Significant Strides in the Treatment of Cystic Fibrosis

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 centuryGerman 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. 1995

Lands LC, et al. 2007Konstan MW, et al. 2007

Oermann 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

VIIV

III

VI

II

ER

Golgi Proteosome

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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