Transcript Document

Solving the Puzzle:
CF Clinical Research 2001
CF Clinical Research
• Needs
• Active Studies
• Opportunities
• “Personalized” Care
Pandora’s Box
Chris Landon M.D FAAP, FCCP.
Pediatric Diagnostic Center
Ventura, California
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
Pathophysiology of Cystic Fibrosis
Modifier Genes
• CFTR dysfunction
or absence
• Infection P. aeruginosa
• Mucus plugging
• Inflammation
Abnormal CF Gene
Environment
Airway Microenvironment in CF
• CFTR dysfunction
or absence
• InfectionP. aeruginosa
• Mucus plugging
• Inflammation
Improving Antimicrobial Activity
in the CF Airway
• 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 Mucociliary Clearance in CF
• 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.)
Modulating Airway Inflammation 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)
Correcting CFTR Dysfunction
• 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 D F508 mutation
DHA (Docosahexanoic acid) in CF
• 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
Early Treatment 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 study
D. 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)
CF Clinical Research and
Comprehensive Care
• 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
Towards “Personalized” CF Care:
Genomics and Proteomics
• Genomics
• Modifier Genes
- Microarrays
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• Proteomics
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• Pathways of Injury
• Individual Variation
• New Treatments
• Individual Treatment
Approaches
Advances in CF Treatment
• 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
Pandemonium - All
The Demons
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Physician
Clinical Nurse Specialist
Dietitian
Respiratory Therapist
Physical Therapist
Pediatric Pulmonologist
Adult Pulmonologist
Pharmacist
Rates of Adherence
TREATMENTS
ADHERENCE
1. Dietary Intake
• 20 - 30% (Passero,1980, Lask,
2. Nebulizer
• 60 -70% (Quittner, 1999)
3. Airway Clearance
• 40 - 49% (Passero, 1980,
1994)
Quittner, 1996, Muszynski, 1988)
4. Overall
• 50% (Gudas , 1991)
Outcome Measures
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
Mob
Action
Peer Pressure in
the Bacterial World
Hypothesis: P. aeruginosa infections of the CF
lung are biofilm infections
• (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.
Biofilm Development
Planktonic bacteria
(free living)
Mature Biofilm
Community
Extracellular matrix
Quorum sensing
Microcolonies
Pili, Twitching
Attachment
Flagella, adhesins
Airway Infection in CF
Newborn, sterile lungs
Host defense defect
Intermittent infection
Bacterial adaptation
Permanent colonization
with P. aeruginosa
CFF Drug Development Process
Drug Discovery
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Drug Evaluation
 Therapeutics
Development
Grants Program
 Therapeutics
Development Network
Basic Research
High-throughput
Screening
Combinatorial Chemistry
Drug Target Identification
=
Rx
Commercialization
Drug Discovery
and Pre-clinical
Testing
Phase
I
Phase
II
Projected Time: 7-9 years
(Cost: < $75 million)
Phase
III
Submission
and
Approval
Therapeutics Development
Program Grants
Abnormal
Gene
Plasmin DNA Complexes
Copernicus Gene System, Inc.
Abnormal
Protein
CPX
SciClone Pharmaceuticals, Inc.
Altered Ion
Transport
Abnormal
Mucous
Secretion
Moli1901 (Duramycin)
Molichem Medicines
Inositol induced chloride secretion
Inologic, Inc.
Long-acting Sodium Channel blocker CYFI, Inc.
Infection &
Inflammation
Tissue
Destruction
Anti-Protease Therapy
Tyloxapol
P-113: antimicrobial peptide
Pa 1806
Other
Center for Blood Research
Discovery Laboratories, Inc.
Periodontix
PathoGenesis Corporation
Acid-stable digestive enzyme therapy Altus Biologics, Inc.
Drug Development Process
Drug Discovery Efforts
FDA Approval
Combinatorial
Chemistry
High-Throughput
Screening
New Drug Targets
Therapeutics
Development
Program
Grants
Phase III
Phase I / II
Solving the Puzzle
Basic Research
Genomics
Proteomics
?
Clinical
Research
CF Clinical Research
• Needs
• Active Studies
• Opportunities
Center
Care
?
• “Personalized” Care