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
declineno 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
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