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New Developments in Cystic Fibrosis

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Presentation on theme: "New Developments in Cystic Fibrosis"— Presentation transcript:

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?


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