HOW DISEASE ALTERING THERAPY IS CHANGING THE GOALS OF TREATMENT IN CF Peter D. Sly MBBS, MD, FRACP, DSc OUTLINE Goals of CF treatment Drivers of early disease neutrophilic inflammation oxidative stress infection Minimizing early lung disease Preserving lung function till new therapies available 1
IVACAFTOR Potentiates opening of CFTR channel with G551D normalizes sweat chloride improves lung function Improves nutrition Case study: 7y girl G551D/G551D ivacaftor: clinical and radiological improvement NOT reversal of structural damage 5m pre ivacaftor pre ivacaftor 7 months of ivacaftor 11 months of ivacaftor 2
GOALS OF CF TREATMENT Prescribing ivacaftor in Australia Cost >$300,000 pa per patient Supply available on PBS for patients who satisfy all: 6y with at least one G551D mutation FEV 1 40% predicted no upper limit Sweat chloride 60mMol/L Chronic sinopulmonary disease or GIT & nutritional abnormalities Continued supply depends on demonstrating sustained benefit (lung function, wt, days in hospital) Not available for primary prevention Thus preserving function is paramount GOALS OF CF TREATMENT 1. To diagnose CF as early as possible New-born screening 2. To preserve lung function CF lung disease begins early, treatment must begin early 3. To optimize growth Growth sub-optimal in early life Maintaining weight / BMI not sufficient 4. To prevent complications / co-morbidities No real evidence that this is possible Current trials with glucose management to prevent CFRD 3
DRIVERS OF EARLY DISEASE IN CF AREST CF early surveillance program 1998: BAL-based micro surveillance program Perth clinic 2002: Infant lung function 2003: Preschool FOT 2005: CFFT funding CT scans Melbourne clinic joined the program 2011: CFFT funding COMBAT CF RCT: Primary prevention of Bx with AZM / placebo from 3m to 3y THE AREST CF PROGRAM Comprehensive early surveillance program CF diagnosed following detection by NBS Initial assessment soon after diagnosis ( 3 months) Annual assessment close to birthday until 6 years Clinical and research components Separate consent for each component Assessments undertaken when clinically stable Very well accepted, >95% complete participation 4
AREST CF ASSESSMENTS CT/BAL GA; EI (25 cmh 2 O), EE (0 cmh 2 O) 3-slice scans; low-dose volumetric scans BAL after CT Infant lung function SF 6 MBW, LF-FOT, RVRTC Preschool lung function FOT, spirometry from 5 years Biomarker discovery and validation Matched BAL, serum, urine Infection, inflammation, metabolomics Epithelial cell biology (Stick) ONSET OF BRONCHIECTASIS 70 60 50 40 30 20 10 0 Prevalence of Structural Changes 3m 1 2 3 4 5 Age of life Bronchiectasis (years) Air Trapping Mott et al 2009, Journal of Cystic Fibrosis Stick et al 2009, Journal of Pediatrics 5
AREST CF Overall results 1285 BAL (305 children), 869 CT (258 children) Lung disease begins early in CF Bx, air trapping from 3 months Infection, including with P. aeruginosa from 3 months May occur in asymptomatic children Neutrophilic inflammation prominent Free NE activity from 3 months Associated with presence, extent and progression of Bx Infection common At least one infection in 78% by 6 years Successful eradication of P. aeruginosa if treated early Early infection on BAL associated with Structural lung disease Abnormal lung function in infancy Low BMI NEUTROPHILIC INFLAMMATION Activated neutrophils secrete both pro- and antiinflammatory compounds H 2 O 2 Elastase Myeloperoxidase Calprotectin NETS NE NE Activation MPO H 2 O 2 6
H 2 O 2 MPO H 2 O 2 + Cl GSH MPO HOCl GSSG + GSA (40%) (32%) HOCl Protein cleavage 3Cl-Tyr NE Elastin destruction desmosines ROS DNA oxidation 8-oxodG Neutrophilic inflammation as an early disease driver 3 months (n=127) 12 months (n=109) 2 years (n=92) 3 years (n=81) BMI Z-score -1.34±1.19-0.42±1.29-0.16±1.46 0.22±0.96 NE positive 28 (23.3%) 19 (18.1%) 20 (21.7%) 19 (25.0%) Neutrophils x10 3 /ml 416±810 482±761 1441±2822 2334±5618 Any infection 22.4% 21.1% 40.2% 46.9% S. aureus 6.4% 5.5% 10.9% 22.2% P. aeruginosa 5.6% 8.3% 5.4% 9.9% Bx point prevalence 29.3% 31.5% 44.0% 61.5% Bx ever (cumulative) 29.3% 46.6% 63.0% 83.7% GT point prevalence 68.0% 68.5% 71.6% 69.5% Sly et al NEJM 2013 7
Longitudinal risk factors for Bx from 3m to 3y Multivariate analysis Odds Ratio (95% CI) GEE with binomial family, logit link and AR(1) correlation matrix Sly et al NEJM 2013 Those with NE in BAL develop Bx earlier Sly et al NEJM 2013 8
Persistent Bx Persistent Negative Negative Resolved Persistent Acquired Acquired Resolved Initial scan Subsequent scan Bx label Detected Persistent Detected Not detected Resolved Not detected Detected Not detected Acquired Negative Sly et al NEJM 2013 Risk factors at 3m for persistent Bx: 12m Odds Ratio (95% CI) Logistic regression; Blue=univariate; Red=multivariate Sly et al NEJM 2013 9
Risk factors at 3m for persistent Bx: 3y Odds Ratio (95% CI) Logistic regression; Blue=univariate; Red=multivariate Sly et al NEJM 2013 Neutrophil-induced oxidative stress as an driver of early lung disease Kettle ERJ 2014 10
Oxidation of GSH is increased in CF Abnormal protein binding of GSH in CF Kettle ERJ 2014 Oxidation of calprotectin anti-bacterial function Magon 2015 submitted 11
Active calprotectin (MLTELEK) oxidized in CF More oxidation with pulmonary infection Magon 2015 submitted DRIVERS OF EARLY DISEASE IN CF Poor nutrition despite NBS [AREST CF] 42 infants studied from diagnosis (3m) to 3y 16 (38%) male, 36 NBS, 6 Mec Ileus, 39 PI 3 m (n=36) 1 y (n=42) 2y (n=42) 3y (n=42) Respiratory symptoms 38% 36% 31% 36% Anti-staph prophylaxis, n (%) 17 (42.5) 31 (73.8) 26 (61.9) 24 (57.1) S. Aureus, n (%) 9 (25.0) 3 (7.1) 6 (14.3) 7 (17.5) P. aeruginosa, n (%) 3 (8.3) 4 (9.5) 4 (9.5) 4 (9.5) Ranganathan, Thorax 2011 12
Initial poor growth that normalizes by 1y (group data) Ranganathan, Thorax 2011 Free NE activity associated with worse growth over 3y Staph infection associated with worse growth over 3y Staph prophylaxis associated with better growth over 3y, p=0.013 Ranganathan, Thorax 2011 13
MINIMIZING EARLY LUNG DISEASE Treatment options depend on disease mechanisms Inflammation: anti-inflammatories anti-neutrophil therapies: AZM? NE inhibitors? 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 Personal assessment may be more informative GOALS OF CF TREATMENT In the era of disease-altering therapy the goals of CF treatment should be: preserving lung function optimizing nutrition inimizing co-morbidities / complications until patient-specific disease-altering therapy is available. Personalized assessment of disease mechanisms and optimal therapeutic strategies likely to be required Point-of-care biomarkers of active disease in early life would be helpful 14