Dose-finding and 24-h monitoring for efficacy and safety of aerosolized Nacystelyn in cystic fibrosis

Abstract

The aim of the present studies was to investigate the tolerability and activity of a novel mucolytic drug, Nacystelyn (NAL), for the treatment of cystic fibrosis (CF) lung disease.In study 1, involving 10 CF patients, the main objective was to determine the tolerability and potential efficacy of a range of single doses of NAL in comparison to a placebo, in order to establish an optimal dose for further testing. On five consecutive scheduled treatment days, patients inhaled either from two (4 mg) to eight puffs (16 mg) of a single dose of NAL from the range, administered in an open-label fashion, or 12 puffs of active NAL (24 mg) versus 12 puffs of placebo, administered in a randomized double-blind fashion. Pulmonary function data were unaffected and clinically-adverse effects were limited to wheezing in some patients that inhaled 12 puffs of either placebo or active drug. Subsequent rheological analysis of their sputum showed a dose-dependent decrease in sputum viscoelasticity, accompanied by a decrease in sputum solids content and an increase in chloride and sodium concentrations.In study 2, involving 12 CF patients, the clinical safety and mucolytic activity of a single dose of NAL was monitored over 24 h. On different scheduled treatment days, 7 days apart, patients inhaled a single dose of 12 puffs of active NAL (24 mg) or 12 puffs of placebo drug in a randomized, double-blind sequence, with sputum samples taken at intervals before and after inhalation. Mucus rigidity decreased following NAL inhalation, with the maximum effect observed at 4 h; the 1-, 2-and 4-h NAL rheology results were significantly different from placebo. No adverse effects were observed.The drug was well tolerated in both studies. Sputum results were predictive of improved clearability by ciliary and cough transport mechanisms.

Getting Drugs Across Biological Barriers

“…Mucolytic agents, such as N-acetylcysteine, [229] nacystelyn, [230] and gelsolin, [231] may be used to enhance particle transport. Mucolytics disentangle the cross-linked mucus network and reduce the viscoelasticity of mucus.…”

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

“…Clinical trials have demonstrated the safety of NAL in healthy adults, smokers, and people with CF [96,97]. In a multicenter phase 2 trial, a placebo-controlled, double-blinded, randomized trial lasting 24 weeks demonstrated an improvement in mucus viscoelasticity in expectorated sputum and decreased self-reported respiratory infections with NAL aerosol administration (8 or 16 mg bid).…”

Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways

“…9 At the same time, no adverse effects were observed in CF patients, even at a high dose of 24 mg given via inhaler. 10 Presently, multiple phase I and phase II clinical trials are being undertaken in Europe and USA to assess the efficacy of NAL treatment in CF patients. Studies conducted in humans have also indicated that NAL prevents respiratory outburst of peripheral blood polymorphonuclear cells, indicating that it may have potential in reducing damage to lungs caused by an active inflammatory response, 11 which could be of a potential benefit in the context of adenoviral vectormediated CF gene therapy.…”