Stakeholder Opinions - Tuberculosis - Development pipeline shows signs of life

ABOUT DATAMONITOR HEALTHCARE 2
About the Infectious Diseases and Respiratory pharmaceutical analysis team 2
CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of the analysis 3
Datamonitor insight into the Tuberculosis market 3
Contributing experts 5
Related reports 6
Upcoming related reports 6
CHAPTER 2 DISEASE BACKGROUND 8
Disease definition 8
Etiology and symptomatology 8
Mycobacterium tuberculosis 9
Pathogenesis 10
Management of tuberculosis 10
Vaccination 10
Combination therapy is used to treat tuberculosis 11
The DOTS programme has improved treatment outcomes in many high burden countries 12
Industry interest in the antituberculosis therapy market has remained low 13
Public-private partnerships to drive future drug and vaccine development 14
Epidemiological trends 16
US 18
Europe 20
Japan 22
Epidemiological trends in Brazil, Russia, India and China and rest of the world 24
India 24
China and Asia Pacific 27
Russia 28
Brazil 29
Drug resistant tuberculosis is a growing problem in high burden countries 29
HIV epidemic fueling a rise in tuberculosis cases 32
The immigrant population in US and Europe is at high risk 35
CHAPTER 3 PRESENTATION AND DIAGNOSIS 37
Presentation 37
Culture and microscopy form the mainstay of tuberculosis diagnosis 38
Cost and access to newer technologies limits uptake in high-burden countries 40
Diagnosis of latent tuberculosis infection 41
Tuberculin skin test (TST) 42
Interferon-gamma release assays 42
Diagnosis of active tuberculosis infections 43
Laboratory cultures 43
Sputum smear microscopy 45
Nucleic-acid amplification tests 47
Serology 49
Drug susceptibility tests 50
Solid media 50
Liquid media 51
CHAPTER 4 VACCINATION 52
The immune response against tuberculosis 52
The current vaccine against tuberculosis: Bacillus Calmette-Guerin 52
BCG vaccine efficacy is highly variable 53
The duration of protection has not been determined 54
BCG vaccination is most commonly practiced in high-burden countries 54
Mycobacterial antigens for vaccine development 55
Challenges associated with vaccine development 56
Safety 56
HIV infection 56
Late-stage clinical trials 57
Immunization strategies 57
Prime-boost vaccination strategy 58
Types of vaccines in development 58
Live mycobacterial vaccines 59
Subunit and DNA vaccines 60
Pipeline analysis 61
AERAS-402/Crucell Ad35 (Aeras and Crucell) 64
Phase II 64
Phase I 64
Datamonitor comments 65
MVA85A (Aeras, Emergent BioSolutions and the University of Oxford) 65
Phase II 65
Phase I 65
GSK-692342/AS02 (Aeras and GlaxoSmithKline) 66
Phase II 67
Ag85B and ESAT-6 (Intercell AG/Sanofi Pasteur) 68
Phase I 68
Future outlook for tuberculosis vaccines 68
High-risk groups in seven major markets 69
Supplying public and private sectors in developing countries with TB vaccines 70
CHAPTER 5 TREATMENT 72
Current market overview 72
Treatment regimens 78
First line drugs 79
Rifamycins 79
Isoniazid 80
Pyrazinamide 80
Ethambutol 81
Fixed dose combinations 81
Second-line drugs are required for resistant strains 81
Treating multi drug resistant organisms 82
Duration of treatment for MDR-TB and XDR-TB is substantially longer 85
Directly Observed Therapy, Short Course (DOTS) programme 85
Payment for drugs and services 86
Treatment for HIV infected patients 86
Antiretroviral therapy 86
Drug-drug interactions and toxicity 87
Immune reconstitution inflammatory syndrome (IRIS)/paradoxical reactions 87
Sequencing of treatments 88
Challenges associated with tuberculosis drug development 89
Complex pathobiology of Mycobacterium tuberculosis 89
Development of drug combinations 90
Long duration of studies 90
Unmet needs 91
Multidrug-resistant and extensively drug resistant tuberculosis 91
Increasing patient compliance 92
Tackling latent tuberculosis infection 92
Pipeline analysis 93
Fluoroquinolones 93
Gatifloxacin (Bristol-Myers Squibb and Kyorin Pharmaceuticals) 94
Moxifloxacin (Bayer and Schering Plough) 96
Datamonitor comments 98
TMC207 (Tibotec/Johnson & Johnson) 99
Drug overview 99
Clinical trials 99
Datamonitor comments 102
Nitroimidazoles 104
PA-824 (Chiron PathoGenesis and TB Alliance) 104
OPC-67683 (Otsuka Pharmaceuticals) 106
SQ109 (Sequella and National Institutes of Health) 108
Drug overview 108
Clinical trials 108
BIBLIOGRAPHY 109
Journal papers 109
Websites 116
Other 116
APPENDIX A 120
Contributing experts 120
APPENDIX B 121
About Datamonitor 121
About Datamonitor Healthcare 121
About the Infectious Diseases and Respiratory analysis team 122
List of Tables
Table 1: Prevalence of tuberculosis in the seven major markets, 2006/2007 18
Table 2: Numbers and rates of newly notified tuberculosis patients in Japan, 2005-07 23
Table 3: Number of multidrug resistant tuberculosis (MDR-TB )cases estimated in the top 10 high burden countries 30
Table 4: Summary of commercial Nucleic Acid Amplification Tests (NAAT) for tuberculosis 48
Table 5: Overview of vaccines in development for prevention and treatment of tuberculosis, 2009 62
Table 6: Overview of Phase II studies for GSK-692342 in tuberculosis 67
Table 7: Overview of drugs in development for treatment of TB 93
Table 8: Overview of clinical trials for gatifloxacin, 2009 95
Table 9: Clinical development program for moxifloxacin for the treatment of pulmonary tuberculosis 97
Table 10: Overview of Phase II clinical trials for TMC207, 2009 101
Table 11: Overview of Phase IIa study for PA-824 in tuberculosis 105
Table 12: Overview of Phase II studies for OPC-67683 107
List of Figures
Figure 1: Estimated number of new cases of tuberculosis worldwide by country, 2006 17
Figure 2: Number of tuberculosis cases and deaths in the US, 1993-2007 19
Figure 3: Number of tuberculosis cases in the five major European markets, 2002-06 21
Figure 4: Non-UK born tuberculosis cases by world region of birth in the UK, 2007 22
Figure 5: Total number and rates of newly notified cases of tuberculosis in Japan, 2005-07 23
Figure 6: Tuberculosis incidence among the 22 high burden countries in 2006 24
Figure 7: Prevalence of tuberculosis per 100,000 population by region and sex in India, 2005-06 26
Figure 8: Prevalence of medically treated tuberculosis in India, 2005-06 27
Figure 9: Multidrug resistant tuberculosis (MDR-TB) cases in the US, 1993-2007 31
Figure 10: Cases of primary multidrug resistant tuberculosis (MDR-TB) in Europe, 2008 32
Figure 11: Estimated HIV prevalence in new tuberculosis cases by country, 2006 33
Figure 12: Geographical distribution of estimated HIV-positive tuberculosis cases, 2006. 34
Figure 13: Trends in tuberculosis cases in US and foreign-born persons in the US, 1987-2007 36
Figure 14: Percentage of tuberculosis cases of foreign origin in Europe, 2006 37
Figure 15: Advantages and disadvantages of laboratory cultures for tuberculosis testing 45
Figure 16: Advantages and disadvantages of sputum smear microscopy in tuberculosis testing 47
Figure 17: Advantages and disadvantages of nucleic acid amplification tests in tuberculosis testing 49
Figure 18: Overview of the drugs commonly used in treatment of tuberculosis, 2007 72
Figure 19: Timeline of tuberculosis therapy, 1950-2010 73
Figure 20: Distribution of global antituberculosis therapy sales by region, 2007 74
Figure 21: Volume and value of antituberculosis therapies by molecule type, 2003-07 75
Figure 22: First- and second-line tuberculosis drug market value by country, 2007 77
Figure 23: Drug targets for Mycobacterium tuberculosis 78
Figure 24: The World Health Organization grouping of first and second-line drugs for the treatment of tuberculosis, 2008 83
Figure 25: Treatment strategies for multidrug-resistant tuberculosis (MDR-TB) 84
Figure 26: Treatment strategies for extensively drug resistant tuberculosis (XDR-TB) 85
Figure 27: Survival over time in the integrated versus the sequential arms in the SAPiT trial 89