GBIHC344MR CRC APAC 12th Feb'15 Sample 1-3,5-8,20,31,32,35 ... · use patterns, pricing, and market...

THERAPY ANALYSIS

Colorectal Cancer Therapeutics in Asia-Pacific Markets to 2020 - Improved Regional

Healthcare Access to Drive Uptake of High-Cost Targeted Therapies

Report Code: GBIHC344MR Published: October-2014

© GBI Research. This is a licensed product and is not to be photocopied

GBIHC344MR / Published OCT 2014

GBI Research Report Guidance

The report begins with an executive summary detailing the key points driving the CRC market in four APAC markets: Australia, India, China and Japan.

Chapter two provides an introduction to CRC, detailing the etiology, epidemiology, diagnostic techniques, disease staging and typical prognoses for patients. An analysis of current treatment algorithms and options is also included.

Chapter three offers detailed analysis of the drugs currently marketed for this indication: 5-FU, Xeloda, Camptosar, Eloxatin, Avastin, Zaltrap, Vectibix, Stivarga and Erbitux. This includes key characteristics, covering safety and efficacy, clinical trial outcomes, tolerability, dosing, administration, historical sales, prices and overall competitive strength. These products are also compared in a comprehensive heat map.

Chapter four provides detailed analysis of the pipeline for CRC, by stage of development, molecule type, program type, mechanism of action and molecular target. It also analyses recent clinical trials in this indication by enrollment, duration and failure rate. Finally, promising late-stage pipeline molecules are analyzed and assessed in terms of their potential competitive strength.

Chapter five supplies market forecasts for the CRC market, including epidemiology, treatment use patterns, pricing, and market size, for the 2013–2020 period. The APAC markets are covered and data are presented at a country level with further analysis of key market drivers and barriers.

Chapter six describes the major deals that have taken place in the global CRC market in recent years. This coverage analyzes licensing and co-development agreements, segmented by stage of development, year, molecule type, mechanism of action and value. Network graphs for these deals by location of company headquarters are also included.

An appendix is included in chapter seven. This lists key definitions, explanations of abbreviations, details of the methodology and sources used.


GBIHC344MR / Published OCT 2014

Executive Summary

The Colorectal Cancer (CRC) therapeutics market in the four Asia-Pacific (APAC) countries of India, Australia, China and Japan was worth $XX billion in 2013 and is expected to grow at a Compound Annual Growth Rate (CAGR) of XX% to $XX billion by 2020. Japan had the largest market in 2013, with a value of $XX billion, or a XX% share of the combined market of the four countries. It was followed by China, with $XXm, or XX%; Australia, with $XXm, or XX%; and India, which had the lowest market share and value, with XX% and $XXm, respectively, but is expected to witness the fastest growth over the forecast period, with a CAGR of XX%. The respective CAGRs of China, Australia, and Japan during the forecast period are estimated to be XX%, XX%, and XX%.

The use of targeted therapies is expected to increase in the Asia-Pacific (APAC) markets (for the purposes of this report, APAC refers to Australia, China, India and Japan only), as patient access to these more expensive agents improves. The moderate uptake of late-stage pipeline products panitumumab and Xilonix, following their expected approval, is expected to drive additional growth within this market. Others such as ramucirumab, TAS-102, TS-1, MelCancerVac will also contribute. The total value of the CRC market will increase slightly over the forecast period, owing to the increased uptake of branded drugs, and the number of premium-priced agents, the gradual increase in the use of targeted therapies, and a rise in the incident population, will create growth in the market.

Colorectal Cancer Therapeutics, Market Size ($bn), Asia-Pacific, 2013–2020

2013 2014 2015 2016 2017 2018 2019 2020

Mar

ket s

ize

($bn

)

Low variance Medium variance High variance Projected

Source: GBI Research, Proprietary Pipeline Products Database; GBI Research, Proprietary Marketed Products Database

The CRC pipeline is highly robust, with potential drug candidates across various phases of clinical development. With nearly XX active pipeline molecules, the majority of the investigational drug candidates are being evaluated for the treatment of CRC in advanced stages, either as first-line or second-line therapies. The current investigational pipeline candidates include new combination therapies and targeted therapies, as well as promising immunotherapies and chemotherapy drug candidates. As well as these active progressing pipeline molecules, the pipeline also includes nearly XX molecules that are either inactive or discontinued.

The use of targeted therapies is expected to increase in the Asia-Pacific markets, as patient access to these more expensive agents improves.


GBIHC344MR / Published OCT 2014 Page 5

1 Table of Contents 1 Table of Contents .............................................................................................................................. 5

1.1 List of Tables ........................................................................................................................... 7 1.2 List of Figures ......................................................................................................................... 7

2 Introduction ........................................................................................................................................ 8 2.1 Colorectal Cancer ................................................................................................................... 8 2.2 Symptoms ............................................................................................................................... 8 2.3 Epidemiology .......................................................................................................................... 8 2.4 Pathophysiology ..................................................................................................................... 9

2.4.1 Histology ......................................................................................................................... 9 2.4.2 Genetic Basis .................................................................................................................. 9 2.4.3 Etiology ........................................................................................................................... 9

2.5 Diagnosis ...............................................................................................................................11 2.5.1 Digital Rectal Examination .............................................................................................11 2.5.2 Fecal Occult Blood Test.................................................................................................11 2.5.3 Flexible Sigmoidoscopy .................................................................................................11 2.5.4 Colonoscopy ..................................................................................................................11 2.5.5 Virtual Colonoscopy.......................................................................................................12 2.5.6 Double Contrast Barium Enema ....................................................................................12

2.6 Prognosis and Disease Staging ............................................................................................13 2.7 Treatment Options .................................................................................................................14

2.7.1 Surgery and Radiation Therapy .....................................................................................14 2.7.2 Chemotherapy ...............................................................................................................15 2.7.3 Targeted Therapies .......................................................................................................15 2.7.4 Resistance to Pharmacological Therapies ....................................................................16 2.7.5 Treatment Guidelines ....................................................................................................17

3 Marketed Products ...........................................................................................................................20 3.1 Key Marketed Products .........................................................................................................20

3.1.1 Immunotherapies ...........................................................................................................20 3.1.2 Targeted Therapies .......................................................................................................23

3.2 Hyperthermic Intraperitoneal Chemotherapy .......................................................................28 3.3 Heat Map for Marketed Products ..........................................................................................29

4 Pipeline Analysis ...............................................................................................................................31 4.1 Overall Pipeline ......................................................................................................................31

4.1.1 Pipeline Analysis by Molecule Type ..............................................................................32 4.1.2 Pipeline Analysis by Mechanism of Action ....................................................................33

4.2 Clinical Trials ..........................................................................................................................35 4.2.1 Failure Rate ....................................................................................................................35 4.2.2 Clinical Trial Size ............................................................................................................37 4.2.3 Duration..........................................................................................................................39

4.3 Promising Drug Candidates in Pipeline.................................................................................41 4.3.1 Lonsurf (TAS-102 (tipiracil + trifluridine)) – Taiho Pharmaceutical .................................41 4.3.2 Cyramza – ramucirumab – Eli Lilly and Company.........................................................42 4.3.3 TS-1/Teysuno (tegafur + gimeracil + oteracil) – Taiho Pharmaceutical .........................42 4.3.4 CPP-1X (eflornithine hydrochloride) + sulindac – Cancer Prevention Pharmaceuticals

........................................................................................................................................43 4.3.5 MelCancerVac – DanDrit Biotech .................................................................................44 4.3.6 Xilonix – XBiotech..........................................................................................................45 4.3.7 Nintedanib – Boehringer Ingelheim ..............................................................................46

5 Market Forecast to 2020 ..................................................................................................................47 5.1 Asia-Pacific Market ................................................................................................................47



5.1.1 Treatment Use Patterns .................................................................................................47 5.1.2 Market Size ....................................................................................................................47

5.2 Australia .................................................................................................................................49 5.2.1 Treatment Use Patterns .................................................................................................49 5.2.2 Annual Cost of Therapy .................................................................................................49 5.2.3 Market Size ....................................................................................................................50

5.3 India........................................................................................................................................51 5.3.1 Treatment Use Patterns .................................................................................................51 5.3.2 Annual Cost of Therapy .................................................................................................52 5.3.3 Market Size ....................................................................................................................53

5.4 China ......................................................................................................................................54 5.4.1 Treatment Use Patterns .................................................................................................54 5.4.2 Annual Cost of Therapy .................................................................................................55 5.4.3 Market Size ....................................................................................................................56

5.5 Japan......................................................................................................................................57 5.5.1 Treatment Use Patterns .................................................................................................57 5.5.2 Annual Cost of Therapy .................................................................................................58 5.5.3 Market Size ....................................................................................................................59

5.6 Drivers and Barriers ...............................................................................................................60 5.6.1 Drivers ............................................................................................................................60 5.6.2 Barriers ...........................................................................................................................62

6 Deals and Strategic Consolidations .................................................................................................63 6.1 Licensing Agreements ...........................................................................................................63

6.1.1 Major Licensing Deals....................................................................................................64 6.2 Co-development Agreements ...............................................................................................65

6.2.1 Major Co-development Agreements .............................................................................67 7 Appendix ...........................................................................................................................................68

7.1 All Pipeline Drugs by Phase ..................................................................................................68 7.1.1 Discovery .......................................................................................................................68 7.1.2 Preclinical .......................................................................................................................69 7.1.3 IND/CTA-Filed ................................................................................................................70 7.1.4 Phase I ............................................................................................................................70 7.1.5 Phase II ...........................................................................................................................71 7.1.6 Phase III ..........................................................................................................................72

7.2 Market Forecasts to 2020 .....................................................................................................72 7.2.1 Asia-Pacific .....................................................................................................................72 7.2.2 Australia .........................................................................................................................72 7.2.3 India ................................................................................................................................73 7.2.4 China ..............................................................................................................................73 7.2.5 Japan ..............................................................................................................................73

7.3 Market Definitions ..................................................................................................................74 7.4 Abbreviations .........................................................................................................................74 7.5 References .............................................................................................................................77 7.6 References for Heat Map ......................................................................................................81 7.7 Research Methodology .........................................................................................................82

7.7.1 Coverage........................................................................................................................82 7.7.2 Secondary Research ......................................................................................................82 7.7.3 Primary Research ...........................................................................................................82 7.7.4 Therapeutic Landscape .................................................................................................83 7.7.5 Geographical Landscape ...............................................................................................86 7.7.6 Pipeline Analysis ............................................................................................................86

7.8 Expert Panel Validation .........................................................................................................86



7.9 Contact Us .............................................................................................................................86 7.10 Disclaimer ..............................................................................................................................86

1.1 List of Tables Table 1 Colorectal Cancer Therapeutics, Global, TNM Staging, 2013 .............................................14 Table 2 Surgical Options for Colorectal Cancer................................................................................15 Table 3 Colorectal Cancer Therapeutics, Global, All Pipeline Products (Discovery), 2014 ..............68 Table 4 Colorectal Cancer Therapeutics, Global, All Pipeline Products (Preclinical), 2014 .............69 Table 5 Colorectal Cancer Therapeutics, Global, All Pipeline Products (IND/CTA-Filed), 2013 ......70 Table 6 Colorectal Cancer Therapeutics, Global, All Pipeline Products (Phase I), 2014 ..................70 Table 7 Colorectal Cancer Therapeutics, Global, All Pipeline Products (Phase II), 2014 .................71 Table 8 Colorectal Cancer Therapeutics, Global, All Pipeline Products (Phase III), 2014 ................72 Table 9 Colorectal Cancer Therapeutics, Asia-Pacific, Forecast Data, 2013–2020 ........................72 Table 10 Colorectal Cancer Therapeutics, Australia, Forecast Data, 2013–2020 .............................72 Table 11 Colorectal Cancer Therapeutics, India, Forecast Data, 2013–2020 ...................................73 Table 12 Colorectal Cancer Therapeutics, China, Forecast Data, 2013–2020 ..................................73 Table 13 Colorectal Cancer Therapeutics, Japan, Forecast Data, 2013–2020 .................................73 Table 14: Colorectal Cancer Market, References for Heat Map ..........................................................81

1.2 List of Figures Figure 1: Colorectal Cancer Therapeutics, Global, European Society for Medical Oncology

Treatment Guidelines (Colorectal Cancer at Stage I to III) ...................................................17 Figure 2: Colorectal Cancer Therapeutics, Global, European Society for Medical Oncology

Treatment Guidelines (Colorectal Cancer at Stage IV) ........................................................18 Figure 3: Colorectal Cancer Therapeutics, Global, Heat Map (Marketed Products) ..........................30 Figure 4: Colorectal Cancer Therapeutics, Global, Pipeline by Stage of Development and Program

Type, 2013 .............................................................................................................................31 Figure 5: Colorectal Cancer Therapeutics, Global, Pipeline by Molecule Type and Stage of

Development, 2013 ...............................................................................................................32 Figure 6: Colorectal Cancer Therapeutics, Global, Pipeline by Mechanism of Action and Stage of

Development, 2013 ...............................................................................................................34 Figure 7: Colorectal Cancer Therapeutics, Global, Clinical Trial Failure Rate (%), 2013 .....................36 Figure 8: Colorectal Cancer Therapeutics, Global, Clinical Trial Size, 2013 .......................................38 Figure 9: Colorectal Cancer Therapeutics, Global, Clinical Trial Duration (months), 2013 .................40 Figure 10: Colorectal Cancer Therapeutics, Asia-Pacific, Treatment Use Patterns (‘000) ,2013–2020

...............................................................................................................................................47 Figure 11: Colorectal Cancer Therapeutics, Asia-Pacific, Market Size ($bn), 2013–2020 ...................48 Figure 12: Colorectal Cancer Therapeutics, Australia, Treatment Use Patterns (‘000), 2013–2020 ..49 Figure 13: Colorectal Cancer Therapeutics, Australia, Annual Cost of Therapy ($), 2013–2020 ........50 Figure 14: Colorectal Cancer Therapeutics, Australia, Market Size ($m), 2013–2020 ........................51 Figure 15: Colorectal Cancer Therapeutics, India, Treatment Use Patterns (‘000), 2013–2020 .........52 Figure 16: Colorectal Cancer Therapeutics, India, Annual Cost of Therapy ($), 2013–2020 ..............53 Figure 17: Colorectal Cancer Therapeutics, India, Market Size ($m), 2013–2020 ...............................54 Figure 18: Colorectal Cancer Therapeutics, China, Treatment Use Patterns (‘000), 2013–2020 .......55 Figure 19: Colorectal Cancer Therapeutics, China, Annual Cost of Therapy ($), 2013–2020 .............56 Figure 20: Colorectal Cancer Therapeutics, China, Market Size ($m), 2013–2020 .............................57 Figure 21: Colorectal Cancer Therapeutics, Japan, Treatment Use Patterns (‘000), 2013–2020 .......58 Figure 22: Colorectal Cancer Therapeutics, Japan, Annual Cost of Therapy ($), 2013–2020 ............59 Figure 23: Colorectal Cancer Therapeutics, Japan, Market Size, 2013–2020 .....................................60 Figure 24: Colorectal Cancer Therapeutics, Global, Licensing Deals by Geography, 2006–2014 .....63 Figure 25: Colorectal Cancer Therapeutics, Global, Licensing Deals by Phase, Value, Mechanism of

Action, 2006–2014 ...............................................................................................................64 Figure 26: Colorectal Cancer Market, Global, Co-development Deals by Geography and by Value,

2006–2014 ...........................................................................................................................66 Figure 27: GBI Research Market Forecasting Model ............................................................................85



2 Introduction

This report contains estimations for 2013 and forecasts to 2020 of Colorectal Cancer (CRC) therapeutics in the Asia-Pacific (APAC) markets of Australia, India, China and Japan (for the purposes of this report, APAC refers to Australia, China, India and Japan only). The five-year prevalence population of CRC in these countries was XX in 2013 and is expected to increase at a moderate Compound Annual Growth Rate (CAGR) of XX% to XX in 2020. The five-year prevalence is based on annual incidence over five years and takes into account the five-year survival rate. This produces a figure that reflects the number of surviving patients who were diagnosed with CRC in the previous five years and are therefore more likely to undergo pharmacological treatment for the disease than those diagnosed XX or more years earlier. The treatment population for CRC in Australia, India, China and Japan amounted to an estimated XX in 2013 and is expected to register modest growth to reach XX in 2020, at a CAGR of XX%.

2.1 Colorectal Cancer

CRC is the third-most commonly diagnosed cancer and the fourth leading cause of mortality (Haggar and Boushey, 2009). In most developed nations, CRC mortality decreased between 1990 and 2008, attributed to improved early diagnosis and the enactments of national screening programs, aimed at higher-risk parts of the population (generally those over XX years old). In developing nations, as diets become increasingly westernized, incidence is increasing, and national screening programs are still largely nascent.

2.2 Symptoms

CRC sometimes arises without any symptoms or can take XX to XX years to develop, and many symptoms are not apparent until the latter stages of the tumor process. For this reason, regular screening is vital for the detection of tumors in the early stages before advanced progression when it is more curable, in order to improve patient survival and reduce the cost of CRC treatment.

In spite of this, many cases of CRC are only diagnosed when the patient undergoes an emergency admission into hospital, due to complicating symptoms of the disease.

Typical symptoms of CRC, as assessed by the primary care physician, are blood in stool, constipation and diarrhea lasting more than several days, and abdominal discomfort. When physical symptoms are assessed, the patient is then typically referred to secondary care, where a colonoscopy can be administered.

2.3 Epidemiology

The incidence of CRC is far higher than for the other cancers of the Gastrointestinal (GI) tract. An estimated XX, of XX cancer incident cases in 2008, were CRC, equivalent to XX% of all cancers (WHO, 2012). Esophageal, gastric, liver and pancreatic cancers accounted for far smaller percentages of the total incident cancer population; there are more patients with CRC than with all of these types of cancer combined.

The five-year prevalence population of CRC in APAC markets was estimated at XX in 2013 and is expected to increase at a moderate CAGR of XX% to XX in 2020. The five-year prevalence is based on annual incidence over five years and takes into account the five-year survival rate. This produces a figure that reflects the number of surviving patients diagnosed with CRC in the previous five years that are therefore more likely to undergo pharmacological treatment for the disease than those diagnosed XX or more years earlier. The treatment population for CRC in the APAC regions amounted to an estimated XX in 2013 and is expected to register modest growth to reach XX in 2020 at a CAGR of XX%. Despite its high frequency, incidence has been steadily decreasing in the US since the 1980s. Elsewhere, the incidence of CRC is increasing steadily (Jemal et al., 2011). Incidence is higher in the US and Europe than in Japan due to differences in dietary composition, although incidence in Japan is rapidly rising due to the westernization of the Japanese diet, which has been ongoing since the 1970s (Kuriki and Tajima, 2006; Jemal et al., 2010a). Most cases are diagnosed before distant metastasis has occurred, due to the frequent presentation of early-stage symptoms. This contributes to a high five-year survival rate being observed in CRC in comparison with other malignancies of the GI tract, such as gastric cancer. The median age of CRC diagnosis is XX (NCI, 2013a). As such, aging populations are expected to drive a growing prevalence of this disease during the forecast period to 2020 and beyond.

CRC is the third-most commonly diagnosed cancer and the fourth leading cause of mortality



3 Marketed Products

3.1 Key Marketed Products

3.1.1 Immunotherapies

3.1.1.1 5-Fluorouracil

5FU is a pyrimidine analog and acts as an antimetabolite and antineoplastic agent. It is formulated as a solution for injection for the Intravenous (IV) route of administration. 5FU may be used alone or in combination with other medications for its palliative action in the management of common malignancies such as colon cancer and breast cancer. 5FU interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. 5FU can also be incorporated into RNA in place of Uridine Triphosphate (UTP), producing a fraudulent RNA. The drug is available in 1mg, XXmg, XXmg, XXmg and XXmg strength.

5FU is thought to be the binding of the deoxyribonucleotides of the drug, which is 5-fluoro-2'-deoxyuridine monophosphate (FdUMP), and the folate cofactor, which is N5–10-methylenetetrahydrofolate, to Thymidylate Synthase (TS) to form a covalently bound ternary complex. This results in the inhibition of the formation of thymidylate from uracil, which leads to the inhibition of DNA and RNA synthesis and cell death. 5FU can also be incorporated into RNA in place of UTP, producing a fraudulent RNA and interfering with RNA processing and protein synthesis.

The mechanism of action of 5FU is mainly related to competitive inhibition of thymidylate synthetase, the enzyme catalyzing the methylation of deoxyuridylic acid to thymidylic acid. The consequent thymidine deficiency results in inhibition of DNA synthesis, thus inducing cell death. Moreover, moderate inhibition of RNA and incorporation of 5FU into RNA have been observed. The predominant mechanism of antitumor action appears to be dependent, at least in part, on individual tumor intracellular metabolism. It can be used to treat many types of cancers, including cancer of the colon, rectum, breast, stomach, head, and neck.

3.1.1.2 Xeloda (Capecitabine) – F. Hoffmann-La Roche

Capecitabine (Xeloda) is a fluoropyrimidine carbamate with antineoplastic activity. The drug is formulated in the form of tablet for oral administration. It is enzymatically converted to 5FU in the tumor, where it inhibits DNA synthesis and slows the growth of tumor tissue. Xeloda is used as a single agent for the adjuvant treatment of Dukes’ C colon cancer after surgery and as a first-line treatment of metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Xeloda is used for the treatment of metastatic breast cancer in combination with docetaxel, after failure of prior anthracycline-containing chemotherapy. The drug is also used as a monotherapy in the treatment of metastatic breast cancer that is not improved after the treatment with other medicines such as paclitaxel and anthracycline-containing medicine such as doxorubicin. Xeloda is also indicated for the first-line treatment of advanced gastric cancer in combination with a platinum-based regimen.

In April 30, 1998, Roche declared that the FDA had approved Xeloda for the treatment of patients with metastatic breast cancer that is resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or patients that are resistant to paclitaxel and for whom further anthracycline therapy is not indicated. On June 15, 2005, the FDA approved Xeloda for the adjuvant (post-surgery) treatment of patients with Dukes' C colon cancer.

Capecitabine is a TS inhibitor. It is a prodrug that is enzymatically converted to 5FU (antimetabolite) in the tumor, where it inhibits DNA synthesis and slows growth of tumor tissue. Both normal and tumor cells metabolize 5-FU to FdUMP and 5-Fluorouridine Triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor N5-10-methylenetetrahydrofolate binds to TS to form a covalently bound ternary complex. This bound complex inhibits the formation of thymidylate from 2'-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of UTP during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis. On March 26, 2007, Roche submitted a supplemental New Drug Application (sNDA) to the FDA for the use of Xeloda in combination with oxaliplatin with or without Avastin in the treatment of metastatic CRC.



4 Pipeline Analysis

4.1 Overall Pipeline

The CRC pipeline is highly robust, with potential drug candidates across various phases of clinical development. With nearly XX active pipeline molecules, the majority of the investigational drug candidates are being evaluated for the treatment of CRC in advanced stages, either as first-line or second-line therapies. The current investigational pipeline candidates include the new combination therapies, targeted therapies and promising immunotherapies, as well as chemotherapy drug candidates. As well as these active progressing pipeline molecules, the pipeline also includes nearly XX molecules that are either inactive or discontinued.

As displayed in the following figure, from XX active progressing pipeline molecules, XX (XX%) are in the Phase II stage of development, XX (XX%) are in the Preclinical stage of development, XX (XX%) are in Phase I, and XX XX(XX%) are in Phase III. As well as these, a substantial number of active drug candidates are in the discovery stage. As shown in panel B, most of the pipeline drugs are novel, and a few are either generic or products that have already been marketed for other indications.

Figure 4: Colorectal Cancer Therapeutics, Global, Pipeline by Stage of Development and Program Type, 2013

Phase I Phase II Phase III

Generic Novel Repositioned

Discovery

Preclinical

Phase I

Phase II

Phase III

IND/CTA-filed

A) Colorectal cancer pipeline by stage of development

B) Colorectal cancer pipeline by program type

Source: GBI Research, Proprietary Pipeline Products Database

CTA: Clinical Trial Application; IND: Investigational New Drug

With nearly XX active pipeline molecules, the majority of the investigational drug candidates are being evaluated for the treatment of CRC in advanced stages, either as first-line or second-line therapies



4.1.1 Pipeline Analysis by Molecule Type

The pipeline for CRC appears to be highly robust, with a diverse range of molecule types. The investigational pipeline consists of XX active molecules across various stages of clinical development, of which nearly XX are either discontinued or inactive. Small molecules dominate the CRC pipeline, with XX drug candidates, or a XX% share. MAbs occupy a share of XX% in the overall pipeline having XX drug candidates. Figure 5 displays the share of various molecule types in the CRC pipeline.

Of the three phases of clinical development, the number of small molecules is highest in Phase II, with XX molecules, followed by Preclinical and Phase I, with XX and XX molecules, respectively, and Phase III, with five.

Figure 5: Colorectal Cancer Therapeutics, Global, Pipeline by Molecule Type and Stage of Development, 2013

Biosimilar

Cell therapy

Gene therapy

Peptide

Protein

Small molecule

Vaccine

Discovery Preclinical Phase I Phase II Phase III

Pip

elin

e m

olec

ules

Biosimilar Cell therapy Gene therapy Peptide Protein Small molecule Vaccine

B) Colorectal cancer pipeline by molecule typeand stage of development

A) Colorectal cancer pipeline by molecule type


Small molecules dominate the CRC pipeline, with XX drug candidates, or a XX% share



4.2 Clinical Trials

The risk of developing a new chemical entity for the pharmaceutical market is well-documented, and the failure rate of pipeline oncology products appears to be rising in Phase II and III (Lacombe and Liu, 2013). This, in turn, has driven up the average cost of bringing a pharmaceutical product onto the market (Dickson, 2009). With companies therefore seeking to maximize the profitability of their pipeline portfolios, efficient risk management and the selection of only the most promising compounds has become an essential task for pharmaceutical companies.

Additionally, the cost of running clinical trials is high, with the result that clinical pipeline product failures are highly expensive. As the cost of clinical trials is partly driven by the number of patients enrolled, median and mean clinical trial enrollment is a key measure of the relative clinical trial costs for different molecule types.

4.2.1 Failure Rate

Analysis of CRC clinical trials since 2006 reveals a high failure rate of XX% across all stages of clinical development. Attrition rates of molecules in individual stages of development were XX%, XX% and XX% for Phase I, Phase II and Phase III trials, respectively. The overall failure rates for drugs across the entire industry at each individual phase are estimated to be XX% for Phase I, XX% for Phase II and XX% for Phase III (Adams et al., 2010).

This indicates that the attrition rates of CRC molecules in Phase III is higher to that of the overall pharmaceutical industry, and that failure rates are higher than the industry average in Phase I and Phase II.

The overall attrition rate of small molecules was found to be XX%, which is almost equal to the overall rate of attrition of all CRC drugs. The attrition rate of mAbs was XX%. The failure rates of mAbs are markedly higher in Phase II trials than in Phase I and Phase III, and for small molecules, it is markedly higher in Phase III then in Phase I and Phase II. As displayed in the following figure, the failure rate of growth factor inhibitors or antagonists, which occupy a dominant share in the CRC pipeline, is similar to that of cytotoxic agents across all stages of clinical development.

Analysis of CRC clinical trials since 2006 reveals a high failure rate of XX% across all stages of clinical development



Figure 7: Colorectal Cancer Therapeutics, Global, Clinical Trial Failure Rate (%), 2013

Phase I

Phase II

Phase III

mAbs Small molecule Overall

Phase I

Phase II

Phase III

Specific receptor agonist/antagonist Specific enzyme inhibitors Overall

Overall Small molecule mAbs

Failu

re ra

te (%

)

Source: GBI Research, Proprietary Clinical Trials Database

mAbs: Monoclonal antibody



5 Market Forecast to 2020

5.1 Asia-Pacific Market

5.1.1 Treatment Use Patterns

The five-year prevalence population of CRC in the APAC regions was estimated at XX in 2013 and is expected to increase at a moderate CAGR of XX% to XX in 2020. The five-year prevalence is based on annual incidence over five years and takes into account the five-year survival rate. This produces a figure that reflects the number of surviving patients who were diagnosed with CRC in the previous five years and are therefore more likely to undergo pharmacological treatment for the disease than those diagnosed XX or more years earlier.

The treatment population for CRC in the APAC regions amounted to an estimated XX in 2013 and is expected to register modest growth to reach XX in 2020 at a CAGR of XX%.

Figure 10: Colorectal Cancer Therapeutics, Asia-Pacific, Treatment Use Patterns (‘000) ,2013–2020

2013 2014 2015 2016 2017 2018 2019 2020

Pat

ient

s ('0

00)

Five-year prevalence population Treatment population


5.1.2 Market Size

The CRC therapeutics market in the APAC region was worth $XX billion in 2013 and is expected to grow at a CAGR of XX% to reach $XX billion by 2020. Japan had the largest market in 2013 with a value of $XX billion, or a share of XX%, followed by China with $XXm or XX% and Australia with $XXm or XX%. India had the lowest market share and value at XX% and $XXm, but is expected to witness the fastest growth over the forecast period with a CAGR of XX%, compared with China’s XX%, Australia’s XX% and Japan’s XX%.

The use of targeted therapies is expected to increase in the APAC markets as patient access to these more expensive agents improves. The moderate uptake of late-stage pipeline products panitumumab and Xilonix, following the expected approval of these drugs, is expected to drive additional growth within this market. Others such as ramucirumab, TAS-102, TS-1, and MelCancerVac will also contribute. The total value of the CRC market will increase slightly over the forecast period due to the increased uptake of branded drugs. Market growth will be the result of the launch of a

The five-year prevalence population of CRC in the APAC regions was estimated at XX in 2013 and is expected to increase at a moderate CAGR of XX% to XX in 2020

The CRC therapeutics market in the APAC region was worth $XX billion in 2013 and is expected to grow at a CAGR of XX% to reach $XX billion by 2020



number of premium-priced agents, plus a gradual increase in the use of targeted therapies and a rise in the incident population.

Figure 11: Colorectal Cancer Therapeutics, Asia-Pacific, Market Size ($bn), 2013–2020

2013 2014 2015 2016 2017 2018 2019 2020

Mar

ket s

ize

($bn

)

Low variance Medium variance High variance Projected




6 Deals and Strategic Consolidations

6.1 Licensing Agreements

A total of XX licensing deals for drugs indicated for CRC were identified from 2006 to 2014, of which XX had a disclosed deal value, comprising an aggregate deal value of $XX billion. The vast majority of these deals were out-licensed by companies headquartered in the US. In the APAC region the deals were mostly concentrated in South Korea, Japan and Australia.

Almost all deals for which the molecule type of the drug is known concern small molecules, reflecting dominance in the developmental pipeline. The mechanism of action for drugs involved in licensing deals is mostly unknown, but with a slightly higher number of deals concerning cytotoxic agents, growth factor inhibitors and protein kinase inhibitors.

Figure 24: Colorectal Cancer Therapeutics, Global, Licensing Deals by Geography, 2006–2014

A) Licensing deal distribution

C) Licensing deals by region

Asia-Pacific Europe North America

B) Licensing deals by value

>$10 million $10–50 million

$50–100 million $100–200 million

>$200 million

Source: GBI Research, Proprietary Deals Database

Node sizes, arrow sizes and edge thicknesses correspond to the volume of deals occurring, with larger nodes, larger arrows and thicker edges indicating a higher volume of deals.

A total of XX licensing deals for drugs indicated for CRC were identified from 2006 to 2014, of which XXhad a disclosed deal value, comprising an aggregate deal value of $XX billion



7 Appendix

7.1 All Pipeline Drugs by Phase

7.1.1 Discovery

Table 3 Colorectal Cancer Therapeutics, Global, All Pipeline Products (Discovery), 2014

Product name Company Molecule type Mechanism of action Stage of development




7.1.2 Preclinical

Table 4 Colorectal Cancer Therapeutics, Global, All Pipeline Products (Preclinical), 2014





7.1.3 IND/CTA-Filed

Table 5 Colorectal Cancer Therapeutics, Global, All Pipeline Products (IND/CTA-Filed), 2013



7.1.4 Phase I

Table 6 Colorectal Cancer Therapeutics, Global, All Pipeline Products (Phase I), 2014





7.1.5 Phase II

Table 7 Colorectal Cancer Therapeutics, Global, All Pipeline Products (Phase II), 2014





7.1.6 Phase III

Table 8 Colorectal Cancer Therapeutics, Global, All Pipeline Products (Phase III), 2014



7.2 Market Forecasts to 2020

7.2.1 Asia-Pacific

Table 9 Colorectal Cancer Therapeutics, Asia-Pacific, Forecast Data, 2013–2020

Year 2013 2014 2015 2016 2017 2018 2019 2020 CAGR

(%)

Five-year prevalence population ('000)

Treatment population ('000)

Minimum market size ($m)

Projected market size ($m)

Maximum market size ($m)


7.2.2 Australia

Table 10 Colorectal Cancer Therapeutics, Australia, Forecast Data, 2013–2020

Year 2013 2014 2015 2016 2017 2018 2019 2020 CAGR

(%)









7.2.3 India

Table 11 Colorectal Cancer Therapeutics, India, Forecast Data, 2013–2020

Year 2013 2014 2015 2016 2017 2018 2019 2020 CAGR

(%)







7.2.4 China

Table 12 Colorectal Cancer Therapeutics, China, Forecast Data, 2013–2020

Year 2013 2014 2015 2016 2017 2018 2019 2020 CAGR

(%)







7.2.5 Japan

Table 13 Colorectal Cancer Therapeutics, Japan, Forecast Data, 2013–2020

Year 2013 2014 2015 2016 2017 2018 2019 2020 CAGR

(%)









7.3 Market Definitions

The market includes the Asia-Pacific markets of Australia, India, China and Japan.

The prevalence population is the estimated number of people at any given point of time that are affected by colorectal cancer.

The prescription population refers to the number of people taking pharmacological treatment for colorectal cancer.

7.4 Abbreviations

5T4: Trophoblast glycoprotein

ACoT: Annual Cost of Therapy

AE: Adverse Event

ALK: Anaplastic Lymphoma Kinase

Ang: Angiopoietin

APAC: Asia-Pacific

APC: Adenomatous Polyposis Coli

ASCO: American Society of Clinical Oncology

ASR: Age Standardized Incidence Rate

ATP: Adenosine Triphosphate

BSC Best Supportive Care

CAGR: Compound Annual Growth Rate

CDK: Cyclin-Dependent Kinases

CEA: Carcinoembyonic Antigen

cGMP-PDE: cyclic Guanosine Monophosphate-Phosphodiesterase

CI: Confidence Interval

CMS: Centers for Medicare & Medicaid Services

CNS: Central Nervous System

CR: Crude Incidence Rate

CRC: Colorectal Cancer

CTA: Clinical Trial Application

DFMO: Difluoromethylated Ornithine

DFS: Disease Free Survival

DPP4: Dipeptidyl Peptidase

DPCO: Drug Price Control Order

DPD: Dihydropyrimidine Dehydrogenase

DRE: Digital Rectal Examination

DTH: Delayed Type Hypersensitivity

dThd: degrading deoxythymidine

EAPC: Estimation of Annual Percentage Change

ECOG: Eastern Cooperative Oncology Group

EGFR: Epidermal Growth Factor Receptor

EMA: European Medicines Agency



EPCAM: Epithelial Cell Adhesion Molecule

FA: Folinic Acid

FAP: Familial Adenomatous Polyposis

FAS: Fatty Acid Synthase

FDA: Food and Drug Administration

FdUMP: 5-fluoro-2'-deoxyuridine monophosphate

FFPE: Formalin-Fixed Paraffin Embedded

FGF: Fibroblast Growth Factor

FGFR: Fibroblast Growth Factor Receptor

FLT3: FMS-Like Tyrosine Kinase 3

FOB: Fecal Occult Blood

FU: 5-fluorouracil

FUTP: 5-Fluorouridine Triphosphate

GBM: Glioblastoma Multiforme

GEJ: Gastroesophageal Junction

GI: Gastrointestinal

GIST: Gastrointestinal Stromal Tumors

HDAC: Histone Deacetylases

HER: Human Epidermal Growth Factor Receptor

HGFR: Hepatocyte Growth Factor Receptor

HIPEC: Hyperthermic Intraperitoneal Chemotherapy

HNPCC: Non-Polyposis Colorectal Cancer

HR: Hazard Ratio

IDO: Indoleamine Pyrrole 2,3-Dioxygenase

IGF-1R: Insulin Like Growth Factor 1 Receptor

IgG1: Immunoglobulin G1

IL: Interleukin

IND: Investigational New Drug

IAP: Inhibitor of Apoptosis

IPF: Idiopathic Pulmonary Fibrosis

ITP: Idiopathic Thrombocytopenic Purpura

IV: Intravenous

JAK: Janus Kinase 2

K-Ras V-Ki-ras2: Kirsten rat sarcoma viral oncogene homolog

LSD-1: Lysine Specific Demethylase 1

LV: Leucovorin

LOXL2: Lysyl Oxidase-Like 2

mAb: monoclonal antibody

MAP: Mitogen-Activated Protein



MAPC: Mean Annual Percentage Change

MAPK: Mitogen-Activated Protein Kinase

MMP: Matrix Metalloproteinase

MCC: Mutated-in-Colon-Cancer

mCRC: metastatic Colorectal Cancer

MHLW: Ministry of Health, Labor and Welfare

MAPK: Mitogen Activated Protein Kinase

MLH1: MutL Homolog

MSH: MutS Homolog

mTOR: mammalian Target of Rapamycin

MUC: Mucin

NCI: National Cancer Institute

NEDL: National Essential Drug List

NHI: National Health Insurance

NRDL: National Reimbursement Drug List

NSCLC: Non-Small-Cell Lung Cancer

OPRT: Orotate Phosphoribosyl-Transferase

ODC: Ornithine Decarboxylase

OS: Overall Survival

p53: tumor protein 53

PACES: Preventing Adenomas of the Colon with Eflornithine and Sulindac

PARP-1: Poly (ADP-Ribose) Polymerase 1

PDE: Phosphodiesterase

PDGF: Platelet Derived Growth Factor

PDGFR: Platelet Derived Growth Factor Receptor

PEG: Polyethylene Glycol

PFS: Progression-Free Survival

PI3K: Phosphatidylinositol-3-Kinase

PIGF: Placental Growth Factor

PKB: Protein Kinase B

PMS: Postmeiotic Segregation Increased

PS: Performance Statuses

RCC: Renal Cell Carcinoma

RhD: Rhesus D

RR: Response Rate

sNDA: supplemental New Drug Application

SWOG: Southwest Oncology Group

TACSTD2: Tumor Associated Calcium Signal Transducer 2

TGA: Therapeutic Goods Administration



TKI: Tyrosine Kinase Inhibitor

TLR: Toll-Like Receptor

TNIK: TRAF2 and NCK-Interacting Protein Kinase

TNM: Tumor, Nodes and Metastasis

TPI: Thymidine Phosphorylase Inhibitor

TRIPS: Trade Related Aspects of Intellectual Property Rights

TS: Thymidylate Synthase

TTP: Thrombotic Thrombocytopenic Purpura

uPA-R: Urokinase Plasminogen Activator Surface Receptor

UTP: Uridine Triphosphate

V2R: Vasopressin V2 Receptor

V1aR: Vasopressin V1a Receptor

V1bR: Vasopressin V1b Receptor

VEGF: Vascular Endothelial Growth Factor

VEGFR: Vascular Endothelial Growth Factor Receptor

wAMD: wet Age-Related Macular Degeneration

7.5 References

Abdullah L and Chow E (2013). Mechanisms of chemoresistance in cancer stem cells. Clinical and Translational Medicine; 2(1): 3.

Amado RG, et al. (2008). Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. Journal of Clinical Oncology; 26(10):1626–1634.

Balmaña J, et al. (2010). Familial colorectal cancer risk: ESMO Clinical Practice Guidelines. Annals of Oncology; 21(suppl 5): v78-v81.

Bibeau, et al. (2006). Assessment of epidermal growth factor receptor (EGFR) expression in primary colorectal carcinomas and their related metastases on tissue sections and tissue microarray. Virchows Archiv; 449(3): 281–287.

Calle EE and Thun MJ (2004). Obesity and cancer. Oncology; 23(38): 6365–6378.

Cappell MS (2005). The pathophysiology, clinical presentation, and diagnosis of colon cancer and adenomatous polyps. The Medical Clinics of America: 89(1): 1–42, vii.

Center MM, et al. (2009a). International trends in colorectal cancer incidence rates. Cancer Epidemiology, Biomarkers and Prevention; 18(6): 1688–1694.

Center MM, et al. (2009b). Worldwide variations in colorectal cancer. CA: A Cancer Journal for Clinicians; 59(6): 366–378.

Chiron M, et al. (2014). Differential antitumor activity of aflibercept and bevacizumab in patient-derived xenograft models of colorectal cancer. Molecular Cancer Therapeutics; 13(6):1636–44.

Colagiuri B, et al. (2012). Does Assessing Patients’ Expectancies About Chemotherapy Side Effects Influence Their Occurrence? Journal of Pain and Symptom Management; Epub.

Corley DA, et al. (2014). Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med; 370(14): 1298–1306.Dolgin E (2009), FDA narrows drug label usage. Nature Publishing Group. Available from: http://www.nature.com/news/2009/090824/full/4601069a.html [Accessed on: September 10, 2014]

Douillard JY, et al. (2010). Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) vs. FOLFOX4 alone as first-line treatment in patients with



7.6 References for Heat Map

Table 14: Colorectal Cancer Market, References for Heat Map

Number Reference

1 Giantonio B et al. (2007). Bevacizumab in Combination With Oxaliplatin, Fluorouracil, and Leucovorin (FOLFOX4) for Previously Treated Metastatic Colorectal Cancer: Results From the Eastern Cooperative Oncology Group Study E3200. Journal of Clinical Oncology; 25 (12): 1,539–1,544.

2 Grothey A et al. (2012). Bevacizumab Beyond First Progression Is Associated With Prolonged Overall Survival in Metastatic Colorectal Cancer: Results From a Large Observational Cohort Study (BRiTE). Journal of Clinical Oncology; 26 (33): 5,326–5,344.

3 Hurwitz H et al. (2004). Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. New England Journal of Medicine; 350 (23): 2,335–2,342.

4 Kabbinavar et al. (2005). Combined Analysis of Efficacy: The Addition of Bevacizumab to Fluorouracil/Leucovorin Improves Survival for Patients With Metastatic Colorectal Cancer.

5 Kabbinavar F et al. (2009). Addition of Bevacizumab to Fluorouracil-Based First-Line Treatment of Metastatic Colorectal Cancer: Pooled Analysis of Cohorts of Older Patients From Two Randomized Clinical Trials. Journal of Clinical Oncology; 23 (16): 3,706–3,712.

6 Miller K et al. (2005). Randomized Phase III Trial of Capecitabine Compared With Bevacizumab Plus Capecitabine in Patients With Previously Treated Metastatic Breast Cancer. Journal of Clinical Oncology; 23 (4): 792–799.

7 Saltz L et al. (2008). Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study. Journal of Clinical Oncology; 26 (12): 2,013–2,019.

8 Grothey A et al. (2012). CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. doi: 10.1016/S0140-6736(12)61900-X. Epub 2012 Nov 22.

9 Kim T W (2014). "CONCUR: A randomized, placebo-controlled phase 3 study of regorafenib (REG) monotherapy in Asian patients with previously treated metastatic colorectal cancer (mCRC)", European Society for Medical Oncology (ESMO) 2014 Congress, Category: Gastrointestinal tumors, colorectal, Session: Proffered Paper session, Poster No.: 500O, 27 Sep 2014

10 Van Cutsem et al. (2013). Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014 Jan;50(2):320-31. doi: 10.1016/j.ejca.2013.09.013. Epub 2013 Oct 16.

11 Amado R et al. (2008). Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer. Journal of Clinical Oncology; 26 (10): 1,626–1,634.

12 Cutsem E et al. (2007). Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer. Journal of Clinical Oncology; 25 (13): 1,658–1,664.

13 Douillard J et al. (2010). Randomized, Phase III Trial of Panitumumab With Infusional Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX4) Versus FOLFOX4 Alone As First-Line Treatment in Patients With Previously Untreated Metastatic Colorectal Cancer: The PRIME Study. Journal of Clinical Oncology; 28 (31): 4,697–4,705.

14 Hecht J et al. (2009). A Randomized Phase IIIB Trial of Chemotherapy, Bevacizumab, and Panitumumab Compared With Chemotherapy and Bevacizumab Alone for Metastatic Colorectal Cancer. Journal of Clinical Oncology; 27 (5): 672–680.

15 Peeters M et al. (2010). Randomized Phase III Study of Panitumumab With Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) Compared With FOLFIRI Alone As Second-Line Treatment in Patients With Metastatic Colorectal Cancer. Journal of Clinical Oncology; 28 (31): 4,706–4,713.

16 Tol J et al. (2008). A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity. Annals of Oncology; 19: 734–738.

17 Maughan T et al. (2011). Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomized phase 3 MRC COIN trial. Lancet; 377: 2,103–2,114.

18 Sobrero A et al. (2008). EPIC: Phase III Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer. Journal of Clinical Oncology; 26 (14): 2,311–2,319.

Source: GBI Research



7.7 Research Methodology

GBI Research’s dedicated research and analysis teams consist of experienced professionals with advanced statistical expertise and marketing, market research and consulting backgrounds in the medical devices industry.

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. The following research methodology is followed for all databases and reports.

7.7.1 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 extensive 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.

The coverage is further streamlined and strengthened with additional inputs from GBI Research’s expert panel.

7.7.2 Secondary Research

The research process begins with extensive secondary research using internal and external sources to gather 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

7.7.3 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:

Provides first-hand information on market size, market trends, growth trends, competitive landscape and future outlook

Helps to validate and strengthen secondary research findings



Further develops the analysis team’s expertise and market understanding

Primary research involves email correspondence, telephone interviews and face-to-face interviews for each market, category, segment and sub-segment across a range of geographies.

The participants who typically take part in the process include, but are not limited to:

Industry participants: CEOs, VPs, marketing/product managers, market intelligence managers and national sales managers

Distributors, paramedics and representatives from hospital stores, laboratories and pharmacies

Outside experts: investment bankers, valuation experts, research analysts specializing in specific medical equipment markets

Key opinion leaders: physicians and surgeons that specialize in the therapeutic areas in which specific medical equipment is used

7.7.4 Therapeutic Landscape

Revenues for each indication, geographically, 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 eight regions.

The annual cost of therapy for each indication is arrived at by considering the cost and 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-use 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.

The forecasting model used by 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 that are prescribed drug treatment (prescription population).

Prescription population is calculated as the percentage of the 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 that suffers 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 into the forecasting model to account for patient switching and compliance behavior.

To account for differences in patient affordability of drugs across various geographies, macro-economic 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 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 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. Increase or decrease in prevalence rate, 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 on the growth of the market. The year 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 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 that 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.



7.7.4.1 Market Size by Geography

The treatment-use pattern and annual cost of therapy in each country has been factored in when deriving the individual country market size.

Forecasting Model for Therapeutic Areas

Figure 27: GBI Research Market Forecasting Model

D is ease P opu lati onGener al Po pulatio n 743,535,048

Q uali fying c ondi tion 1 (Age /S ex/O c c upation e tc )Q uali fying c ondi tion 2 (Age /S ex/O c c upation e tc )

Preva l ence t issu e va lve disease 0.2% 1,784,484 Q uali fying c ondi tion (c om plic ation, s eve rity)DIS EA SE D P OPU LA T IO N 1,784,484

T r eatm en t Flow P a ttern sT rea tm ent S eek i ng R at e (Sy m ptom s / Dis Awareness) 89% 1,588,191 Diagn os is Rat e (C lin ical and D iagn os tic Tes t s) 75% 1,191,143

Prescr iption R ate ( Ph ys ician P ercep t io n, Tr eatm ent E ffectiv e n ess )Tis s ue V a lve 70% 833,800 O ther T reatm ents for Valve (Su r g/M ed /N one) -

F ulfi llm en tA vailab ilit y NAW illingness to Us e (Pa tient Perc eptions) NAReady to U se (S u rge ry elig ib ility , R eus e etc ) NA

Affo rd abil it y a t PriceHE as % of G DP s pendA verage Inc om e (per individua l)P at ien t O u t-o f -poc ket Budge t (A nnual)

Budget al loc a tion to one-t im e s urge ryBudget al loc a tion to o the r h ealth needs

A verage Pay or CoverageP at ien t L iab ilityTarge t Pr ic e ( @ 20% pat liab )A SP for C os t o f T herapy

T O TA L P AT IEN T V OLU M E SPro du ct P urch ase Fr equ en c y 1

T OT AL U NIT VO LU MES

Pr icin g pe r Un it 18 ,000$ In f lat ionP rice D ec reas e due to c om pet it ion

M ar ket Va lu e

G BI R esear ch M ar ket Siz in g M o del

Source: GBI Research

The preceding figure represents a typical forecasting model followed by GBI Research. As discussed previously, the model is built on treatment flow patterns. The model starts with the general population, then the 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.



7.7.5 Geographical Landscape

GBI Research analyzes eight major geographies: 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 impact upon the market during the forecast period in order to provide the best-case and worst-case scenarios.

7.7.6 Pipeline Analysis

This section provides a list of molecules at various stages in the pipeline for various indications. The list is sourced from an internal database and validated for 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 companies and news reports are also used to source 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.

7.8 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.

7.10 Disclaimer

All Rights Reserved.

No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher, GBI Research.

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