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GLGi: Cystic Fibrosis . September 18, 2007 San Francisco. Council Member Biography:

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glgi cystic fibrosis

GLGi: Cystic Fibrosis

September 18, 2007

San Francisco

Council Member Biography:
  • Carlos Milla, MD, is an Associate Professor in the Department of Pediatrics at Stanford University. Prior he was the Director of Minnesota Cystic Fibrosis Center at the University of Minnesota. Dr Milla is trained in epidemiology and is on the faculty of the Center for Excellence in Pulmonary Biology. He has extensive experience in treatment of childhood respiratory illnesses and has an active research program in cystic fibrosis. Dr. Milla’s main areas of interest include inflammatory responses that lead to airway disease. He has actively participated in multiple cystic fibrosis-related clinical studies, and has accumulated extensive experience on implementation and conduct of clinical trials. Dr. Milla is familiar with different regulatory issues involved in the conduct of clinical studies, particularly those related to development of new therapies.

© 2007 Gerson Lehrman Group Inc., All Rights Reserved

Table of Contents
  • Review the features of Cystic Fibrosis
  • Review the current treatment paradigm and available therapies
  • Review the outstanding therapeutic needs in this patient population
  • Review therapies under development and potential impact

© 2007 Gerson Lehrman Group Inc., All Rights Reserved

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Gerson Lehrman Group

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cystic fibrosis
Cystic Fibrosis
  • Multisystemic process with defective ion transport across mucosal surfaces.
  • Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein (1480 aa’s) is affected.
  • Gene in chromosome 7 (250 kb).
  • Lung Manifestations: Chronic inflammatory process.
us incidence of cf by race
US Incidence of CF by Race
  • White 1:3,000
  • Black 1:15,000
  • Hispanic 1:9,500
  • Native 1:10,000
  • Asian 1:30,000
  • Global 1:4,000
us carriage rate by race
US Carriage Rate by Race
  • White 1:25
  • Black 1:60
  • Hispanic 1:45
  • Native 1:50
  • Asian 1:90
  • Global 1:30

The Evolution of Survival in CF:1936 - 2005


Median Survival Age (Years)

cf manifestations
CF Manifestations

Obstructive Lung Disease


Chronic Infection

Chronic Sinusitis

Nasal Polyposis

Pancreatic Insufficiency



Male Infertility

Bowel Obstruction


High Cl- in Sweat

Adapted from Welsh and Smith. Sci Am. 1995;273:52-59.


Pathogenesis of lung disease in cystic fibrosis

Defective CF gene

Defective/deficient CFTR

Bronchial obstruction



Abnormal airway surface milieu


Davis & Konstan, AJRCCM 2000


CFTR Gene Mutation

Defective CFTR

Deranged Airway Environment

essentials of medical management in cf
Essentials of Medical Management in CF
  • Optimize airway clearance
  • Optimize pancreatic enzyme replacement and nutritional status
  • Minimize airway injury
    • Respiratory illnesses
    • Environmental factors
  • Treat aggressively symptomatic episodes
  • Judicious use of Antibiotics
    • Evolving trend of more aggressive Rx
    • Balance micro + clinical benefit with safety/burden of care
    • Role of prophylactic antibiotics debatable (S. aureus)

“Prophylactic” Therapeutic Approach

  • Establish therapeutic intervention in pre-symptomatic stage
  • Early changes are reversible, however once bronchiectasis develops, damage is irreversible
  • Best treatment is prevention, daily program ofairway clearance is best preventative measure
  • Consistent routine that is followed rigorously is necessary to prevent or delay any progression
  • Chronic suppressive antibiotics if infection present
  • Role of antiinflammatory therapy has been established, but side effect profile less than optimal
airway clearance
Airway Clearance
  • Chest physiotherapy by manual percussion and postural drainage ‘Gold standard’
  • An array of alternative techniques available
  • 20 – 30 minutes per session
  • 2 sessions per day, increase during symptomatic episodes
aerosol therapy
Aerosol Therapy
  • Bronchodilators Albuterol Ipratropium
  • Mucolytics N-Acetylcysteine Hypertonic Saline rH-DNase
  • Antibiotics Tobramycin (Colistin, Aztreonam)
  • Anti-inflammatory Budenoside, fluticasone, others Na Cromoglycate (Azithromycin)
the patient perspective treatment burden
The Patient Perspective: Treatment Burden
  • Stenzel
  • Photo by Derek Powazek












Current treatments of cystic fibrosis lung disease

Defective CF gene

Defective/deficient CFTR

Abnormal airway surface milieu

Hypertonic saline

Airway clearance


Bronchial obstruction

Systemic antibiotics

Inhaled antibiotics






lung transplantation


Adapted from Davis P, AJRCCM 2000

ptc therapeutics ptc 124 for stop mutations defects
PTC Therapeutics: PTC 124 for Stop Mutations defects
  • Drug well tolerated
  • 18 out of 42 patients from the two studies had responded with a change of at least -5 mV in chloride secretion TEPD
  • 15 out of 42 patients had chloride secretion TEPD values higher than -5 mV
  • Mild, statistically significant reductions in blood neutrophil counts
  • Mild improvements in Liver enzymes

2006 NACFC

inspire denufosol p 2 y 2 agonist
Inspire: Denufosol (P2Y2 Agonist)

Deterding RR et al, AJRCCM 2007

gilead aztreonam lysinate for inhalation
Gilead: Aztreonam Lysinate for Inhalation

McKoy K et al. 30th European CF Conference, June 2007

respirtech hfcwo vest
RespirTech: HFCWO Vest

Kempainen R et al, Chest, in press

n acetyl cysteine high dose effects
N-Acetyl Cysteine: High-Dose effects
  • Increases Glutathione in blood Neutrophils
  • Decreases Sputum Neutrophil count and sputum elastase activity
  • Decreases IL-8 in Sputum
  • Statistically significant decrease in incidence of pulmonary exacerbations (22% vs 78%) and number of episodes per subject.
  • Proceeding to larger Phase III confirmatory study

Tirouvanziam R et al PNAS 2006

Conrad C, 2007 CFTDN meeting

pancreatic enzyme replacement therapy pert studies
Pancreatic Enzyme Replacement Therapy (PERT) Studies
  • Pancreatic enzyme preparations of porcine or bovine origin were available in the United States for treatment of exocrine pancreatic insufficiency (PI) prior to the enactment of the FDA.
  • Outbreak of severe Colitis in the mid 90’s associated with high dose products
  • In the late 90’s the FDA determined that PERT did not meet the requirements of an OTC preparation and made a decision that all PERT products must go through an NDA process
  • Guidance for Industry drafted and all PERT manufacturers required to file NDA for their product by 2008.
altus pharmaceuticals altu 135 pert
Altus Pharmaceuticals: ALTU-135 PERT

Borowitz et al, J Peds 2006

altus pharmaceuticals altu 135 pert32
Altus Pharmaceuticals: ALTU-135 PERT

Borowitz et al, J Peds 2006

the cystic fibrosis foundation drug development pipeline
The Cystic Fibrosis Foundation Drug Development Pipeline


Phase III

Phase II

Phase II

Phase I

Pre-clin. – Sept. ‘07