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2623791 
Journal Article 
Abstract 
Denufosol tetrasodium - an investigational inhaled therapy with aerosol and pharmacokinetic properties suitable for early intervention in CF lung disease 
Navratil, T; Evans, C; Schaberg, A; Johnson, F; Durham, T; Smiley, L; Herje, N; Burke, B; Ren, CL; Ratjen, FA; Moss, RB; Accurso, FJ 
2010 
Yes 
American Journal of Respiratory and Critical Care Medicine
ISSN: 1073-449X
EISSN: 1535-4970 
181 
A6581 
English 
WOS:000208771005200 
is part of a larger document 3452678 Proceedings of the American Thoracic Society 2010 International Conference, May 14-19, 2010, New Orleans
Background: CF lung disease arises from defective CFTR and subsequent ion transport defect leading to impaired mucociliary clearance (MCC). Disease progression begins in small airways as early as at 4 months of age. With newborn screening for CF and evidence for early onset of the disease, early intervention with disease-modifying treatments is needed. The ability to treat small airways combined with a favorable safety profile are requisite characteristics for such therapies. Denufosol is a novel chloride channel activator currently in Phase 3 clinical trials. Denufosol stimulates chloride transport via Ca2+ -activated Cl- channel, inhibits Na+ absorption and increases ciliary beat frequency, thereby enhancing MCC. This work examines the potential of denufosol as an early intervention agent.

Methods: In vitro and clinical data were used for this analysis. Aerosol droplet size distribution was measured using the Next Generation Impactor and by Laser diffraction. A double-blind, placebo-controlled, randomized 24-week Phase 3 trial (TIGER-1) was conducted in 352 CF patients to compare inhaled denufosol 60 mg TID, delivered by the LC Star, to placebo TID followed by a 24-week open-label extension. Patients were ≥5 yrs (mean 14.6 yrs), had FEV1 ≥75% predicted (mean 93%) and were receiving standard CF treatment except hypertonic saline. Efficacy was assessed by pulmonary function tests including FEF25%-75% which reflects small airway function. The systemic exposure of denufosol in plasma was evaluated by measuring denufosol concentrations after inhalation of the first dose and after chronic treatment.

Results: In vitro device performance testing demonstrated that denufosol had the capability to reach small airways (median droplet size: 3.4 to 3.8 µm; Mass Median Aerodynamic Diameter: 2.4 µm). The ability to reach small airways was supported by a significant improvement relative to placebo in FEF25%-75% in patients <110% predicted FEV1 (p=0.025). Following inhalation, there was little to no systemic exposure to denufosol, no evidence of accumulation with chronic dosing, and no evidence of any systemic adverse effects including liver enzyme levels, blood biochemistry and differential blood cell counts.

Conclusions: Denufosol is an investigational treatment designed to overcome the basic defect in CF lung by restoring ion transport and MCC. The size of denufosol droplets emitted by the LC Star is suitable for delivery to the smaller airways which is supported by FEF25%-75% results. Denufosol’s mechanism of action combined with ability to target small airway and the lack of systemic exposure makes this a potentially promising therapy for early intervention in CF lung disease. 
American Thoracic Society 2010 International Conference 
New Orleans, LA 
May 14-19, 2010