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

Robin Deterding, George Retsch-Bogart, Laura Milgram, Ron Gibson, Cori L Daines, Pamela L. Zeitlin, Carlos Milla, Bruce Marshall, Lisa LaVange, Jean Engels, Dave Mathews, JoAnn Gorden, Amy Schaberg, Judy Williams, Bonnie Ramsey

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Denufosol tetrasodium (INS37217) is a selective P2Y2 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 P2Y2 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 P2Y2 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 (FEV1) 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.

Original languageEnglish (US)
Pages (from-to)339-348
Number of pages10
JournalPediatric Pulmonology
Volume39
Issue number4
DOIs
StatePublished - Apr 2005
Externally publishedYes

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Purinergic P2Y2 Receptors
Cystic Fibrosis
Inhalation
Multicenter Studies
Placebos
Safety
Pediatrics
Mucociliary Clearance
Lung
Maximum Tolerated Dose
Nebulizers and Vaporizers
Forced Expiratory Volume
Cough
Lung Diseases
denufosol tetrasodium
Thorax
Therapeutics
Epithelium
Clinical Trials
Pharmaceutical Preparations

Keywords

  • Cystic fibrosis
  • Denufosol tetrasodium
  • FEV
  • Inhalation solution
  • INS37217
  • Lung function

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pulmonary and Respiratory Medicine

Cite this

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. / Deterding, Robin; Retsch-Bogart, George; Milgram, Laura; Gibson, Ron; Daines, Cori L; Zeitlin, Pamela L.; Milla, Carlos; Marshall, Bruce; LaVange, Lisa; Engels, Jean; Mathews, Dave; Gorden, JoAnn; Schaberg, Amy; Williams, Judy; Ramsey, Bonnie.

In: Pediatric Pulmonology, Vol. 39, No. 4, 04.2005, p. 339-348.

Research output: Contribution to journalArticle

Deterding, R, Retsch-Bogart, G, Milgram, L, Gibson, R, Daines, CL, Zeitlin, PL, Milla, C, Marshall, B, LaVange, L, Engels, J, Mathews, D, Gorden, J, Schaberg, A, Williams, J & Ramsey, B 2005, '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', Pediatric Pulmonology, vol. 39, no. 4, pp. 339-348. https://doi.org/10.1002/ppul.20192
Deterding, Robin ; Retsch-Bogart, George ; Milgram, Laura ; Gibson, Ron ; Daines, Cori L ; Zeitlin, Pamela L. ; Milla, Carlos ; Marshall, Bruce ; LaVange, Lisa ; Engels, Jean ; Mathews, Dave ; Gorden, JoAnn ; Schaberg, Amy ; Williams, Judy ; Ramsey, Bonnie. / 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. In: Pediatric Pulmonology. 2005 ; Vol. 39, No. 4. pp. 339-348.
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