Emerging Therapies for Cystic Fibrosis

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Whats new in CF treatment?
Jane Davies
Royal Brompton
Hospital
Imperial College, London, UK
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Choo-Kang LR, Zeitlin PL. Curr Opin Pulm Med 2000

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Gentamicin

• Double blind, placebo controlled
• CF subjects
• .D/D
• Homo/heterozygous stop mutation
• Gentamicin drops to nose tds, 2 weeks
• Nasal PD
• Nasal brushing CFTR staining

Wilschanski M et al. N Engl J Med.
20033491433-41.
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CFTR staining
Negative control Untreated
Treated
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High throughput screening

• Assay random/ selected chemicals
• Screen 5-10,000 daily
• Assays for limited function only
• Chemically modify each hit
• Early hits being explored
• Promising approach

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Curcumin

• Active compound in turmeric
• Used for centuries in herbal medicine
• Anti-inflammatory, lowers cholesterol,
  anti-cancer, wound healing
• CF
• fed to CF mice, 3 days, high dose
• Nasal PD, rectal PD
• In vitro CFTR localisation
• Egan ME et al. Science. 2004304600

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DF508/DF508
Egan ME et al. Science. 2004304600
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Egan ME et al. Science. 2004304600
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Egan ME et al. Science. 2004304600
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The cure?
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Several other investigators no effect Appears
not to work in humans ? CFF-funded
clinical trial
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Correction of ion transport MCC
Normal
CF
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Matsui H et al. Cell 1998 95 1005-15
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Matsui H et al. Cell 1998 95 1005-15
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Matsui H et al. Cell 1998 95 1005-15
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Improving MCC

• Normalise ion transport
• Reduce sodium hyperabsorption
• Amiloride, benzamil
• Increase chloride secretion
• UTP etc
• synthetic ion channels
• Increase ASL/ mucus layer water content
• Osmotic agents mannitol, HS, icodextrin
• Increase mucus secretion
• P2Y2 receptor agonist (CBF, surfactant)

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MCC with Mannitol
40

30
20



10
0
Rx
Cough
Post-Rx
Total
Mannitol
Control
Robinson et al. ERJ 1999 14 678-85
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P2Y2 receptor agonists

• Enhance CBF
• Increase mucus secretion
• Stimulate Cl- secretion
• Increase surfactant production
• In clinical trials TDN

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New antibacterial approaches
100
P. aeruginosa S. aureus H. influenzae
80
60
patients
40
20
0
0-1 2-5 6-10 11-15 16-20 21-25
26-30 31-35 36
CF Foundation National CF Registry 1994
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New antibacterial approaches

• Anti-biofilm strategies
• Dry powder inhaled antibiotics
• IgY
• Synthetic defensins
• Vaccination?

100
P. aeruginosa S. aureus H. influenzae
80
60
patients
40
20
0
0-1 2-5 6-10 11-15 16-20 21-25
26-30 31-35 36
CF Foundation National CF Registry 1994
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Ig Y antibodies
Pediatr Pulmonol. 2003 Jun35(6)433-40.
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Whitely et al. Nature 2001
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Novel drug development Issues

• Delivery
• Topical delivery hindered by barriers
• Disease stage
• Initial trials usually in adults may not be best
  target group eg. anti-inflammatories
• Assessment of efficacy
• Rate of lung function decline
• Slow
• Large numbers required
• Time to exacerbation problems re routine
  management
• Other end-points difficult (MCC) or uncertain
  relevance (ion transport)
• (Survival)