title: Safety and tolerability of denufosol tetrasodium inhalation solution, a novel P2Y2 receptor agonist: results of a phase 1/phase 2 multicenter study in mild to moderate cystic fibrosis.
abstract: Denufosol tetrasodium (INS37217) is a selective P2Y(2) agonist that stimulates ciliary beat frequency and Cl(-) secretion in normal and cystic fibrosis (CF) airway epithelia, and is being investigated as an inhaled treatment for CF. The Cl(-) secretory response is mediated via a non-CFTR pathway, and the driving force for Cl(-) secretion is enhanced by the effect of P2Y(2) activation to also inhibit epithelial Na(+) transport. Denufosol is metabolically more stable and better tolerated, and may enhance mucociliary clearance for a longer period of time than previously investigated P2Y(2) agonists. The goal of this phase 1/phase 2 study was to assess the safety and tolerability of single and repeated doses of aerosolized denufosol in subjects with CF. The study was a double-blind, placebo-controlled, multicenter comparison of ascending single doses of denufosol (10, 20, 40, and 60 mg, administered by inhalation via the Pari LC Star nebulizer) vs. placebo (normal saline), followed by a comparison of twice-daily administration of the maximum tolerated dose (MTD) of denufosol or placebo for 5 days. Thirty-seven adult (18 years of age or older) and 24 pediatric (5-17 years of age) subjects with CF were evaluated in five cohorts. Subjects were randomized in a 3:1 ratio to receive either denufosol or placebo within each cohort. The percent of subjects experiencing adverse events was similar between the denufosol and placebo groups. The most common adverse event in subjects receiving denufosol was chest tightness in adult subjects (39%) and cough in pediatric subjects (56%). Three (7%) subjects receiving denufosol and one (7%) subject receiving placebo experienced a serious adverse event. Forced expiratory volume in 1 sec (FEV(1)) profiles following dosing were similar across treatment groups, with some acute, reversible decline seen in both groups, most notably in subjects with lower lung function at baseline. In conclusion, doses up to 60 mg of denufosol inhalation solution were well-tolerated in most subjects. Some intolerability was noted among subjects with lower baseline lung function. Based on the results of this phase 1/phase 2 study, the Therapeutics Development Network (TDN) of the Cystic Fibrosis Foundation (CFF) and Inspire Pharmaceuticals, Inc., recently completed a multicenter, 28-day, phase 2 safety and efficacy clinical trial of denufosol inhalation solution in CF subjects with mild lung disease.
authors.affiliation: Department of Pediatrics, Children's Hospital, Denver, Colorado 80218, USA. deterding.robin@tchden.org
authors.forename: Robin
authors.initials: R
authors.lastname: Deterding
authors.forename: George
authors.initials: G
authors.lastname: Retsch-Bogart
authors.forename: Laura
authors.initials: L
authors.lastname: Milgram
authors.forename: Ron
authors.initials: R
authors.lastname: Gibson
authors.forename: Cori
authors.initials: C
authors.lastname: Daines
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Zeitlin
authors.forename: Carlos
authors.initials: C
authors.lastname: Milla
authors.forename: Bruce
authors.initials: B
authors.lastname: Marshall
authors.forename: Lisa
authors.initials: L
authors.lastname: Lavange
authors.forename: Jean
authors.initials: J
authors.lastname: Engels
authors.forename: Dave
authors.initials: D
authors.lastname: Mathews
authors.forename: Joann
authors.initials: J
authors.lastname: Gorden
authors.forename: Amy
authors.initials: A
authors.lastname: Schaberg
authors.forename: Judy
authors.initials: J
authors.lastname: Williams
authors.forename: Bonnie
authors.initials: B
authors.lastname: Ramsey
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D002648:Child; D003550:Cystic Fibrosis / Q000188:drug therapy*; D003845:Deoxycytosine Nucleotides / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D058910:Purinergic P2 Receptor Agonists; D058473:Receptors, Purinergic P2Y2; D014529:Uridine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D003845:Deoxycytosine Nucleotides; C546385:P2RY2 protein, human; D058910:Purinergic P2 Receptor Agonists; D058473:Receptors, Purinergic P2Y2; C465279:denufosol tetrasodium; D014529:Uridine