Significant Strides in the Treatment of Cystic Fibrosis
Rebekah F. Brown, MDCenter 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. 2007Rowe 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
Airway lumen—Normal function
CFTR
Cl-
ENaC
Na+
NaCl
NaCl NaCl
NaClH2O
H2O
Simplified Diagram
Na+Inhibits
intracellular
Without Cystic Fibrosis
cilia
Airway Lumen
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.
Mucus
CFTR Models of Disease in CF
Airway lumen—CF
CFTR
Cl-
ENaC
Na+H2O
InhibitsH2O
Cl-
Simplified Diagram
intracellular
Cystic Fibrosis
cilia
Airway lumen—patient with CF
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
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 bronchodilator• H hypertonic saline• A airway clearance• P pulmozyme• I inhaled corticosteroid• I 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 studyElkins MR, et al. 2006
Donaldson SH, et al. 2006Rosenfeld 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
• Lung function improvement sustained at least 2 years
• Chronic use associated with 15% reduction in odds of subsequent year mortality
Dornase Alfa (Pulmozyme, recombinant human DNAse1,
rhDNAse)
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• Infection with specific bacteria
Khan TZ, et al. 1995Balough K, et al. 1995Konstan MW, et al. 1997Armstrong DS, et al. 1997Noah TL, et al. 1997Muhlebach MS, et al. 1999Sly PD, et al. 2009Stick 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. 1985Matthews WJ, et al. 1980
Rosenstein BJ, et al. 1991Lai 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
– Used if asthma + CFEscotte S, et al. 2003Escotte S, et al. 2002
Ren CL, et al. 2002Balfour-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 reduced by 88% Konstan MW, et al. 1995
Lands LC, et al. 2007Konstan MW, et al. 2007
Oermann CM, et al. 1999Konstan 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. 1995Lands LC, et al. 2007
Konstan MW, et al. 2007Oermann CM, et al. 1999Konstan MW, et al. 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 immunomodulatory effects Jaffe A, et al. 1998
Wolter J, et al. 2002Equi A, et al. 2002
Saiman L, et al. 2003Hoffmann N, et al. 2007
Clement A, et al. 2006Southern KW, et al. 2012
New Categories of Therapies in CF
Human GeneticsNucleus: 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
I—absenceII—premature
degradationIII—disordered
regulationIV—defective Cl
conductance or channel gating
V—reduced numberVI—accelerated
turnover
VI
IV
III
VI
II
ER
GolgiProteosome
Adapted from Rowe S et al. NEJM. 2005; 352.
Two Broad Categories of CFTR Mutations
• Mutations affect1. 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
effects? Zhang L, et al. 2009Pettit 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. 2011McKone EF, et al. 2011
Pettit RS, 2012Hanrahan 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
power) Clancy JP, et al. 2012Van Goor F, et al. 2011
Boyle MP, et al. 2011Pettit 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, 2012Wilschanski M, et al. 2011
Kerern E, et al. 2008Hirawat S, et al. 2007
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