A Phase IIa Open Label Study to Evaluate the Safety, Tolerability and Efficacy of S-1226 Administered by Nebulization in Subjects with Cystic Fibrosis Lung Disease

ABSTRACT Rationale There are approximately 35,000 people with Cystic Fibrosis (CF) in North America. This condition is characterized by impaired airway clearance resulting in chronic infection and bronchiectasis. Current airway clearance treatments include nebulized hypertonic saline and Recombinant Human DNase, which may be limited by bronchospasm and cost, respectively. S-1226, a novel biophysical therapeutic agent combines carbon dioxide (CO 2 ) enriched air (a bronchodilator) with nebulized perflubron (PFOB), (a synthetic surfactant). They act synergistically to open airways, enhance mucus clearance, and increase blood oxygenation. We report preliminary results from a Phase II clinical trial. Methods An open label, single-center, Phase IIa study of subjects (≥14 years) with mild-moderate (FEV 1 40-80%) CF lung disease treated with multiple ascending doses of S-1226 (week one), followed by the highest tolerated dose for 5 consecutive days (week two). Each dose of S-1226 comprised three successive treatments of 3mL of perflubron nebulized (Circulaire®II) for two-minutes with CO 2 concentrations ranging from 4 to 12%. The oxygen concentration was maintained at ambient levels. Treatments were administered twice daily. Efficacy measurements included spirometry, lung clearance index (LCI), lung volumes, blood oxygenation (SPO 2 ), sputum weight and the respiratory domain of quality of life (QOL) questionnaire (CFQ-R). Safety included adverse event (AE) and tolerance monitoring, vital signs, and assessment of end-tidal CO 2 . Results We report preliminary data on safety and efficacy for six CF subjects. All subjects tolerated all doses of S-1226. There were 5 reported AEs in 3 subjects. All were mild and resolved spontaneously. End-tidal CO 2 immediately after treatment was comparable to baseline. SpO 2 (baseline 91-95%) rapidly improved in all subjects with treatment. Five of six subjects had improvements in their LCI. Three subjects that were compliant in collecting mucus showed increases of 14%, 29% and 64% over baseline. Percent predicted FEV 1 response was variable, decreasing initially with return to pre-treatment values at two weeks. Four of the six subjects reported improvements in CFQ-R scores, three of which showed a clinically important difference (> 4 points). An important observation was that S-1226 controlled irritant (but not productive) cough in all five subjects and at all concentrations of S-1226. Conclusions All doses of S-1226 were safe and well tolerated. Treatments with up to 12% extrinsic CO 2 over short periods of time did not result in an elevation of end-tidal CO 2. The preliminary efficacy results, including overall improved oxygen saturation, CFQ-R scores, increased expectorated mucus and LCI values provide evidence for potential beneficial effects of S-1226 for CF lung disease but require larger trials and longer-term treatments to fully assess efficacy in CF.

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