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CF Education Day
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March 15, 2008
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Agenda - Morning
Keynote - Bob Beall, President CFF
Newborn Screening - Jackie Zirbes
New Treatments: VX770 - Daya Upadhyay
Counseling Project - Jessica Herbold, Director, Counseling Center, Institute of Transpersonal Psychology
New Treatments: MP-376 - Zoe Davies
Infection Control Guidelines - Kathy Matthews
New Treatments: NAC - Carol Conrad
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Agenda - AfternoonNew Treatments: SB656933 - Rick Moss
Keynote II: Treating Exacerbations - Chris Goss
Exacerbation Biology - Carol Conrad
Respiratory Equipment & Meds - Colleen Dunn
Chest CT Natural History - Terry Robinson
Take Your Salt - Julie Matel
New Treatments: KB001 - Carlos Milla
New Treatments: Denufosol - Rick Moss
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SB-656933
KB-001
Chest CT (Novartis/CFF-TDN) Exacerbation Biology (CFF)
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Pathophysiologic Classification ofCFTR Mutations
Normal I II III IV V
NonsenseG542X
Frameshift394delTT
Splice junction1717-1G A
Missense MissenseG551D
MissenseR117H
AlternativeSplicing
3849+10kbC T
AA deletionF508
MissenseA455E
Nosynthesis
Block inprocessing
Alteredconductance
Block inregulation
Reducedsynthesis
VX770
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Therapeutic Approaches to CFKeyed to Pathophysiologic Stage
Abnormal Genes
Abnormal CFTR Protein
Altered Ion Transport
Abnormal Mucus Secretion
Infection & Inflammation
Tissue Destruction
Organ DestructionRespiratory
Failure
Transplantation
Proper Ion Transport
“Potentiation”
Gene TherapyModifier Genes
Protein rescue“Correction”
Anti-Inflammatories Anti-InfectivesBronchodilators
X X
Current:None None
In Development:
rhDNaseHypertonic Saline
Physiotherapy
Anti-InflammatoriesAnti-Infectives
Stem Cells
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Modulating Airway Inflammation in CF
• Dornase alfa - Pulmozyme®
- Early administration of rhDnase slows the decline in lung function - Reduces inflammation (BEAT trial)
• Down-regulation of inflammatory mediators- -1 proteinase inhibitor - Glutathione repletion: N-acetylcysteine
• Down-regulation of neutrophil influx/activation- SB656933 (GlaxoSmithKline): blocking CXCR2
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Elizur et al, Chest 2008;133:489
Inflamed Airways in CFInflammation in CF starts early, is persistent, and is based on epithelial
disease with exaggerated, ineffective white cell (PMN) response
PMN
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Chemokines
Rolling Activation Adhesion Diapedesis
4000µm/sec40µm/sec seconds minutes ~10 minutes
Lung Tissue
Chemokines
IL-8 CXCR2
PMN
Epithelium
Airway
CXCR2
SB656933
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NeutrophilNeutrophil
Neutrophil
chemotaxis
MacrophageMacrophageMacrophage
accumulation
CXCR2
CXCR2
T-CellsT-Cells
Protease, ROS Release
Alveolar wall destruction,
EMPHYSEMA
Alveolar wall destruction,
EMPHYSEMA
Goblet cellsGoblet cells
CXCR2 IL-8, Gro-a
release
TNF-a, IL-1GM-CSF Release
NeutrophilAccumulation
CXCR2 Mucus Hypersecretion
CHRONIC
BRONCHITIS
CHRONIC
BRONCHITIS
Chronic inflammation,
AIRWAYS OBSTRUCTION
Chronic inflammation,
AIRWAYS OBSTRUCTION
IL-8 & Gro- Release NeutrophilNeutrophilMacrophageMacrophage EpitheliumEpithelium FibroblastsFibroblasts
SB-656933: Oral CXCR2 Antagonist
SB-656933: Oral CXCR2 Antagonist
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Open Label Dose Ascending Single Dose Study of SB-656933
(GlaxoSmithKline)
Eligibility: Age ≥16 yr
Stable, FEV1>40%
Cohort 1--50 mg; Cohort 2--300 mg
Objectives: Safety, PK (metabolism), PD (biomarker efficacy)
Sites: Stanford, Pittsburgh
Status: Enrolling (5 in, 3-4 more needed)
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Normal Cystic Fibrosis
Mucus Clearance Is a Key Component of NormalMucus Clearance Is a Key Component of NormalLung Defense, Depends on Adequate Surface Lung Defense, Depends on Adequate Surface
Liquid Volume, and Is Defective in Cystic FibrosisLiquid Volume, and Is Defective in Cystic Fibrosis
?
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Improving Mucociliary Clearance in CF • Airway Clearance Therapies (ACT)
- Conventional Chest Physical Therapy (CPT), Flutter Device, High Frequency Chest Wall Oscillation
(“Vest”), Intrapulmonary Percussive Ventilation (IPV), Exercise (Shear Stress)• Inhaled Hypertonic Saline
- Disrupts ionic bonds in airway secretions- Positive trials in Australia, US (NEJM 2006)
• Purinergic Agonists- Activate alternative chloride channel- Increase ciliary activity- Inhaled denufosol (Inspire, Phase III)
• ENaC Inhibitors (Gilead - Phase I completed; others)
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Depleted airway surface liquid (ASL) layer and hyper – viscous mucus
Paralyzed muco- ciliary transport
Pathogenesis of cystic fibrosis lung disease
Matsui et al., Cell 95;1005, 1998
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Na+
Activation of P2Y2 Receptors on the Airway Surface Stimulates Chloride Secretion through an “Alternative”
Chloride Channel, bypassing Defective CFTR
Increases chloride and liquid secretion
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Activation of P2Y2 Receptors on the Airway Surface
Na+
Increases mucin secretion
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Activation of P2Y2 Receptors on the Airway Surface
Na+
Increases cilia beat frequency
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Effects of Denufosol in CF Patients with Milder Lung Disease: Improvement in Lung Function
Smiley, et al., ECFS, Copenhagen, 2006
08-102N=33
Pts with 75% predictednormal FEV1 at baseline
*Avg. FEV1 = 97.2%
08-103N=89
Pts with 75% predictednormal FEV1 at baseline
*Avg. FEV1 = 93.0%
08-104N=24
Pts with 75-90% predictednormal FEV1 at baseline
and no TOBI use*Avg. FEV1 = 83.0%
*Average FEV1 % predicted of normal pre-dose on Day 1
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
FEV1 FEV1 FEV1 FEF25%-75%FEF25%-75%FEF25%-75%
Difference from Placebo in Percent Change from Baseline to Day 28* for FEV1 and FEF25%-75%
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Evidence for a Reduction in Exacerbations in CF Patients Treated with Denufosol
Study 08-103N=89
Study 08-104N=41
Pts with 75% predictednormal FEV1 at baseline
Pts with 75%-90% predictednormal FEV1 at baseline
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TIGER-2 (Transport of Ions to Generate Epithelial RehydrationPhase 3 International Randomized Double-
blind Placebo-Controlled
Denufosol 60 mg or placebo inhaled 3 times daily for 6 months
≥5 years old, FEV≥75%
Stable
No hypertonic saline
Status: Enrolling (4-6 subjects) mid April