Stakeholder Opinions: Celiac Disease - Licensing opportunities exist in untapped market

ABOUT DATAMONITOR HEALTHCARE 2

About the Immunology & Inflammation pharmaceutical analysis team 2

CHAPTER 1 EXECUTIVE SUMMARY 3

Strategic scoping and focus 3

Datamonitor insight into the disease market 3

Related reports 5

Upcoming reports 5

CHAPTER 2 DISEASE OVERVIEW 7

Definition of celiac disease 8

What is celiac disease? 8

Pathogenesis 10

Understanding of the pathogenesis has increased in recent times 10

Genetic component to celiac disease 10

HLA involvement in celiac disease 11

HLA testing used as a negative predictor of celiac disease 11

Clinical presentation of celiac disease 12

Symptoms of celiac disease 12

Clinical manifestation of celiac disease varies greatly with age 12

Classical symptoms are associated with gastrointestinal involvement 13

The celiac disease iceberg 14

Typical celiac disease 15

Atypical celiac disease 16

Individuals who could potentially develop celiac disease 17

Non-responsive, refractory celiac disease 18

Reassessment of celiac disease diagnosis is necessary to confirm refractory disease 18

Classification of refractory celiac disease involves phenotype of intraepithelial lymphocytes 19

Management of celiac disease 20

Strict adherence to a gluten-free diet remains the cornerstone of treatment 20

Monitoring adherence to a gluten-free diet 22

Treatment of celiac disease complications 23

Management of refractory celiac disease 23

Corticosteroids are first-line treatments in refractory celiac disease patients 24

Evidence suggests budesonide demonstrates efficacy in some patients 24

Datamonitor estimates $3m budesonide sales in celiac disease in 2008 27

Immunosuppressants such as azathioprine and ciclosporin are used as second-line therapy in refractory celiac disease 28

Chemotherapeutic agents used in type II refractory celiac disease 29

Anti-TNFs are effective rescue therapies in refractory celiac disease where there are limited alternatives 29

High-dose chemotherapy and autologous stem cell transplantation could provide effective therapy in type II refractory celiac disease patients 30

CHAPTER 3 EPIDEMIOLOGY 31

Wide range in celiac disease prevalence among distinct populations 32

Celiac disease prevalence in specific "at-risk" population subgroups 33

First-degree relatives 33

Autoimmune diseases 33

Genetic diseases 34

Prevalence of celiac disease in the seven major markets 34

Datamonitor estimates there are between 4m and 7.5m celiac disease sufferers in the seven major markets in 2009 34

Over two million celiac disease sufferers in the US 35

Celiac disease is extremely rare in Japan and few epidemiology studies exist 37

France lacks population-based studies for celiac disease 39

Lower celiac disease prevalence in Germany than in the UK 40

There is an abundance of robust epidemiology studies for celiac disease originating from Italy 41

Spain has the smallest celiac disease population in the seven major markets 43

UK prevalence of celiac disease is the highest of the major EU regions 44

Outside the seven major markets 46

Potential worldwide celiac disease population could be upwards of 25 million 46

CHAPTER 4 DIAGNOSIS OF CELIAC DISEASE 48

Differential diagnosis is crucial to exclude other diseases 49

Accurate diagnosis relies on a number of different techniques 49

Triad of examination, biopsy and gluten-free diet confirm diagnosis of celiac disease 49

Serological tests are a cheap and non-invasive method for identification of patients with potential celiac disease 52

Endoscopy alone is not sufficient to diagnose celiac disease 54

Video capsule endoscopy is a growing area of potential use 54

Biopsy is still gold-standard in celiac disease diagnosis 57

Histologic grading is based on the Marsh score 58

Serologic algorithm may obviate the need for biopsy 60

Celiac disease vs. irritable bowel syndrome 62

Celiac disease and irritable bowel syndrome have overlapping characteristics 62

Evidence suggests between 3-11% of irritable bowel syndrome patients have evidence of celiac disease 62

Multiple physician specialties are involved in celiac disease diagnosis and management 64

Most referrals to specialist celiac centers come from primary care 65

Celiac disease diagnosis continues to be plagued by problems 67

Diagnosis rates in the US lag behind rates in Europe 67

Diagnostic delay is common in both primary and secondary care 71

Low awareness from primary care physicians is a major contributor to low diagnosis rates 72

The potential of point-of-care and home testing kits in celiac disease 73

The Biocard celiac disease test kit offers potential for a quick and accurate diagnosis. 73

Home testing kits may help to drive up diagnosis rates but only if the patient then presents to secondary care 76

CHAPTER 5 UNMET NEEDS 78

Celiac disease is an area of significant unmet need 79

Summary of unmet needs 79

Pharmacological treatments for celiac disease 79

Efforts to increase diagnosis rates 81

Better celiac disease awareness in the general population and among primary care is essential 82

Advocacy groups are active in the area of raising disease awareness 82

Better ways to monitor adherence to a gluten-free diet 83

Investigate prevalence of celiac disease in patients with IBS 84

Alternative diagnostic approach to invasive endoscopy and biopsy 84

Regulatory guidance on clinical trial design 84

CHAPTER 6 COMMERCIAL POTENTIAL 86

Celiac disease presents as a potentially lucrative market 87

Pharmacological treatment will not replace the gluten-free diet 87

Market access strategies in celiac disease 87

Scenario one: pharmacological treatments offered to patients with persistent symptoms despite gluten-free diet 87

Scenario two: pharmacological treatments targeted at wider celiac disease population 91

Pricing determined by high unmet need, level of gluten sensitivity and type of celiac disease 91

Celiac disease patient population and market valuation model 95

Datamonitor estimates that celiac disease will grow quickly to become a billion-dollar market 95

CHAPTER 7 NEW PRODUCT DEVELOPMENT AND PIPELINE ANALYSIS 103

Clinical trial design 104

Gluten challenge in celiac disease patients on a gluten-free diet 104

Clinical trial endpoints 104

Primary endpoints 104

Secondary endpoints 105

There is no industry guidance on celiac disease clinical trial design 107

Villous atrophy will remain the most important factor to consider for regulatory agency approval 108

Companies involved in celiac disease R&D 109

Small, privately held, biopharmaceutical companies are the power houses in the field of celiac disease 109

Celiac disease pipeline overview in 2009 110

The celiac disease pipeline is small and not significantly advanced 110

Pipeline candidates target several different mechanisms 111

Key opinion leaders believe that enzymatic degradation of gluten holds the most promise for celiac disease 113

Phase II 114

AT-1001 (larazotide acetate, SPD-550; Alba Therapeutics, Shire) 114

AT-1001 is in development for celiac disease, but also other gastrointestinal disorders 114

Alba Therapeutics estimates AT-1001 could launch for celiac disease in the US by 2011 115

Shire's in-licensing deal for AT-1001 strengthens the drug's commercial potential 116

Alba values AT-1001's US market value at over $0.5billion 117

Clinical trial data overview 117

Alba will present Phase IIb clinical trial data at DDW 2009 121

While the drug failed to meet its primary endpoint, AT-1001's Phase IIa clinical trial data were encouraging 121

CCX-282 (Traficet-EN; ChemoCentryx) 123

CCX-282 in development for celiac and Crohn's disease 123

GlaxoSmithKline could exercise its option to commercialize CCX-282 with proof-of-concept data 126

Phase I 127

ALV-003 (Alvine Pharmaceuticals) 127

ALV-003 is an oral, two-enzyme cocktail designed to degrade dietary gluten 127

Alvine Pharmaceuticals initiated a Phase I proof-of-concept study in human volunteers and celiac disease patients 127

Early-phase candidates 130

Celiac disease vaccine (Nexpep) 130

Celiac disease is well suited to a therapeutic peptide-based vaccine 130

Nexpep aims to put a peptide-based vaccine into Phase I trials in H1 2009 130

HLA class II antigen modulator (Artielle) 131

PMC-100 series (FunZyme) 132

Transglutaminase 2 inhibitors (Numerate) 133

CHAPTER 8 BIBLIOGRAPHY 134

Journal papers 134

Websites 142

Datamonitor reports 146

APPENDIX 147

Contributing experts 147

Report methodology 147

About Datamonitor 148

About Datamonitor Healthcare 148

About the Immunology & Inflammation analysis team 149

Disclaimer 150

List of Tables

Table 1: Symptoms, manifestations and conditions associated with celiac disease 13

Table 2: Budesonide response in patients with refractory celiac disease, 2007 26

Table 3: Budesonide response in patients with refractory celiac disease according to subjects' characteristics, 2007 27

Table 4: Estimated sales of budesonide in celiac disease in the US and four major EU markets, 2008 28

Table 5: Range of prevalence of celiac disease in different populations, 2009 32

Table 6: Estimated celiac disease population in the seven major markets, split by region, 2009 35

Table 7: Prevalence of celiac disease in the US, 2009 35

Table 8: Summary of serological testing for celiac disease in a non-at-risk population, US, 2003 37

Table 9: Prevalence of celiac disease in Japan, 2009 39

Table 10: Prevalence of celiac disease in France, 2009 40

Table 11: Prevalence of celiac disease in Germany, 2009 41

Table 12: Prevalence of celiac disease in Italy, 2009 42

Table 13: Prevalence of celiac disease in Spain, 2009 44

Table 14: Prevalence of celiac disease in the UK, 2009 45

Table 15: Estimated celiac disease prevalence and population size in select regions outside the seven major markets, 2009 47

Table 16: Sensitivity and specificity of serologic tests for celiac disease in adults and children 53

Table 17: The modified Marsh classification 59

Table 18: Prevalence of organic diseases in patients meeting symptom-based criteria for irritable bowel syndrome 63

Table 19: Estimates of the prevalence of celiac disease among patients with irritable bowel syndrome 63

Table 20: Proportion of diagnosed versus undiagnosed celiac disease patients in the seven major markets and Finland, 2009 69

Table 21: Celiac disease drug pricing analogues and the cost per day ($) 93

Table 22: Celiac disease patient population and market valuation model, 2009-19 98

Table 23: R&D pipeline in celiac disease, 2009 112

Table 24: AT-1001: Phase II clinical trial overview, 2009 119

Table 25: AT-1001: Phase I clinical trial overview, 2009 120

Table 26: CCX-282: Phase II clinical trial overview, 2009 125

Table 27: ALV-003: Clinical trial overview, 2009 129

List of Figures

Figure 1: Interaction of gluten, with environmental, immune and genetic factors in celiac disease 9

Figure 2: Illustration of the pathogenesis of celiac disease, 2008 11

Figure 3: The celiac disease iceberg 15

Figure 4: Reasons for recurrent symptoms in refractory celiac disease 19

Figure 5: Factors that influence compliance to a gluten-free diet 21

Figure 6: Treatment of type I and type II refractory celiac disease 24

Figure 7: Design and outcome of the celiac disease prevalence study in Japan 38

Figure 8: Range in the size of celiac disease population in Italy, 2009 42

Figure 9: Overview of the design and findings of West et al.'s prevalence study in the UK, 2003 45

Figure 10: Flowchart of celiac disease diagnosis, 2009 51

Figure 11: Mucosal characteristics of celiac disease observed with capsule endoscopy 55

Figure 12: Relationship between number of duodenal biopsies and confirmation of diagnosis of celiac disease 58

Figure 13: Correlation between mucosal injury and the extent of malabsorption and symptoms in celiac disease 59

Figure 14: Source of referrals to a specialist adult celiac disease clinic in a district hospital in South Wales, 2006 67

Figure 15: Datamonitor's estimated diagnosis rates in the US, the five EU markets and Japan, 2009-19 71

Figure 16: Procedure for performing the Biocard home test for celiac disease 74

Figure 17: Overview of the unmet needs in celiac disease, 2009 79

Figure 18: Segmentation of celiac disease patients according to response to gluten-free diet in seven major markets, 2009 89

Figure 19: Penetration rates in the gluten-free diet non-responsive and responsive celiac disease populations, 2009-19 96

Figure 20: Celiac disease seven major market value scenario matrix, 2019 102

Figure 21: The celiac disease rating scale (CeDARS) 106

Figure 22: Classification of companies involved in celiac disease product R&D, 2009 110

Figure 23: Celiac disease treatment strategies, 2009 111

Figure 24: Assessment of mechanism of action of drugs in development for celiac disease, 2009 113

Figure 25: Mechanism of action of AT-1001 115

Figure 26: Ad hoc analysis of LAMA ratio on day 21 versus day seven 122

Figure 27: Artielle ImmunoTherapeutics's RTL technology 132