportion of pipeline products in the clinical stages of development are small molecules, which account for XX% of the overall pipeline, irrespective of the stage of development followed by peptides as illustrated in Figure 10, Panel A. In each phase, the pipeline encompasses a diverse range of molecules, which act upon various signaling targets. The individual molecular targets that currently dominate the IBS pipeline are 5-Hydroxytryptamine (5-HT) modulators, followed by the neurokinin receptor antagonist. A series of tables containing an exhaustive list of all pipeline molecules, along with their respective companies and molecular targets is available in the appendix, with a separate table for each stage of development.

Gastrointestinal Therapeutics in Asia-Pacific Market – Pipeline Analysis

Figure 8: Gastrointestinal Therapeutics Market, Global, Irritable Bowel Syndrome, Pipeline, (%), 2013

A) IBS therapeutics pipeline by stage

Discovery

Preclinical

Phase I n = XX Phase II

Phase III

Pre-registration

B) IBS therapeutics pipeline by program type

Novel n = XX Generic

C) IBS therapeutics pipeline by route of administration

Intradermal

Intravenous n = XX Oral

Subcutaneous

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

Gastrointestinal Therapeutics in Asia-Pacific Market – Market Forecast to 2019

5.4 China 5.4.1 Treatment Usage Patterns Figure 20 shows the treatment usage forecast for the indications of IBS, UC and CD in the GI therapeutics market in China. In 2012, the combined prevalence of these three indications amounted to approximately XX million, which is expected to increase to reach XX million in 2019, increasing at a CAGR of XX%. The treatment population amounted to an estimated XX million in 2012, which is expected to reach XX million in 2019, increasing at a CAGR of XX%. 5.4.2 Annual Cost of Therapy The average ACoT for the indications of IBS, UC and CD in China amounted to an estimated $XX in 2012, and is expected to grow at a CAGR of XX% to reach $XX in 2019. The average value of ACoT has been calculated based on total revenue of all the three indications divided by the total treatment population of all the three indications. There is significant variation in ACoT among these three indications. The ACoT for CD is the highest among these three indications. This value amounted to $XX in 2012 and is expected to grow at a CAGR of XX% to reach $XX in 2019. IBS had an ACoT of $XX in 2012, and this value is expected to grow at a CAGR of XX% to reach $XX in 2019. This growth is due to the expected launch of linaclotide during the forecast period. Similarly, in UC the ACoT is expected to grow at a CAGR of XX% from $XX in 2012 to $XX in 2019, due to the expected approval of Remicade for the treatment of UC in coming years. 5.4.3 Market Size The value of the market for GI therapeutics in China is expected to reach $XXm in 2019, growing at a CAGR of XX% from $XXm in 2012. The IBS market, which dominated the GI market in China, had an estimated value of $XXm or XX% of the total GI market in 2012, which is expected to increase at a CAGR of XX% to reach $XXm in 2019. The CD market generated an estimated $XXm of sales in 2021, a total that is expected to have reached $XXm by 2019, growing at a CAGR of XX%. Major growth is expected to be seen in the UC market, due to the expected approval of Remicade, from $XXm in 2012 to $XXm in 2019.

Gastrointestinal Therapeutics in Asia-Pacific Market – Market Forecast to 2019

Figure 20: Gastrointestinal Therapeutics Market, China, Market Size, 2012–2019

A) Treatment usage pattern (million) Patients Patients

2012 2013 2014 2015 2016 2017 2018 2019 Prevalence population Treatment population B) Annual cost of therapy Annual cost of therapy ($)therapy ofAnnual cost

2012 2013 2014 2015 2016 2017 2018 2019 IBS UC CD C) Revenue Revenue($m)

2012 2013 2014 2015 2016 2017 2018 2019

IBS UC CD

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

7 Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix 7.1 Market Definitions Market Coverage The prevalence population is the estimated number of people at any given point of time who are affected by Irritable Bowel Syndrome, Ulcerative Colitis, and Crohn’s Disease. The prescription population refers to the number of patients suffering from Irritable Bowel Syndrome, Ulcerative Colitis, and Crohn’s Disease who have been prescribed pharmacological treatments. 7.2 Abbreviations 5-ASA 5-Aminosalicylic Acid µg: microgram ACoT: Annual Cost of Therapy A4b7: Alpha 4 beta 7 ACG: American College of Gastroenterology BLA: Biologic License Application CAGR: Compound Annual Growth Rate CC: Chemokine (C-C Motif) Receptor CCKAR: Cholecystokinin A receptor CD: Crohn’s Disease CFTR: Cystic Fibrosis Transmembrane Conductance Regulators cfu/ml: colony forming unit per milliliter CRF: Corticotropin Release Factor CRP: C-reactive protein EMA: Endomysial Antibodies ENS: Enteric Nervous System ESR: Erythrocyte Sedimentation Rate FBC: Full Blood Count Fc: Fragment crystallizable GR: Glucocorticoid Receptor GI: Gastrointestinal GLP: Glucagon-like Peptide GSK: GlaxoSmithKline HMGB: High Mobility Group protein Box IL-1α: Interleukin-1α IND/CTA: Investigational New Drug/Clinical Trial Application IBD: Irritable Bowel Disease IBS: Irritable Bowel Syndrome IBS-A/M: Irritable Bowel Syndrome-Alternating/Mixed IBS-C: Irritable Bowel Syndrome with Constipation

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

IBS-D: Irritable Bowel Syndrome with Diarrhea JAK: Janus Kinase LFA: Lymphocyte Function-Associated Antigen LOX: Lipoxygenase MAA: Marketing Authorization Application MAP: Mitogen-Activated Protein MMP: Matrix Metalloproteinases Mg: milligram ml: milliliter NFκB: Nuclear Factor Kappa B NK: Nuerokinin NSAID: Non-Steroidal Anti-Inflammatory Drug PEG: Polyethylene Glycol R&D: Research & Development RNA: Ribonucleic Acid ROS: Reactive Oxygen Species SIBO: Small Intestine Bacterial Overgrowth SSRI: Selective Serotonin Reuptake Inhibitor TNF-α: Tumor Necrosis Factor-α TRPV-1: Transient Receptor Potential Vanilloid 1 TCA: Tricyclic Antidepressant TLR: Toll-like Receptor TTG: Tissue Transglutaminase UD: Unit Dose UC: Ulcerative Colitis UCB: Union Chimique Belge VCAM: Vascular Cell Adhesion Molecule VLA: Very Late Antigen US FDA: US Food and Drug Administration WBC: White Blood Cell

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

7.3 Sources  Anderson CA, et al. (2011). Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nature Genetics; 43(3): 246-252.  Braegger CP, et al. (1992). Tumour necrosis factor alpha in stool as a marker of intestinal inflammation, Lancet; 339(8785):89-91.  CCFA (2011).Colitis medication options Crohn’s and Colitis Foundation of America. Available from: http://www.ccfa.org/what-are-crohns-and-colitis/what-is-ulcerative-colitis/colitis-medication.html [Accessed on August 10, 2013]  CCFA (2012a). Crohn’s Diagnosis & Testing: Crohn’s and Colitis Foundation of America. Available from: http://www.ccfa.org/what-are-crohns-and-colitis/what-is-crohns-disease/crohns-diagnosis- testing.html [Accessed on August 10, 2013]  CCFA (2012b). Epidemiology of IBD: Crohn’s and Colitis Foundation of America. Available from: http://www.ccfa.org/resources/epidemiology.html [Accessed on August 10, 2013]  Cleveland Clinic (2013). Crohn’s Disease. Cleveland Clinic. Available from: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/gastroenterology/crohns- disease/ [Accessed on August 13, 2013]  Corrao G, et al. (1998). Risk of inflammatory bowel disease attributable to smoking, oral contraception and breastfeeding in Italy: a nationwide case-control study. Cooperative Investigators of the Italian Group for the Study of the Colon and the Rectum (GISC). International Journal of Epidemiology; 27(3): 397-404.  Crowell MD (2004). Role of serotonin in the Pathophysiology of the irritable bowel syndrome. British Journal of Pharmacology; 141(8): 1285-1293.  D'Odorico A, et. al. (2001). Reduced Plasma Antioxidant Concentrations and Increased Oxidative DNA Damage in Inflammatory Bowel Disease. Scandinavian Journal of Gastroenterology; 36 (12):1289-1294  Ekbom A, et al. (1990). Ulcerative colitis and colorectal cancer. The New England Journal of Medicine; 323(18): 1228–1233.  Evangelos J, et al. (2009). Small Intestinal Bacterial Overgrowth: Novel Insight in the Pathogenesis and Treatment of Irritable Bowel Syndrome. Annals of Gastroenterology; 22(2): 1,108–7,471.  Fedorak RN, et al. (2012). Canadian Digestive Health Foundation Public Impact Series 3: Irritable bowel syndrome in Canada. Incidence, prevalence, and direct and indirect economic impact. Canadian Journal of Gastroenterology; 26(5): 252-256.  Fukudo S, et al. (1998). Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with irritable bowel syndrome. Gut; 42: 845–849.  Halpern GM, et al. (1996). Treatment of irritable bowel syndrome with Lacteol Fort: a randomized, double-blind, cross-over trial. The American Journal of Gastroenterology; 91(8):1579-1585.  Hartley MG, et al. (1992). The rectal mucosa-associated microflora in patients with ulcerative colitis; Journal of Medical Microbiology; 36(2): 96–103.  Henriksen M, et al. (2006). Ulcerative colitis and clinical course: Results of a 5-year population-based follow-up study (the IBSEN study). Inflammatory Bowel Diseases; 12 (7): 543–550.  Kathleen A, et al. (2003). Inflammatory Bowel Disease Part I: Ulcerative Colitis – Pathophysiology and  Conventional and Alternative Treatment Options: Alternative Medicine Review, 8; 247- 283.  Kefalides PT, et al. (2002). Ulcerative colitis: Diagnosis and management: Journal of Clinical Outcomes Management, 8; 40-44.  Kornbluth A, et al. (2004). Ulcerative Colitis Practice Guidelines in Adults (Update): American College of Gastroenterology, Practice Parameters Committee. The American Journal of Gastroenterology; 99: 1,371–1,385.

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

7.4 All Pipeline Drugs by Phase 7.4.1 Discovery

Table 10: Gastrointestinal Therapeutics Market, Global, Pipeline (Discovery), 2013 Product name Company Indication Disulfide Rich Peptides For Inflammatory Bowel Diseases LIBS Nexvax-2 Adalimumab biosimilar ONS-3015 ROR-gamma program Adalimumab biosimilar SQ-641

Source: GBI Research, Proprietary Pipeline Products Database [accessed September 10, 2013]

7.4.2 Preclinical

Table 11: Gastrointestinal Therapeutics Market, Global, Pipeline (Preclinical), 2013 Product name Company Indication M-0012 M-0014 MDT-006 PBI-1737 RQ-00202730 RQ-00310941 YH-12852 mesalamine + N-acetylcysteine ANs-42 AW/EPO-002 AW/EPO-003 AW/EPOPD-01 AW/EPOPD-02 AW/EPOPD-06 BLI-1006 ESN-282 GP-1200 Iacvita IP-1510 Leukothera MD-707 PH-46A Prozumab QBECO SSI

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

TP-07 AbGn-168H ABK-16 AMX-256 ANs-42 AZ-17 BL-5040 CT-637 ITP-01 Interleukin-6 Disulfide Rich Peptides Antagonist

Program Interleukin-17 Antagonist Leukothera MP-196 PBI-1737 PH-46A SelK-2 STNM-01 Xpro-1595

Source: GBI Research, Proprietary Pipeline Products Database [accessed September 10, 2013]

7.4.3 IND/CTA-filed

Table 12: Gastrointestinal Therapeutics Market, Global, Pipeline (IND/CTA-filed), 2013 Product name Company Indication Adalimumab Biosimilar

Source: GBI Research, Proprietary Pipeline Products Database [accessed September 10, 2013]

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

7.4.4 Phase I

Table 13: Gastrointestinal Therapeutics Market, Global, Pipeline (Phase I), 2013 Product name Company Indication ASP-7147 DA-6886 larazotide acetate mexiletine hydrochloride ROSE-010 AVX-470 GS-5745 HE-3286 infliximab biosimilar infliximab biosimilar infliximab biosimilar LMW Heparin MMX ORE-1001 SAR-252067 SP-333 rifabutin + clarithromycin + clofazimine Allogenic Adipose-Derived Stem Cells AMG-139 Atrosab bertilimumab CrohnsVax CyCron larazotide acetate QBECO SSI SAR-252067 semapimod SGX-203 SYN-1002 VGX-1027 ZP-1848 zucapsaicin

Source: GBI Research, Proprietary Pipeline Products Database [accessed September 10, 2013]

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

7.4.5 Phase II

Table 14: Gastrointestinal Therapeutics Market, Global, Pipeline (Phase II), 2013 Product name Company Indication Mosapride + Bacillus subtilis + Streptococcas feacium AST-120 AZD-1722 crofelemer DSP-6952 elobixibat LX-1031 LX-1033 ONO-2952 plecanatide rifaximin solabegron hydrochloride mesalamine + N-acetylcysteine metenkefalin + tridecactide AJG-511 AJM-300 AM-3301 AMG-181 anrukinzumab Anti-CD3 Mab ASP-3291 bertilimumab BL-7040 budesonide catridecacog CyCol dersalazine eldelumab etrolizumab GLPG-0974 GSK-1399686 GSK-2245840 GWP-42003 interferon beta-1a LMW Heparin MMX LT-02 MultiStem Natura-Alpha OvaSave

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

PC-SOD PF-00547659 telotristat etiprate tralokinumab TSO vatelizumab VB-201 RPC-1063 vidofludimus metenkefalin + tridecactide Alequel AMG-181 cenplacel-L clazakizumab eldelumab FFP-102 GED-0301 HMPL-004 laquinimod sodium mesalamine CR NI-0401 NN-8828 OvaSave PF-00547659 PF-04236921 rifaximin teduglutide tetomilast TNF-Kinoid tofacitinib TRK-170 TSO vidofludimus

Source: GBI Research, Proprietary Pipeline Products Database [accessed September 10, 2013]

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

7.4.6 Phase III

Table 15: Gastrointestinal Therapeutics Market, Global, Pipeline (Phase III), 2013 Product name Company Indication asimadoline dexloxiglumide eluxadoline ibodutant linaclotide rifaximin budesonide budesonide DIMS-0150 HMPL-004 infliximab levocarnitine propionate hydrochloride mesalamine mesalamine CR mesalamine ER tofacitinib adalimumab AJM-300 budesonide infliximab metronidazole remestemcel-L ustekinumab vedolizumab

Source: GBI Research, Proprietary Pipeline Products Database [accessed September 10, 2013]

7.4.7 Pre-Registration

Table 16: Gastrointestinal Therapeutics Market, Global, Pipeline (Pre-Registration), 2013 Product name Company Indication mesalamine infliximab biosimilar vedolizumab

Source: GBI Research, Proprietary Pipeline Products Database [accessed September 10, 2013]

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

7.4.8 Undisclosed

Table 17: Gastrointestinal Therapeutics Market, Global, Pipeline (Undisclosed), 2012 Product name Company Indication AM-3301 GIC-1001 YKP-10811 adalimumab Biosimilar alicaforsen sodium clotrimazole FX-003 GED-0507 SD-010 rifabutin + clarithromycin + clofazimine adalimumab biosimilar ApoCell GLPG-0634 IBI-303 IBP-M004-AM ORE-1001

Source: GBI Research, Proprietary Pipeline Products Database [accessed September 10, 2013]

7.5 Market Forecasts to 2019 7.5.1 Asia-Pacific Markets

7.5.1.1 Irritable Bowel Syndrome

Table 18: Gastrointestinal Therapeutics Asia-Pacific Markets, Irritable Bowel Syndrome, Market Forecast, 2012–2019 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence population ('000) Prescription population ('000) ACoT ($) Revenue

($m)

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

7.5.1.2 Ulcerative Colitis

Table 19: Gastrointestinal Therapeutics Market, Asia-Pacific Markets, Ulcerative Colitis, Market Forecast, 2012–2019 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence population

('000) Prescription population

('000) ACoT ($) Revenue ($m)

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

7.5.1.3 Crohn’s Disease

Table 20: Gastrointestinal Therapeutics Market, Asia-Pacific Markets, Crohn’s Disease, Market Forecast, 2012–2019 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence population ('000) Prescription population

('000) ACoT ($) Revenue ($m)

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

7.5.2 Australia

7.5.2.1 Irritable Bowel Syndrome

Table 21: Gastrointestinal Therapeutics Market, Australia, Irritable Bowel Syndrome, Market Forecast, 2012–2019 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence population ('000) Prescription population

('000) ACoT ($) Revenue ($m)

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

7.5.2.2 Ulcerative Colitis

Table 22: Gastrointestinal Therapeutics Market, Australia, Ulcerative Colitis, Market Forecast, 2012– 2019 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence population ('000) Prescription population ('000) ACoT ($) Revenue ($m)

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

7.5.2.3 Crohn’s Disease

Table 23: Gastrointestinal Therapeutics Market, Australia, Crohn’s Disease, Market Forecast, 2012– 2019 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence population ('000) Prescription population ('000) ACoT ($) Revenue ($m)

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

7.5.3 India

7.5.3.1 Irritable Bowel Syndrome

Table 24: Gastrointestinal Therapeutics Market, India, Irritable Bowel Syndrome, Market Forecast, 2012–2019 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence population ('000) Prescription population ('000) ACoT ($) Revenue ($m)

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

7.5.3.2 Ulcerative Colitis

Table 25: Gastrointestinal Therapeutics Market, India, Ulcerative Colitis, Market Forecast, 2012–2019 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence population ('000) Prescription population ('000) ACoT ($) Revenue ($m)

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

7.5.3.3 Crohn’s Disease

Table 26: Gastrointestinal Therapeutics Market, India, Crohn’s Disease, Market Forecast, 2012–2019 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence population ('000) Prescription population ('000) ACoT ($) Revenue ($m)

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

7.5.4 China

7.5.4.1 Irritable Bowel Syndrome

Table 27: Gastrointestinal Therapeutics Market, China, Irritable Bowel Syndrome, Market Forecast, 2012–2019 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence population ('000) Prescription population ('000) ACoT ($) Revenue ($m)

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

7.5.4.2 Ulcerative Colitis

Table 28: Gastrointestinal Therapeutics Market, China, Ulcerative Colitis, Market Forecast, 2012– 2019 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence population ('000) Prescription population ('000) ACoT ($) Revenue ($m)

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

7.5.4.3 Crohn’s Disease

Table 29: Gastrointestinal Therapeutics Market, China, Crohn’s Disease, Market Forecast, 2012–2019 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence population ('000) Prescription population ('000) ACoT ($) Revenue ($m)

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

7.5.5 Japan

7.5.5.1 Irritable Bowel Syndrome

Table 30: Gastrointestinal Therapeutics Market, Japan, Irritable Bowel Syndrome, Market Forecast, 2012–2019 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence population ('000) Prescription population

('000) ACoT ($) Revenue ($m)

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

7.5.5.2 Ulcerative Colitis

Table 31: Gastrointestinal Therapeutics Market, Japan, Ulcerative Colitis, Market Forecast, 2012– 2019 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence population ('000) Prescription population ('000) ACoT ($) Revenue ($m)

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

7.5.5.3 Crohn’s Disease

Table 32: Gastrointestinal Therapeutics Market, Japan, Crohn’s Disease, Market Forecast, 2012–2019 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence population ('000) Prescription population ('000) ACoT ($) Revenue ($m)

Source: GBI Research Proprietary Products Database [accessed October 16, 2013]

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

7.6 Research Methodology GBI Research’s dedicated research and analysis teams consist of experienced professionals with marketing, market research and consulting backgrounds in the pharmaceutical industry as well as advanced statistical expertise. GBI Research adheres to the codes of practice of the Market Research Society (www.mrs.org.uk) and the Strategic and Competitive Intelligence Professionals (www.scip.org). All GBI Research databases are continuously updated and revised. 7.6.1 Coverage The objective of updating GBI Research coverage is to ensure that it represents the most up-to-date vision of the industry possible. Changes to the industry taxonomy are built on the basis of extensive research of company, association and competitor sources. Company coverage is based on three key factors: market capitalization, revenues and media attention/innovation/market potential. An exhaustive search of 56 member exchanges is conducted and companies are prioritized on the basis of their market capitalization. The estimated revenues of all major companies, including private and governmental, are gathered and used to prioritize coverage. Companies which are making the news, or which are of particular interest due to their innovative approach, are prioritized. GBI Research aims to cover all major news events and deals in the pharmaceutical industry, updated on a daily basis. The coverage is further streamlined and strengthened with additional inputs from GBI Research’s expert panel (see below). 7.6.2 Secondary Research The research process begins with exhaustive secondary research on internal and external sources in order to source qualitative and quantitative information relating to each market. The secondary research sources that are typically referred to include, but are not limited to:  Company websites, annual reports, financial reports, broker reports, investor presentations and SEC filings  Industry trade journals, scientific journals and other technical literature  Internal and external proprietary databases  Relevant patent and regulatory databases  National government documents, statistical databases and market reports  Procedure registries  News articles, press releases and web-casts specific to the companies operating in the market. 7.6.3 Primary Research GBI Research conducts hundreds of primary interviews a year with industry participants and commentators in order to validate its data and analysis. A typical research interview fulfills the following functions:  It provides first-hand information on the market size, market trends, growth trends, competitive landscape and future outlook.  It helps to validate and strengthen secondary research findings.  It further develops the analysis team’s expertise and market understanding.

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

 Primary research involves email and telephone interviews as well as face-to-face interviews for each market, category, segment and sub-segment across geographies. The participants who typically take part in such a process include, but are not limited to:  Industry participants: CEOs, VPs, marketing/product managers, market intelligence managers and national sales managers  Hospital stores, laboratories, pharmacies, distributors and paramedics  Outside experts: investment bankers, valuation experts, research analysts specializing in specific medical equipment markets  Key opinion leaders: physicians and surgeons specializing in different therapeutic areas corresponding to different kinds of medical equipment. 7.6.4 Therapeutic Landscape Revenues for each indication, geography-wise, are arrived at by utilizing the GBI Research market forecasting model. The global revenue for each indication is the sum value of the revenue generated by all seven regions. The annual cost of therapy for each indication is arrived at by considering the cost of the drugs, dosage of the drugs and the duration of the therapy. The generic share of the market for each indication is obtained by calculating the prescription share for generic drugs and the respective cost of treatment. The treatment usage pattern which includes quantitative data on the diseased population, treatment- seeking population, diagnosed population and treated population for an indication, is arrived at by referring to various sources as mentioned below. GBI Research uses the epidemiology-based treatment flow model to forecast market size for therapeutic indications. Epidemiology-based Forecasting The forecasting model used at GBI Research makes use of epidemiology data gathered from research publications and primary interviews with physicians to represent the treatment flow patterns for individual diseases and therapies. The market for any disease segment is directly proportional to the volume of units sold and the price per unit. Sales = Volume of Units sold X Price per Unit The volume of units sold is calculated on the average dosage regimen for that disease, duration of treatment and number of patients who are prescribed drug treatment (prescription population). Prescription population is calculated as the percentage of population diagnosed with a disease (diagnosis population). Diagnosis population is the population diagnosed with a disease expressed as a percentage of the population that is seeking treatment (treatment-seeking population). Prevalence of a disease (diseased population) is the percentage of the total population who suffer from a disease/condition. Data on the treatment seeking rate, diagnosis rate and prescription rate, if unavailable from research publications, are gathered from interviews with physicians and are used to estimate the patient volumes for the disease under consideration. Therapy uptake and compliance data are fitted in the forecasting model to account for patient switching and compliance behavior. To account for differences in patient affordability of drugs across various geographies, macroeconomic data such as inflation and GDP; and healthcare indicators such as healthcare spending, insurance coverage and average income per individual are used. Annual cost of therapy is calculated using product purchase frequency and the average price of the therapy. Product purchase frequency is calculated from the dosage data available for the therapies and drug prices are gathered from public sources. The epidemiology-based forecasting model uses a bottom-up methodology and it makes use of estimations in the absence of data from research publications. Such estimations may result in a final market value which is different from the actual value. To correct this ‘gap’ the forecasting model uses ‘triangulation’ with the

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

help of base year sales data (from company annual reports, internal and external databases) and sales estimations. Analogous Forecasting Methodology Analogous forecasting methodology is used to account for the introduction of new products, patent expiries of branded products and subsequent introduction of generics. Historic data for new product launches and generics penetration are used to arrive at robust forecasts. Increase or decrease of prevalence rates, treatment seeking rate, diagnosis rate and prescription rate are fitted into the forecasting model to estimate market growth rate. The proprietary model enables GBI Research to account for the impact of individual drivers and restraints in the growth of the market. The year of impact and the extent of impact are quantified in the forecasting model to provide close-to-accurate data sets. Diseased Population The diseased population for any indication is the prevalence. The prevalence rates are usually obtained from various journals, online publications, sources such as the World Health Organization (WHO) or associations and foundation websites for that particular disease. Prescription Population For any disease, multiple treatment options exist. For example, in cancer treatment various treatment options such as surgery, radiation therapy and drug therapy are available. The prescription population is defined as the number of patients who are prescribed drug therapy. This is calculated as a percentage of the diagnosis population. The prescription population is primarily driven by the age at which the disease is diagnosed, the disease stage, patient health and the cost of drug treatment.

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

7.6.4.1 Market Size by Geography The treatment usage pattern and annual cost of treatment in each country has been taken into consideration in deriving individual country market size.

Figure 25: GBI Research Market Forecasting Model

GBI Research Market Sizing Model

D isease Population General Po pulation 743,535,048 Qualifying condition 1 (Age/Sex/Occupation etc) Qualifying condition 2 (Age/Sex/Occupation etc) Prevalence tissue valve disease 0.2% 1,784,484 Qualifying condition (com plication, severity) DISEASED POPULATION 1,784,484

Treatment Flow Patterns Treatm ent Seeking Rate (Symptoms/Dis Awareness) 89% 1,588,191 Diagn osis Rate (Clinical and Diagn ostic Tests) 75% 1,191,143 Prescription Rate (Physician Perceptio n, Treatment Effectiv e n ess) Tissue Valve 70% 833,800 Other Treatm ents for Valve (Surg/M ed/N one) - Fulfillm en t A vailabilit y NA W illingness to Use (Patient Perceptions) NA Ready to U se (Surgery eligibility, R euse etc) NA Afford ability at Price HE as % of GDP spend Average Incom e (per individual) Patient Out-of-pocket Budget (Annual) Budget allocation to one-time surgery Budget allocation to other h ealth needs Average Payor Coverage P atient Liability Target Price (@20% pat liab) ASP for Cost of Therapy TOTAL PATIENT VOLUMES Pro duct Purchase Frequency 1 TOTAL UNIT VOLUMES

Pricing per Un it $ 18,000 Inflation Price D ec rease due to com petition

Market Value Source: GBI Research

The above figure represents a typical forecasting model followed in GBI Research. As discussed previously, the model is built on the treatment flow patterns. The model starts with the general population, then diseased population as a percentage of the general population and then follows the treatment seeking population as a percentage of the diseased population and diagnosed population as a percentage of the treatment seeking population. Finally, the total volume of units sold is calculated by multiplying the treated population by the average dosage per year per patient. 7.6.5 Geographical Landscape GBI Research analyzes four geographical locations: Australia, India, China and Japan. The total market size for each country is provided, which is the sum value of the market sizes of all the indications for that particular country. The maximum and minimum estimated market sizes are then provided by adjusting all variables expected to affect the market during the forecast period in order to provide the best and worst case scenarios.

Gastrointestinal Therapeutics in Asia-Pacific Market – Appendix

Articles from research journals and agency publications such as Gastrointestinal, National Institute of Health and ClinicalTrials.gov are the source of data for the estimation of market size and making forecasts. 7.6.6 Pipeline Analysis This section provides a list of molecules at various stages in the pipeline for various indications. The list is sourced from internal database and validated for the accuracy of phase and mechanism of action at ClinicalTrials.gov and company websites. The section also includes a list of promising molecules which is narrowed down based on the results of the clinical trials at various stages and the novelty of mechanism of action. A heat map, sourced from relevant clinical trials, is provided in order to compare these products to one another in addition to currently marketed products. The latest press releases issued by the company and news reports are also the source of information for the status of the molecule in the pipeline. This list of pipeline molecules, in conjunction with a list of ongoing and completed clinical trials, is analyzed in this section, and a full breakdown of pipeline molecules and clinical trials by Phase, molecule type and molecular target is provided. 7.7 Expert Panel Validation GBI Research uses a panel of experts to cross verify its databases and forecasts. GBI Research expert panel comprises marketing managers, product specialists, and international sales managers from pharmaceutical companies, academics from research universities and key opinion leaders from hospitals. Historic data and forecasts are relayed to GBI Research’s expert panel for feedback and are adjusted in accordance with their feedback.

7.9 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, GBI Research.