Significant Strides in the Treatment of Cystic Fibrosis Rebekah F. Brown, MD Center Director, Cystic Fibrosis Center at Vanderbilt Objectives 1. At the end of this presentation, participants will have an understanding of the pathophysiology of cystic fibrosis and targets of treatment for children and adults with cystic fibrosis. 2. Provide an overview of the advancements in treatment of children and adults with cystic fibrosis. What is Cystic Fibrosis? • Autosomal recessive • Most common life shortening inherited disease in Caucasians – 1 in 2500-3000 births • CF Transmembrane Regulator (Cl- channel) defect – Affects lungs, GI tract, liver, pancreas, sweat glands, vas deferens Davies J et al. 2007 Rowe S et al. 2005 Historical Perspective • “The child will soon die whose forehead tastes salty when kissed”—17th century German Children’s Songs and Games from Switzerland • 1938 -- CF of the pancreas – Dr. Dorothy Andersen (pathologist) • 1943 “mucoviscidosis” – Dr. Sydney Farber (pathologist) Historical Perspective • 1948 heat wave in New York – Dr. Paul di Sant’Agnese – Hyponatremic dehydration – CF – Sweat with excessive salt content (1953)sweat chloride as diagnostic test for CF Joseph Levy Memorial Lecture & Ettore Rossi Medal Lecture at European CF Conference in Birmingham in 2004 by Dr. Jim Littlewood Historical Perspective • 1980s Improved Survival – Acid resistant pancreatic enzymes – Fat soluble vitamin replacement – Nasal potential difference—Knowles 1981 • Late 1980s – CF defect noted on Chromosome 7 Historical Perspective • 1989 – CFTR (CF transmembrane conductance regulator) gene – Delta F508 mutation—most common • > 1700 mutations www.genet.sickkids.on.ca/cftr STILL NO CURE…YET CFTR Models of Disease in CF Simplified Diagram Airway lumen—Normal function Na+ NaCl NaCl Inhibits Cl- H2O CFTR NaCl NaCl ENaC Na+ H2O intracellular Without Cystic Fibrosis Airway Lumen Mucus cilia Airway surface fluid Cilia have room to beat back and forth--clear the airway of particles, bacteria, etc. Plenty of fluid to allow inflammatory cells to find and kill bacteria, viruses, etc. CFTR Models of Disease in CF Simplified Diagram Airway lumen—CF Inhibits H2O ClCFTR Cl- ENaC Na+ H2O intracellular Cystic Fibrosis Airway lumen—patient with CF Mucus cilia Airway surface fluid Cilia matted down in thick mucus and cannot rid airway of foreign particles. Necrosis of neutrophils releases DNA and actin thick, tenacious mucus What does this mean for a patient? CF Clinical Disease • Sinopulmonary – Chronic Sinusitis and Nasal polyposis – Bronchiectasis, Reduced lung function – Respiratory Failure • GI – – – – – Pancreatic insufficiency Failure to Thrive/Malnutrition Meconium ileus/Distal Intestinal Obstruction Syndrome Liver Disease CF Related Diabetes CF with Mosaicism CF with Pneumothorax, bronchiectasis, mucous plugging Right Lower Lobe—non-CF patient Right Lower Lobe in Cystic Fibrosis Right Upper Lobe in Cystic Fibrosis CF Related Liver Disease Treatment of Pulmonary Disease • Daily, maintenance airway clearance • Early and aggressive treatment of exacerbations • Treatment of Pseudomonas colonization • Elimination of smoke exposure Treatment of GI Disease • Pancreatic enzyme replacement therapy • Fat soluble vitamin supplementation – A, D, E, and K • Early and aggressive treatment of constipation and malabsorption • Nutritional supplementation Cystic Fibrosis Patient Registry 2011 Other Manifestations of CF • Absence of the vas deferens – Men diagnosed at infertility clinics • Sweat – Risk for hyponatremic, hypochloremic dehydration Treatment of Cystic Fibrosis Airway Clearance Medications Airway Clearance “Be Happy” • • • • • • B H A P I I bronchodilator hypertonic saline airway clearance pulmozyme inhaled corticosteroid inhaled antibiotic Hypertonic Saline (7% Normal Saline) • Increase 1 hour rates of mucus clearance • Increase 24 hour rates of mucus clearance compared to baseline • Improved FEV1 (mean 4-6%) • Bronchospasm—bronchodilator pretreatment • Infants: no improvement compared to isotonic saline in one study Elkins MR, et al. 2006 Donaldson SH, et al. 2006 Rosenfeld M, et al. 2012 Dornase Alfa (Pulmozyme, recombinant human DNAse1, rhDNAse) • Cleaves DNA in mucus – Possible action in cleaving DNA in biofilm of bacteria improving sensitivity to antibiotics • Reduced risk of exacerbations by 28% Shak S, et al. 1995 Jones AP, et al. 2010 Wagener JS, et al. 2012 Kaplan JB, et al. 2012 Sawicki GS, et al. 2012 Dornase Alfa (Pulmozyme, recombinant human DNAse1, rhDNAse) • Lung function improvement sustained at least 2 years • Chronic use associated with 15% reduction in odds of subsequent year mortality Shak S, et al. 1995 Jones AP, et al. 2010 Wagener JS, et al. 2012 Kaplan JB, et al. 2012 Sawicki GS, et al. 2012 Inhaled Antibiotics • Usually inhaled tobramycin • Alternate month on/month off to reduce antibiotic resistance • Only available in nebulized form—time consuming • Also use aztreonam, vancomycin, colistimethate Airway Clearance Devices • Vibrate secretions off airway wall – Patient performs huff cough to mobilize secretions out of airway • Manual Chest Percussion • Vest physiotherapy • Patient effort dependent devices: variable or fixed positive expiratory pressure DAY IN THE LIFE OF A CF PATIENT Be Happy • • • • • • • Bronchodilator (5–15 min) Wait 15 min Hypertonic saline (15-20 min) Airway Clearance (30 min) Dornase alfa (5 min) Inhaled Corticosteroids (5-15 min) Inhaled Antibiotic (15-20 min) Total 1 ½ hours CF Patient’s Day When Well • • • • • Airway clearance = 100 minutes x 2 Pancreatic enzymes with every meal, snack, etc. Vitamins, acid blockers, ursodiol (liver disease) Eat, eat, eat to maintain good nutrition Go to school +/- work +/- extracurricular activities • Have a life! Inflammation in Cystic Fibrosis Inflammation in Cystic Fibrosis • Begins in early infancy – Bronchoalveolar lavage fluid from infants with increased neutrophils, proinflammatory mediators in airways and neutrophil elastase – Inflammation excessive to bacterial burden • Neutrophil dominated phenotype of inflammation Khan TZ, et al. 1995 Balough K, et al. 1995 MW, et al. 1997 • Infection with specific bacteria Konstan Armstrong DS, et al. 1997 Noah TL, et al. 1997 Muhlebach MS, et al. 1999 Sly PD, et al. 2009 Stick SM, et al. 2009 Anti-Inflammatory Medications • Ideal medication – Start early – Prevent disease progression – Minimal side effects – Minimal effects on bacterial burden or colonization Corticosteroids • Systemic – Improved lung function – Significant side effects—impaired glucose tolerance, growth impairment, cataracts • Continued even after steroids discontinued • Discontinuation of steroids lead to quicker rate of FEV1 declineno longer significantly different from placebo group – Other risks: osteopenia/osteoporosis Auerbach HS, et al. 1985 Matthews WJ, et al. 1980 Rosenstein BJ, et al. 1991 Lai HC, et al. 2000 Corticosteroids • Inhaled – Inhibit NFĸB activation, decreased LPS-induced release of IL-6 and IL-8 – No benefit demonstrated when given to CF patients • Insufficient evidence to determine if beneficial or harmful – Discontinuation CF patients in UK—no significant harm during short observation Escotte S, et al. 2003 Escotte S, et al. 2002 – Used if asthma + CF Ren CL, et al. 2002 Balfour-Lynn IM, et al. 2006 Ibuprofen • High dose ibuprofen based on pharmacokinetics for peak plasma concentrations 50-100 micrograms/ml – Doses typically 20-30 mg/kg • Less decline in lung function, less weight loss, fewer hospitalizations, less CXR findings • 5-13 y/o—annual rate of decline of FEV1 Konstan MW, et al. 1995 reduced by 88% Lands LC, et al. 2007 Konstan MW, et al. 2007 Oermann CM, et al. 1999 Konstan MW, et al. 2008 Ibuprofen • Less than 10% of CF patients on ibuprofen • Why? – Pharmacokinetics not locally available – Side effects/safety • GI hemorrhage requiring hospitalization higher • Renal failure • Recommendation to consider in CF patients with mild disease Konstan MW, et al. 1995 Lands LC, et al. Konstan MW, et al. Oermann CM, et al. Konstan MW, et al. 2007 2007 1999 2008 Azithromycin • Decreases rate of pulmonary exacerbations • Improves lung function • Question of use in absence of Pseudomonas • Anti-inflammatory properties felt to be secondary to both antimicrobial and Jaffe A, et al. 1998 Wolter J, et al. 2002 immunomodulatory effects Equi A, et al. 2002 Saiman L, et al. Hoffmann N, et al. Clement A, et al. Southern KW, et al. 2003 2007 2006 2012 New Categories of Therapies in CF Human Genetics Nucleus: mRNA transcription and splicing ER: translation and folding Golgi: protein maturation Vesicles: protein transport Cell Surface Membrane Human Genetics—Types of Mutations Normal gene: DURING THE LECTURE PEOPLE SLEPT UNTIL THE END Missense mutation: DURING THE LECTURE PEOPLE SWEPT UNTIL THE END Nonsense (stop codon) mutation: DURING THE LECTURE PEOPX Deletion: DURING THE LECTURE SLEPT UNTIL THE END Insertion: DURING THE LECTURE PEOPLE SLEPT QUIETLY UNTIL THE END Frameshift: DURING THE LECTURE PEOPLE SEPTU NTILTH EEN D Classes of CFTR Defects IV VI III Golgi II Proteosome ER I V I—absence II—premature degradation III—disordered regulation IV—defective Cl conductance or channel gating V—reduced number VI—accelerated turnover Adapted from Rowe S et al. NEJM. 2005; 352. Two Broad Categories of CFTR Mutations • Mutations affect 1. Quantity – Little to no protein (Classes I and II) – Some protein (Classes V and VI) 2. Function – Gating defect (Class III)—channel does not open – Conductance defect (Class IV)—”narrow channel” opens but not as much Cl transported Mutation Class Specific Medications: The Future of CF Treatment • Treat the underlying defect • How much CFTR function is needed? – Carriers mostly asymptomatic with 50% function – <10%--absence of vas deferens – <5%--Other CF manifestations – Increase CFTR function to 20-25%therapeutic Zhang L, et al. 2009 effects? Pettit RS, 2012 Hanrahan JW, et al. 2012 Potentiators • Potentiators activate the CFTR channel that is already present at the plasma membrane • FDA approved 2/2012—ivacaftor (VX-770) – Greater than 6 y/o with G551D mutation (gating defect) – Improvement in pulmonary function, weight gain, sweat chloride, decreased pulmonary exacerbation rate Ramsey BW, et al. 2011 McKone EF, et al. 2011 Pettit RS, 2012 Hanrahan JW, et al. 2012 Correctors • Correct the trafficking – moves the CFTR channel out to the cell surface – Help the most common mutation, F508del • Example: VX-809 Studies ongoing in combination with ivacaftor/VX-770 • Phase 2 study – Decreased sweat chloride – No significant change in spirometry (lack of Clancy JP, et al. 2012 power) Van Goor F, et al. 2011 Boyle MP, et al. 2011 Pettit RS, 2012 Hanrahan JW, et al. 2012 Medications that Read Through mRNA Premature Stop Codons • Applications also in other diseases such as Duchenne’s muscular dystrophy • Initially found gentamicin, but side effects • Ataluren (PTC-126) studies ongoing – CFTR function (NPD) improved – Trends toward increased pulmonary function – Trends toward increased weight Pettit R, 2012 Wilschanski M, et al. 2011 Kerern E, et al. 2008 Hirawat S, et al. 2007 References • • • • • • 1. 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