Gastrointestinal

Solving the Puzzle:

Respira

tory

Psychosocial

Diabetes

CF Clinical Research

• Needs

• Active Studies

• Opportunities

• “Personalized” Care

Undernutrition

Pandora’s BoxChris Landon M.D FAAP, FCCP.Pediatric Diagnostic CenterVentura, California

CF Clinical Research 2001

CF Clinical Research Needs

• “Better” Clinical Trials - Series of Cochrane Library reports- Cheng et al. Pediatr Pulmonol, 2000

• Research Mandates - Adequate power - Appropriate duration - Meaningful outcome measures - Multicenter design

- Account for individual variation

• Rapid Testing of New Treatments- Clinical trial networks

Modifier Genes

• CFTR dysfunction or absence

• Infection - P. aeruginosa

• Mucus plugging

• Inflammation

Abnormal CF Gene Environment

Pathophysiology of Cystic Fibrosis

• CFTR dysfunction or absence

• Infection- P. aeruginosa

• Mucus plugging

• Inflammation

Airway Microenvironment in CF

• Inhaled tobramycin - Tobi® (Pathogenesis/Chiron)- Compelling results from follow-up of multicenter trials

• RSV vaccine - (Wyeth-Lederle, P. Hiatt et al)- Multicenter trial

- Potential for short and long term reduction in morbidity

• Dextran - (D. Speert et al) - Multiple actions including - Interference with Pseudomonas attachment to epithelium.

• Xylitol - (J. Zabner et al)- 5 carbon sugar, improves antimicrobial properties of

airway surface liquid.

Improving Antimicrobial Activity in the CF Airway

• Airway Secretion Clearance Study (American Biosystems Inc., CFF)

- Comparison of Conventional Chest Physical

Therapy, Flutter Device, and High Frequency Chest Wall Oscillation

- 22 centers

• Inhaled Hypertonic Saline - Disrupts ionic bonds in airway secretions- Multicenter trial in Australia (P. Bye et al.)

• Purinergic Agonists - (Inspire Pharmaceuticals Inc.) - Activate alternative chloride channel- Increase ciliary activity- Phase I trial (P. Noone et al.)

Improving Mucociliary Clearance in CF

• Dornase alfa - Pulmozyme® (Genentech Inc.)- Does early administration of rhDnase slow the decline in lung function?- Multicenter, International trial

• Elastase inhibitors- Recombinant alpha-one-antitrypsin (PPL Therapeutics plc) - DMP 777 - specific intracellular inhibitor- rMNEI - Monocyte/Neutrophil Elastase

Inhibitor (CBRI)

Modulating Airway Inflammation in CF

• Treatment of stop mutations - (Wilschanski et al.)- Aminoglycoside treatment (e.g. gentamicin) overcomes stop mutations e.g. G542X

• Correcting trafficking defects - (P. Zeitlin et al)- Short chain fatty acids can assist trafficking

through endoplasmic reticulum- Aimed at F508 mutation

Correcting CFTR Dysfunction

• Lipid abnormalities in CF (S. Freedman and J. Alvarez) - AA is increased in CF cells - DHA is decreased in CF cells

- AA is pro-inflammatory- DHA treatment in murine models protects against lung infection.

• Lipid abnormality confirmed in:- Murine models- Tissue culture- Human epithelial cells

• Lumarel® (Genzyme, Inc.) – no longer under development

DHA (Docosahexanoic acid) in CF

• Acquisition of P. aeruginosa- Early intermittent colonization with different strains- Later, one predominant strain

(J. Burns et al., Multicenter BAL trial; P. Farrell, M. Rock et al. Wisconsin studyD. Armstrong et al.)

• Early Diagnosis through Newborn Screening - Improves growth and nutrition - Avoids complications of infancy

(P. Farrell et al.)

• Link Between Early Impaired Growth and Later Decreased Pulmonary Function.

(W. Morgan, and the ESCF)

Early Treatment in CF

• CF Related Diabetes- Improved definition (A. Moran et al.)- Links to lung disease (C. Milla et al.)

• CF Liver Disease- Guidelines (R. Sokol et al.)- Modifier genes (K. Friedman et al.)

• CF Bone Disease- Diagnosis and treatment (R. Aris et al.)

• Adult Centers- Reproduction- Psychosocial stresses

CF Clinical Research andComprehensive Care

+ =

• Genomics - Microarrays

• Proteomics

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• Modifier Genes

• Pathways of Injury

• Individual Variation

• New Treatments

• Individual Treatment Approaches

Towards “Personalized” CF Care:Genomics and Proteomics

• New treatments are being added to the regimen

~ time

~ complexity

• Need to Measure Adherence

~ new electronic monitors (Doser, Nebulizer Monitor)

~ daily diary measure

• Include Quality of Life as Secondary Outcome

Advances in CF Treatment

Pandemonium - All The Demons

• Physician• Clinical Nurse Specialist• Dietitian• Respiratory Therapist• Physical Therapist• Pediatric Pulmonologist• Adult Pulmonologist• Pharmacist

TREATMENTS

1. Dietary Intake

2. Nebulizer

3. Airway Clearance

4. Overall

ADHERENCE

• 20 - 30% (Passero,1980, Lask, 1994)

• 60 -70% (Quittner, 1999)

• 40 - 49% (Passero, 1980,

Quittner, 1996, Muszynski, 1988)

• 50% (Gudas , 1991)

Rates of Adherence

Pre, Post, 6, 12, & 18 Months:

1. Improved Adherence to:

~ Nebulized Treatments

~ Metered Dosed Inhalers

~ Airway Clearance

~ Enzymes

2. Reduced Morbidity (Days in hospital, IV’s)

3. Reduced Family Conflict

4. Increased Quality of Life

Outcome Measures

Mob Action

Peer Pressure in the Bacterial World

• (N. Hoiby and J. W. Costerton)• What is a Biofilm?

- A structured community of bacterial cells enclosed in a self-produced polymeric matrix.

- Biofilms are a protective mode of growth that allow survival in hostile environments.

- Bacteria in biofilms are inherently resistant to killing.

Hypothesis: P. aeruginosa infections of the CF lung are biofilm infections

Planktonic bacteria(free living)

AttachmentFlagella, adhesins

MicrocoloniesPili, Twitching

CommunityExtracellular matrix

Quorum sensing

Mature Biofilm

Biofilm Development

Newborn, sterile lungs

Permanent colonizationwith P. aeruginosa

Intermittent infection

Bacterial adaptation

Host defense defect

Airway Infection in CF

Basic Research High-throughput

Screening Combinatorial Chemistry Drug Target Identification

Drug DiscoveryDrug Discovery

Commercialization

= Rx

Therapeutics DevelopmentGrants Program

TherapeuticsDevelopment Network

Drug EvaluationDrug Evaluation

Drug Discoveryand Pre-clinical

Testing

Projected Time: 7-9 yearsProjected Time: 7-9 years(Cost: < $75 million)(Cost: < $75 million)

PhaseIII

Submission and

Approval

PhaseII

PhaseI

CFF Drug Development Process

Plasmin DNA Complexes Copernicus Gene System, Inc.

CPX SciClone Pharmaceuticals, Inc.

Moli1901 (Duramycin) Molichem Medicines

Inositol induced chloride secretion Inologic, Inc.

Long-acting Sodium Channel blocker CYFI, Inc.

Anti-Protease Therapy Center for Blood ResearchTyloxapol Discovery Laboratories, Inc.P-113: antimicrobial peptide PeriodontixPa 1806 PathoGenesis Corporation

Acid-stable digestive enzyme therapy Altus Biologics, Inc.Other

AbnormalGene

AbnormalProtein

Altered IonTransportAbnormalMucousSecretion

Infection &InflammationTissueDestruction

Therapeutics DevelopmentProgram Grants

FDA Approval

Phase III

Phase I / II

Drug Discovery Efforts

Combinatorial ChemistryHigh-Throughput ScreeningNew Drug Targets

TherapeuticsDevelopment

ProgramGrants

Drug Development Process

CF Clinical Research

• Needs

• Active Studies

• Opportunities

• “Personalized” Care

ClinicalResearch

Basic ResearchGenomicsProteomics

Center Care

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Solving the Puzzle