PHASE 2 & 3 TRIALS OF HIGH-DOSE ORAL N-ACETYLCYSTEINE IN CYSTIC FIBROSIS

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DESCRIPTION (provided by applicant): Cystic fibrosis is a genetic, orphan disease, affecting about 30,000 people in the United States. Early after birth, neutrophilic inflammation largely contributes to the development of lung disease, the main cause of morbidity and mortality in CF. Another hallmark of CF is redox imbalance, shown previously in plasma and airway fluid. Recently, the applicant observed that redox imbalance in CF also occurs intracellularly, in blood neutrophils, featuring low levels of reduced glutathione (GSH). GSH, the main cellular antioxidant, modulates many functions in neutrophils. NAC is a GSH prodrug, capable of replenishing GSH in neutrophils when used orally in high doses. In 2004 - 2005, the applicant conducted a Phase 1 study, which established excellent safety and tolerability of high-dose oral NAC (0.6 to 1 g/d, 3 times daily, for 4 weeks) in patients with moderately severe lung disease. This study also yielded important data suggesting drug efficacy towards both redox and inflammatory defects seen in CF. Next, they submitted an Investigational New Drug application to FDA for a Phase 2 study, which is currently ongoing. This double-blind, placebo-controlled study for 12 weeks and uncontrolled for an additional 12 weeks, aims at establishing treatment efficacy of 2.7 g/d of oral NAC in CF patients. Based on previous experience in humans, the applicant does not anticipate risks of particular severity or seriousness in this Phase 2 study. Treatment safety is ensured by clinical monitoring and patient reporting of adverse effects. Drug effects are assessed on sputum live neutrophil count (primary outcome measurement, measured by microscopy) and on four secondary outcome measurements, namely functional expiratory volume in 1 second (measured by spirometry), intracellular GSH in blood neutrophils (measured by flow cytometry), sputum neutrophil elastase activity (measured by enzyme-linked immunosorbent assay), and whole blood GSH (measured by high performance liquid chromatography). Pending positive results in the Phase 2 trial (first year of support), the applicant envisions a large Phase 3 trial with specific provisions to assay drug efficacy in the CF pediatric population (second and third years of support). In children and adults with cystic fibrosis, the uncontrolled entry of neutrophils, a type of white blood cell, into the lungs, contributes to tissue destruction. The applicant aims to test whether a chemical readily found in the body can prevent neutrophil entry in lungs and stop the fatal decline in lung function seen in patients. To this end, pharmaceutical-grade N-acetylcysteine will be given orally in high doses.