GBIHC342MR MDD Therapeutics in Major Developed Markets to ... · Some pipeline drugs are expected to be launched during the forecast period, such as brexpiprazole, cariprazine, amitifadine,

Major Depressive Disorder Therapeutics in Major Developed Markets to 2020 New Launches and Modest Uptake of New Adjunctive Treatments to Offset Patent Expiries

GBI Research Report Guidance

© GBI Research. This is a licensed product and is not to be photocopied GBIHC342MR / Published OCT 2014 Page 2

GBI Research Report Guidance

Chapter two provides an overview of MDD, in terms of symptoms, etiology, pathophysiology, diagnosis, classification, epidemiology, prognosis, staging and treatment options.

Chapter three provides detailed profiling and comparative heatmap analysis in terms of safety and efficacy of currently marketed MDD products.

Chapter four presents a detailed pipeline analysis for MDD, including individual product profiles, a comparative efficacy and safety profile heatmap analysis of the most promising pipeline products, as well as analysis of the distribution of molecule types across the MDD developmental pipeline. In addition, detailed analyses of the clinical trial failure rates, the clinical trial durations by Phase and clinical trial sizes, by participant numbers.

Chapter five provides market forecasts for countries across the globe, with special attention given to the major developed countries: the US, Canada, the UK, France, Germany, Italy, Spain and Japan. The multiple-scenario forecasts take into account a range of factors that are likely to vary and provide a clear perspective of the level of the potential degree of variance in market size.

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

© GBI Research. This is a licensed product and is not to be photocopied GBIHC342MR / Published OCT 2014

Page 3

Executive Summary

Executive Summary

Market to Decline until 2017 but then Grow Steadily until 2020

Major Depressive Disorder (MDD) therapeutics in the major developed markets was estimated to be worth $XX billion in 2013 and is expected to decline at an overall negative Compound Annual Growth Rate (CAGR) of XX% in the 2013–2020 forecast period to $XX billion. The decline is only expected to last until 2017 at a negative CAGR of XX% due to key patent expiries, but is then expected to grow until 2020 at a CAGR of XX% due to expected new launches. The key patent expiries include those of blockbuster drugs such as Actavis (Lundbeck/Forest Laboratories), Lexapro (escitalopram) (Mitsubishi Tanabe Pharma/Mochida), Cymbalta (duloxetine) (Eli Lilly), Abilify (aripiprazole) (Otsuka Pharmaceutical/Bristol-Myers Squibb (BMS)), and Seroquel XR (quetiapine) (AstraZeneca). These drugs hold a total market share of nearly XX% between them and their expiries will lead to the entry of inexpensive generic versions. Seven new pipeline products are expected to be approved during the forecast period, namely brexpiprazole (Otsuka/Lundbeck), cariprazine (Forest (Actavis)/Gedeon Richter/Mitsubishi Tanabe Pharma), ALKS-5461 (Alkermes), GLYX-13 (Naurex), amitifadine (Euthymics Bioscience), tedatioxetine (Lundbeck/Takeda) and ETS6103 (e-Therapeutics). The first four are adjunctive therapies and are expected to achieve a strong market share, as Abilify and Seroquel XR have shown more than $XX billion sales in 2013. Brintellix (vortioxetine) from Lundbeck/Takeda, which was launched in 2014, is expected to lead the market during the forecast period due to its novel multimodal Mechanism of Action (MoA) and its safety profile, which is comparable to that of a Selective Serotonin Reuptake Inhibitor (SSRI). Although all of the expected new launches are likely to face the competition from generic versions of key drugs, they will boost the market from 2017 and trigger a steady growth rate.

Major Depressive Disorder Market, Global, Market Size ($bn), 2013 and 2020

2013 2020

Mar

ket

size

($bn

)

CAGR: XX%

Source: GBI Research, Proprietary Database


Page 9

Introduction

2 Introduction

MDD is characterized by a range of symptoms that affect a patient only once or are recurrent with the same or different intensities. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), the symptoms associated with MDD are fatigue or loss of energy, feelings of worthlessness or guilt for the majority of the day, impaired concentration, indecisiveness, insomnia or hypersomnia, restlessness, recurring thoughts of death and suicide, pessimistic attitude towards everything in life, and not being able to enjoy simple pleasures. Patients with MDD exhibit six or more of these symptoms. Women are generally at higher risk of depression due to hormonal changes during puberty, menstruation, pregnancy, miscarriage and menopause. According to DSM-IV guidelines, MDD is categorized as mild, moderate or severe based on symptoms. Subtypes of MDD include depression with somatic features, depression with psychotic features, atypical depression, postpartum depression, and Seasonal Affective Disorder (SAD).

Table 1: Major Depressive Disorder Market, Global, Symptoms and Associated Features, 2008

MDD subtype Features

DSM: Diagnostic and Statistical Manual for Mental Disorders; SAD: Seasonal Affective Disorder

Source: DSM-IV-TR, 2008

2.1 Etiology

The etiology of MDD is not well understood. MDD has a multifaceted and varied etiology, including genetic, epigenetic, and environmental factors. The most prevalent environmental factor is stress. MDD can be spontaneous, but it often follows a traumatic emotional experience, or it can be a symptom of other conditions, most often neurological (stroke, multiple sclerosis, or Parkinson’s disease), or endocrine (Cushing's disease, hypothyroidism). MDD can also be triggered or precipitated by pharmacological agents or drug abuse (Villanueva, 2013; Wainwright and Galea, 2013).

There is strong evidence to suggest a role of genetics in MDD; however, Genome-Wide Association Studies (GWAS) have been unsuccessful in identifying specific genetic loci, which suggests that it is likely that the effects of multiple genetic loci contribute to the susceptibility of developing MDD (Flint and Kendler, 2014). According to certain studies (family, twin, and adoption studies) the influence of genetic factors causes around XX–XX% of MDD, and the remaining XX–XX% is due to individual specific environmental factors such as lifetime trauma, childhood abuse, low social support, marital problems, and divorce (Sullivan, 2000). This is a positive sign as it indicates that the majority of MDD cases can be controlled via psychosocial intervention.

In contrast to the solid evidence from epidemiological studies on broad risk factor domains, there is no solid evidence for specific genes and specific gene-by-environment interactions in the pathogenesis of MDD. GWAS have indicated that many genes, that have little effect individually, combine and become involved in complex diseases, increasing the difficulty in identifying individual genes (Donnelly, 2008). The limited success of genetic studies of depression has been linked to use of current classification schemes, including the International Classification of Diseases, Tenth Revision (ICD-10) and DSM-IV.


Page 11

Introduction

2.3 Diagnosis

For an appropriate diagnosis of MDD, a patient must experience five of nine symptoms, with one of those five being either depressed mood or loss of interest or pleasure. According to DSM-IV-TR (2000), severity is judged as mild, moderate or severe based on the number of symptoms, the severity of the symptoms, and the degree of functional disability and distress. A thorough diagnostic assessment based on the evaluation of the degree of the severity of the condition is the key to finding appropriate treatment.

A thorough patient assessment is required to establish a diagnosis, rule out other psychiatric disorders and develop a comprehensive treatment plan.

The detailed criteria for the diagnosis of MDD from the DSM-V guidelines, are as follows (DSM-V, 2013):

Some conditions must be screened out, such as those that mimic or co-exist with the symptoms of MDD such as depressed mood due to substance abuse (alcohol, drugs, smoking, medications), and depressed mood due to any other chronic or acute medical condition such as mania, hypomania, bipolar disorder, schizophrenia.


Page 13

Introduction

2.5 Epidemiology

The prevalence rate of MDD varies globally between high-income countries and low-income countries, males and females, and by age group. In the US, the lifetime prevalence rate has increased from the XX% reported in 2005 to XX%, reported in 2011. It was observed that high-income countries have greater lifetime prevalence rate compared to low-income countries with XX% and XX%, respectively (Bromet et al., 2011). In Europe, the prevalence of depression varies but is highest in France with XX%.

The following table gives lifetime and 12-month prevalence rates in different countries:

Table 3: Major Depressive Disorder Market, Global, Prevalence (%), 2011

Country Prevalence rate (lifetime) (%) Prevalence rate (12 months) (%)

US

Canada*

UK*

France

Germany

Italy

Spain

Japan

South Africa

China

Source: Bromet et al, 2011

*Assumption

Individuals who are female, Native American, middle-aged, widowed, separated or divorced, or who have a low income are at a high risk of developing MDD, while individuals who are Asian, Hispanic or black are at lower risk (Deborah, 2005). Women are XX% more likely to develop depression than men. Compared to adults over the age of XX years, XX–XX year olds are XX% more likely to have experienced depression over their lifetime, XX–XX year olds are XX% more likely, and XX–XX year olds are XX% more likely (NIMH, 2014)

The prevalence rate of MDD varies globally between high-income countries and low-income countries


Page 29

Major Depressive Disorder Market to 2020 – Pipeline Products

4 Major Depressive Disorder Market to 2020 – Pipeline Products

4.1 Overall Pipeline

The current developmental pipeline for MDD has potential drug candidates across various Phases of clinical development that are expected to provide comparable safety and efficacy profiles. Approximately XX pipeline molecules are under development for MDD. Of the entire pipeline, XX% (XX) are either inactive or discontinued. The remaining XX% (XX) belongs to the Discovery Phase, Phase I, Phase II, Phase III, Pre-registration, and Preclinical, or undisclosed. The undisclosed pipeline molecules (XX%, three) have either no Phase identified or their Phase of development is currently unknown. Of the active pipeline molecules, the majority of the investigational drug candidates are in Phase II. The pipeline analysis of MDD considered only active molecules (XX molecules). The route of administration for the majority of pipeline drugs is oral (XX%, or XX molecules) followed by an undisclosed route of administration (XX%, XX molecules), and a combinational route of administration (XX%, five molecules), as displayed in Figure 11. Most of the drug dosages in the anti-depressive market are one oral tablet once daily. The majority of the pipeline molecules are novel (XX%, XX molecules) and only XX% is either generic while XX% is repositioned molecules. The novel MoAs include serotonin receptor modulator and dopamine antagonist. Novel molecules currently in Phase III include aripiprazole + sertraline from Otsuka Holdings, amitifadine from Euthymics Biosciences, and brexpiprazole. As displayed in the Figure 11 of XX active progressing pipeline molecules, seven (XX%) are in the Preclinical stage of development, XX (XX%) are in Phase I, XX (XX%) are in Phase II and XX (XX%) are in Phase III. The substantial number of active drug candidates, spread across various stages of clinical development, including the Preclinical and Discovery stages, demonstrates a moderate overall pipeline. Some pipeline drugs are expected to be launched during the forecast period, such as brexpiprazole, cariprazine, amitifadine, tedatioxetine, GLYX-13, ALKS-5461 and TS6103. These new launches are expected to have a moderate effect on the overall anti-depressants market due to major patent expiries and generic erosion.

MDD pipeline appears moderate with few promising adjunctive therapy drugs in late stage of development


Page 30

Major Depressive Disorder Market to 2020 – Pipeline Products

Figure 11: Major Depressive Disorder Market, Global, Pipeline by Stage of Development, Program Type and Route of Administration, 2013

Discovery

Phase I

Phase IIPhase III

Preclinical

Pre-registrationUndisclosed

A) Pipeline by stage of development

Novel

Generic

Repositioned

B) Pipeline by program type

Sublingual

Oral

Intravenous

Combination

Undisclosed

C) Pipeline by route of administration

Dis

cove

ry

Pre

clin

ical

Pha

se I

Pha

se II

Pha

se II

I

Pre

-re

gist

ratio

n

Und

iscl

osed

Num

ber o

f pi

pelin

e m

olec

ules

D) Pipeline by program type and stage of development

Novel Generic Repositioned

Source: GBI Research, Proprietary Pipeline Products Database


Page 47

Market Forecast to 2020

5.1.3.3 Market Revenue

The market revenue for MDD in the top five European markets is expected to decline slowly at a CAGR of XX% from $XX billion in 2013 to $XX billion in 2020 due to key patent expiries of major drugs, the expected penetration of their generic versions and less effective new launches. Of the top five European countries, the UK had the largest market with $XXm in 2013 followed by Germany ($XXm), France ($XXm), Spain ($XXm), and Italy ($XXm). Patent expiries for the three leading products in 2014, Lundbeck’s Lexapro, Eli Lilly’s Cymbalta, Otsuka Pharmaceutical/BMS’s Abilify, and AstraZeneca’s Seroquel XR in 2017, are expected to negatively affect the growth in the MDD market during the forecast period. The launch of Brintellix, the adjunctive therapy, will not offset the loss of value due to patent expiries of key brands. New launches are likely to face intense competition from the inexpensive generics of major drugs. Despite new launches of drugs with novel MoAs, physicians and patients are more comfortable with SSRIs and SNRIs. Adjunctive therapies such as Seroquel XR and Abilify have strong market penetration with a combined sales total of more than $XXbillion. Of the pipeline drugs, four adjunctive therapies (Otsuka/Lundbeck’s brexpiprazole, Forest Actavis/Gedeon Richter/Mitsubishi Tanabe Pharma’s cariprazine, Alkermes’ ALKS-5461, and Naurex’s GLYX-13) are likely to achieve strong penetration due to the popularity of adjunctive therapies. The MDD market in the UK is expected to decline at a negative CAGR of XX% to reach $XXm in 2020. Similarly, Germany is expected to decline at a negative CAGR of XX% to $XXm, Italy will experience a slight increase in CAGR of XX% to $XXm, France at a negative CAGR of XX % to $XXm, and Spain growing at a CAGR of XX% to $XXm.

Figure 25: Major Depressive Disorder Market, Top Five European Markets, Market Size ($m), 2013–2020

2013 2014 2015 2016 2017 2018 2019 2020

Mar

ket s

ize

($m

)

A) UK

2013 2014 2015 2016 2017 2018 2019 2020

Mar

ket s

ize

($m

)

B) France

2013 2014 2015 2016 2017 2018 2019 2020

Mar

ket s

ize

($m

)

C) Germany

2013 2014 2015 2016 2017 2018 2019 2020

Mar

ket s

ize

($m

)

D) Italy

2013 2014 2015 2016 2017 2018 2019 2020

Mar

ket s

ize

($m

)

E) Spain

Low variance

Medium variance

High variance

Projected

Source: GBI Research, Proprietary Marketed Products Database


Page 56

Appendix

7 Appendix

7.1 All Pipeline Drugs by Phase

7.1.1 Discovery

Table 4: Major Depressive Disorder Market, Global, Pharmaceutical Pipeline (Discovery), 2013

Drug/project name Company Molecule type MoA


7.1.2 Preclinical

Table 5: Major Depressive Disorder Market, Global, Pharmaceutical Pipeline (Preclinical), 2013

Drug/project name Company Molecule type MoA


7.1.3 Phase I

Table 6: Major Depressive Disorder Market, Global, Pharmaceutical Pipeline (Phase I), 2013

Drug name Company Molecule type MoA



Page 57

Appendix

7.1.4 Phase II

Table 7: Major Depressive Disorder Market, Global, Pharmaceutical Pipeline (Phase II), 2013



7.1.5 Phase III

Table 8: Major Depressive Disorder Market, Global, Pharmaceutical Pipeline (Phase III), 2013




Page 58

Appendix

7.1.6 Pre-registration

Table 9: Major Depressive Disorder Market, Global, Pharmaceutical Pipeline (Pre-registration), 2013



7.1.7 Undisclosed

Table 10: Major Depressive Disorder Market, Global, Pharmaceutical Pipeline (Undisclosed), 2013



7.2 Market Forecasts to 2019

7.2.1 Global

Table 11: Major Depressive Disorder Market, Global, Forecast Data, 2013–2020

Year 2013 2014 2015 2016 2017 2018 2019 2020 CAGR (%)

Prevalence population (‘000)

Treatment population ('000)

Minimum market size ($m)

Projected market size ($m)

Maximum market size ($m)


7.2.2 US

Table 12: Major Depressive Disorder Market, US, Forecast Data, 2013–2020

Year 2013 2014 2015 2016 2017 2018 2019 2020 CAGR (%)








Page 59

Appendix

7.2.3 UK

Table 13: Major Depressive Disorder Market, UK, Forecast Data, 2013–2020

Year 2013 2014 2015 2016 2017 2018 2019 2020 CAGR (%)







7.2.4 France

Table 14: Major Depressive Disorder Market, France, Forecast Data, 2013–2020

Year 2013 2014 2015 2016 2017 2018 2019 2020 CAGR (%)







7.2.5 Germany

Table 15: Major Depressive Disorder Market, Germany, Forecast Data, 2013–2020

Year 2013 2014 2015 2016 2017 2018 2019 2020 CAGR (%)







7.2.6 Italy

Table 16: Major Depressive Disorder Market, Italy, Forecast Data, 2013–2020

Year 2013 2014 2015 2016 2017 2018 2019 2020 CAGR (%)








Page 60

Appendix

7.2.7 Spain

Table 17: Major Depressive Disorder Market, Spain, Forecast Data, 2013–2020

Year 2013 2014 2015 2016 2017 2018 2019 2020 CAGR (%)







7.2.8 Japan

Table 18: Major Depressive Disorder Market, Japan, Forecast Data, 2013–2020

Year 2013 2014 2015 2016 2017 2018 2019 2020 CAGR (%)







7.2.9 Canada

Table 19: Major Depressive Disorder Market, Canada, Forecast Data, 2013–2020

Year 2013 2014 2015 2016 2017 2018 2019 2020 CAGR (%)







7.3 Market Definitions

Market coverage: Major Depressive Disorder (MDD) in the major developed markets, comprising the US, UK, France, Germany, Italy, Spain, Japan, and Canada.

The prevalence population is the estimated number of people at any given point of time who are affected by MDD.

The prescription rate is the percentage of the prevalence population that has been prescribed any drug therapy.

The prescription population is the number of people taking any drug for MDD.


Page 61

Appendix

7.4 Abbreviations

ACoT: Annual Cost of Therapy

ADT: Antidepressant Therapy

APA: American Psychiatric Association

BMS: Bristol-Myers Squibb

BUP: Buprenorphine

CAGR: Compound Annual Growth Rate

CGI-S: Clinical Global Impression Scale

CNS: Central Nervous System

CRF: Corticotrophin Releasing Factor

CRH: Corticotrophin Releasing Hormone

D2: Dopamine type 2

DSM: Diagnostic and Statistical Manual for Mental Disorders

FDA: Food and Drug Administration

GABA: Gamma Amino Butyric Acid

GAD: Generalized Anxiety Disorder

GPCR: G-Protein Coupled Receptor

GR: Glucocorticoid Receptor

GWAS: Genome Wide Association Studies

HAM-D: Hamilton Rating Scale for Depression

HPA: Hypothalamic Pituitary Adrenal Axis

ICD: International Statistical Classification of Diseases and Related Health Problems

IND: Investigational New Drug

MADRS: Montgomery-Asberg Depression Rating Scale

MAOI: Monoamine Oxidase Inhibitor

MDD: Major Depressive Disorder

mg/ml: milligram/milliliter

mGlu: Metabotropic Glutamate

MoA: Mechanism of Action

MR: Mineralocorticoid Receptor

NaSSA: Noradrenergic and Specific Serotonergic Antidepressants

NDA: New Drug Application

NIMH: National Institute of Mental Health

NK: Neurokinin

NMDA: N-methyl-D-aspartate

OCD: Obsessive Compulsive Disorder

PPAR-γ: Peroxisome Proliferator-Activated Receptor gamma

PR: Progesterone Receptor


Page 62

Appendix

SAD: Seasonal Affective Disorder

SERT: Serotonin Transporter

SNDRI: Serotonin-Norepinephrine-Dopamine Reuptake Inhibitor

SNRI: Serotonin-Norepinephrine Reuptake Inhibitor

SPCD: Sequential Parallel Comparison Design

SSRI: Selective Serotonin Reuptake Inhibitor

TCA: Tricyclic Antidepressants

TRK: Tyrosine Kinase

V1bR: Vasopressin V1b Receptor

WHO: World Health Organization

7.5 References

Abilify [Package Insert] Tokyo: Otsuka Pharmaceutical; 2014

Aidsinfonet (2014). Depression and HIV-Fact Sheet 558. Available from: http://www.aidsinfonet.org/fact_sheets/view/558. [Accessed on July, 15, 2014]

American Cancer Society (2013). Depression. Available from: http://www.cancer.org/treatment/treatmentsandsideeffects/physicalsideeffects/dealingwithsymptomsathome/caring-for-the-patient-with-cancer-at-home-depression. [Accessed on July,15, 2014]

American Society on Aging (1998). Depression Statistics. Depression and Bipolar Alliance. Available from: http://www.dbsalliance.org/site/PageServer?pagename=education_statistics_depression. [Accessed on July,17, 2014]

American Heart Association (2014). Depression After a Cardiac Event or Diagnosis. Available from: http://www.heart.org/HEARTORG/GettingHealthy/StressManagement/HowDoesStressAffectYou/Depression-After-A-Cardiac-Event-or-Diagnosis_UCM_440444_Article.jsp. [Accessed on July, 15, 2014]

APA (2000). Depressive Disorder Coding and Diagnostic Criteria. American Psychiatric Association, Available from: http://www.cqaimh.org/pdf/tool_assist_ddcdc.pdf

APA (2010). Diagnostic and statistical manual of mental disorders. (4th Text Revision ed.) Washington, DC: American Psychiatric Association

APA (2013). Highlights of Changes from DSM-IV-TR to DSM-5. American Psychiatric Association. Available from: http://www.dsm5.org/Documents/changes%20from%20dsm-iv-tr%20to%20dsm-5.pdf

AstraZeneca (2010). Annual Report. Corporate Profile. AstraZeneca, Available from: http://www.astrazeneca.com/cs/Satellite?blobcol=urldata&blobheader=application%2Fpdf&blobheadername1=Content-Disposition&blobheadername2=MDT-Type&blobheadervalue1=inline%3B+filename%3D2010-Annual-report.pdf&blobheadervalue2=abinary%3B+charset%3DUTF-8&blobkey=id&blobtable=MungoBlobs&blobwhere=1285646055594&ssbinary=true

AstraZeneca (2013). Annual Report. Corporate Profile. AstraZeneca. Available from:

http://www.astrazeneca-annualreports.com/2013/_assets/pdfs/AstraZeneca_Annual_Report_2013.pdf

Baillon S, et al. (2014). The Utility of the Edinburgh Depression Scale as a screening tool for depression in Parkinson's disease. International Journal of Geriatric Psychiatry. Available from: http://onlinelibrary.wiley.com/doi/10.1002/gps.4110/abstract. [Accessed on September, 12, 2014]

Bauer M, et al. (2013). World Federation of Societies of Biological Psychiatry guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. The World Journal of Biological Psychiatry; 14(5): 334–385


Page 65

Appendix

Ryan J, et al. (2001). The Prevalence of Comorbid Depression in Adults With Diabetes, A meta-analysis. Diabetes Care; 24:1069–107

Riise T, et al. (2001). Prognostic factors in major depression: A long term follow-up study of 323 patients. Journal of Affective Disorder; 65(3): 297-306

Seroquel XR [Package Insert] Wilmington, DE: AstraZeneca Pharmaceuticals; October 2013

Simon GE (2000). Long term prognosis of depression in primary care. Bulletin of the World Health Organization; 78 (4)

Sullivan PF, et al. (2000). Genetic epidemiology of major depression: Review and Meta-analysis. The American Journal of Psychiatry; 157(10): 1552-62

Villanueva R, et al. (2013). Neurobiology of major depressive disorder. Neural Plasticity; vol. 2013, Article ID 873278, 7 pages, 2013. doi:10.1155/2013/873278

Wainwright SR and Galea LA (2013). The neural plasticity theory of depression: assessing the roles of adult neurogenesis and PSA-NCAM within the hippocampus. Neural Plasticity; vol. 2013, Article ID 805497, 14 pages, 2013. doi:10.1155/2013/805497

WHO (2004). Prevention of Mental Disorders, Geneva. World Health Organization. Available from: http://www.mentalhealth.org.uk/content/assets/PDF/publications/fundamental_facts_2007.pdf?view=Standard

Young EA, et al. (1998). Sex differences and the HPA axis: Implications for psychiatric disease. The Journal of Gender Specific Medicine; 1(1): 21-27

Young EA, et al. (2003). Mineralocorticoid receptors function in major depression. Archives of General Psychiatry; 60(1): 24-8.

7.6 Research Methodology

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

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

All GBI Research databases are continuously updated and revised.

7.6.1 Coverage

The objective of updating GBI Research’s coverage is to ensure that it represents the most up-to-date vision of the industry possible.

Changes to the industry taxonomy are built on the basis of extensive research of company, association and competitor sources.

Company coverage is based on three key factors: market capitalization, revenues and media attention/innovation/market potential.

An exhaustive search of 56 member exchanges is conducted and companies are prioritized on the basis of their market capitalization.

The estimated revenues of all major companies, including private and governmental, are gathered and used to prioritize coverage.

Companies that are making the news, or that are of particular interest due to their innovative approach, are prioritized.

GBI Research aims to cover all major news events and deals in the pharmaceutical industry, updated on a daily basis.

The coverage is further streamlined and strengthened with additional input from GBI Research’s expert panel (see below).


Page 66

Appendix

7.6.2 Secondary Research

The research process begins with exhaustive secondary research using internal and external sources in order to source qualitative and quantitative information relating to each market.

The secondary research sources that are typically referred to include, but are not limited to:

Company websites, annual reports, financial reports, broker reports, investor presentations and SEC filings

Industry trade journals, scientific journals and other technical literature

Internal and external proprietary databases

Relevant patent and regulatory databases

National government documents, statistical databases and market reports

Procedure registries

News articles, press releases and web-casts specific to the companies operating in the market

7.6.3 Primary Research

GBI Research conducts hundreds of primary interviews a year with industry participants and commentators in order to validate its data and analysis. A typical research interview fulfills the following functions:

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

Validates and strengthens secondary research findings

Further develops the analysis team’s expertise and market understanding

Primary research involves e-mail and telephone interviews as well as face-to-face interviews for each market, category, segment and sub-segment across geographies.

The participants that typically take part in such a process include, but are not limited to:

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

Hospital stores, laboratories, pharmacies, distributors and paramedics

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

Key opinion leaders: physicians and surgeons specializing in relevant therapeutic areas

7.6.4 Therapeutic Landscape

Revenues for each indication, geography-wise, are arrived at by utilizing the GBI Research market forecasting model. The global revenue for each indication is the sum value of revenues of all seven regions.

The annual cost of therapy for each indication is arrived at by considering the cost of the drugs, dosage of the drugs and the duration of the therapy.

The generic share of the market for each indication is obtained by calculating the prescription share for generic drugs and the respective cost of treatment.

The treatment 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.


Page 67

Appendix

7.6.4.1 Epidemiology-Based Forecasting

The forecasting model used at GBI Research makes use of epidemiology data gathered from research publications and primary interviews with physicians to represent the treatment flow patterns for individual diseases and therapies. The market for any disease segment is directly proportional to the volume of units sold and the price per unit.

Sales = Volume of Units sold X Price per Unit

The volume of units sold is calculated on the average dosing regimen for that disease, duration of treatment and number of patients who are prescribed drug treatment (prescription population). Prescription population is calculated as the percentage of population diagnosed with a disease (diagnosis population). Diagnosis population is the population diagnosed with a disease expressed as a percentage of the population that is seeking treatment (treatment-seeking population). Prevalence of a disease (diseased population) is the percentage of the total population who suffer from a disease/condition.

Data on the treatment seeking rate, diagnosis rate and prescription rate, if unavailable from research publications, are gathered from interviews with physicians and are used to estimate the patient volumes for the disease under consideration. Therapy uptake and compliance data are fitted in the forecasting model to account for patient switching and compliance behavior.

To account for differences in patient affordability of drugs across various geographies, macroeconomic data, such as inflation and GDP, and healthcare indicators such as healthcare spending, insurance coverage and average income per individual are used.

Annual cost of therapy is calculated using product purchase frequency and the average price of the therapy. Product purchase frequency is calculated from the dosage data available for the therapies, and drug prices are gathered from public sources. The sources for the price of drugs are MIMS India, MIMS China and ZenRx.

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 that is different from the actual value. To correct this ‘‘gap’’ the forecasting model uses ‘‘triangulation’’ with the help of base year sales data (from company annual reports, internal and external databases) and sales estimations.

Analogous Forecasting Methodology

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

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

Diseased Population

The diseased population for any indication is the prevalence. The prevalence population for this report is taken from articles published in various journals, including the American Psychiatric Association, National Institute of Mental Health, and the World Health Report.

Prescription Population

MDD has multiple treatment options depending upon the stage of the disease and previous effectiveness of other similar treatments. Options include lifestyle changes and psychiatric counseling in the case of mild depression and antidepressants and pharmacological treatment in the case of moderate-to-severe depression. The prescription population is defined as the number of patients who are prescribed biologic drug therapy. This is calculated as a percentage of the diagnosis population. Prescription population proportion is taken from articles published in journals such as the World Health Report and the National Institute of Mental Health.


Page 68

Appendix

7.6.4.2 Market Size by Geography

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

Forecasting Model for Therapeutic Areas

Figure 33: GBI Research Market Forecasting Model (Example)

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

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

Preva l ence t issu e va lve disease 0 .2% 1,784,484 Q ualif ying c ondition (c om plic at ion , s eve rity)DIS EA SE D P OPU LA T IO N 1,784,484

T r eatm en t Flow P atte rn sT rea tm ent S eeki ng R ate (Sy m ptom s / Dis Awareness ) 89% 1,588,191 Diagn osis Rat e ( C lin ical and D iagn os tic Test s ) 75% 1,191,143

Prescr iption R ate ( Ph ysic ian P ercep t io n, Tr ea tm ent E ffec tiv e n ess)Tis s ue V alve 70% 833,800 O the r T rea tm en ts fo r Valve (Sur g /M ed/N one ) -

F ulfi llm en tA vai labi lit y NAW illingness to Us e (Pa tient Pe rc ep tions) NAReady to U se (S u rgery e lig ib ility , R eus e e tc ) NA

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

Budget alloc a tion to one-t im e s u rgeryBudget alloc a tion to o the r h ealth needs

A verage Pay or CoverageP at ien t L iabi lityTarge t Pr ic e ( @20% pa t liab )A SP for Cos t of 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 A L UN IT VO LU M ES

Pr ic in g per Un it 18 ,000$ In f lat ionP rice D ec reas e due to c om pet it ion

M ar ket Valu e

G B I R esear ch M ar ke t Siz in g M o de l

Source: GBI Research

The above figure represents a typical forecasting model followed in GBI Research. As discussed previously, the model is built on the treatment flow patterns. The model starts with the general population, then diseased population as a percentage of the general population and then follows the treatment seeking population as a percentage of the diseased population and diagnosed population as a percentage of the treatment seeking population. Finally, the total volume of units sold is calculated by multiplying the treated population by the average dosage per year per patient.

7.6.5 Geographical Landscape

GBI Research analyzes eight major developed geographies: the US, UK, France, Germany, Italy, Spain, Japan, and Canada. The total market size for each country is provided which is the sum value of the market sizes of all the indications for that particular country. The maximum and minimum estimated market sizes are then provided by adjusting all variables expected to impact upon the market during the forecast period in order to provide the best and worst-case scenarios.


Page 69

Appendix

Articles from research journals and agency publications such as the National Institute of Mental Health, American Psychiatric Association and ClinicalTrials.gov are the source of data for the estimation of market size and making forecasts.

7.6.6 Pipeline Analysis

This section provides a list of molecules at various stages in the pipeline for various indications. The list is sourced from internal databases 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 the mechanism of action. A heatmap, sourced from relevant clinical trials, is provided in order to compare these products to one another in addition to currently marketed products. The latest press releases issued by the company and news reports are also a source of information for the status of the molecules in the pipeline. This list of pipeline molecules, in conjunction with a list of ongoing and completed clinical trials, is analyzed in this section, and a full breakdown of pipeline molecules and clinical trials by phase, molecule type and molecular target is provided.

7.7 Expert Panel Validation

GBI Research uses a panel of experts to cross-verify its databases and forecasts.

GBI Research’s 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 and are adjusted in accordance with their feedback.

7.9 Disclaimer

All Rights Reserved.

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