1. New Developments in Cystic Fibrosis
Nuevos desarrollos de Fibrosis Quistica
Daniel J. Weiner, MD
Co-Director, Antonio J. & Janet Palumbo Cystic Fibrosis Center
Medical Director, Pulmonary Function & Exercise Laboratories

2. America’s Most Livable City
PITTSBURGH, PA
America’s Most Livable City
One of the Best Places in the World to Experience
- National Geographic Traveler 2012
One of the Best Places in the World to Experience – National Geographic Traveler 2012

3. Nuevos desarrollos de fibrosis quística

4. Introduction
Cystic Fibrosis is a genetic, chronic and progressive disease, caused by deficient functional CFTR protein
It is manifested by chronic respiratory disease, pancreatic insufficiency, and increased content of electrolytes in sweat
Approximately 30,000 US patients
Median predicted survival (2011): 36.8 years, median age at death 27.1 years
Cystic Fibrosis is a genetic, chronic and progressive disease, caused by deficient functional CFTR protein
It is manifested by chronic respiratory disease, pancreatic insufficiency, and increased content of electrolytes in sweat
Approximately 30,000 US patients
Median predicted survival (2011): 36.8 years, median age at death 27.1 years

5. Cystic Fibrosis in Colombia
Hum Mutat. 2003 Sep;22(3):259.

6. Manifestations of Cystic Fibrosis

7. The “Low Volume” Hypothesis
Matsui, et. al, Cell, 1998

8. Pathophysiology & Treatment of Cystic Fibrosis
Defective CF gene
Gene replacement
Defective/deficient CFTR
Protein repair Rx
Protein assist Rx
Abnormal airway surface milieu
ENaC inhibition
airway clearance
rhDNase
hypertonic saline
Bronchial obstruction
systemic antibiotics
inhaled antibiotics
azithromycin
Infection
Inflammation
corticosteroids
high dose ibuprofen
Bronchiectasis
lung transplantation

9. Antibiotics (inhaled, oral, IV)
“Standard” CF Therapy
Airway Clearance:
Mechanical (CPT, HFCC, oPEP)
Pharmacologic (rhDNAse, hypertonic saline)
Antibiotics (inhaled, oral, IV)
Anti-inflammatories (azithromycin, ibuprofen)
Nutrition: pancreatic enzyme replacement, extra calories, vitamins ADEK

10. Cystic Fibrosis Foundation Therapeutics Pipeline
CHEST 2013; 143(1):207–213 10

11. Inhaled Hypertonic Saline
N Engl J Med 2006;354:

12. Inhaled Hypertonic Saline
“among infants and children younger than 6 years with CF, the use of inhaled hypertonic saline compared with isotonic saline did not
reduce the rate of pulmonary exacerbations over the course of 48 weeks of
treatment”
JAMA. 2012;307(21):

13. N Engl J Med 1999;340:23-30.

14. Inhaled antibiotics CHEST 2009; 135:1223–1232.
J Cystic Fibrosis 2011(10);

15. Dry powdered antibiotics
Well tolerated
Quicker than nebulized medications
Do not require refrigeration

16. CFTR Mutation Classes: Personalized Medicine

17. N Engl J Med 2011;365(18):

18. CFTR Potentiator: Ivacaftor
Orally bioavailable small molecule taken twice daily
Stabilizes NBD-1 in G551D-CFTR
May be helpful for other “gating” mutations
Improves lung function & weight
Very costly

19. CFTR correctors
Thorax 2012;67:12e18

20. Forthcoming CFTR Modulator Studies
Study of Ivacaftor in Cystic Fibrosis subjects 2 through 5 years of age with A CTFR gating mutation
Study of Ivacaftor in subjects with Cystic Fibrosis who have the R117H-CFTR mutation
Rollover study of Ivacaftor in subjects with Cystic Fibrosis and a non G551D CFTR mutation
Pilot study testing the effect of Ivacaftor on lung function in subjects with Cystic Fibrosis and residual CFTR function
Study of VX-809 alone and in combination with VX-770 in Cystic Fibrosis (CF) patients homozygous or heterozygous for the F508del-CFTR mutation
Study of VX-661 alone and in combination with VX-770 in subjects homozygous to the F508del-CFTR mutation

21. What are the best outcome measures?
Clinical Challenges
What are the best outcome measures?
Physiologic: FEV1, LCI, Sweat chloride
Anatomic: Chest CT scans
Clinical: Exacerbations, symptom score, weight gain
How do new therapeutics fit with existing treatment modalities?
Balancing treatment burden with benefit
Combinations of therapies (protocolized care?)
Can we afford new therapeutics?
If early detection (newborn screening) is to have maximal benefit, how early can novel therapies be introduced? How do we study them?

22. New Therapies for Cystic Fibrosis
Pulmonary Function
Exacerbations
Cost
(USD $/month)
rhDNAse
(Fuchs, 1994, 24 weeks, n=968)
FEV1 increase 5.8% (QD) or 5.6% (BID)
RR reduction of 28% (QD) or 37% (BID)
US$ ( COP)
Hypertonic Saline (Elkins, 2006, 48 weeks, n=164)
Non-significant change
RR reduction of 56%, increase in % without exacerbation (76% vs 62%)
US$69.94 ( COP)
TOBI (Ramsey, 1994, 24 weeks, n=520)
FEV1 increase 10% at week 20
RR reduction of hospitalization of 26%; RR reduction of 36% in use of IV anti-pseudomonal abx
US$ ( COP)
Cayston (AIR-CF1, Retsch-Bogart, 2009, n=164)
FEV1 increase of 10% (placebo adjusted) at 7 weeks
Not defined (improvement in CF-RQ symptom scores)
US$ ( COP)
Ivacaftor (Ramsey, 2011, 24 weeks, n=167)
FEV1 increase 10.6% at 24 weeks
RR reduction 55%
US$30, ( COP)

23. Questions?