CF Education Day

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March 15, 2008

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

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

SB-656933

KB-001

Chest CT (Novartis/CFF-TDN) Exacerbation Biology (CFF)

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

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

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

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

Chemokines

Rolling Activation Adhesion Diapedesis

4000µm/sec40µm/sec seconds minutes ~10 minutes

Lung Tissue

Chemokines

IL-8 CXCR2

PMN

Epithelium

Airway

CXCR2

SB656933

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

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)

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

?

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)

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

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

Activation of P2Y2 Receptors on the Airway Surface

Na+

Increases mucin secretion

Activation of P2Y2 Receptors on the Airway Surface

Na+

Increases cilia beat frequency

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%

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

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