NSCLC Therapeutics in Asia-Pacific Markets to 2019 Personalized Therapies Focus on Untapped Segment of Squamous Cell Carcinoma to Expand Treatment Pool

GBI Research Report Guidance

GBI Research Report Guidance  Chapter two provides an overview of the disease, its symptoms, etiology, pathophysiology, diagnosis, classification, epidemiology, prognosis, staging and treatment options.

 Chapter three provides a detailed profiling and comparative heat map analysis in terms of safety and efficacy for currently marketed products in the NSCLC market.

 Chapter four presents a detailed pipeline analysis for the disease, including individual product profiles, a comparative efficacy and safety profile heat map analysis of the most promising pipeline products as well as analyses on the distribution of molecule types across the NSCLC developmental pipeline, the molecular targets of pipeline mAbs and the developmental program types. In addition, detailed analyses of the clinical trial failure rates, the clinical trial durations by phase and clinical trial sizes, by participant numbers.

 Chapter five provides market forecasts for countries across the globe, with special attention given to the APAC countries: India, Australia, China and Japan. The multiple scenario forecasts take into account a range of factors that are likely to vary and provide a clear perspective on the level of the potential degree of variance in the market sizes.

 Chapter six covers the major deals that have taken place in the disease market in recent years. Coverage includes co-development deals and licensing agreements, which are segmented on the basis of geography and total value. A concomitant analysis of the licensing deal values for products by molecule types and molecular targets is also provided.

Executive Summary

Modest growth is driven by Executive Summary the increasing incidence Non-Small Cell Lung Cancer Therapeutics Market to Witness Modest Growth over Forecast Period population and expected launch of premium-priced The launch of premium-priced targeted therapies has changed the Non-Small Cell Lung Cancer (NSCLC) pipeline molecules. treatment paradigm and elevated the NSCLC market during the past decade. This growth is expected to continue at a moderate pace during the forecast period, culminating in growth from $XX billion in 2012 to $XX billion by 2019, in Asia-Pacific (APAC). In 2012, Japan and China had respective shares of XX% and XX% in the NSCLC market of APAC. India and Australia had much lower shares of XX% and XX% respectively. An aging population and increasing number of NSCLC incident cases, especially in China and India, drive the growth in the market. The expected launches of premium-priced novel antibodies and immunotherapies in the first and second lines of therapies, targeting both Non-Squamous NSCLC (NOS NSCLC) and Squamous NSCLC (S NSCLC) patients, widen the eligible treatment population, maximize the patient share and ultimately drive market growth. In spite of many expected drug launches, without the risk of generic erosion of currently entrenched therapies, growth is expected to be marginal due to the dominant generic penetration of a few NSCLC drugs in India. A complex and lengthy regulatory pathway and limited reimbursement from national insurance programs, in China, as well as regular price cuts, in Japan, also limit growth in the APAC market.

Non-Small Cell Lung Cancer Therapeutics, Asia-Pacific, Market Size ($bn), 2012 and 2019 Market size ($bn)size Market

2012 2019

China India Japan Australia

Source: GBI Research Proprietary Marketed Products Database

Table of Contents

1 Table of Contents 1 Table of Contents ...... 6 1.1 List of Tables ...... 8 1.2 List of Figures...... 8 2 Introduction...... 10 2.1 Symptoms ...... 10 2.2 Etiology ...... 11 2.3 Pathophysiology ...... 12 2.4 Co-morbidities and Complications ...... 12 2.5 Diagnosis ...... 13 2.5.1 Physical Examination...... 13 2.5.2 Sputum Cytology ...... 13 2.5.3 Imaging Tests...... 13 2.5.4 Biopsy ...... 14 2.6 Classification...... 15 2.6.1 Adenocarcinoma ...... 15 2.6.2 Squamous Cell Carcinoma ...... 15 2.6.3 Large Cell Carcinoma ...... 15 2.7 Epidemiology ...... 15 2.8 Prognosis and Disease Staging ...... 16 2.8.1 Staging ...... 16 2.9 Treatment Options ...... 18 2.9.1 Surgery and Radiation Therapy ...... 18 2.9.2 Pharmacological ...... 18 2.9.3 Treatment Algorithms and Prescribing Habits ...... 20 3 Marketed Products ...... 23 3.1 Therapeutic Landscape ...... 24 3.1.1 Alimta (pemetrexed disodium) – Eli Lilly and Company ...... 24 3.1.2 Abraxane (nab-paclitaxel) – Celgene ...... 26 3.1.3 Iressa (gefitinib) – AstraZeneca ...... 28 3.1.4 Tarceva (erlotinib hydrochloride) – F. Hoffmann-La Roche ...... 29 3.1.5 Xalkori (crizotinib) – Pfizer ...... 31 3.1.6 Avastin (bevacizumab) – F. Hoffmann-La Roche ...... 32 3.1.7 Gilotrif (afatinib) – Boehringer Ingelheim ...... 34 3.2 Comparative Efficacy and Safety...... 34 4 Pipeline Products ...... 37 4.1 Overall Pipeline...... 37 4.2 Pipeline Analysis by Molecule Type ...... 39 4.3 Pipeline Analysis by Mechanism of Action ...... 41 4.4 Clinical Trials ...... 44 4.4.1 Failure Rate ...... 44 4.4.2 Patient Enrollment and Clinical Trial Size ...... 46 4.4.3 Duration ...... 48 4.5 Promising Drug Candidates in the Pipeline ...... 50 4.5.1 Ramucirumab (IMC-1121B) – Eli Lilly and Company ...... 50 4.5.2 Necitumumab (IMC-11F8) – Eli Lilly and Company ...... 50 4.5.3 Onartuzumab (MetMab) – F. Hoffmann-La Roche ...... 51 4.5.4 Ganetespib (STA-9090) – Synta ...... 52 4.5.5 Nintedanib (BIBF1120) – Boehringer Ingelheim ...... 52 4.5.6 Dacomitinib (PF-00299804) – Pfizer ...... 53 4.5.7 LDK378 – Novartis ...... 54

Table of Contents

4.5.8 Yervoy (ipilimumab) – Bristol-Myers Squibb ...... 54 4.5.9 Nivolumab (BMS-936558/ONO-4538) – Bristol Myers Squibb ...... 55 5 Market Forecast to 2019 ...... 56 5.1 Geographical Markets ...... 56 5.1.1 APAC Market ...... 56 5.1.2 India ...... 57 5.1.3 Australia ...... 60 5.1.4 China ...... 62 5.1.5 Japan ...... 64 5.2 Drivers and Barriers for the Disease Market...... 66 5.2.1 Drivers ...... 66 5.2.2 Barriers ...... 66 6 Deals and Strategic Consolidations ...... 68 6.1 Major Co-development Deals ...... 70 6.1.1 OxOnc Enters Co-development Agreement with Pfizer for Crizotinib ...... 71 6.1.2 SFJ Pharma Enters Co-development Agreement with Pfizer for Dacomitinib ...... 71 6.1.3 Merck Enters Co-development Agreement with Endocyte for Cancer Drug ...... 72 6.1.4 Roche Enters Co-development Agreement with Clovis ...... 72 6.1.5 Abbott Laboratories Enters Co-development Agreement with GlaxoSmithKline ...... 72 6.2 Major Licensing Deals ...... 72 6.2.1 Chugai Enters Licensing Agreement with Roche for Onartuzumab and Lebrikizumab ...... 73 6.2.2 Azaya Enters Licensing Agreement with CANbridge Life Sciences for ATI-1123 ...... 74 6.2.3 Merck Expands Licensing Agreement with Biomira ...... 74 6.2.4 Clovis Enters Licensing Agreement with Avila Therapeutics ...... 74 7 Appendix ...... 75 7.1 All Pipeline Drugs by Phase ...... 75 7.1.1 Discovery ...... 75 7.1.2 Preclinical ...... 75 7.1.3 IND-filed ...... 77 7.1.4 Phase I ...... 78 7.1.5 Phase II ...... 80 7.1.6 Phase III ...... 83 7.1.7 Undisclosed...... 84 7.2 Market Forecasts to 2019 ...... 89 7.2.1 APAC ...... 89 7.2.2 India ...... 90 7.2.3 Australia ...... 90 7.2.4 China ...... 90 7.2.5 Japan ...... 91 7.3 Market Definitions ...... 91 7.4 Abbreviations ...... 91 7.5 Bibliography ...... 94 7.6 Research Methodology ...... 97 7.6.1 Coverage ...... 97 7.6.2 Secondary Research ...... 98 7.6.3 Primary Research ...... 98 7.6.4 Therapeutic Landscape ...... 98 7.6.5 Geographical Landscape ...... 100 7.6.6 Pipeline Analysis...... 101 7.7 Expert Panel Validation ...... 101 7.8 Contact Us ...... 101 7.9 Disclaimer...... 101

Table of Contents

1.1 List of Tables Table 1: Non-Small Cell Lung Cancer Market, Common Symptoms of Non-Small Cell Lung Cancer ...... 11 Table 2: Non-Small Cell Lung Cancer Market, Risk Factors of Non-Small Cell Lung Cancer Market ...... 12 Table 3: Non-Small Cell Lung Cancer Market, American Joint Committee on Cancer’s Tumor Node Metastasis Staging System, 2010 ...... 17 Table 4: Non-Small Cell Lung Cancer Market, Global, Pharmaceutical Pipeline (Discovery), 2013 ...... 75 Table 5: Non-Small Cell Lung Cancer Market, Global, Pharmaceutical Pipeline (Preclinical), 2013 ...... 75 Table 6: Non-Small Cell Lung Cancer Market, Global, Pharmaceutical Pipeline (IND-filed), 2013 ...... 77 Table 7: Non-Small Cell Lung Cancer Market, Global, Pharmaceutical Pipeline (Phase I), 2013...... 78 Table 8: Non-Small Cell Lung Cancer Market, Global, Pharmaceutical Pipeline (Phase II), 2013 ...... 80 Table 9: Non-Small Cell Lung Cancer Market, Global, Pharmaceutical Pipeline (Phase III), 2013 ...... 83 Table 10: Non-Small Cell Lung Cancer Market, Global, Pharmaceutical Pipeline (Undisclosed), 2013 ...... 84 Table 11: Non-Small Cell Lung Cancer Market, Asia-Pacific, Market Forecast, 2012–2019 ...... 89 Table 12: Non-Small Cell Lung Cancer Market, India, Market Forecast, 2012–2019 ...... 90 Table 13: Non-Small Cell Lung Cancer Market, Australia, Market Forecast, 2012–2019 ...... 90 Table 14: Non-Small Cell Lung Cancer Market, China, Market Forecast, 2012–2019 ...... 90 Table 15: Non-Small Cell Lung Cancer Market, Japan, Market Forecast, 2012–2019 ...... 91

1.2 List of Figures Figure 1: Non-Small Cell Lung Cancer Market, Asia-Pacific, Distribution of Prevalence Population, 2012– 2019 ...... 16 Figure 2: Non-Small Cell Lung Cancer Market, Treatment Algorithm for Early and Advanced Localized Tumors Stages IIIA and IIIB, 2013 ...... 20 Figure 3: Non-Small Cell Lung Cancer Market, Treatment Algorithm for Early and Advanced Localized Tumors Stages IIIA and IIIB, 2013 ...... 21 Figure 4: Non-Small Cell Lung Cancer Market, Treatment Algorithm for Advanced Metastatic Tumors, 2013 ...... 22 Figure 5: Non-Small Cell Lung Cancer Market, Global, Annual Sales, 2012 ...... 24 Figure 6: Non-Small Cell Lung Cancer Market, Global, Alimta (pemetrexed disodium) Annual Sales ($bn), 2004–2012 ...... 25 Figure 7: Non-Small Cell Lung Cancer Market, Global, Abraxane (nab-paclitaxel) Annual Sales ($m), 2009– 2012 ...... 27 Figure 8: Non-Small Cell Lung Cancer Market, Global, Iressa (gefitinib) Annual Sales ($m), 2005–2012 ....28 Figure 9: Non-Small Cell Lung Cancer Market, Global, Tarceva (erlotinib) Annual Sales ($bn), 2006–2012 30 Figure 10: Non-Small Cell Lung Cancer Market, Global, Xalkori (crizotinib) Annual Sales ($m), 2012–2013 .31 Figure 11: Non-Small Cell Lung Cancer Market, Global, Avastin (bevacizumab) Annual Sales ($bn), 2006– 2012 ...... 33 Figure 12: Non-Small Cell Lung Cancer Market, Global, Comparative Safety and Efficacy of Marketed Products (Heat Map), 2013...... 35 Figure 13: Non-Small Cell Lung Cancer Market, Global, Pipeline by Stage of Development, Program Type and Route of Administration, 2013 ...... 38 Figure 14: Non-Small Cell Lung Cancer Market, Global, Pipeline by Molecule Type and Stage of Development, 2013...... 40 Figure 15: Non-Small Cell Lung Cancer Market, Global, Pipeline by Mechanism of Action, 2013 ...... 42 Figure 16: Non-Small Cell Lung Cancer Market, Global, Pipeline by Mechanism of Action, Molecule Type and Stage of Development (Number), 2013 ...... 43 Figure 17: Non-Small Cell Lung Cancer Market, Global, Clinical Trial Failure Rate (%), 2013 ...... 45 Figure 18: Non-Small Cell Lung Cancer Market, Global, Clinical Trial Size (Participants), 2013 ...... 47 Figure 19: Non-Small Cell Lung Cancer Market, Global, Pipeline Clinical Trial Duration (months), 2013 .....49 Figure 20: Non-Small Cell Lung Cancer Market, Asia-Pacific, Market Size, 2012–2019 ...... 57 Figure 21: Non-Small Cell Lung Cancer Market, India, Market Size, 2012–2019 ...... 59 Figure 22: Non-Small Cell Lung Cancer Market, Australia, Market Size, 2012–2019 ...... 61 Figure 23: Non-Small Cell Lung Cancer Market, China, Market Size, 2012–2019 ...... 63 Figure 24: Non-Small Cell Lung Cancer Market, Japan, Market Size, 2012–2019 ...... 65

Table of Contents

Figure 25: Non-Small Cell Lung Cancer Market, Global Deals by Value, Year and Stage of Development, 2006–2013 ...... 69 Figure 26: Non-Small Cell Lung Cancer Market, Global, Deals by Phase, Molecule Type and Mechanism of Action, 2006–2013 ...... 70 Figure 27: Non-Small Cell Lung Cancer Market, Global, Co-development Deals by Geography, 2006–2013 71 Figure 28: Non-Small Cell Lung Cancer Market, Global, Licensing Deals by Geography, 2006–2013 ...... 73 Figure 29: GBI Research Market Forecasting Model (Example) ...... 100

Introduction

2 Introduction Lung cancer is the most common cancer accounting Non-Small Cell Lung Cancer (NSCLC) is a leading cause of cancer morbidity and mortality worldwide, with an for XX% and XX% of all alarming increase in developing countries. Lung cancer is the most common cancer for males, accounting cancer deaths in males and for XX% of all new cancer cases and XX% of all cancer deaths. It accounts for XX% of cancer-related deaths females repectively. among females (Jemal et al., 2011). Approximately XX–XX% of lungs cancers are NSCLCs. Adenocarcinoma is the dominant histologic sub-type of NSCLC, accounting for about XX% of all lung cancers. Other sub-types are Squamous Cell Carcinoma (SCC), which accounts for XX–XX% of all lung cancers, and Large Cell Carcinoma (LCC), which accounts for about XX–XX% of all lung cancers (ACS, 2013). The majority of NSCLC cases are diagnosed in the advanced stages after the disease has invaded locally or after metastasis to distant sites. Diagnosed patients have an extremely poor prognosis and low survival rates. Conventional treatment options for advanced-stage NSCLC patients have been dominated by platinum- based chemotherapy regimens. However, the advent of targeted therapies such as Iressa (gefitinib), Tarceva (erlotinib), Xalkori (crizotinib) and Gilotrif (afatinib) for specific molecular sub-populations that have distinctive gene mutations has remodeled the NSCLC treatment landscape. During the forecast period, the competitive landscape will continue to evolve with the expected launch of potential new targeted therapies. The robust NSCLC pipeline and promising drug candidates are capable of addressing the many unmet needs in the NSCLC market. The expected launch of pipeline candidates ramucirumab, necitumumab and Yervoy, during the forecast period, will address the treatment options for SCC, which currently has targeted therapy. In addition, the launch of the first-in-class Programmed Cell Death Protein (PD) 1 immunotherapy, nivolumab, will be a significant contributor to market growth during the forecast period. The NSCLC market will continue to grow during the forecast period, driven by the aging population and the increasing incidence in the Asia-Pacific (APAC) region, as well as the expected launch of premium-priced pipeline agents. 2.1 Symptoms The signs and symptoms of NSCLC are not usually manifested during the early stages of the disease. However, the symptoms develop to be recognizable as the disease aggravates. The onset of symptoms is not immediate, and they typically take a long time to progress. The most common symptoms of lung cancer include:

 Chest pain  Coughing, which may present as hemoptysis (coughing up blood)  Dyspnea (shortness of breath)  Weight loss  Hoarseness  Infections such as bronchitis and pneumonia Additional symptoms can be caused due to primary local invasion into thoracic structures or distant metastases, which include:

 Dysphagia (difficulty in swallowing)  Facial edema  Bone pain  Neurological defects, such as weakness or numbness of limbs, dizziness, balance problems, or seizures  Pulmonary fibrosis  Supraclavicular lymphadenopathy

Marketed Products

3.1.3 Iressa (gefitinib) – AstraZeneca Iressa was the first EGFR-TK inhibitor to be approved for use in lung cancer treatment. Similar to Tarceva, Iressa is a kinase inhibitor that selectively targets EGFR. It is designed to specifically target the tumor with no need to use maximum tolerated dose. Iressa was approved by FDA under accelerated approval regulations in May 2003 for the treatment of advanced or malignant NSCLC. The Australian TGA also approved the product, in the same year. However, due to its failure to provide superior OS compared with standard chemotherapy in all patients, regardless of EGFR mutation, Iressa’s marketing status was revoked in the US by the FDA in 2005. Iressa received its first approval for NSCLC in Japan in 2002. It received the regulatory approval in 2004 and 2005 in India and China respectively. The EU approved the drug in 2009, and it is also reimbursed for conditional first-line treatment in the UK (NICE, 2010). In 2012, the Pharmaceutical Management Agency, or Pharmac, announced that it would be funding gefitinib (Iressa) for lung cancer, also. Iressa has been marketed by AstraZeneca since its launch in 2002. It is also being investigated in Phase III trials for treatment of breast cancer and SCC of the head and neck. The following figure displays the annual sales of Iressa from 2005 to 2012, as well as market approvals and important events in the life cycle of Iressa.

Figure 8: Non-Small Cell Lung Cancer Market, Global, Iressa (gefitinib) Annual Sales ($m), 2005–2012

2012: Pharmac approval for funding

2010: NICE approval for NSCLC Revenue($m)

2009: EC approval for NSCLC with EGFR mutations 2005: Approval in China for NSCLC

2005 2006 2007 2008 2009 2010 2011 2012

2002: Approval in Japan to treat locally advanced or metastatic NSCLC 2003: FDA and TGA approval for locally advanced or metastatic NSCLC 2004: Approval in India for NSCLC

Source: GBI Research, Proprietary Marketed Products Database Note: NICE: National Institute for Health and Care Excellence

Pipeline Products

4.2 Pipeline Analysis by Molecule Type The developmental pipeline of NSCLC appears to be highly active with diverse molecule types. The pipeline is dominated by small molecules with XX drug candidates or XX% of the overall pipeline. When segregated on the basis of stage of development, the number of small molecules is highest in Phase II trials, which account for XX% of the Phase II product candidates, followed by the preclinical stage (XX%) and Phase I (XX%). The share of small molecules is markedly higher (XX%) in the confirmatory Phase III trials also, in comparison with other molecule types. In the overall pipeline, mAbs also occupy a major share, followed by small molecules. Of the investigational products, XX drug candidates (XX%) are found to be mAbs. The share of mAbs is highest in the Phase I stage of development (XX%) followed by Phase III (XX%), Phase II (XX%) and the preclinical stage (XX%). Of the XX NSCLC pipeline products that are currently IND/CTA-filed, one molecule is a mAb. As well as these two major molecule types, vaccines also occupy a significant share (XX%, XX molecules). The number of molecules which are categorized as biosimilars, proteins and peptides is significantly less in comparison with small molecules and mAbs.

Pipeline Products

Figure 14: Non-Small Cell Lung Cancer Market, Global, Pipeline by Molecule Type and Stage of Development, 2013

A) NSCLC pipeline by molecule type

Biosimilar

Cell therapy

Gene therapy

Monoclonal antibody

Peptide

Protein

Small molecule

Vaccine

B) NSCLC pipeline by molecule type and by phase Pipeline(number)molecules filed - PhaseI PhaseII PhaseIII Discovery Preclinical registration - IND/CTA Pre Biosimilar Cell therapy Gene therapy Monoclonal antibody

Peptide Protein Small molecule Vaccine Source: GBI Research, Proprietary Pipeline Products Database

Pipeline Products

4.4.3 Duration The mean clinical trial duration for Phase III NSCLC clinical trials was slightly higher than the average for oncology and the overall industry average. At Phases I and II, it was comparable. This implies that the cost of running clinical trials for NSCLC cancer products might be moderately higher than for oncology, and the industry as a whole. The average duration of a macular degeneration clinical trial was found to be XX, XX and XX months for Phase I, Phase II and Phase III respectively. In all the stages of development, the mean clinical trial durations differed among molecule types. The clinical trial duration for the two prominent molecule types (small molecules and mAbs) are comparable across all the phases. The duration for small molecules was slightly higher when compared with mAbs in Phase II and III and vice-versa for Phase I clinical trials. As seen in Figure 19, in comparison with all other molecule types, clinical trial duration is found to be longer for vaccines and shorter for peptides and proteins.

Pipeline Products

Figure 19: Non-Small Cell Lung Cancer Market, Global, Pipeline Clinical Trial Duration (months), 2013

A) Phase I Trial duration (months)Trial

Overall Small molecules Monoclonal Vaccines Peptides antibodies Third quartile Second quartile Indiction average Industry average Therapy area average B) Phase II Trial duration (months)Trial

Overall Small molecules Monoclonal Vaccines Peptides antibodies Third quartile Second quartile Indication average Industry average Therapy area average C) Phase III Trial duration (months)Trial

Overall Small molecules Monoclonal Vaccines Peptides antibodies Third quartile Second quartile Indication average

Industry average Therapy area average Source: GBI Research, Proprietary Clinical Trials Database

Market Forecast to 2019

5.1.2.2 Annual Cost of Therapy The Annual Cost of Therapy (ACoT) for NSCLC in India is estimated to have been $XXm in 2012. Among all the APAC markets, the Indian market is considered to have the lowest ACoT. Though the ACoT for NSCLC in India is low compared with other regions it is expected to grow at a rapid pace, at a CAGR of XX%, reaching $XXm by the end of the forecast period. The key reason for the low ACoT in India is due to the entrenchment of generic drugs and recent patent rulings that allow for the marketing of generic versions of NSCLC drugs in India. Another factor for its having the lowest cost of treatment is the price reductions, due to new pricing regulations. The recent price regulations, made possible by the Drug Price Control Order, regulate the price of the products that are included in India’s 2011 National List of Essential Medicines. This meant dominant cytotoxic cancer drugs, such as cisplatin, gemcitabine hydrochloride, paclitaxel and carboplatin, and a few other drugs by both local and international pharmaceutical companies, reducing their prices by up to XX%. The expected launch of promising small molecules in the pipeline, including nintedanib, Gilotrif, dacomitinib and LDK378, and the increasing incidence population will contribute to the growth of overall treatment costs during the forecast period.

5.1.2.3 Market Size The availability of generic chemotherapies, including pemetrexed (Alimta) and the generic targeted therapies erlotinib (Tarceva) and gefitinib (Iressa), downsizes the NSCLC market in India. The market for NSCLC in India is estimated to have been $XXm in 2012 and is expected to grow to $XXm in 2019, at a CAGR of XX%. In a best-case scenario, it is expected to grow at a CAGR of XX% to $XXm by the end of 2019, while in a worst-case scenario it is expected to grow at a CAGR of XX% to $XXm by the end of the forecast period. The dominance of generics in India limits the launch of premium-priced branded drugs by pharma giants. For example, crizotinib was approved for ALK-positive NSCLC by the Indian Central Drugs Standard Control Organization (CDSCO) in 2011; however, Pfizer has not yet launched Xalkori on the Indian market. The expected launch of promising pipeline targeted therapies, including Gilotrif, Novartis’ LDK378, Lilly’s necitumumab, Boehringer Ingelheim's nintedanib, is also expected to be delayed. Drug manufacturers may even prevent the launch of branded drugs in Indian market to avoid patent litigations and generic competition.

Market Forecast to 2019

Figure 21: Non-Small Cell Lung Cancer Market, India, Market Size, 2012–2019

A) Treatment usage pattern Population(‘000)

2012 2013 2014 2015 2016 2017 2018 2019

Prevalance population Treatment population

B) Annual cost of treatment Annual cost of treatment ($) treatment ofAnnual cost

2012 2013 2014 2015 2016 2017 2018 2019

Low variance Medium variance High variance Projected C) Revenue Market size($m) Market

2012 2013 2014 2015 2016 2017 2018 2019 Low variance Medium variance High variance Projected

Source: GBI Research, Proprietary Marketed Products Database Note: The projected figure is taken to be the most likely scenario, with a high probability of minor variance from that point. Higher variance outcomes are believed to be plausible but less likely.

Appendix

7 Appendix 7.1 All Pipeline Drugs by Phase 7.1.1 Discovery

Table 4: Non-Small Cell Lung Cancer Market, Global, Pharmaceutical Pipeline (Discovery), 2013 Drug/project name Company Molecule type MOA BB-003 bevacizumab biosimilar bevacizumab biosimilar BV-6 ImmTAC Targeting

MAGE A3 JPI-283 THR-53 VI-14442 ZSG-101 ZSG-102 BB-003

Source: GBI Research, Proprietary Pipeline Products Database

7.1.2 Preclinical

Table 5: Non-Small Cell Lung Cancer Market, Global, Pharmaceutical Pipeline (Preclinical), 2013 Drug/project name Company Molecule type MOA AIK-4 AL-8326 ALT-802 Anti Ferritin Gemcitabine

Paclitaxel NanomAbs ARN-5032 AZ-64 AZD-3463 BAL-27862 bevacizumab biosimilar bevacizumab biosimilar BL-8040 CBI-701g CBL-0137 CEP-28122 CEP-37440 Ceramide Analogues Certax CFAK-Y15 CGEN-25008

Appendix

CNVN-202 in combination

with MK-2206 CNX-222 Compound-13d COTI-2 docetaxel docetaxel Drug Targeting Carbonic

Anhydrase IX Drug Targeting Netrin-1 Drug Targeting Pan-PIM

Kinase Drug Targeting

Phosphofructokinase-2 Drug-Resistant Lung Cancer

Program Drugs Targeting RAS Mutant

Tumors EDC-1 gemcitabine GH-501a GO-203-2c GT-468iMABs HIF-143 hMABs For Cancer IC-1207 IL-17E IMA-930 iMAB-027 ImmTAC Targeting MAGE-A3

HLA-A1 Interferon Lambda-1 Linked

Fab Dimer LOR-253 MDX-1 Vaccine MG-516 MiR-Rxlet-7 MPT-0B098 MT-103 MT-477 NT-113 NUC-3373 NUC-3641 ORIL-007 paclitaxel paclitaxel

Appendix

Pseudovirions For Cancer Revercom SGI-7079 SIMM-559 SL-052 STP-801 SVC-112 TAS-2913 TF-011-Monomethyl

Auristatin E Tri-Specific Anti-Her-1/Her3

Zybodies Tumor Vaccine Vaccine For Non-Small Cell

Lung Cancer VE-822 X-379

Source: GBI Research, Proprietary Pipeline Products Database

7.1.3 IND-filed

Table 6: Non-Small Cell Lung Cancer Market, Global, Pharmaceutical Pipeline (IND-filed), 2013 Drug name Company Molecule type MOA BACPT DP bevacizumab Biosimilar IMGN-289 OSI-930 QBI-139

Source: GBI Research, Proprietary Pipeline Products Database

Appendix

7.1.4 Phase I

Table 7: Non-Small Cell Lung Cancer Market, Global, Pharmaceutical Pipeline (Phase I), 2013 Drug name Company Molecule type MOA AEOL-10150 AL-3818 AL-6802 antroquinonol AT-13387 AT-406 AZD-4547 AZD-8186 AZD-9291 BIIB-022 carfilzomib CC-223 Celecoxib in

combination with RT cetuximab biobetter CHP-MAGE-A4

Vaccine CO-1686 CRS-207 CST-101 CUDC-101 CV-9202 dalotuzumab DCVax-Lung Debio-0932 demcizumab docetaxel docetaxel liposomal doxorubicin EMD-521873 foretinib HM-61713 HMPL-309 HMPL-504 imgatuzumab IMGN-853 IMO-2055 INC-280 KML-001 L-DOS-47

Appendix

LY-2812176 margetuximab marizomib MEDI-4736 MEK-162 melflufen mepacrine MGA-271 MGCD-265 MGN-1703 MM-10001 MORAb-066 NMS-E628 NRC-AN-019 orantinib PankoMab GEX panobinostat PB-357 Peptide Based Therapeutic Cancer Vaccine PR-509 PR-610 PRAME Vaccine radretumab resminostat RG-7599 rilotumumab romidepsin Semi-Allogeneic Human Fibroblasts

Transfected With DNA Simotinib

Hydrochloride solitomab trebananib TSR-011 vinorelbine tartrate

liposomal X-396 XMT-1001 levoleucovorin

calcium

Source: GBI Research, Proprietary Pipeline Products Database

Appendix

7.1.5 Phase II

Table 8: Non-Small Cell Lung Cancer Market, Global, Pharmaceutical Pipeline (Phase II), 2013 Drug name Company Molecule type MOA alisertib AP-26113 apatorsen AUY-922 axitinib AXL-1717 bavituximab belinostat BMS-690514 buparlisib cabozantinib

(S)-malate CADI-05 CAP-7.1 CBP-501 in combination with [cisplatin] in combination with [pemetrexed disodium] cisplatin cixutumumab CNVN-202 cositecan CRLX-101 CV-9201 CYC-202 dabrafenib docetaxel targeted nanoparticles dovitinib

lactate DPV-001 entinostat etirinotecan

pegol farletuzumab ficlatuzumab fosbretabulin

disodium GI-4000 GlutaDON

Appendix

GSK-2302032A HBI-8000 HS-110 ISIS-EIF4ERx ixabepilone lambrolizumab lenvatinib linifanib linsitinib LY-2875358 MelCancerVac MK-2206 in combination with selumetinib sulfate neratinib NGR-hTNF olaratumab ORA-101 paclitaxel- loaded

polymeric micelle palbociclib parsatuzumab patritumab pegdinetanib Pegylated

Endostatin pelareorep pentamidine

isethionate pertuzumab PGG beta-

glucan pictilisib ponatinib poziotinib pralatrexate PT-107 PX-866 retaspimycin

hydrochloride RG-7446 RG-7853 S-488410

Appendix

sabarubicin salirasib sapacitabine SAR-256212 selumetinib

sulfate SPI-1620 suramin

hexasodium tamibarotene tergenpumatuc

el-L TG-4010 tigatuzumab tivantinib trametinib dimethyl sulfoxide veliparib vintafolide volasertib Vx-001 letrozole dasatinib

Source: GBI Research, Proprietary Pipeline Products Database

Appendix

7.1.6 Phase III

Table 9: Non-Small Cell Lung Cancer Market, Global, Pharmaceutical Pipeline (Phase III), 2013 Drug name Company Molecule type MOA (tegafur in combination with gimeracil in combination with oteracil potassium) ardeparin sodium belagenpumatucel-L bevacizumab bevacizumab biosimilar BV-NSCLC-001 canfosfamide hydrochloride celecoxib in combination with [carboplatin] in combination with [gemcitabine

hydrochloride] in combination with [pemetrexed disodium] cisplatin liposomal crizotinib custirsen sodium dacomitinib dimesna eribulin mesylate erlotinib hydrochloride ganetespib GSK-1572932A GSK-2132231A ipilimumab KD-019 LDK-378 motesanib diphosphate necitumumab nimotuzumab nintedanib nivolumab onartuzumab racotumomab ramucirumab Recombinant Human Endostatin in combination with [cisplatin] in combination with [vinorelbine tartrate] sorafenib tosylate tacedinaline

Appendix

tecemotide tertomotide vandetanib YN-968D1

Source: GBI Research, Proprietary Pipeline Products Database

7.1.7 Undisclosed

Table 10: Non-Small Cell Lung Cancer Market, Global, Pharmaceutical Pipeline (Undisclosed), 2013 Drug name Company Molecule type MOA ABT-510 ABT-751 AC-480 acridine carboxamide AE-941 AEG-35156 agatolimod sodium alanosine amatuximab anatumomab

mafenatox AP-11014 apaziquone apricoxib aprinocarsen sodium AT-101 Autologous Dexosomes Loaded With Tumor- Specific Peptides AV-412 batabulin sodium bevacizumab biosimilar bevacizumab Biosimilar bevacizumab Biosimilar bevacizumab biosimilar BI-2536 BKT-RP3 BMS-184476 BMS-275183 bortezomib brivanib alaninate brostallicin canertinib

dihydrochloride

Appendix

cantuzumab mertansine CDP-791 cediranib maleate celecoxib celecoxib in combination with zileuton in combination with [carboplatin] in combination with [gemcitabine hydrochloride] CEP-9722 cetuximab CG-201 CG-8123 CI-1040 cilengitide CIMAvax-EGF Peptide

Vaccine clazakizumab conatumumab conatumumab crenolanib CT-47609 CT-47613 CU-903 DHA-Paclitaxel dinaciclib docetaxel docetaxel liposomal DRF-1042 drozitumab Drug Targeting TREM-1 dulanermin edrecolomab efatutazone elesclomol elisidepsin enzastaurin

hydrochloride EP-2101 everolimus exisulind Ferritizumab figitumumab ganitumab

Appendix

gataparsen sodium gemcitabine elaidate GSK-249553 ILX-295501 imetelstat sodium INGN-401 iniparib INNO-305 IRX-4204 ISIS-EIF4ERx ispinesib Kahalalide F KOS-1584 KOS-862 KW-2170 L-Vax lapatinib ditosylate lenalidomide litronesib lometrexol sodium lonafarnib LY-2584702 LY-355703 mapatumumab marimastat matuzumab matuzumab milataxel mitomycin

microparticle MKC-1 ML-133 mAb Targeting Epidermal Growth Factor Receptor motesanib diphosphate motesanib diphosphate motexafin gadolinium MPI-443803 muparfostat naptumomab

estafenatox NBI-3001 NOV-002

Appendix

NRX-194204 NTX-250 NTX-400 NTX-420 NTX-500 NTX-800 NY-ESO-1 Plasmid DNA

Cancer Vaccine oblimersen sodium ombrabulin ONS-1010 ONS-1020 ortataxel OSI-632 OSI-817 OSI-930 P-2045 paclitaxel paclitaxel paclitaxel SR padeliporfin panitumumab patupilone pazopanib

hydrochloride PB-357 PD-0325901 pelitinib pelitrexol perifosine PFK-015 pivanex PKI-166 plinabulin PR-104 prinomastat PRLX-93936 PRX-321 R-100 R-440 rabusertib ranpirnase rebimastat Recombinant

Appendix

Angiostatin Protein regorafenib RG-4733 Rh-Apo2L ridaforolimus rubitecan S-3304 sagopilone satraplatin sepantronium bromide serdemetan SGN-15 SHT-00268C soblidotin SRL-172 sulofenur talactoferrin alfa talotrexin ammonium tamibarotene tariquidar TAS-106 tasidotin hydrochloride tasisulam sodium temozolomide teprotumumab tirapazamine tirapazamine in combination with [carboplatin] in combination with [paclitaxel] tivantinib tivozanib TLC-178 tosedostat tovetumab tozasertib tremelimumab TriAb Triapine tucotuzumab

celmoleukin tyroservatide UNBS-1450 UNBS-3078

Appendix

UNBS-3243 urelumab V-930 V-934 V-935 vadimezan vatalanib vinflunine ditartrate vinorelbine tartrate vinorelbine tartrate

nanoliposomal volociximab vorinostat vosaroxin XL-999 Zaltrap zalutumumab zibotentan

Source: GBI Research, Proprietary Pipeline Products Database

7.2 Market Forecasts to 2019 7.2.1 APAC

Table 11: Non-Small Cell Lung Cancer Market, Asia-Pacific, Market Forecast, 2012–2019 Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Incidence per 100,000 Five-year prevalence population (‘000) Treatment population (‘000) Maximum revenue ($bn) Projected revenue ($bn) Minimum revenue ($bn)

Source: GBI Research, Proprietary Database

Appendix

7.2.2 India

Table 12: Non-Small Cell Lung Cancer Market, India, Market Forecast, 2012–2019 CAGR Year 2012 2013 2014 2015 2016 2017 2018 2019 (%) Incidence per 100,000 Five-year prevalence

population (‘000) Treatment population (‘000) ACoT ($) Maximum revenue ($m) Projected revenue ($m) Minimum revenue ($m)

Source: GBI Research, Proprietary Database

7.2.3 Australia

Table 13: Non-Small Cell Lung Cancer Market, Australia, Market Forecast, 2012–2019 Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Incidence per 100,000 Prevalence population (‘000) Treatment population (‘000) ACoT ($) Maximum revenue ($m) Projected revenue ($m) Minimum revenue ($m)

Source: GBI Research, Proprietary Database

7.2.4 China

Table 14: Non-Small Cell Lung Cancer Market, China, Market Forecast, 2012–2019 Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Incidence per 100,000 Prevalence population (‘000) Treatment population (‘000) ACoT ($) Maximum revenue ($m) Projected revenue ($m) Minimum revenue ($m)

Source: GBI Research, Proprietary Database

Appendix

7.2.5 Japan

Table 15: Non-Small Cell Lung Cancer Market, Japan, Market Forecast, 2012–2019 Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Incidence per 100,000 Prevalence population (‘000) Treatment population (‘000) ACoT ($) Maximum revenue ($m) Projected revenue ($m) Minimum revenue ($m) Source: GBI Research, Proprietary Database

7.3 Market Definitions Market coverage: Non-Small Cell Lung Cancer (NSCLC) in four countries in the Asia-Pacific (APAC) region: Australia, China, India and Japan. Prevalence population: The estimated number of people at any given point of time who are affected by lung cancer. Prescription rate: The percentage of the Non-Small Cell Lung Cancer (NSCLC)-suffering population that has been prescribed any drug therapy. Prescription population: The number of people taking any drug for Non-Small Cell Lung Cancer (NSCLC). 7.4 Abbreviations -ve: negative +ve: positive ACoT: Annual Cost of Therapy ALK: Anaplastic Lymphoma Kinase ALT: Alanine Aminotransferase APAC: Asia-Pacific ASCO: American Society of Clinical Oncology ATP: Adenosine Triphosphate BMS: Bristol-Myers Squibb CAGR: Compound Annual Growth Rate CD: Cluster of Differentiation CDSCO: Central Drugs Standard Control Organization CFDA: China Food and Drug Administration cm: centimeters COPD: Chronic Obstructive Pulmonary Disease CT: Computed Tomography CTA: Clinical Trial Application

CTLA: Cytotoxic T-Lymphocyte Antigen DHFR: Dihydrofolate Reductase

Appendix

EBRT: External Beam Radiation Therapy EBUS: Endobronchial Ultrasound EGFR: Epidermal Growth Factor Receptor EMSI: EGFR Mutant-Selective Inhibitor EURTAC: European Tarceva vs Chemotherapy FDA: Food and Drug Administration FGFR: Fibroblast Growth Factor Receptor FNAB: Fine Needle Aspiration Biopsy GBM: Glioblastoma Multiforme GF: Growth Factor GFR: Growth Factor Receptor GI: Gastrointestinal GSK: GlaxoSmithKline HDAC: Histone Deacetylases HER: Human Epidermal Growth Factor Receptor HGF: Hepatocyte Growth Factor HGFR: Hepatocyte Growth Factor Receptor HSP: Heat Shock Protein IAP: Inhibitor of Apoptosis IgG1: Immunoglobulin G1 IL: Interleukin ILD: Interstitial Lung Disease IND: Investigational New Drug kg: kilogram LCC: Large Cell Carcinoma LDH: Lactate Dehydrogenase mAb: Monoclonal Antibody m2: square meter of body surface area mBC: Metastatic Breast Cancer mCRC: Metastatic Colorectal Cancer MET: Metabolic Equivalent of Task mg: milligram MMP: Matrix Metalloproteinase MPM: Malignant Pleural Mesothelioma MRP: Multidrug Resistance Protein MRI: Magnetic Resonance Imaging MOA: Mechanism of Action MUC-1: Mucin 1

Appendix

N0: No lymph node metastasis N1: Lymph node metastases within the lungs including hilar lymph nodes NICE: National Institute for Health and Care Excellence NRDL: National Reimbursement Drug List NSCLC: Non-Small Cell Lung Cancer NOS NSCLC: Non-Squamous Non-Small Cell Lung Cancer ORR: Overall Response Rate OS: Overall Survival PARP: Poly (ADP-Ribose) Polymerases PCR: Polymerase Chain Reaction PD: Programmed Cell Death Protein PDGFR: Platelet-Derived Growth Factor Receptor PDL: Programmed Cell Death Ligand PET: Positron Emission Tomography PFS: Progression-Free Survival Pt: Platinum RT: Radiation Therapy SATURN: Sequential Tarceva in Unresectable NSCLC sb-P + C: solvent-based paclitaxel plus carboplatin SBRT: Stereotactic Body Radiation Therapy SCC: Squamous Cell Carcinoma SCLC: Small Cell Lung Cancer S NSCLC: Squamous Non-Small Cell Lung Cancer SFDA: State Food and Drug Administration TB: Tuberculosis TBNA: Transbronchial Needle Aspiration TGA: Therapeutic Goods Administration TK: Tyrosine Kinase TKI: Tyrosine-Kinase Inhibitor TNF: Tumor Necrosis Factor TNM: Tumor Node Metastasis TLR: Toll-Like Receptor TTNB: Transthoracic Needle Biopsy VEGF: Vascular Endothelial Growth Factor VEGFR: Vascular Endothelial Growth Factor Receptor

Appendix

7.5 Bibliography  Abraxane [package insert]. Summit, NJ: Celegene Corporation; June 2013. Available from: http://www.abraxane.com/downloads/Abraxane_PrescribingInformation.pdf

 Adams C and Brantner V (2010). Spending on New Drug Development. Health Economics; 19: 130–141.  Alimta [package insert]. Indianapolis, IN: Eli Lilly and Company; May 2013. Available from: http://pi.lilly.com/us/alimta-pi.pdf

 ACS (2013). Lung Cancer (Non-Small Cell). American Cancer Society. Available from: http://www.cancer.org/acs/groups/cid/documents/webcontent/003115-pdf.pdf

 Ammanagi AS, et al. (2012). Sputum cytology in suspected cases of carcinoma of lung (Sputum cytology a poor man's bronchoscopy!). Lung India; 29(1): 19–23  Asahina H, et al. (2005). Transbronchial biopsy using endobronchial ultrasonography with a guide sheath and virtual bronchoscopic navigation. Chest; 128: 1761–1765  AIHW (2011). Lung cancer in Australia: An overview. Australian Institute of Health and Welfare. Available from: http://www.aihw.gov.au/WorkArea/DownloadAsset.aspx?id=10737421095&libID=10737421094 [Accessed on January 4, 2013]

 Bergethon K, et al. (2012). ROS1 rearrangements define a unique molecular class of lung cancers. Journal of Clinical Oncology; 30: 863–870  Brahmer R, J et al. (2013). Immune Checkpoint Inhibitors: Making Immunotherapy a Reality for the Treatment of Lung Cancer. Cancer Immunology; 1: 365–372  Camidge R, et al. (2012). Final results of a phase 2, open-label study of ramucirumab (IMC-1121B; RAM), an IGG1 MAB targeting VGFR-2, with paclitaxel and carboplatin as first-line therapy in patients (PTS) with stage IIIB/IV NSCLC (NCT00735696). European Society of Medical Oncology; Abstract #1287  Cappuzzo F, et al. (2010). Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomized, placebo-controlled phase 3 study. Lancet Oncology; 11: 521–529  CDC (2012). Lung Cancer: Basic Information about Lung Cancer. Centers for Disease Control and Prevention. Available from: http://www.cdc.gov/cancer/lung/basic_info/index.htm [Accessed on January 16, 2013]

 CFDA (2013). Provisions for Drug Registration. China Food and Drug Administration. Available from http://eng.sfda.gov.cn/WS03/CL0768/61645.html.

 Ciuleanu, et al. (2009). Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomized, double-blind, phase 3 study. The Lancet; 374(9699): 1432–1440

 Colagiuri B, et al. (2012). Does Assessing Patients' Expectancies About Chemotherapy Side Effects Influence Their Occurrence? Journal of Pain and Symptom Management; [E-pub ahead of print]  Connor S, et al. (2000). Image-guided automated needle biopsy of 106 thoracic lesions: a retrospective review of diagnostic accuracy and complication rates. European Radiology; 10(3): 490–494  Cullen M (2003). Chemotherapy for non-small cell lung cancer: the end of the beginning. Thorax; 58: 352–356

 Doebele R, et al. (2012). A phase 2 randomized open-label study of ramucirumab (IMC 1121B;RAM) in combination with platinum-based chemotherapy in patients (PTS) with recurrent or advanced non- small cell lung cancer (NSCLC): Results from non-squamous (NSQ) pts (NCT01160744). European Society of Medical Oncology; Abstract #1245  Engelman, et al. (2007). PF00299804, an Irreversible Pan-ERBB Inhibitor, Is Effective in Lung Cancer Models with EGFR and ERBB2 Mutations that Are Resistant to Gefitinib. Cancer Research; 67: 11924-32

Appendix

 Socinski MA, et al. (2013). A multicenter Phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer. Clinical Cancer Research; 19: 3068–3077  Spigel DR, et al. (2011). Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. American Society of Clinical Oncology; Abstract #7505  Tammemagi CM, et al. (2003). Impact of comorbidity on lung cancer survival. International Journal of Cancer; 103: 792–802  Tanizaki J, et al. (2011). MET tyrosine kinase inhibitor crizotinib (PF-02341066) shows differential antitumor effects in non-small cell lung cancer according to MET alterations. Journal of Thoracic Oncology; 6: 1624–1631  Thatcher N, et al. (2005). Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomized, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet; 366: 1527–1537  Vineis P, et al. (2005). Environmental tobacco smoke and risk of respiratory cancer and chronic obstructive pulmonary disease in former smokers and never smokers in the EPIC prospective study. British Medical Journal; 330(7486): 277  World Health Organization (2010). Visual Impairment and Blindness 2010. World Health Organization. Available from: http://www.who.int/blindness/data_maps/VIFACTSHEETGLODAT2010full.pdf

 Yao X, et al. (2012). Fine-needle aspiration biopsy versus core-needle biopsy in diagnosing lung cancer: a systematic review. Current Oncology; 19(1): e16–27  Yoshmini I, et al. (2003). A Comparison of Trends in the Incidence Rate of Lung Cancer by Histological Type in the Osaka Cancer Registry, Japan and in the Surveillance, Epidemiology and End Results Program, USA. Japanese Journal of Clinical Oncology; 33(2): 98–104 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 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 that are making the news, or that 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.

Appendix

The coverage is further streamlined and strengthened with additional input 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 in validating and strengthening the secondary research findings.  It further develops the analysis team’s expertise and market understanding. Primary research involves e-mail and telephone interviews as well as face-to-face interviews for each market, category, segment and sub-segment across geographies. The participants that 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 revenues of 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.

Appendix

GBI Research uses the epidemiology-based treatment flow model to forecast market size for therapeutic indications.

7.6.4.1 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 treatment 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 sources for the price of drugs are MIMS India, MIMS China and ZenRx. 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 that is different from the actual value. To correct this ‘‘gap’’ the forecasting model uses ‘‘triangulation’’ with the 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 the subsequent introduction of generics. Historical data for new product launches and generics penetration are used to arrive at robust forecasts. The increase or decrease of prevalence rates, the treatment seeking rate, the diagnosis rate and the 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 population for this report is taken from articles published in various journals, including the Annals of Oncology, Journal of Clinical Epidemiology, and New England Journal of Medicine. Prescription Population NSCLC has multiple treatment options depending upon the stage of the disease and previous effectiveness of other similar treatments. Options for treatment of NSCLC include surgical intervention, radiation therapy, chemotherapy, targeted therapy and immunotherapy. The prescription population is defined as the number of patients who are prescribed biologic drug therapy. This is calculated as a percentage of the diagnosis population. Prescription population proportion is taken from articles published in various journals, including the Annals of Oncology, British Medical Journal, Current Oncology and Lancet Oncology.

Appendix

7.6.4.2 Market Size by Geography The treatment usage pattern and annual cost of therapy in each country has been factored in while deriving the individual country market size. Forecasting Model for Therapeutic Areas

Figure 29: GBI Research Market Forecasting Model (Example)

GBI Research Market Sizing Model

D isease Population General Po pulation 743,535,048 Qualifying condition 1 (Age/S ex/Occupation etc) Qualifying condition 2 (Age/S ex/Occupation etc) Prevalence tissue valve disease 0 .2% 1,78 4,4 8 4 Qualifying condition (com plication, severity) DISEASED POPULATION 1,78 4,4 8 4

Treatment Flow Patterns Treatm ent Seeking R ate (Symptoms/Dis Awareness) 8 9% 1,58 8,1 9 1 Diagn osis Rate (Clinical and Diagn ostic Tests) 7 5% 1,19 1,1 4 3 Prescription R ate (Physician Perception, Treatment Effectiv e ness) Tissue V alve 7 0% 83 3,8 0 0 Other Treatments for Valve (Surg/M ed/None) - Fulfillm en t A vaila bilit y NA W illingness to Use (Patient Perceptions) NA Ready to U se (Surgery eligibility, Reuse etc) NA Affo rd 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 Patient Liability Target Price (@20% pat liab) ASP for Cost of Therapy TOTAL PATIENT VOLUMES Product Purchase Frequency 1 TOTAL UNIT VOLUMES

Pricing per Un it $ 18 ,00 0 In flation Price Dec 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 geographies in APAC: Australia, China, India 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 impact upon the market during the forecast period in order to provide the best and worst-case scenarios.

Appendix

Articles from research journals and agency publications such as The Oncologist, Journal of Clinical Oncology, Lancet Oncology, Annals of Oncology, 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, international sales managers from pharmaceutical companies, academics from research universities and key opinion leaders from hospitals. Historical 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.