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

Low disease awareness, poor diagnosis rates, combined with a lack of pharmaceutical industry involvement, has kept celiac disease from the limelight. However, this is changing as evidenced by Shire's recent involvement in the pipeline. Datamonitor believes a drug for celiac disease is up to 5 years away and this untapped gastrointestinal indication has the potential to become a lucrative market.

Report Highlights
A drug launch in celiac disease is up to 5 years away. Datamonitor estimates that under optimal conditions drug sales could reach $8 billion by 2019 in the seven major markets. Two market access strategies are available to companies, which are dictated by the targeted celiac disease subpopulation and drug price point.

The pipeline is small, and not advanced past Phase II, but candidates show various approaches to potentially treating celiac disease. Small, venture-backed biopharmaceutical companies power R&D, but Shire's recent in-licensing of the lead pipeline candidate AT-1001 (Alba Therapeutics) shows the promise of future Big Pharma involvement.

Low disease awareness among primary care physicians is a major factor behind low diagnosis rates5% in the US to 25% in the EUin celiac disease. Continued efforts to increase awareness, especially once a drug comes to market, will drive celiac disease diagnosis rates up to 50%-60% by 2019, which will expand the overall patient population.
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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
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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
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
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