Obesity Therapeutics to 2019 - MarketResearchChapter four provides in-depth analysis of the obesity...

Obesity Therapeutics to 2019 Safety Concerns Hinder Drug Performance Despite Large Market Opportunity

GBI Research Report Guidance

© GBI Research. This is a licensed product and is not to be photocopied GBIHC302MR / Published AUG 2013

GBI Research Report Guidance

Chapter two gives an overview of obesity, its etiology, epidemiology, comorbidities and the current treatment options.

Chapter three provides in-depth information surrounding the currently marketed products for obesity, including details on their efficacy and safety.

Chapter four provides in-depth analysis of the obesity pharmacotherapy pipeline including breakdown by stage of development and the most common molecular targets.

Chapter five gives predicted market forecasts for anti-obesity drugs globally and for the major global pharmaceutical markets of the US, UK, France, Spain, Italy and Japan up to 2019.


Executive Summary

Executive Summary

The Obesity Therapeutics Market has Few Candidates in Late-stage Development, Limiting Market Growth

Only XX% of the developmental pipeline is currently in the late stages of development, with only XX drug candidate in Pre-registration and XX in Phase III. This therefore limits the number of drugs with the potential to be approved during the forecast period and subsequently the potential for market growth. Over two thirds of the pipeline molecules (XX%) are in the discovery or Pre-registration Phases of development, suggesting a recent surge in interest in anti-obesity drugs. This may be a reflection of the continued increase in the prevalence of obesity and a need for additional treatment to the currently favored option of lifestyle modification, through dieting and increased exercise.

Obesity Therapeutics Market, Global, Pipeline by Phase

Di

PC

PI

PIIPIII PR

Source: GBI Research’s Proprietary Pipeline Database

Di: Discovery; PC: Preclinical; PI: Phase I; PII: Phase II; PIII: Phase III; PR: Pre-registration

The Growth of the Anti-obesity Drugs Market is Restricted by High Attrition Rates

The successful transition of anti-obesity drugs from Phase I to market is very difficult. The development of more than XX% of products is terminated before reaching Pre-registration. This may contribute to the low number of drug candidates seen at the later stages of the developmental pipeline Figure 1. Furthermore, previously approved drugs, including Sanofi-Aventis’ Acomplia (rimonabant) and Knoll Pharmaceutical’s/Abbott Laboratories’ Meridia (sibutramine), were withdrawn from the market in 2008 and 2010 respectively due to the emergence of serious side effects post-marketing, such as severe depression, anxiety, suicidal thoughts, and cardiovascular complications, including heart failure. This has resulted in a stagnant anti-obesity market over the past decade, with only orlistat being proven safe as a long-term treatment for obesity (Figure 3).


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Table of Contents

1 Table of Contents

1 Table of Contents ................................................................................................................................. 5 1.1 List of Tables ............................................................................................................................. 8 1.2 List of Figures............................................................................................................................ 9

2 Introduction........................................................................................................................................10 2.1 Etiology and Pathophysiology ...................................................................................................10 2.2 Classification............................................................................................................................10 2.3 Epidemiology ...........................................................................................................................11

2.3.1 The US .............................................................................................................................11 2.3.2 Obesity in the Top Five European Markets ........................................................................11 2.3.3 Japan ...............................................................................................................................11

2.4 Comorbidities ..........................................................................................................................12 2.4.1 Type 2 Diabetes................................................................................................................12 2.4.2 Hypertension ...................................................................................................................12 2.4.3 Dyslipidemia ....................................................................................................................12 2.4.4 Respiratory Problems .......................................................................................................13 2.4.5 Osteoarthritis ...................................................................................................................13 2.4.6 Cancer Risk ......................................................................................................................13

2.5 Economic Burden .....................................................................................................................13 2.6 Current Therapy Options ..........................................................................................................13

2.6.1 Lifestyle and Behavioral Modifications ..............................................................................13 2.6.2 Bariatric Surgery ..............................................................................................................14 2.6.3 Pharmacotherapy ............................................................................................................14 2.6.4 Treatment Algorithms and Prescription Habits ..................................................................16 2.6.5 Method of Determining Treatment Effectiveness...............................................................17

2.7 Why Develop Therapeutic Anti-obesity Drugs? .........................................................................17 3 Marketed Products .............................................................................................................................19

3.1 Amphetamine-like Drugs ..........................................................................................................19 3.1.1 Overview .........................................................................................................................19 3.1.2 Efficacy Profile .................................................................................................................20 3.1.3 Safety Profile....................................................................................................................20

3.2 Qsymia, Vivus, Inc. ...................................................................................................................20 3.2.1 Overview .........................................................................................................................20 3.2.2 Efficacy Profile .................................................................................................................21 3.2.3 Safety Profile....................................................................................................................22 3.2.4 Discussion ........................................................................................................................23

3.3 Orlistat ....................................................................................................................................23 3.3.1 Overview .........................................................................................................................23 3.3.2 Efficacy Profile .................................................................................................................24 3.3.3 Safety Profile....................................................................................................................26 3.3.4 Discussion ........................................................................................................................26

3.4 Belviq, Arena Pharmaceuticals .................................................................................................27 3.4.1 Introduction .....................................................................................................................27 3.4.2 Efficacy Profile .................................................................................................................27 3.4.3 Safety Profile....................................................................................................................28 3.4.4 Discussion ........................................................................................................................28

3.5 Low Long-term Success Rate of Marketed Anti-Obesity Drugs ...................................................29 3.6 Discussion................................................................................................................................30

4 Pipeline ..............................................................................................................................................34 4.1 Overview of Pipeline by Phase, Molecule Type and Molecular Target ........................................34 4.2 Clinical Trial Duration and Size..................................................................................................37


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Table of Contents

4.2.1 Clinical Trial Duration .......................................................................................................37 4.2.2 Clinical Trial Size...............................................................................................................39

4.3 Clinical Trial Failure, Attrition Rate and Reasons for Clinical Trial Failure ....................................40 4.4 Primary and Secondary Endpoints ............................................................................................42 4.5 Late-stage Drugs of the Developmental Pipeline .......................................................................44

4.5.1 Contrave, Orexigen Therapeutics ......................................................................................44 4.5.2 Cametor, Norgine BV ........................................................................................................46 4.5.3 Victoza, Novo Nordisk ......................................................................................................48 4.5.4 Tesofensine (NeuroSearch) ...............................................................................................51

4.6 Discussion................................................................................................................................51 5 Market Forecasts ................................................................................................................................55

5.1 Global Market ..........................................................................................................................55 5.2 The US .....................................................................................................................................57

5.2.1 Epidemiology and Treatment Usage Patterns ....................................................................57 5.2.2 Annual Cost of Therapy ....................................................................................................57 5.2.3 Market Size ......................................................................................................................58

5.3 Europe.....................................................................................................................................59 5.3.1 Treatment Usage Patterns................................................................................................59 5.3.2 Annual Cost of Therapy ....................................................................................................61 5.3.3 Market Size ......................................................................................................................62

5.4 Japan .......................................................................................................................................64 5.4.1 Treatment Usage Patterns................................................................................................64 5.4.2 Annual Cost of Therapy ....................................................................................................64 5.4.3 Market Forecast ...............................................................................................................64

5.5 Discussion................................................................................................................................65 5.6 Drivers and Barriers of the Anti-obesity Market ........................................................................66 5.7 Obesity Market Drivers ............................................................................................................66

5.7.1 Obesity is a Very Prevalent Disease with Large Potential Target Populations Globally ........66 5.7.2 Recent Approval of Qsymia to Drive Market Growth Providing its Long-term Safety is Proved

........................................................................................................................................66 5.7.3 Diversification of Molecular Targets..................................................................................66

5.8 Obesity Market Barriers ...........................................................................................................67 5.8.1 Low Treatment Rate .........................................................................................................67 5.8.2 Reimbursement Issues ......................................................................................................67

6 Licensing and Co-Development Deals ..................................................................................................68 6.1 Licensing Deals ........................................................................................................................68

6.1.1 EMD Serono Enters into Collaboration and Licensing Agreement with Theratechnologies ...69 6.1.2 Amylin Pharma Enters into Licensing Agreement with Takeda Pharma ..............................69 6.1.3 Palatin Technologies Extends License Agreement with AstraZeneca ...................................70 6.1.4 Zealand Pharma Enters into Licensing and Collaboration Agreement with Boehringer

Ingelheim .........................................................................................................................70 6.2 Co-development Deals .............................................................................................................71

6.2.1 Isis Enters into Collaboration Agreement with Ortho-McNeil .............................................72 6.2.2 Orexigen Therapeutics Enters into Co-development Agreement with Takeda Pharma for

Contrave ..........................................................................................................................72 7 Appendix ............................................................................................................................................73

7.1 References ..............................................................................................................................73 7.2 Abbreviations ..........................................................................................................................77 7.3 All Pipeline Drugs by Phase ......................................................................................................80

7.3.1 Discovery .........................................................................................................................80 7.3.2 Preclinical ........................................................................................................................81 7.3.3 Phase I .............................................................................................................................84


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Table of Contents

7.3.4 Phase II ............................................................................................................................85 7.3.5 Phase III ...........................................................................................................................85 7.3.6 Pre-Registration ...............................................................................................................86

7.4 Market Forecasts to 2019 ........................................................................................................86 7.4.1 Global ..............................................................................................................................86 7.4.2 The US .............................................................................................................................86 7.4.3 UK ...................................................................................................................................87 7.4.4 France .............................................................................................................................87 7.4.5 Germany ..........................................................................................................................87 7.4.6 Italy .................................................................................................................................88 7.4.7 Spain ...............................................................................................................................88 7.4.8 Japan ...............................................................................................................................88

7.5 Methodology ...........................................................................................................................89 7.6 Secondary Research .................................................................................................................89 7.7 Therapeutic Landscape ............................................................................................................89 7.8 Epidemiology-Based Forecasting ..............................................................................................90 7.9 Market Size by Geography .......................................................................................................91 7.10 Pipeline Analysis ......................................................................................................................92 7.11 Contact Us ...............................................................................................................................92 7.12 Disclaimer................................................................................................................................92


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Table of Contents

1.1 List of Tables

Table 1: BMI Classifications ..................................................................................................................11 Table 2: Key Components of Pathways Thought to be Related to Obesity ..............................................15 Table 3: Treatment Options Dependent on BMI ....................................................................................17 Table 4: Obesity Therapeutics, Leading Brand Names of Phentermine ...................................................19 Table 5: Efficacy Results* for Qsymia at 52 Weeks ................................................................................22 Table 6: Changes in Key Safety Parameters in Patients Treated with Qsymia .........................................22 Table 7: Sales Data for Xenical ($m), 2008–2011 ...................................................................................24 Table 8: Efficacy Results for Orlistat as an Initial and Maintenance Therapy ...........................................25 Table 9: Safety Results of Orlistat .........................................................................................................26 Table 10: Efficacy Results for Belviq ........................................................................................................28 Table 11: Placebo-adjusted Safety Results for Belviq ...............................................................................28 Table 12: Obesity Therapeutics Market, Global, Common Molecular Targets in the Obesity Pipeline........36 Table 13: Obesity Therapeutics Market, Global, Average Clinical Trial Size for the Most Common Modes of

Action Amongst Pipeline Drugs, 2006–2013 .............................................................................39 Table 14: Obesity Therapeutics Market, Global, Average Clinical Trial Duration for the Main Modes of

Action Amongst Pipeline Drugs, 2013 ......................................................................................39 Table 15: Contrave, Phase III Clinical Trial Results ...................................................................................44 Table 16: Contrave, Efficacy Results, Phase III Clinical Trial ......................................................................45 Table 17: Cametor, Efficacy Results of a Phase II Clinical Trial ..................................................................46 Table 18: Cametor, Safety and Efficacy Results, Phase III Clinical Trial ......................................................47 Table 19: Victoza, Clinical Trial Results, Phase III Clinical Trial, 2009 .........................................................49 Table 20: Victoza, Clinical Trial Results, Phase III Clinical Trial, 2009 .........................................................50 Table 21: Victoza ,Safety and Efficacy Results, Phase III Clinical Trial, 2009 ..............................................50 Table 22: Obesity Therapeutics Market, Europe, Current Prevalence Rate of the Population Which is

Obese or Overweight, 2012–2019 ...........................................................................................59 Table 23: Obesity Therapeutics Market: Global, Developmental Pipeline, Discovery Phase ......................80 Table 24: Obesity Therapeutics Market: Global, Developmental Pipeline, Preclinical Phase .....................81 Table 25: Obesity Therapeutics Market: Global, Developmental Pipeline, Phase I ....................................84 Table 26: Obesity Therapeutics Market: Global, Developmental Pipeline, Phase II ...................................85 Table 27: Obesity Therapeutics Market: Global, Developmental Pipeline, Phase III ..................................85 Table 28: Obesity Pharmacotherapy Market: Global, Developmental Pipeline, Pre-Registration ...............86 Table 29: Obesity Therapeutics Market, Global, Market Forecasts, 2012–2019 ........................................86 Table 30: Obesity Therapeutics Market, US, Market Forecasts, 2012–2019 .............................................86 Table 31: Obesity Therapeutics Market, UK, Market Forecasts, 2012–2019 .............................................87 Table 32: Obesity Therapeutics Market, France, Market Forecasts, 2012–2019 .......................................87 Table 33: Obesity Therapeutics Market, Germany, Market Forecasts, 2012–2019....................................87 Table 34: Obesity Therapeutics Market, Italy, Market Forecasts, 2012–2019 ...........................................88 Table 35: Obesity Therapeutics Market, Spain, Market Forecasts, 2012–2019 .........................................88 Table 36: Obesity Therapeutics Market, Japan, Market Forecasts, 2012–2019 .........................................88


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Table of Contents

1.2 List of Figures

Figure 1: Obesity, Global, Prevalence (%), 1990–2010 ............................................................................12 Figure 2: Effects of Topiramate on Food Intake ......................................................................................21 Figure 3: Obesity Therapeutics Market, Obesity Drug Approvals and Market Removals ...........................30 Figure 4: Obesity Therapeutics Market, Heat Map Comparing the Safety and Efficacy of Marketed Drugs

...............................................................................................................................................32 Figure 5: Obesity Therapeutics Market, Heat Map Comparing the Performance of Marketed Drugs in

Major Safety Parameters.........................................................................................................33 Figure 6: Obesity Therapeutics Market, Global, Pipeline by Phase and Molecule Type and Molecular

Target .....................................................................................................................................35 Figure 7: Obesity Therapeutics Market, Global, Clinical Trial Duration by Phase and Molecule Type, 2006–

2013 .......................................................................................................................................38 Figure 8: Obesity Therapeutics Market: Global, Clinical Trial Size by Phase and Molecule Type, 2006–2013

...............................................................................................................................................40 Figure 9: Obesity Therapeutics Market, Global, Clinical Trial Failure and Attrition Rates by Phase and

Molecule Type, 2006–2013 .....................................................................................................41 Figure 10: Obesity Therapeutics Market, Global, Clinical Trial Primary and Secondary Endpoints, 2006–2013

...............................................................................................................................................43 Figure 11: Heat Map Comparing the Safety and Efficacy of Marketed and Key Pipeline Drugs ...................53 Figure 12: Heat Map Comparing the Performance of Marketed and Key Pipeline Drugs in Major Safety

Parameters .............................................................................................................................54 Figure 13: Obesity Therapeutics Market, Global, Epidata and Market Forecasts, 2012–2019 .....................56 Figure 14: Obesity Therapeutics Market, US, Epidata and Market Forecasts, 2012–2019 ..........................58 Figure 15: Obesity Therapeutics Market, Europe, Treatment Patterns, 2012–2019 ...................................60 Figure 16: Obesity Therapeutics Market, Europe, Annual Cost of Therapy, 2012–2019 .............................61 Figure 17: Obesity Therapeutics Market, Europe, Market Forecasts, 2012–2019 .......................................63 Figure 18: Obesity Therapeutics Market, Japan, Epidata and Market Forecast, 2012–2019 .......................65 Figure 19: Obesity Therapeutics Market, Global, Status, Value and Number of Licensing Deals, 2006–2013

...............................................................................................................................................68 Figure 20: Obesity Therapeutics Market, Global, Licensing Deals by Phase, Molecule Type and Value, 2006–

2013 .......................................................................................................................................69 Figure 21: Obesity Therapeutics Market, Global, Status, Value and Number of Co-development Deals,

2006–2011 .............................................................................................................................71 Figure 22: Obesity Market, Global, GBI Research Market Sizing Model .....................................................91


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Introduction

2 Introduction

2.1 Etiology and Pathophysiology

Obesity is one of the major growing health concerns in the developed world, and has gained increased media attention over last decade as prevalence rates have continued to grow. Being overweight or obese is a major risk factor in the development of many chronic diseases, including cardiovascular diseases, cancer, and diabetes, all of which incur economic and healthcare costs. As such, attention is being turned to treating obesity as the underlying cause of these chronic and expensive-to-treat diseases. Efforts have historically focused on schemes to encourage overweight and obese patients to undertake lifestyle changes to lower their weight, but as a continuing issue, the development of a pharmacological therapy is being sought to help tackle the problem of obesity and its comorbidities.

Obesity in most countries is defined as an accumulation of excess body fat, with a person being considered obese if their Body Mass Index (BMI) is over XX kilograms per square meter (kg/m2) (Cooke and Bloom, 2006). In East Asian populations, which are more susceptible to the health effects of gaining weight, a person with a BMI of more than XXkg/m2 is considered clinically obese.

There are two distinct patterns of obesity in the general population: central and peripheral. Central obesity, which is more common in males, is associated with increased adipose tissue in the anterior chest wall, anterior abdominal wall, and visceral organs (Zammit et al., 2010). Peripheral obesity, more common in women, is the deposition of fat in peripheral subcutaneous (sc) tissue. In most cases, obesity is the result of an individual consuming more energy than required, creating an energy imbalance with the excess energy stored as fat. However, there is evidence that some individuals may be more susceptible to obesity due to genetic factors, endocrine disorders or psychiatric illness. For example, Lep, which is a cytokine-like peptide mainly expressed by adipocytes, is now believed to be a regulator of fat metabolism and fat uptake. Mice with a homozygous mutation in the obesity of leptin gene, which encodes leptin, have been demonstrated to develop hereditary obesity. Similarly, mutations in the B2-adrenergic receptor gene (ADRB2) which encodes a lipolytic receptor protein, has been implicated in several diseases including hypertension and obesity (Martinez-Hernandez et al., 2007). Several genetic syndromes such as Prader-Willi syndrome and Cohen syndrome are also known to result in obesity.

2.2 Classification

Whether an individual is obese, overweight, or of normal weight is commonly determined by their BMI and where this falls within the World Health Organization’s defined categories, as outlined Table 1. An individual’s BMI is calculated by dividing a person’s mass in kilograms by their height in meters squared. Although not a direct measure of body fat, it is inexpensive and simple to calculate compared to methods such as underwater weighing and dual-energy x-ray absorptiometry, making it easy for healthcare professionals and the public to use. Other inexpensive methods of determining body fat include an individual’s waist circumference.

There are limitations to the use of BMI as a diagnostic tool for obesity. Although a high BMI generally equates to high adiposity, this is not always the case, as individuals with increased muscle mass may have a high BMI without similarly high adiposity (Daniels, 2009).


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Pipeline

4 Pipeline

4.1 Overview of Pipeline by Phase, Molecule Type and Molecular Target

Figure 6 highlights the distribution of pipeline products across all stages of development for anti-obesity therapeutics. The distribution is atypical in comparison to the vast majority of other indications, with a disproportionally large number (XX) currently in the Preclinical Phase, with only three drug candidates in late-stage development. This trend may reflect a reduced interest in obesity drugs in recent years as a result of the numerous market withdrawals and application failures of other obesity drugs as a result of safety concerns. In 2009, Sanofi’s Acomplia (rimonabant) was removed from the European market (not approved elsewhere) due to AEs of suicidal thoughts and severe depression. More recently, in 2010, Abbott Laboratories’ Meridia (sibutramine) was withdrawn from the market due to its psychiatric AEs. The data suggests that due to the increased growth of obesity as a global endemic, which is anticipated to get worse, interest in drugs for obesity has been re-ignited.

Small molecules are the most common across the entire pipeline, accounting for XX%, with peptides/proteins accounting for XX%. When trends across the Phases are analyzed, the only molecule types observed at the later Phases of Pre-registration, Phase III and Phase II are small molecules and proteins/peptides, whereas other forms of molecule type (including oligonucleotides and vaccines) are seen in Phases I and Preclinical, suggesting a growing level of innovation in recent years.

Treatment options for obesity typically target either central mechanisms, controlling appetite and/or energy expenditure, or peripheral mechanisms acting systemically (for example affecting the absorption of food) (Cooke and Bloom, 2006). Pipeline drugs for obesity can be categorized into the five main categories of molecular targets seen throughout the pipeline Figure 6. Over a third (XX%) of all drug candidates in the pipeline fall into the category of centrally acting appetite regulators, XX% more than the combined percentage distribution of all other pipeline molecules for which the molecular target is known. Some XX% of the pipeline has no known/disclosed molecular target.

Further supporting the level of innovation of therapeutics for obesity, recent improvements in the understanding of peptidergic signaling from the GI tract to control hunger and satiety has opened up a new range of potential molecular targets including ghrelin, cholecystokinin, peptide YY and glucagon-like-peptide-1. The potential of these new molecular targets is reflected in their frequency in the developmental pipeline, as outlined in Table 12. Glucagon-like-peptide agonists are particularly promising, as they have already been approved for the treatment of diabetes (Rodgers et al., 2012).

The distribution is atypical […] with a large number currently in the Preclinical Phase, with only three drug candidates in late-stage development


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Pipeline

Figure 6: Obesity Therapeutics Market, Global, Pipeline by Phase and Molecule Type and Molecular Target

3018%

8451%

2213%

2717%

21%

Di PC

PI PII

PIII

3924%

8752%

85%

3219%

Peptide/ProteinSmall MoleculeOtherUnknown/Undisclosed

0

10

20

30

40

50

60

70

80

90

Di PC PI PII PIII PR

Unknown/Undisclosed Other Peptide/Protein Small Molecule

Pipeline Distribution by Molecule Type and Phase

Pipeline Distribution by Molecule Type

Pipeline Distribution by PhaseA

B

C

n=166

n=166


Di: Discovery; PC: Preclinical; PI: Phase I; PII: Phase II; PIII: Phase III; PR: Pre-registration


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Pipeline

Table 12: Obesity Therapeutics Market, Global, Common Molecular Targets in the Obesity Pipeline

Phase

Molecular target Description Di PC PI PII PIII PR

5-HT (serotonin) receptor agonists

Cannabinoid receptor antagonists

Ghrelin receptor agonists

GLP agonists

Leptin receptor agonists

Dopamine reuptake agonists

Targets of growth hormone

Pancreatic lipase inhibitors

DGAT


GLP-1: Glucagon-Like Peptide 1


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Pipeline

4.2 Clinical Trial Duration and Size

4.2.1 Clinical Trial Duration

As expected, the average duration for clinical trials increases as obesity drug candidates progress thorough the stages of development, from an approximate average of XX months in Phase I to XX months in Phase II and XX months in Phase III Figure 7. These figures are slightly below the average for the relevant therapy area (metabolic disorders) for both Phase II and III by a margin of one to two months, and significantly below the industry average at Phases I, II and III by seven, eight and five months respectively, which may be a result of easily measurable primary and secondary weight loss-related endpoints measured over a set time period. The range of clinical trials at each Phase increases between Phase I and II, a potential result of the change in endpoints and trial parameters between Phase I, when safety of the drug is most often tested, to a wider variation in endpoints at Phase II, with different endpoints in Phase II requiring different lengths of time to analyze.

Further analysis of molecule-type specific trends in the clinical trial duration suggests that for Phases I and II, the average clinical trial durations is longer for proteins/peptides than for small molecules by a degree of two and XX months in Phase I and II respectively. Conversely, in Phase III, average clinical trial duration is shorter for proteins/peptides than for small molecules, however this data may be affected by the small population sizes for proteins/peptides.

Clinical trial data for specific molecular targets are limited, but the averages are provided for those molecular targets with a large enough sample sizes in Table 13. There are no noticeable differences between Phases I and II, but there is a large and significant variation in clinical trial duration of XX months between trials of drugs targeting fat synthesis and those targeting energy expenditure (metabolism).


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Pipeline

Figure 7: Obesity Therapeutics Market, Global, Clinical Trial Duration by Phase and Molecule Type, 2006–2013

0

10

20

30

40

50

60

70

80

Phase I Phase II Phase III

Obesity Therapy Area (Metabolic Disorders) Industry Wide

Clinical Trial Durations Across Entire Pipeline

Clinical Trial Durations – Small Molecules (SM) versus Proteins/Peptides (PP)

n=75

n=99

n=90

A

B

0

10

20

30

40

50

60

70

80

90

100

SM PP SM PP SM PP

Phase I Phase II Phase III

Obesity Therapy Area (Metabolic Disorders) Industry WideAverages:

Averages:

n=55

n=13

n=70

n=22

n=78

n=9


Abbreviations: SM: Small Molecule; PP: Protein/Peptide


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Market Forecasts

5.2.3 Market Size

In 2012, the US market accounted for XX% of the total market size across the top five countries in the EU, Japan and the US, with US revenues of approximately $XXm attributed to the sales of orlistat and amphetamine-like drugs (predominantly Phentermine). Phentermine has been available as a weight loss drug since the 1950s, its patent having expired long before it made any impact on the market. Orlistat’s patent expired in 2009 and generic versions are available in the US and EU.

The only drugs likely to boost revenues in the US are Qsymia and potentially Cametor if it gains approval, as their superior efficacy to orlistat will strengthen prescription volumes. Sales of these drugs, the increase in the prevalence of obesity, and inflation, are expected to be the major driving forces until the anticipated approval of Novo Nordisk’s Victoza for obesity in 2019. Its high efficacy will increase variation in the market, potentially increasing the prescription volumes of anti-obesity drugs as a whole, especially as Victoza is already marketed for type 2 diabetes and so is familiar to healthcare professionals.

GBI Research expects the market in the US to grow at a CAGR of XX% from 2012 to a value of approximately $XX billion in 2019, accounting for an estimated 82% of the global market. In a peak market size scenario, the CAGR is estimated to be XX% with revenues of $XX billion. A CAGR of XX% is predicted for a lower market size scenario, corresponding to market revenues of $XX billion.

Figure 14: Obesity Therapeutics Market, US, Epidata and Market Forecasts, 2012–2019

0

20

40

60

80

100

120

140

160

180

2012 2013 2014 2015 2016 2017 2018 2019

Patie

nts

(Mill

ions

)

Treatment Patterns

Prevalence Population Diagnosed Population Treatment Population

0

500

1000

1500

2000

2500

2012 2013 2014 2015 2016 2017 2018 2019

Treatment PopulationA

Patie

nts

(‘000

’s)

0

200

400

600

800

1,000

1,200

1,400

2012 2013 2014 2015 2016 2017 2018 2019

Ann

ual C

ost o

f Tre

atm

ent (

$)

Annual Cost of Treatment ($)

Low Variance Medium Variance High Variance Projected

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

2012 2013 2014 2015 2016 2017 2018 2019

Mar

ket S

ize

($m

)

Market Size ($m)

CAGR 2012—2019Projected Figures: 12.9%Minimum: 8.1%Maximum: 16.7%

CBCAGR 2012—2019Projected Figures: 22.7%Minimum: 17.5%Maximum: 26.8%

Source: GBI Research


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Appendix

7 Appendix

7.1 References

Adan R (2013). Mechanisms underlying current and future anti-obesity drugs. Trends in Neurosciences; 36(12): 133–140

Allison D, et al. (2012). Controlled-released phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring); 20(2): 330–342

Arterburn DE, et al. (2004). The efficacy and safety of sibutramine for weight loss: a systematic review. Archives of Internal Medicine; 164(9): 994–1003

Asakawa A, et al. (2003). Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. An International Journal of Gastroenterology and Hepatology; 52: 947–952

Aspden RM (2011). Obesity punches above its weight in osteoarthritis. Nature Reviews Rheumatology; 7(1): 65–68

Astrup A, et al. (2008). Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomized, double-blind, placebo-controlled trial. The Lancet; 372(9653): 1906–1913

Astrup A, et al. (2009). Effects of liraglutide in the treatment of obesity: a randomized, double-blind, placebo-controlled study. The Lancet; 374(9701): 1606–1616

Ballinger A and Peikin S (2002). Orlistat: its current status as an anti-obesity drug. European Journal of Pharmacology; 440(2–3): 109–117

Black S (2004). Cannabinoid receptor antagonists and obesity. Current Opinion in Investigational Drugs; 5(4): 389–394

Bramlage P, et al. (2004). Hypertension in overweight and obese primary care patients is highly prevalent and poorly controlled. American Journal of Hypertension; 17(10): 904–910

Bullock B, et al. (1996). Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology; 137(7): 2968–2978

Calle EE and Kaaks R (2004). Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Reviews Cancer; 4(8): 579–591

Cooke D and Bloom S (2006). The obesity pipeline: current strategies in the development of anti-obesity drugs. Nature Reviews Drug Discovery; 5(11): 919–931

Cummings D, et al. (2002). Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. New England Journal of Medicine; 346(21): 1623–1630

Daniels S (2009). The use of BMI in the clinical setting. Pediatrics; 124: S35

Davidson M (1999). Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: A randomized controlled trial. The Journal of the American Medical Association; 281(3): 235–242

DHHS (2012). Health, United States. DHHS Publication No. 2013-1232. US Department of Health and Human Services. Available at: http://www.cdc.gov/nchs/data/hus/hus12.pdf#063 [Accessed May 5, 2013]

Drucker D (2001). Minireview: the glucagon-like peptides. Endocrinology; 142(2): 521–527

FDA (2007). Guidance for industry developing products for weight management. Food and Drug Administration. Available from: http://www.fda.gov/downloads/Drugs/.../Guidances/ucm071612.pdf.

Fegal K, et al. (2002) Prevalence and trends in obesity among US adults, 1999-2000. The Journal of the American Medical Association. 288(14): 1723–1727

Fegal K, et al. (2010). Prevalence and trends in obesity among US adults 1999-2008. The Journal of the American Medical Association; 303(3): 235–241


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Appendix

Feng H and Zheng L, et al. (2012). The role of leptin in obesity and the potential for leptin replacement therapy. Endocrine; 44(1): 33–39.

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Field B, et al. (2009). Obesity treatment: novel peripheral targets. British Journal of Clinical Pharmacology; 68(6): 830–843

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7.2 Abbreviations

11βHSD: 11 beta-hydroxysteroid dehydrogenase

5-HT: Serotonin receptor

ACC: Acetyl-coenzyme A carboxylase

AChR: Acetylcholine receptor

ACoT: Annual Cost of Therapy

ADP: Poly adenosine diphosphate

AE: Adverse event

AgRP: Agouti-Related Peptide

AGTR2: Angiotensin II Receptor Type 2

AMPK: AMP Activated Protein Kinase

bid: twice daily (bis in die)

BMI: Body Mass Index

BMP: Bone Morphogenetic Protein

bpm: beats per minute

CAGR: Compound Annual Growth Rate

CB1: Cannabinoid Receptor 1

CNS: Central Nervous System

CPT1: Carnitine Palmitoyl Transferase

CT-1: Cardiotrophin-1

DGAT-1: Diglyceride Acyltransferase 1

Di: Discovery

DRI: Dopamine Reuptake Inhibitor

EMA: Europeans Medicines Agency

ER-Beta: Estrogen Receptor Beta

FAS: Fatty Acid Synthase

FDA: Food and Drug Administration

FGFR4: Fibroblast Growth Factor Receptor 4


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GDP: Gross Domestic Product

GH: Growth Hormone

GHRH: Growth Hormone Releasing Hormone

GI: Gastrointestinal

GLP-1: Glucagon-Like Peptide 1

GR: Glucocorticord Receptor

GSHR: Growth Hormone Secretagogue Receptor

HIV: Human Immunodeficiency Virus

HSD: Hydroxysteroid Dehydrogenase

IKK: IKappaB Kinase

IMPDH: Inosine Monophosphate Dehydrogenase

kg/m2: kilograms per square meter

LEP-R: Leptin Receptor

Lo: Lorquess

MAO: Monoamine Oxidase B Inhibitor

MC: Melanocortin

MC4R: Melanocortin 4 receptor

MCHR1: Melanin-concentrating Hormone Receptor

Metap2: Methionin Aminopeptidase 2

mmol/L: millimole per litre

MSH: Melanocyte-Stimulating Hormone

MTP: Microsomal triglyceride transfer protein

nAChR: Nicotinic acetylcholine receptor

NB16: Naltrexone 16mg/day plus 360mg/day sustained-release bupropion

NB32: Naltrexone 32mg/day plus 360mg per day sustained-release bupropion

NNR: Nicotinic Receptor

NPY2R: Neuropeptide Y Receptor Y2



NR: Nuclear Receptor

NRI: Norepinephrine Reuptake Inhibitor

O: Orlistat

P: Placebo

PARP: Ribose Polymerase

PC: Preclinical

Ph/To: Phentermine/Topiramate

PI3K: Phosphatidylinositol 3-Kinase

pmol/L: picomole per litre


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POMC: Pro-opiomelanocortin

PPAR-Alpha: Peroxisome Proliferator-activator Receptor Alpha

PR: Pre-Registration

PTP1B: Protein Tyrosine Phosphatase 1B

qd: once daily (quaque die)

SAE: Serious Adverse Event

sc: subcutaneous

SCD1: Stearoyl CoA Desaturase-1

SGLT2: Low affinity Sodium Glucose Cotransporter

SIRT-1: NAD Dependent Deacetylase Sirtuin 1

SNAP-25: Synaptosomal Associated Protein 25

SNDRI: Serotonin-norepinephrine-dopamine Reuptake Inhibitor

SR: Sustained Release

SREBP: Sterol Regulatory Binding Protein

TBK1: TANK–binding Kinase 1

Them1: Thioesterase Superfamily Member 1

tid: three times a day (ter in die)

TLR-4: Toll-like Receptor 4

To: Topiramate

TRPV4: Transient Receptor Potential Cation Channel, Subfamily V, Member 4


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7.3 All Pipeline Drugs by Phase

7.3.1 Discovery

Table 23: Obesity Therapeutics Market: Global, Developmental Pipeline, Discovery Phase

Product name Company Alias name Mechanism of action

TGFTX-2 Program

MKG-02

Drug For Obesity

JD-0100 Series

JD-0200 Series

JD-0300 Series

5-HT6 Program

Drug For Type 2 Diabetes And Obesity

Lipid Absorption Inhibitor

CPT-1 Inhibitors

Ghrelin Receptor Antagonists

ST-2425

Drug For Obesity And Diabetes

TBK1/ IKKe Inhibitors

cianidanol

UCP Activator

Histamine-3 Antagonist

Drug Acting On Nicotinic Acetylcholine Receptor Alpha-4 Beta-2 For Obesity And Metabolic Disorders

Drug For Obesity

Target 2 For Type 2 Diabetes/Obesity

Target 4 For Type 2 Diabetes/Obesity

EDP-21

Drug For Obesity

NLF-MO

Program For Diabetes And Obesity

Drugs Targeting Acetyl-CoA Carboxylase

DLN-200

DLN-400

Selective PI3K-Gamma Inhibitor

Adiponectin Secretagogue


See abbreviations at the following link: 7.2


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7.3.2 Preclinical

Table 24: Obesity Therapeutics Market: Global, Developmental Pipeline, Preclinical Phase


11ßHSD Enzyme Inhibitor

AEZS-123

Nuclear Receptor program

TZP-301

PYN-22

Cardiotrophin-1

SPX-8818309

ZP-2435

Stearoyl-CoA Desaturase-1 Drug Development Program

Leptin

NOX-B11

SBM-TFC-039

JD-2000 Series

JD-5000 Series

JD-6000 Series

FAS-267

Drug For Obesity

SRT-1720

2-Hydroxyoleic Acid

Fumagillin

VRS-859 + AMX-808

ANG-2004

GRC-9332

ND-0801

onabotulinumtoxinA

Drug For Obesity

OB-3 peptide

Fatostatin

recombinant human Zinc-a2-glycoprotein

IMPDH Inhibitors for obesity

Leptin Mimetic

OBE-2001

FGFR Program

MOD-1001

oxyntomodulin

RP-1000

GPR12 Antagonist

GPR85 Antagonist


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CD14 Project

PGC GLP-1

PD-4048

PD-4074

Drug For Obesity

PD-2024

PD-4074 + PD-4048

Compound-21

GPR39 Antagonist

GPR173 Antagonist

GPR27 Antagonist

SUVN-504

ZYGL-241

MOD-6030

OBE-1999

OBE-2000

OBE-2002

TH-1173

FAS-115

PTP1B inhibitors

Beta3 Selective Agents

Drug Targeting GPR21

JH-17

JH-18

Enterocyte-Directed DGAT-1 Inhibitor Program

WIN-902A

AM-454

ThermoStem Program

ITE

ALRN-5281

Anti-miR-103/107

Beta-LGND2

TRPV4 Program

Drug Targeting Retinaldehyde Dehydrogenase 1

Drug Targeting Thioesterase Superfamily Member 1

BMP-7 Program

Benzimidazole Derivative

AM-251

DLN-300

CP-640186

GI-17000


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Appendix

xl-100

Irisin

KDT-600

Ghrelin Receptor Antagonists

Drug Targeting TRIP-Br2




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Appendix

7.3.3 Phase I

Table 25: Obesity Therapeutics Market: Global, Developmental Pipeline, Phase I


Oral PYY

ALB-127158(a)

S-234462

betahistine hydrochloride

BMS-830216

TT-401

TT-402

ISIS-FGFR4Rx

Adipotide

Y-242

GSK-2374697

DS-7250

F-652

MB-12066




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7.3.4 Phase II

Table 26: Obesity Therapeutics Market: Global, Developmental Pipeline, Phase II


GFT-505

tesofensine

tesamorelin acetate

CORT-108297

(bupropion SR + zonisamide SR)

AOD-9604

canagliflozin

HPP-404

PRX-00933

(fluticasone propionate + salmeterol xinafoate)

BGP-15

ertugliflozin

LCQ-908

ZYOG-1

RM-493

CKD-732

leptin

bupropion hydrochloride

diacerein

ZGN-440

acipimox

KD-026

salmeterol xinafoate

GSK-2890457

exenatide Once Monthly

BHV-091009



7.3.5 Phase III

Table 27: Obesity Therapeutics Market: Global, Developmental Pipeline, Phase III


cetilistat

liraglutide




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Appendix

7.3.6 Pre-Registration

Table 28: Obesity Pharmacotherapy Market: Global, Developmental Pipeline, Pre-Registration


(bupropion SR + naltrexone SR)



7.4 Market Forecasts to 2019

7.4.1 Global

Table 29: Obesity Therapeutics Market, Global, Market Forecasts, 2012–2019

Year 2012 2013 2014 2015 2016 2107 2018 2019 CAGR

Prevalence population (million)

Diagnosis population (million)

Treatment population (million)

Maximum revenue ($m)

Projected revenue ($m)

Minimum revenue ($m)


7.4.2 The US

Table 30: Obesity Therapeutics Market, US, Market Forecasts, 2012–2019

Year 2012 2013 2014 2015 2016 2107 2018 2019 CAGR




Maximum ACOT ($)

Projected ACOT ($)

Minimum ACOT ($)






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7.4.3 UK

Table 31: Obesity Therapeutics Market, UK, Market Forecasts, 2012–2019

Year 2012 2013 2014 2015 2016 2107 2018 2019 CAGR




Maximum ACOT ($)

Projected ACOT ($)

Minimum ACOT ($)





7.4.4 France

Table 32: Obesity Therapeutics Market, France, Market Forecasts, 2012–2019

Year 2012 2013 2014 2015 2016 2107 2018 2019 CAGR




Maximum ACOT ($)

Projected ACOT ($)

Minimum ACOT ($)





7.4.5 Germany

Table 33: Obesity Therapeutics Market, Germany, Market Forecasts, 2012–2019

Year 2012 2013 2014 2015 2016 2107 2018 2019 CAGR




Maximum ACOT ($)

Projected ACOT ($)

Minimum ACOT ($)






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7.4.6 Italy

Table 34: Obesity Therapeutics Market, Italy, Market Forecasts, 2012–2019

Year 2012 2013 2014 2015 2016 2107 2018 2019 CAGR




Maximum ACOT ($)

Projected ACOT ($)

Minimum ACOT ($)





7.4.7 Spain

Table 35: Obesity Therapeutics Market, Spain, Market Forecasts, 2012–2019

Year 2012 2013 2014 2015 2016 2107 2018 2019 CAGR




Maximum ACOT ($)

Projected ACOT ($)

Minimum ACOT ($)





7.4.8 Japan

Table 36: Obesity Therapeutics Market, Japan, Market Forecasts, 2012–2019

Year 2012 2013 2014 2015 2016 2107 2018 2019 CAGR




Maximum ACOT ($)

Projected ACOT ($)

Minimum ACOT ($)






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Appendix

7.5 Methodology

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

GBI Research adheres to the codes of practice of the Market Research Society (www.mrs.org.uk) and the Strategic and Competitive Intelligence Professionals (www.scip.org).

All GBI Research databases are continuously updated and revised.

7.6 Secondary Research

The research process begins with exhaustive secondary research on internal and external sources being carried out 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 US Securities and Exchanges Commission (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 Therapeutic Landscape

Revenues for each indication are calculated by utilizing the GBI Research market forecasting model. The global revenue for each indication is the sum value of revenues of all seven countries covered in this report.

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, 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.


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7.8 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 (treatment population). Treatment population is calculated as the percentage of population diagnosed with a disease (diagnosis population). The prevalence of a disease (diseased population) is the percentage of the total population that suffers from a disease/condition.

Data on and diagnosis and prescription rates, 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.

The 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 source for the price of drugs are RxUSA, ZenRx, the UK Prescription Cost Analysis, the British National Formulary and data from the Japan Pharmaceutical Information Center (JAPIC).

The epidemiology-based forecasting model uses a bottom-up methodology and it makes use of estimations in the absence of data from research publications. Such estimations may result in a final market value which is different from the actual value. To correct this ‘gap’ the forecasting model uses ‘triangulation’ with the help of base year sales data (from company annual reports, internal and external databases) and sales estimations.

Analogous Forecasting Methodology

Analogous forecasting methodology is used to account for the introduction of new products, patent expiries of branded products and subsequent introduction of generics. Historic data for new product launches and generics penetration are used to arrive at robust forecasts. Increase or decrease of prevalence rates, treatment seeking rate, diagnosis rate and prescription rate are fitted into the forecasting model to estimate market growth rate.

The proprietary model enables GBI Research to account for the impact of individual drivers and restraints in the growth of the market. The year of impact and the extent of impact are quantified in the forecasting model to provide close-to-accurate data sets.


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Appendix

7.9 Market Size by Geography

The treatment usage pattern and annual cost of treatment in each country has been factored in while deriving the individual country market size.

Forecasting Model for Therapeutic Areas

Figure 22: Obesity Market, Global, GBI Research Market Sizing Model

D is ease P opu lati onGener al Po pu la tio n 743 ,535 ,048

Q ualify ing c ondition 1 (Age/S ex/O c c upa tion e tc )Q ualify ing c ondition 2 (Age/S ex/O c c upa tion e tc )

Preval ence t issu e va lve disease 0.2% 1 ,784 ,484 Q ualify ing c ondition (c om plic at ion , s eve rity)DIS EA SE D P OPU LAT IO N 1,784 ,484

T r eatm en t Flow P atte rn sT reatm ent S eek i ng R at e (Sy m ptom s/ Dis A wareness) 89% 1,588 ,191 Diagn os is Rat e ( C lin ica l and D iagn ostic Test s ) 75% 1,191 ,143

Prescr iption R ate (Ph ys ic ian P ercep t io n, Tr ea tm ent E ffec tiv e n ess)Tis s ue V a lve 70% 833 ,800 O ther T rea tm en ts for Va lve (Surg /M ed /N one) -

F ulfi llm en tA vailab ilit y NAW illingness to Us e (Pa tient Pe rc eptions) NAReady to U se (S urge ry e ligib ility , R eus e e tc ) NA

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

Budget alloc a tion to one-t ime s urge ryBudget alloc a tion to othe r h ealth needs

A verage Pay or CoverageP at ien t Liab ili tyTarget Pr ic e ( @20% pa t liab )A SP for Cos t o f T herapy

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

T OT AL UN IT V O LU MES

Pr icin g per Un it 18,000$ In flationP rice D ec reas e due to c om pet it ion

M ar ket Valu e

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


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 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 the 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.


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7.10 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. 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.

The clinical trial size, duration and failure rate analyses utilize our proprietary databases.

7.12 Disclaimer

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