AEROSOLIZED RECOMBINANT HUMAN DNASE-I FOR THE TREATMENT OF CYSTIC-FIBROSIS

Respiratory symptoms, recurrent infectious exacerbations, and progress ive lung destruction in cystic fibrosis can be attributed to bacterial persistence and the accumulation of viscous purulent secretions in th e airways. Purulent secretions contain high concentrations of extracel lular DNA, a viscous material released by leukocytes. To evaluate the potential clinical utility of recombinant human DNase I (rhDNase or Pu lmozyme), the human enzyme was cloned, sequenced, and expressed. In in vitro studies, rhDNase has been shown to reduce the viscoelasticity, reduce the adhesiveness, and improve the mucociliary transportability of cystic fibrosis sputum. In short-term phase 1 and phase 2 clinical trials, rhDNase has been shown to be safely tolerated and to improve t he FEV(1), FVC, and symptoms of dysp- nea. Along-term placebo-controll ed phase 3 study was performed in 968 adults and children(greater than or equal to 5 years) with cystic fibrosis to determine the effect of rhDNase on the risk of respiratory exacerbations requiring parenteral antibiotics and on the FEV(1). Compared with placebo-treated patients, patients treated with rhDNase once daily or twice daily experienced a reduced risk of respiratory exacerbations by 28% (p=0.04) and 37% (p= 0.01), respectively, and had a mean improvement in FEV(1) of 5.8% (p<0 .01) and 5.6% (p<0.01), respectively. Compared with placebo-treated pa tients, patients treated with rhDNase spent 2.7 fewer days receiving p arenteral antibiotics (p=0.04) and spent 1.3 fewer days in the hospita l(p=0.06) over the 6-month treatment period. Inhalation of rhDNase did not cause anaphylaxis but was associated with upper airway symptoms t ie, voice alteration, hoarseness, pharyngitis) that were generally mil d and transient. In conclusion, aerosol administration of rhDNase was safely tolerated, reduced the risk of infectious exacerbations requiri ng parenteral antibiotics, and improved pulmonary function and patient well-being.