[Clinical development of rhDNase in the United States]

On the basis of the hypothesis that an increased concentration of high-molecular weight DNA contributes to the abnormal viscoelastic properties of sputum, airway obstruction, and recurrent exacerbations of respiratory symptoms requiring parenteral antibiotics, a series of clinical trials have been conducted in the USA to evaluate human desoxyribonuclease I (rhDNase) delivered as an aerosol to patients with cystic fibrosis. In preliminary phase II, placebo-controlled trials, rhDNase was administered as short-term or intermittent treatment, for up to 14 consecutive days. These trials demonstrated that rhDNase aerosols were followed by an improvement of forced expiratory volume in one second (FEV1) and were safe. A randomized, double-blind, placebo-controlled phase III study was initiated to investigate whether the once-daily and twice-daily administration of rhDNase for 24 weeks would decrease the frequency of respiratory exacerbations requiring parenteral antibiotics and improve pulmonary function. A total of 968 patients with cystic fibrosis were treated for 24 weeks as outpatients. As compared with placebo, the treatment with rhDNase once daily and twice daily reduced the risk of respiratory exacerbations by 28% (p = 0.04) and 37% (p < 0.01), respectively. A slight improvement in pulmonary function was also observed in these two groups: FEV1 increased by a mean (+/- ET) of 5.8 +/- 0.7% and 5.6 +/- 0.7%, respectively. Overall, the treatment was well tolerated.