ABOUT DATAMONITOR HEALTHCARE 2
About the Infectious Disease and Respiratory (ID&R) pharmaceutical analysis team 2

CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of the analysis 3
Datamonitor insight into the cystic fibrosis market 3
Contributing experts 4
Related reports 5

CHAPTER 2 CYSTIC FIBROSIS DISEASE BACKGROUND 7
Overview of cystic fibrosis 7
The vicious cycle of obstruction, inflammation and infection 9
Cystic fibrosis patient segmentation 12
Segmentation by mutation: most patients suffer from a ∆F508 mutation 12
Segmentation by bacterial colonization: Staphylococcus aureus and Pseudomonas aeruginosa are the most common bacterial infections in the cystic fibrosis lung 17
Segmentation by race: cystic fibrosis is most prevalent in Caucasians 20
Segmentation by gender: gender does not impact risk of cystic fibrosis 21
Segmentation by co-morbidities: diabetes and bone disease are most common co-morbidities 22
Epidemiology of cystic fibrosis 24

CHAPTER 3 DIAGNOSIS AND TREATMENT OF CYSTIC FIBROSIS 27
Diagnosis of cystic fibrosis 27
Clinical scoring systems in cystic fibrosis 30
Current treatment of cystic fibrosis 34
Mucolytics 34
Antibiotics 36
Anti-inflammatories 41
Pancreatic enzyme replacement therapy (PERT) 43
Nutritional supplements 44
Unmet needs in cystic fibrosis 45
Causative therapy of cystic fibrosis is on top of everyone's list 45
New antibiotics are needed to fight infections more successfully 45
Easier and less frequent drug administration may improve compliance 46
Lack of a cystic fibrosis animal model hampers preclinical development 48
More pediatric clinical trials are needed 49

CHAPTER 4 R&D APPROACH 51
The cystic fibrosis pipeline is highly active 51
Cystic Fibrosis Foundation plays an important role in the development of new drugs 53
Clinical trial design in cystic fibrosis 55
There are a limited number of cystic fibrosis patients available for clinical trials 55
Orphan drug status has certain advantages 58
Endpoints in cystic fibrosis clinical trials 59

CHAPTER 5 TREATMENTS THAT TARGET THE UNDERLYING CAUSES OF CYSTIC FIBROSIS 64
Gene therapies and gene manipulation 65
Viral vectors 65
Non-viral vectors 68
Gene therapies in clinical development 69
pGM169/GL67A (academic institutes) 69
DNA nanoparticles (Copernicus Therapeutics) 70
Gene manipulation therapies in early development 71
Late-stage gene therapies recently discontinued 72
Protein repair treatments 72
Protein repair treatments for class I mutations 73
Ataluren (PTC124, PTC Therapeutics/Genzyme) 73
Protein repair treatments for class II mutations 76
Miglustat (Actelion) 76
VX-809 (Vertex Pharmaceuticals) 77
Curcumin (Seer Pharmaceuticals) 77
Other protein repair treatments for class II mutations 78
Protein repair treatments for class III mutations 79
VX-770 (Vertex Pharmaceuticals) 79
Alternative chloride channel activators 80
Denufosol tetrasodium/INS37217 (Inspire Pharmaceuticals) 81
Duramycin (lancovutide, Moli1901, AOP Orphan Pharmaceuticals/Lantibio) 84
Other alternative chloride channel activators 85
Epithelial sodium channel (ENaC) inhibitors 85
QAU145 (Novartis) 86
552-02 (Parion Sciences) 86
GS-9411 (Gilead Sciences/Parion Sciences) 87
INO-4995 (ISM Therapeutics) 87
Aerolytic (AER 002, Aerovance) 87

CHAPTER 6 TREATMENTS THAT TARGET INFECTIONS COMMON IN THE CYSTIC FIBROSIS LUNG 89
Antibiotics for the treatment of infections 89
Many new developments come in PARI Pharma's eFlow nebulizer 90
At least six direct competitors may threaten TOBI's monopoly in the near future 92
Aztreonam lysine (Gilead/PARI Pharma) 93
Marketing factors 94
Status update 96
Clinical trial data 97
Tobramycin (Novartis) 101
Tobramycin inhalation powder (TIP, Novartis/Nektar Therapeutics) 101
TOBI in the eFlow nebulizer (Novartis/PARI Pharma) 103
TOBI for young children (Novartis) 104
MP-376 (nebulized levofloxacin, Mpex Pharmaceuticals/PARI Pharma) 104
Cipro Inhale (dry powder ciprofloxacin, Bayer/Nektar Therapeutics) 105
GS 9310/11 (nebulized combination of fosfomycin and tobramycin, Gilead) 106
Liposomal formulations 107
ARD-3100 (ciprofloxacin, Aradigm/Tekmira Pharmaceuticals) 108
Arikace (TR-02/amikacin, Transave/PARI Pharma) 109
Antibiotics in early development 111
Zysolin (nanoparticle-encapsulated formulation of tobramycin, AlphaRx) 111
Bacteriophages (Biocontrol and MondoBiotech) 111
P113D (Demegen) 112
Panaecin (Gallium nitrate, Aridis Pharmaceuticals) 113
Academic institutes studying antibiotics 114
Intranasal tobramycin 114
Azithromycin 114
Linezolid 117
Itraconazole 118
Amiloride 118
Monoclonal antibodies for the treatment of bacterial infections 119
Aurexis (tefibazumab, Inhibitex) 120
KB001 (KaloBios) 121
Aerucin (Aridis Pharmaceuticals) 121
Immunization against bacterial infections 122

CHAPTER 7 TREATMENTS THAT TARGET THE MUCUS IN THE CYSTIC FIBROSIS LUNG 124
Mucolytics 125
Pulmozyme (Genentech) 125
Inhaled heparin as a mucolytic 129
VR496 (inhaled heparin, Vectura) 130
PGX-200 (inhaled heparin, ParinGenix) 130
Hyperosmolar agents 130
Bronchitol (mannitol, Pharmaxis) 131
Marketing factors 132
Clinical trial data 133
The Cystic Fibrosis Therapeutics Development Network is studying hypertonic saline in infants 137

CHAPTER 8 TREATMENTS THAT TARGET INFLAMMATION IN THE CYSTIC FIBROSIS LUNG 138
Nebulized alpha-1 antitrypsin therapy to target neutrophil elastase 139
AAT (nebulized alpha-1 antitrypsin, Kamada/PARI Pharma) 140
AZD9668 (AstraZeneca) 141
Respriva (nebulized alpha-1 antitrypsin, Arriva Pharmaceuticals) 141
Influencing airway inflammation by augmenting the nitric oxide pathway 141
INOmax (inhaled nitric oxide, Ikaria) 143
Pyruvate (N115, EmphyCorp) 143
Academic institutes studying compounds that augment the nitric oxide pathway 145
Nebulized L-arginine (The Hospital for Sick Children) 145
Pioglitazone (University of Southern California) 146
Simvastatin (University Hospitals of Cleveland and Akron's Children's Hospital) 146
AZD1236 (matrix metalloproteinase inhibitor, AstraZeneca) 147
Xolair (omalizumab, Novartis) 148
Other anti-inflammatory compounds in early development 148
SB656933 (IL-8/CXCR2 antagonist, GlaxoSmithKline) 148
Triolex (HE-3286, Hollis-Eden Pharmaceuticals) 151
Academic institutes studying other anti-inflammatory compounds 151
Antioxidants 151
Sildenafil (Viagra, University of New Mexico) 153
Digitoxin (FDA's Office of Orphan Products Development) 154

CHAPTER 9 OTHER APPROACHES TO TREATING CYSTIC FIBROSIS LUNG DISEASE 155
Aerosolized surfactant replacement therapy (Discovery Labs) 155
Spiriva (tiotropium, Boehringer Ingelheim) 156
RGN-457 (thymosin beta-4, RegeneRx Biopharmaceuticals) 157
Amitriptyline (University Hospital Tübingen) 157

CHAPTER 10 TREATMENTS THAT TARGET CYSTIC FIBROSIS-RELATED PANCREATIC INSUFFICIENCY 159
Pancreatic enzyme replacement therapies 159
Companies performing FDA-required clinical trials for marketed products 160
New pancreatic enzyme replacement therapies 163
Zentase (EUR-1008, Eurand) 163
Trizytek (ALTU-135, Cystic Fibrosis Foundation Therapeutics) 165
Exinalda (Biovitrum/AstraZeneca) 167
Nutritional supplements 168
Academics studying nutritional supplements 168
BIBLIOGRAPHY 170
Articles and reports 170
Datamonitor reports 217
Press releases 217
Websites 221

APPENDIX 222
Contributing experts 222
About Datamonitor 222
About Datamonitor Healthcare 223
Datamonitor Healthcare's therapy area capabilities 223
About the Disease analysis team 224
Disclaimer 225

List of Tables
Table 1: Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations by class 13
Table 2: Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation arrays by country 15
Table 3: Disease occurrence of cystic fibrosis per country in the seven major markets, 2004 21
Table 4: Epidemiology overview of cystic fibrosis in the six major markets, 2008 25
Table 5: Review of different cystic fibrosis scoring systems 32
Table 6: Overview of recent Cochrane reviews on the role of antibiotics in cystic fibrosis 39
Table 7: Reasons for poor compliance of cystic fibrosis patients with different treatments 47
Table 8: Age groups studied in Phase III trials for cystic fibrosis lung disease 50
Table 9: The five cystic fibrosis clinical trials currently ongoing or recruiting with the highest number of patients (expected to be) enrolled, 2009 57
Table 10: Advantages of orphan drug status in the US and Europe 58
Table 11: Outcome measures in clinical trials of cystic fibrosis patients 62
Table 12: Compounds that target the underlying cause of cystic fibrosis, 2009 64
Table 13: Rough estimate of the number of cystic fibrosis patients within each class of mutations, by country, 2009 73
Table 14: Overview of three Phase II trials for denufosol tetrasodium for the treatment of cystic fibrosis 82
Table 15: Antibiotics in clinical development by the pharmaceutical industry for the treatment of lung infections in cystic fibrosis, 2009 89
Table 16: Compounds in development in PARI Pharma's eFlow nebulizer, 2009 91
Table 17: Phase III clinical trial summary for aztreonam lysine in cystic fibrosis, 2009 99
Table 18: Overview of ongoing clinical trials with Transave's Arikace (liposomal amikacin) in cystic fibrosis 110
Table 19: Preclinical compounds in development for the treatment of lung infections in cystic fibrosis, 2009 111
Table 20: Antibiotics in development by academic institutes for the treatment of lung infections in cystic fibrosis, 2009 114
Table 21: Overview of clinical trials currently ongoing in academic institutes with azithromycin in cystic fibrosis 116
Table 22: Monoclonal antibodies in development for the treatment and or prevention of lung infections in cystic fibrosis, 2009 119
Table 23: Compounds that target the mucus in the cystic fibrosis lung, 2009 125
Table 24: Clinical trial summary for Pulmozyme in young children with cystic fibrosis 127
Table 25: Phase II clinical trial summary for Bronchitol (mannitol) in cystic fibrosis 135
Table 26: Overview of Phase III trials currently ongoing with Bronchitol in cystic fibrosis 136
Table 27: Compounds that target inflammation in the cystic fibrosis lung, 2009 139
Table 28: Overview of Phase I clinical trials currently ongoing with SB656933 in cystic fibrosis 150
Table 29: Overview of the top five pancreatic enzyme replacement products in the US, 2007 161
Table 30: Pancreatic enzyme replacement therapies in development for cystic fibrosis-related pancreatic insufficiency, 2009 163
Table 31: Phase III efficacy results of Trizytek in the US cohort 167
Table 32: Overview of nutritional supplements currently studied in cystic fibrosis by academic institutes 169

List of Figures
Figure 1: Median predicted survival age of cystic fibrosis patients in the US, 1985-2006 9
Figure 2: Several possible mechanisms explain the increased susceptibility of the cystic fibrosis lung to infections 11
Figure 3: Molecular consequences of mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene 12
Figure 4: Prevalence of the ∆F508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation among cystic fibrosis patients, across Europe 14
Figure 5: Respiratory infections by age group in cystic fibrosis patients in the US, 2006 18
Figure 6: Age-specific prevalence of no, non-mucoid, and mucoid Pseudomonas aeruginosa from birth to age 16 20
Figure 7: Percentage of cystic fibrosis patients in the US with each co-morbidity, 2006 23
Figure 8: The cystic fibrosis diagnostic process for neonatal and newborn screening 28
Figure 9: Recommended general process for diagnosing cystic fibrosis in individuals not diagnosed via neonatal or newborn screening 29
Figure 10: Number of pipeline cystic fibrosis drugs by class and type of sponsor, 2009 52
Figure 11: Number of pipeline cystic fibrosis drugs by class and phase of development, 2009 53
Figure 12: Different approaches used over time with adenovirus vectors in cystic fibrosis gene therapy 66
Figure 13: Phase II design and primary outcomes of Ataluren (PTC124) in cystic fibrosis 75
Figure 14: Timeline of recent developments for denufosol tetrasodium in cystic fibrosis, October 2007-December 2008 83
Figure 15: PARI Pharma's eFlow nebulizer 92
Figure 16: Overview of new formulations of antibiotics in clinical development for cystic fibrosis, 2009 93
Figure 17: Timeline of recent developments of aztreonam lysine for cystic fibrosis, October 2006-February 2009 97
Figure 18: Cohorts in Phase I trial comparing TIP with TOBI, and the T326 dry powder inhaler used in this trial 103
Figure 19: Phase II design and primary outcome measure of fosfomycin/tobramycin for inhalation 106
Figure 20: Timeline of recent developments of Bronchitol for cystic fibrosis, October 2007-December 2008 131
Figure 21: Possible causes and effects of low exhaled nitric oxide in cystic fibrosis lungs 142
Figure 22: Price per standard unit of the top five pancreatic enzyme replacement therapies in the US, 2003-07 162
Figure 23: Timeline of recent developments of Zentase for cystic fibrosis-related pancreatic