Stakeholder Insight Inflammatory Bowel Disease Debate over early aggressive treatment continues

CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of the analysis 3
Datamonitor insight into the inflammatory bowel disease market 4
Contributing experts 5
Previous and related reports 6
CHAPTER 2 INTRODUCTION AND SCOPE 8
Coverage of the Stakeholder Insight Survey 8
Epidemiology and patient segmentation 8
Diagnosis 8
Treatment options and guidelines 9
Treatment trends 9
Key prescribing influences 9
Brand assessment 9
CHAPTER 3 COUNTRY TREATMENT TREES 10
Introduction to treatment trees 10
US 11
Japan 15
France 19
Germany 23
Italy 27
Spain 31
UK 35
CHAPTER 4 EPIDEMIOLOGY AND PATIENT SEGMENTATION 39
Disease definition 40
Classification of inflammatory bowel disease 40
Crohn's disease 40
Ulcerative colitis 40
Montreal classification of Crohn's disease and ulcerative colitis 41
Etiology 43
Genes associated with inflammatory bowel disease influence phenotype 44
Smoking 45
Appendectomy 45
Oral contraceptives 46
Infection with a pathogenic organism 46
Abnormal immune response to gut flora 47
Pathogenesis 48
Crohn's disease and ulcerative colitis are mediated by Th1 and Th2 lymphocytes, respectively 48
Disease incidence and prevalence 49
Crohn's disease 51
Ulcerative colitis 52
US 53
Europe 56
France 56
Germany 57
Italy 57
Spain 59
UK 60
Japan 61
Patient segmentation according to disease severity 64
Severity is measured using different disease activity scales 64
Majority of Crohn's disease and ulcerative colitis patients suffer mild to moderate disease 65
CHAPTER 5 DIAGNOSIS OF INFLAMMATORY BOWEL DISEASE 68
Diagnosis 69
Diagnosis of inflammatory bowel disease combines many avenues of investigation 69
Initial investigation begins with laboratory tests 70
Endoscopy is the most direct way of diagnosing inflammatory bowel disease 71
Radiology is a crucial adjunct to endoscopy 71
Serological markers are not yet used for clinical diagnosis 72
A high diagnosis rate is observed in inflammatory bowel disease 73
Just over 70% of Crohn's disease patients are diagnosed 73
Physicians report a higher diagnosis rate for ulcerative colitis than Crohn's disease 75
Complications arising in Crohn's disease and ulcerative colitis 76
Abscesses, strictures and fistulae are the most commonly physician-reported complications in Crohn's disease patients 77
Over 25% of Crohn's disease patients suffer from nutritional deficiencies 78
Bleeding is reported by almost all gastroenterologists in patients with ulcerative colitis 79
Almost half of ulcerative colitis patients experience bleeding complications 80
Association of IBD with immune disorders and co-morbidities 82
Anemia and anxiety and depression are the most commonly associated co-morbidities in inflammatory bowel disease 82
Patients with inflammatory bowel disease also suffer from irritable bowel disease 83
Immune-mediated diseases occur at greater frequency among patients with inflammatory bowel disease 83
CHAPTER 6 TREATMENT OPTIONS AND GUIDELINES 85
Treatment options 86
Non-pharmacological treatment of inflammatory bowel disease 86
Diet 86
Probiotics 86
Pharmacological treatment 87
Antibiotics 87
Anti-diarrheals and anti-spasmodics 87
Topical and oral aminosalicylates 88
Corticosteroids 89
Traditional immunosuppressants 89
Targeted biologics 89
Pharmacological versus non-pharmacological 91
Majority of patients with inflammatory bowel disease are treated pharmacologically 91
There are some patients who do not receive any therapy for inflammatory bowel disease 94
Treatment guidelines 97
Several treatment guidelines exist for the treatment of inflammatory bowel disease 97
Guidelines published by the British Society of Gastroenterology 97
NICE guidelines on the use of infliximab for Crohn's disease 99
NICE is appraising the use of infliximab for ulcerative colitis 100
American College of Gastroenterology guidelines for Crohn's disease 101
American College of Gastroenterology guidelines for ulcerative colitis 102
The European Crohn's and Colitis Organisation has published consensus guidelines for Crohn's disease 103
CHAPTER 7 TREATMENT TRENDS 105
Changes in therapy 106
Disease severity influences treatment 106
Despite lack of evidence to support efficacy, Crohn's disease and ulcerative colitis patients receive antibiotics at all levels of severity 106
Anti-spasmodics and anti-diarrheals are used as accompanying therapies for all severities of Crohn's disease and ulcerative colitis 107
Up to 60% of Crohn's disease and ulcerative colitis patients receive oral aminosalicylates 111
Topical aminosalicylates are used more for ulcerative colitis than Crohn's disease 113
Use of corticosteroids increases with disease severity 115
Gradual increase in use of immunosuppressants according to Crohn's disease severity 117
Immunosuppressants are largely reserved for moderate and severe ulcerative colitis patients 119
Use of biologics in Crohn's disease occurs in moderate-to-severe disease, but to a limited extent in mild patients 120
Use of biologic increases significantly with severity of ulcerative colitis 121
Monotherapy versus combination therapy 122
Increasing disease severity promotes use of combination therapy 122
First-line therapy 127
Oral 5-ASAs are used first-line for Crohn's disease 127
Corticosteroids are being prescribed at first-line for Crohn's disease 129
A combination of oral and topical 5-ASAs is the preferred first-line treatment regimen for ulcerative colitis 129
Almost 45% of Crohn's disease patients move to a second-line therapy 131
About a third of ulcerative colitis patients progress to treatment with second-line therapy 131
Second-line therapy 132
Immunosuppressants are the most commonly prescribed drug class by gastroenterologists at second-line for Crohn's disease 132
Biologics are prescribed at second-line for Crohn's disease 134
Corticosteroids are prescribed at second-line for ulcerative colitis 134
Immunosuppressants are also prescribed at second-line for ulcerative colitis 135
Almost a quarter of Crohn's disease patients progress from second-line to third-line treatment 135
A fifth of ulcerative colitis patients progress from second-line to third-line treatment 136
Third-line therapy 137
Biologics alone, or in combination with immunosuppressants, are the most commonly prescribed therapies for Crohn's disease at third-line 137
Like Crohn's disease, biologics are prescribed most frequently by gastroenterologists for ulcerative colitis 139
Surgery 141
Surgery is more effective for ulcerative colitis than Crohn's disease 141
Just under a third of Crohn's disease patients will eventually require surgery 142
Almost half as many patients with ulcerative colitis will eventually require surgery than those with Crohn's disease 143
Ulcerative colitis patients receive pharmacological therapy for longer than Crohn's disease patients before requiring surgery 144
"Step-up" versus a "top-down" approach to the treatment of inflammatory bowel disease 145
Current algorithms promote use of a "step-up" approach, but a "top-down" approach is now being suggested 145
Is there scope for a "top-down" approach? 146
Clinical trial data provide evidence showing a "top-down" approach is more effective than "step-up" 146
A "top-down" approach may change the natural history of Crohn's disease 147
There are a number of advantages and risks associated with a "top-down" treatment approach 149
The SONIC study will assess early use of azathioprine, infliximab or both in combination 149
Only 20% of severe Crohn's disease patients receive a "top-down" treatment approach 150
The potential for side effects ranks as the leading reason for not using a "top-down" approach in Crohn's disease 152
Similar percentage of ulcerative colitis and Crohn's disease patients receive a "top-down" treatment approach 153
The potential for side effects is also the leading reason for not using a "top-down" approach in ulcerative colitis 154
Gastroenterologists also reported that a lack of evidence and experience prevents use of a "top-down" approach 155
CHAPTER 8 PRESCRIBING INFLUENCES 158
Factors influencing physician decision making 159
Symptomatic improvement and healing of the mucosa are the most important factors influencing physician prescribing 159
Efficacy 163
Symptomatic improvement 163
Efficacy in promoting mucosal healing 166
Speed of onset of remission 167
Safety 168
Side-effect profile 168
Dosing 170
Convenient dosing and convenient administration frequency 170
Cost 172
Availability (formulary/reimbursement status) 172
Physician factors 173
Familiarity with product 173
Patient factors 174
Patient compliance 174
Other 176
Prevention of colon cancer 176
CHAPTER 9 BRAND ASSESSMENT 177
Brand map 178
How to interpret a brand map 178
5-ASAs: Lialda may offer advantages in a class where there is little differentiation 183
Pentasa (mesalazine) 184
Pentasa is an oral, controlled-release formulation that delivers mesalazine from the duodenum to the rectum 184
New dose of Pentasa reduces the number of pills taken per day 184
Gastroenterologists rated Pentasa well on familiarity and availability 185
Lialda/Mezavant (mesalazine) 185
Lialda is an oral sustained-release, multimatrix formulation of mesalamine 185
Lialda is marketed as a once-daily treatment for ulcerative colitis 186
Lialda has been compared with Asacol in a Phase III clinical trial 187
Gastroenterologists scored Lialda well on side-effect profile 188
Lialda is perceived by gastroenterologists to perform well on patient compliance, convenient dose and convenient administration frequency 189
Asacol (mesalazine) 189
Asacol is a delayed-release formulation of mesalazine, which is marketed by Proctor & Gamble 189
Asacol well perceived on familiarity with product and availability 190
Salofalk (mesalazine) 190
Salofalk is a Eudragit-L-coated pellet formulation of mesalazine 190
Salofalk and Pentasa are equally effective in achieving remission in mild to moderate ulcerative colitis patients 191
Salofalk did not perform well on patient compliance and convenient administration frequency 192
Claversal (mesalazine) 192
Like Salofalk, Claversal is a micropellet formulation of mesalazine 192
Fivasa (mesalazine) 192
In France, Asacol is marketed as Fivasa by Norgine Pharma 192
Salazopyrin (sulfasalazine) 193
Gastroenterologists did not rate Salazopyrin well on side-effect profile 193
Biologics: brand comparison shows that Remicade remains the leader, but Humira is perceived well by physicians 194
Remicade (infliximab) 195
Gastroenterologists rate Remicade well on familiarity with product and symptomatic improvement 195
Mucosal healing is associated most with Remicade than the other biologics 198
Remicade is not associated with a convenient dose and convenient administration frequency 198
More than three-quarters of severe patients with inflammatory bowel disease receive Remicade as their first biologic therapy 199
40% of patients who receive Remicade as their first biologic will terminate therapy 201
Most patients terminate Remicade therapy within the first year 202
An inadequate response is the most common reason for terminating Remicade therapy within the first year 204
Inadequate response remains the most common reason for terminating Remicade therapy after 1 year 206
Over a third of patients who fail Remicade therapy will move on to treatment with Humira 206
Surgery is the next step for many patients who fail Remicade therapy 209
Almost a quarter of Remicade-refractory patients progress to therapy with corticosteroids 209
Despite no evidence of efficacy in Crohn's disease, a small percentage of Remicade-refractory patients go on to receive Enbrel (etanercept) 210
Humira (adalimumab) 211
Humira is a self-administered, humanized anti-TNF monoclonal antibody 211
Clinical trials for Humira demonstrate efficacy in biologic-naïve patients and infliximab-refractory patients with Crohn's disease 211
Gastroenterologists scored Humira better than Remicade on a number of attributes 212
Cimzia (certolizumab pegol) 214
Cimzia is a pegylated, humanized anti-TNF therapy 214
PRECISE 1 and PRECISE 2 trials demonstrated the safety and efficacy of Cimzia, but the therapy was rejected by the FDA 214
Cimzia was rejected for Crohn's disease in the EU in November 2007 215
Cimzia was perceived by gastroenterologists to perform well on convenient dose and administration frequency 216
Tysabri (natalizumab) 218
Tysabri prevents leukocytes migrating into the gut in Crohn's disease 218
The EMEA's CHMP returned a final negative opinion for Tysabri in Crohn's disease in November 2007 218
The ENACT and ENCORE trials demonstrated the efficacy of Tysabri in Crohn's disease 219
Tysabri was not rated well on symptomatic improvement or side-effect profile 220
BIBLIOGRAPHY 222
Journal papers 222
Websites 234
Other 237
APPENDIX A 238
Physician research methodology 238
Physician sample breakdown 238
US 238
Japan 239
France 239
Germany 240
Italy 240
Spain 241
UK 241
Contributing experts 242
APPENDIX B 243
The survey questionnaire 243
1. Patient Segmentation 243
2. Prescribing factors 250
3. Treatment classes and severity 255
4. Treatment of severe disease 265
APPENDIX C 273
About Datamonitor 273
About Datamonitor Healthcare 273
About the Immunology and Inflammation analysis team 274
Disclaimer 275
List of Tables
Table 1: Montreal sub-classification for Crohn's disease, 2005 42
Table 2: Montreal classification for ulcerative colitis covering extent and anatomy, 2005 42
Table 3: Epidemiological studies into incidence and prevalence of Crohn's disease and ulcerative colitis, 1978─2007 49
Table 4: Prevalence and incidence of Crohn's disease in the seven major markets by country, 2007 51
Table 5: Prevalence and incidence of ulcerative colitis in the seven major markets by country, 2007 52
Table 6: Age- and sex-specific and adjusted prevalence of ulcerative colitis in Olmsted County, Minnesota, January 2001 54
Table 7: Age- and sex-specific and adjusted prevalence of Crohn's disease in Olmsted County, Minnesota, January 2001 54
Table 8: Incidence and prevalence of Crohn's disease and ulcerative colitis in the UK, 1995 61
Table 9: Annual prevalence and incidence of Crohn's disease and ulcerative colitis in Japan, 1991 63
Table 10: Number of respondents reporting Crohn's disease patients with each complication, by country, 2007 77