Stakeholder Opinions: Cystic Fibrosis - A pipeline full of hope

Published by: Datamonitor

Published: Mar. 4, 2009 - 232 Pages

Table of Contents

ABOUT DATAMONITOR HEALTHCARE

About the Infectious Disease and Respiratory (ID&R) pharmaceutical analysis team

CHAPTER 1 EXECUTIVE SUMMARY

Scope of the analysis

Datamonitor insight into the cystic fibrosis market

Contributing experts

Related reports

CHAPTER 2 CYSTIC FIBROSIS DISEASE BACKGROUND

Overview of cystic fibrosis

The vicious cycle of obstruction, inflammation and infection

Cystic fibrosis patient segmentation

Segmentation by mutation: most patients suffer from a ∆F508 mutation

Segmentation by bacterial colonization: Staphylococcus aureus and Pseudomonas aeruginosa are the most common bacterial infections in the cystic fibrosis lung

Segmentation by race: cystic fibrosis is most prevalent in Caucasians

Segmentation by gender: gender does not impact risk of cystic fibrosis

Segmentation by co-morbidities: diabetes and bone disease are most common co-morbidities

Epidemiology of cystic fibrosis

CHAPTER 3 DIAGNOSIS AND TREATMENT OF CYSTIC FIBROSIS

Diagnosis of cystic fibrosis

Clinical scoring systems in cystic fibrosis

Current treatment of cystic fibrosis

Mucolytics

Antibiotics

Anti-inflammatories

Pancreatic enzyme replacement therapy (PERT)

Nutritional supplements

Unmet needs in cystic fibrosis

Causative therapy of cystic fibrosis is on top of everyone's list

New antibiotics are needed to fight infections more successfully

Easier and less frequent drug administration may improve compliance

Lack of a cystic fibrosis animal model hampers preclinical development

More pediatric clinical trials are needed

CHAPTER 4 R&D APPROACH

The cystic fibrosis pipeline is highly active

Cystic Fibrosis Foundation plays an important role in the development of new drugs

Clinical trial design in cystic fibrosis

There are a limited number of cystic fibrosis patients available for clinical trials

Orphan drug status has certain advantages

Endpoints in cystic fibrosis clinical trials

CHAPTER 5 TREATMENTS THAT TARGET THE UNDERLYING CAUSES OF CYSTIC FIBROSIS

Gene therapies and gene manipulation

Viral vectors

Non-viral vectors

Gene therapies in clinical development

pGM169/GL67A (academic institutes)

DNA nanoparticles (Copernicus Therapeutics)

Gene manipulation therapies in early development

Late-stage gene therapies recently discontinued

Protein repair treatments

Protein repair treatments for class I mutations

Ataluren (PTC124, PTC Therapeutics/Genzyme)

Protein repair treatments for class II mutations

Miglustat (Actelion)

VX-809 (Vertex Pharmaceuticals)

Curcumin (Seer Pharmaceuticals)

Other protein repair treatments for class II mutations

Protein repair treatments for class III mutations

VX-770 (Vertex Pharmaceuticals)

Alternative chloride channel activators

Denufosol tetrasodium/INS37217 (Inspire Pharmaceuticals)

Duramycin (lancovutide, Moli1901, AOP Orphan Pharmaceuticals/Lantibio)

Other alternative chloride channel activators

Epithelial sodium channel (ENaC) inhibitors

QAU145 (Novartis)

552-02 (Parion Sciences)

GS-9411 (Gilead Sciences/Parion Sciences)

INO-4995 (ISM Therapeutics)

Aerolytic (AER 002, Aerovance)

CHAPTER 6 TREATMENTS THAT TARGET INFECTIONS COMMON IN THE CYSTIC FIBROSIS LUNG

Antibiotics for the treatment of infections

Many new developments come in PARI Pharma's eFlow nebulizer

At least six direct competitors may threaten TOBI's monopoly in the near future

Aztreonam lysine (Gilead/PARI Pharma)

Marketing factors

Status update

Clinical trial data

Tobramycin (Novartis)

Tobramycin inhalation powder (TIP, Novartis/Nektar Therapeutics)

TOBI in the eFlow nebulizer (Novartis/PARI Pharma)

TOBI for young children (Novartis)

MP-376 (nebulized levofloxacin, Mpex Pharmaceuticals/PARI Pharma)

Cipro Inhale (dry powder ciprofloxacin, Bayer/Nektar Therapeutics)

GS 9310/11 (nebulized combination of fosfomycin and tobramycin, Gilead)

Liposomal formulations

ARD-3100 (ciprofloxacin, Aradigm/Tekmira Pharmaceuticals)

Arikace (TR-02/amikacin, Transave/PARI Pharma)

Antibiotics in early development

Zysolin (nanoparticle-encapsulated formulation of tobramycin, AlphaRx)

Bacteriophages (Biocontrol and MondoBiotech)

P113D (Demegen)

Panaecin (Gallium nitrate, Aridis Pharmaceuticals)

Academic institutes studying antibiotics

Intranasal tobramycin

Azithromycin

Linezolid

Itraconazole

Amiloride

Monoclonal antibodies for the treatment of bacterial infections

Aurexis (tefibazumab, Inhibitex)

KB001 (KaloBios)

Aerucin (Aridis Pharmaceuticals)

Immunization against bacterial infections

CHAPTER 7 TREATMENTS THAT TARGET THE MUCUS IN THE CYSTIC FIBROSIS LUNG

Mucolytics

Pulmozyme (Genentech)

Inhaled heparin as a mucolytic

VR496 (inhaled heparin, Vectura)

PGX-200 (inhaled heparin, ParinGenix)

Hyperosmolar agents

Bronchitol (mannitol, Pharmaxis)

Marketing factors

Clinical trial data

The Cystic Fibrosis Therapeutics Development Network is studying hypertonic saline in infants

CHAPTER 8 TREATMENTS THAT TARGET INFLAMMATION IN THE CYSTIC FIBROSIS LUNG

Nebulized alpha-1 antitrypsin therapy to target neutrophil elastase

AAT (nebulized alpha-1 antitrypsin, Kamada/PARI Pharma)

AZD9668 (AstraZeneca)

Respriva (nebulized alpha-1 antitrypsin, Arriva Pharmaceuticals)

Influencing airway inflammation by augmenting the nitric oxide pathway

INOmax (inhaled nitric oxide, Ikaria)

Pyruvate (N115, EmphyCorp)

Academic institutes studying compounds that augment the nitric oxide pathway

Nebulized L-arginine (The Hospital for Sick Children)

Pioglitazone (University of Southern California)

Simvastatin (University Hospitals of Cleveland and Akron's Children's Hospital)

AZD1236 (matrix metalloproteinase inhibitor, AstraZeneca)

Xolair (omalizumab, Novartis)

Other anti-inflammatory compounds in early development

SB656933 (IL-8/CXCR2 antagonist, GlaxoSmithKline)

Triolex (HE-3286, Hollis-Eden Pharmaceuticals)

Academic institutes studying other anti-inflammatory compounds

Antioxidants

Sildenafil (Viagra, University of New Mexico)

Digitoxin (FDA's Office of Orphan Products Development)

CHAPTER 9 OTHER APPROACHES TO TREATING CYSTIC FIBROSIS LUNG DISEASE

Aerosolized surfactant replacement therapy (Discovery Labs)

Spiriva (tiotropium, Boehringer Ingelheim)

RGN-457 (thymosin beta-4, RegeneRx Biopharmaceuticals)

Amitriptyline (University Hospital Tübingen)

CHAPTER 10 TREATMENTS THAT TARGET CYSTIC FIBROSIS-RELATED PANCREATIC INSUFFICIENCY

Pancreatic enzyme replacement therapies

Companies performing FDA-required clinical trials for marketed products

New pancreatic enzyme replacement therapies

Zentase (EUR-1008, Eurand)

Trizytek (ALTU-135, Cystic Fibrosis Foundation Therapeutics)

Exinalda (Biovitrum/AstraZeneca)

Nutritional supplements

Academics studying nutritional supplements

BIBLIOGRAPHY

Articles and reports

Datamonitor reports

Press releases

Websites

APPENDIX

Contributing experts

About Datamonitor

About Datamonitor Healthcare

Datamonitor Healthcare's therapy area capabilities

About the Disease analysis team

Disclaimer

List of Tables

Table 1: Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations by class

Table 2: Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation arrays by country

Table 3: Disease occurrence of cystic fibrosis per country in the seven major markets, 2004

Table 4: Epidemiology overview of cystic fibrosis in the six major markets, 2008

Table 5: Review of different cystic fibrosis scoring systems

Table 6: Overview of recent Cochrane reviews on the role of antibiotics in cystic fibrosis

Table 7: Reasons for poor compliance of cystic fibrosis patients with different treatments

Table 8: Age groups studied in Phase III trials for cystic fibrosis lung disease

Table 9: The five cystic fibrosis clinical trials currently ongoing or recruiting with the highest number of patients (expected to be) enrolled, 2009

Table 10: Advantages of orphan drug status in the US and Europe

Table 11: Outcome measures in clinical trials of cystic fibrosis patients

Table 12: Compounds that target the underlying cause of cystic fibrosis, 2009

Table 13: Rough estimate of the number of cystic fibrosis patients within each class of mutations, by country, 2009

Table 14: Overview of three Phase II trials for denufosol tetrasodium for the treatment of cystic fibrosis

Table 15: Antibiotics in clinical development by the pharmaceutical industry for the treatment of lung infections in cystic fibrosis, 2009

Table 16: Compounds in development in PARI Pharma's eFlow nebulizer, 2009

Table 17: Phase III clinical trial summary for aztreonam lysine in cystic fibrosis, 2009

Table 18: Overview of ongoing clinical trials with Transave's Arikace (liposomal amikacin) in cystic fibrosis

Table 19: Preclinical compounds in development for the treatment of lung infections in cystic fibrosis, 2009

Table 20: Antibiotics in development by academic institutes for the treatment of lung infections in cystic fibrosis, 2009

Table 21: Overview of clinical trials currently ongoing in academic institutes with azithromycin in cystic fibrosis

Table 22: Monoclonal antibodies in development for the treatment and or prevention of lung infections in cystic fibrosis, 2009

Table 23: Compounds that target the mucus in the cystic fibrosis lung, 2009

Table 24: Clinical trial summary for Pulmozyme in young children with cystic fibrosis

Table 25: Phase II clinical trial summary for Bronchitol (mannitol) in cystic fibrosis

Table 26: Overview of Phase III trials currently ongoing with Bronchitol in cystic fibrosis

Table 27: Compounds that target inflammation in the cystic fibrosis lung, 2009

Table 28: Overview of Phase I clinical trials currently ongoing with SB656933 in cystic fibrosis

Table 29: Overview of the top five pancreatic enzyme replacement products in the US, 2007

Table 30: Pancreatic enzyme replacement therapies in development for cystic fibrosis-related pancreatic insufficiency, 2009

Table 31: Phase III efficacy results of Trizytek in the US cohort

Table 32: Overview of nutritional supplements currently studied in cystic fibrosis by academic institutes

List of Figures

Figure 1: Median predicted survival age of cystic fibrosis patients in the US, 1985-2006

Figure 2: Several possible mechanisms explain the increased susceptibility of the cystic fibrosis lung to infections

Figure 3: Molecular consequences of mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene

Figure 4: Prevalence of the ∆F508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation among cystic fibrosis patients, across Europe

Figure 5: Respiratory infections by age group in cystic fibrosis patients in the US, 2006

Figure 6: Age-specific prevalence of no, non-mucoid, and mucoid Pseudomonas aeruginosa from birth to age 16

Figure 7: Percentage of cystic fibrosis patients in the US with each co-morbidity, 2006

Figure 8: The cystic fibrosis diagnostic process for neonatal and newborn screening

Figure 9: Recommended general process for diagnosing cystic fibrosis in individuals not diagnosed via neonatal or newborn screening

Figure 10: Number of pipeline cystic fibrosis drugs by class and type of sponsor, 2009

Figure 11: Number of pipeline cystic fibrosis drugs by class and phase of development, 2009

Figure 12: Different approaches used over time with adenovirus vectors in cystic fibrosis gene therapy

Figure 13: Phase II design and primary outcomes of Ataluren (PTC124) in cystic fibrosis

Figure 14: Timeline of recent developments for denufosol tetrasodium in cystic fibrosis, October 2007-December 2008

Figure 15: PARI Pharma's eFlow nebulizer

Figure 16: Overview of new formulations of antibiotics in clinical development for cystic fibrosis, 2009

Figure 17: Timeline of recent developments of aztreonam lysine for cystic fibrosis, October 2006-February 2009

Figure 18: Cohorts in Phase I trial comparing TIP with TOBI, and the T326 dry powder inhaler used in this trial

Figure 19: Phase II design and primary outcome measure of fosfomycin/tobramycin for inhalation

Figure 20: Timeline of recent developments of Bronchitol for cystic fibrosis, October 2007-December 2008

Figure 21: Possible causes and effects of low exhaled nitric oxide in cystic fibrosis lungs

Figure 22: Price per standard unit of the top five pancreatic enzyme replacement therapies in the US, 2003-07

Figure 23: Timeline of recent developments of Zentase for cystic fibrosis-related pancreatic insufficiency, December 2007-February 2009

Figure 24: Timeline of recent developments of Trizytek for cystic fibrosis-related pancreatic insufficiency, June 2007-February 2009

Abstract

Introduction

With cystic fibrosis patients still dying prematurely and only two products currently approved for the treatment of this disease, the market is wide open for new entrants. Not only will novel symptomatic treatments and re-formulations lead to improved treatment paradigms, truly disease-modifying compounds are in late-stage development and will significantly change the market.

Scope

• Disease background, segmentation and epidemiology of cystic fibrosis in the US and five major European countries
• Summary of the drug classes currently used for the treatment of cystic fibrosis lung disease and cystic fibrosis-related pancreatic insufficiency
• An overview of unmet needs, the cystic fibrosis pipeline and clinical trial design
• In-depth outline of around 85 compounds studied for the treatment of cystic fibrosis by the pharmaceutical industry and academic institutes

Highlights

It is clear that, although cystic fibrosis only affects around 52,000 patients in the five major European countries and the US, the pipeline is highly active with over 50 pharmaceutical companies involved. As many as 13 of the compounds studied by the pharmaceutical industry are currently in late-stage development.

The promise of gene therapy has yet to materialize, and mutation specific correcting therapy is eagerly anticipated. There are at least four protein repair treatments in clinical development for three different classes of mutations, although it is likely that combination strategies are required in order to enhance their efficacy.

Disease-modifying treatments that are not mutation-specific include alternative chloride channel activators and epithelial sodium channel inhibitors. Compounds in the former class are furthest along in development; however, it is likely that a combination of the two classes will be necessary for full correction of the airway surface liquid.

Reasons to Purchase

• Understand and capitalize on clinical unmet needs in the market through both lifecycle management of marketed drugs and new product development
• Assess the cystic fibrosis pipeline both through background reading and via the interactive Excel-based pipeline summary
• Identify physician awareness and perceptions surrounding future treatments and new developments for cystic fibrosis

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