New treatments for CF
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Transcript of New treatments for CF
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NEW TREATMENTS FOR CF
Peter D. Sly MBBS, MD, FRACP, DSc
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EARLY INTERVENTION IN CF
What are we trying to achieve? Who should be treated? What are the treatment options? What is the evidence that early intervention
works?
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EARLY INTERVENTION IN CF
What are we trying to achieve? CF lung disease begins early and is progressive
3m (n=127)
1y (n=109)
2y (n=92) 3y (n=81)
Bronchiectasis
Prevalence 29.3% 31.5% 44.0% 61.5%
Incident rate 29.3% 23.5% 24.5% 52.8%
Ever present 29.3% 46.6% 63.0% 83.7%
Gas Trapping
Prevalence 68.0% 68.5% 71.6% 69.2%
Incident rate 68.0% 45.7% 36.4% 42.9%
Sly et al NEJM 2013
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PERSISTENCE OF BRONCHIECTASIS
Never: 74 (25%)
Resolved: 25 (12%)
Developed: 89 (30%)
Persistent: 98 (33%)
Bronchiectasis
Never: 74 (25%)
Resolved: 25 (12%)
Developed: 89 (30%)
Persistent: 98 (33%)
Bronchiectasis
301 paired scans 1y apart from 143 children (0.2-6.5y). Bx persistent in 73% and extent increased in 63%
Progression in 63%
Mott Thorax 2012
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GAS TRAPPING ON CT
What does Gas trapping mean? Uneven emptying of lung units
Is it associated with disease? Increases risk of bronchiectasis [Sly NEJM 2013]
Weak association with M2/MO but not LCI [Hall PLoS ONE 2011;6:e23932]
Can it be treated? No data in infants
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WHO SHOULD BE TREATED?
Respiratory symptoms Pulmonary infection
Absent (n=93)
Present (n=19)
p Absent (n=94)
Present (n=27)
p
Neutrophils (x103/ml)
326.4 947.5 0.031 303.3 822.4 0.02
Neutrophils (%) 17.9 30.5 0.017 17.5 28.8 0.013
IL-8 (pg/ml) 815.4 1607.9 0.03 988.0 1123.3 0.22
NE activity (%) 19.4 52.6 0.007 19.1 40.7 0.021
Bx (%) 23.7 55.0 0.005 24.2 46.2 0.029
GT (%) 72.0 68.4 0.40 68.1 74.1 0.46
Absence of symptoms does not mean absence of disease
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WHAT ARE THE TREATMENT OPTIONS?
Treatment options depend on disease mechanisms
Inflammation: anti-inflammatories Infection: antibiotic prophylaxis Thicker mucus: mucolytics Dehydrated ELF: HS, eNaC blockers Impaired mucociliary clearance: HS, DNAse Impaired anti-oxidant defence: anti-oxidants; GSH Gene defect: gene therapy, CFTR correctors, potentiators
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NON-STEROIDAL ANTI-INFLAMMATORIES
Cochrane Review (Lands & Stanojevic 2013, Issue 6)
5 trials (3 IBP), 334 subjects 5-39y, max 4y FU Data in children:
Konstan 1991: 13 IBP, 5 placebo; 300/400/600mg BD Konstan 1995: 42 IBP, 43 placebo; 20-30mg/kg Lands 2007: 142 (6-18y); 20-30 mg/kg
Outcomes Reduced decline in lung function (combined analyses) FEV1% mean dif 1.16 [0.07-2.25] – NS >13y FVC% 1.27 [0.26-2.28] – NS >13y FEF25-75% 1.72 [0.10-3.34] – NS >13y
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PROPHYLACTIC ANTI-STAPH ANTIBIOTICS
Cochrane review [Smyth & Walters 2012, Issue 12] 4 studies, 401 children 0-7y randomized Fewer children with ≥1 isolation of Staph But:
Complete eradication not achieved in most No difference in:
Isolation of other microbes Lung function (infant or spirometry) Nutrition (weight or height) Hospitalization, days in hospital, other antibiotics CXR score
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DORNASE ALFA Major results form studies in adults:
Improved lung function/ decreased rate of decline
Decreased exacerbations Improved QOL
Pulmozyme Early Intervention Trial (PEIT)Pulmozyme(n=239)
Placebo(n=235)
Age (yrs) 8.3 (1.4) 8.4 (1.5)
Male/female 126/113 121/114
FVC (% predicted) 103 (12) 102 (12)
FEV1 (% predicted) 96 (15) 95 (16)
Weight-for age percentile (%)
47 (28) 43 (28)
BHR/asthma symptoms (%) 38 39
Clubbing (%) 32 36
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FEV1 % predicted
Quan J Pediatr 2001; Robinson Pediatr Pulmonol 2002
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DORNASE ALFA Impact on ventilation inhomogeneity and gas
trapping 17 children (6-18y, mean 10.32y), FEV1≥80% 4w cross-over, placebo-controlled Dornase alfa:
Improved LCI 0.90±1.44; p=0.022, FEF25-75 6.1%±10.34%
[Amin, ERJ 2011;37:806-812]
25 children (6-18y), FVC ≥85%, FEV1≥70% 12m placebo-controlled RCT Improved gas trapping:
3m 13% v 48%, p=0.023; 12m 15% v 61%, p=0.053[Robinson Chest 2005;128:2327-35]
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HYPERTONIC SALINE Major results from adult studies
Improved lung function / decreased rate of decline
Reduced acute exacerbations / improved QOL Increased mucociliary clearance
Inhaled HS in infants and children <6y (ISIS)HS (7%) n=158 Placebo (0.9%)n=163
Age, y• <30m• ≥30m
2.2 (1.4)95 (60.1%)63 (39.9%)
2.3 (1.5)96 (58.9%)92 (56%)
Male n(%) 84 (53%) 92 (56%)
Medication• Dornase alfa• Albuterol
61 (39%)115 (73%)
65 (40%)120 (74%)
Positive culture• Ps a• Staph aureus
60 (38.0%)98 (62.0%)
69 (42.3%)124 (76.1%)
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HYPERTONIC SALINE
No reduction in exacerbations; 40% of subjects on dornase alfa
Rosenfeld JAMA 2012;307:2269-77
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HYPERTONIC SALINE
Impact on ventilation inhomogeneity 20 children (6-18y, mean 10.5); FEV1 96±12% Cross-over; 4 week treatment (HS/P), 4w wash-
out Decreased LCI; 1.16±0.94 (0.27-2.05), p=0.016 No change in spirometry, QOL
[Amin Thorax 2010;65:379-83]
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HYPERTONIC SALINE
Impact on mucociliary clearance 12 children (8.9-12.4y), FEV1 108%, single dose 7%
HS MC by radio-aerosol clearance Improved MC in some, esp if low at baseline
Laube BMC Pulm Med 2011;11:45
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DORNASE ALFA V HYPERTONIC SALINE
14 children, mean age 13.3y, FEV1 75.6% 3 w treatment (D 2.56mg/HS 5.85%), 3w WO FEV1 HS 7.7% (14%) v D 9.3% (11.7%),
p<0.05
Ballmann JCF 2002
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AZITROMYCIN
ages Pa N
Equi 2002 8-18 +/- 41
Wolter 2002 Adult +/- 60
Saiman 2003 6-adult + 185
Rotschild 2005 5-36 +/- 21
Clement 2006 6-adult +/- 82
Stenkamp 2007 8-adult +/- 38
O’Connor 2009 6-18 +/- 17
Kabra 2010 Children +/- 47
Saiman 2010 6-18 - 260
AZM: ↑ lung function, QOL, wt gain , ↓ exacerbations
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AZITROMYCIN
Potential mechanisms ↓ neutrophilic inflammation ↑ anti-oxidant defences ↓ viral LRI Prevent “pro-inflammatory” microbiome
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AZITROMYCIN
• ↓ neutrophilic inflammation Most evidence from erythromycin in DPB ↓ pro-inflammatory cytokines
BEC, neutrophils, monocytes ↓neutrophil accumulation
Inhibit ICAM-1, ↓ IL-8, ↓ migration ? ↓ neutrophil activation
↓ NE[Kanoh Clin Micro Rev 2010; Frielander Chest 2010]
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AZITROMYCIN
↑ anti-oxidant defence ↓ neutrophilic inflammation → MPO → ↓ OS AZM prevents OS-induced upregulation of GSTs
Catalyses oxidation of GSH to detoxify oxidants Further ↓ available GSH[Bergamini AJRCMB 2009]
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AZITROMYCIN
↓ viral LRI AZM → ↓ exacerbations in RCTs AZM → ↑ HRV-induced IFN, ↓ HRV replication in AEC
? ↓ spread of virus from URT to LRT[Gielen ERJ 2010; Zaheer AJRCMB 2010]
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Kreindler. Pharmacology & Therapeutics Volume 125, Issue 2 2010 219 - 229
GENE POTENTIATORS/CORRECTORS
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IVACAFTOR
Potentiates opening of CFTR channel with G551D “normalizes” sweat chloride improves lung function Improves nutrition
Case study: 7y girl G551D/G551D
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5m pre ivacaftor 7 months of ivacaftor
pre ivacaftor 11 months of ivacaftor
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NEW OPTIONS IN CLINICAL TRIAL
Lumacaftor Gene corrector – “escorts” CFTR to cell surface
(F508) Ataluren
Allows read through premature stop codon Neutrophil elastase inhibitors
ONO-6818; AZD9668
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EARLY INTERVENTION IN CF
Summary Lung disease begins early in CF Lack of symptoms does not mean no disease Treatment must start early to prevent disease Lack of RCTs in infants to guide treatment