DENUFOSOL (denufosol.htm) See statement from the CF Foundation Jan 3rd 2011

2005 Deterding R, Retsch-Bogart G, Milgram L, Gibson R, Daines C, Zeitlin PL, Milla C, Marshall B, Lavange L, Engels J, Mathews D, Gorden J, Schaberg A, Williams J, Ramsey B. 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. Pediatr Pulmonol 2005; 39:339-348. [PubMed]
Denufosol tetrasodium is a selective P2Y2 agonist that stimulates ciliary beat frequency and Cl secretion in normal and CF airway epithelia enhanced by the effect of P2Y2 activation to also inhibit epithelial sodium transport. 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 (Deterding RR et al. Am J Respir Crit Care Med 2007; 176:662-669 below; Kellerman D et al. Pulm Pharmacol Ther 2008; 21:600-607). [PubMed]

2007 Deterding RR, Lavange LM, Engels JM, Mathews DW, Coquillette SJ, Brody AS, Millard SP, Ramsey BW, for the Cystic Fibrosis Therapeutics Development Network and the Inspire 08-103 Working Group. Phase 2 randomized safety and efficacy trial of nebulized denufosol tetrasodium in cystic fibrosis. Am J Resp Crit Care 2007; 176:362-369.
Denufosol tetrasodium is a selective P2Y(2) agonist that enhances mucosal hydration and mucus clearance by activating Cl(-) secretion and inhibiting epithelial Na(+) transport through a non-cystic fibrosis transmembrane conductance regulator mechanism in the lung. The study was a randomized, double-blind, multi-center, 28-day, phase II clinical trial of Denufosol tetrasodium inhalation solution (20, 40, or 60 mg) versus placebo (normal saline). Denufosol patients (pooling active doses) had significantly higher changes from baseline in respiratory function than placebo patients at the end of the study. The authors concluded that Denufusol administered three times daily for 28 days appeared to be safe and well tolerated in this population with mild cystic fibrosis and provided preliminary evidence of potential benefit in lung function.
One a number of drugs showing promise to correct or reduce the effects of the basic defect on the airway surface liquid (also Deterding et al, 2005 above). Phase III studies followed.

2007 Deterding RR, Lavange LM, Engels JM, Mathews DW, Coquillette SJ, Brody AS, Millard SP, Ramsey BW, for the Cystic Fibrosis Therapeutics Development Network and the Inspire 08-103 Working Group. Phase 2 randomized safety and efficacy trial of nebulized denufosol tetrasodium in cystic fibrosis. Am J Resp Crit Care 2007; 176:362-369. [PubMed]
Denufosol tetrasodium is a selective P2Y(2) agonist that enhances mucosal hydration and mucus clearance by activating Cl(-) secretion and inhibiting epithelial Na(+) transport through a non-cystic fibrosis transmembrane conductance regulator mechanism in the lung. The study was a randomized, double-blind, multi-center, 28-day, phase 2 clinical trial of denufosol tetrasodium inhalation solution (20, 40, or 60 mg) versus placebo (normal saline). Denufosol patients (pooling active doses) had significantly higher changes from baseline in respiratory function than placebo patients at the end of the study. The authors concluded that Denufosol administered three times daily for 28 days appeared to be safe and well tolerated in this population with mild cystic fibrosis and provided preliminary evidence of potential benefit in lung function.

This is one of a number of drugs showing promise to correct or reduce the effects of the basic defect on the airway surface liquid (also Deterding et al, 2005 above). In June 2008, Inspire announced the results of its first Phase 3 trial with Denufosol (Tiger 1). The trial demonstrated statistical significance for its primary endpoint of change in FEV1 from baseline compared to placebo. By late 2010 Inspire had completed enrolment to a further Phase 111 trial (Tiger 2).

2010 Moss RB, Schaberg A, Tian W, Xue X, Ramsey B, Accurso FJ. Denufosol improved lung function and was well tolerated in adolescents with cystic fibrosis. NACFC Baltimore 2010. Pediatr Pulmonol 2010; Suppl 33: Abstract # 256

Analysis of an adolescent subgroup of the Tiger -1 trial 24 week trial followed by open label 24 weeks. Change FEV1 for denufosol group +112ml (+4%) compared with placebo group -10ml (-0.6%). At week 48 the denufosol group had increase in FEV1 +226ml (+8.8%) and the change from baseline FEF25-75 was +192ml (+10.5%). The treated and placebo groups were on a considerable amount of other therapy e.g. pulmozyme 81% vs 76%, macrolides 42/47, inhaled antibiotics 39/47. Approximately half the patients were chronically infected with P. aeruginosa.

2010 Accurso FJ. Denufosol efficacy in patients with minimally impaired baseline lung function and on minimal background therapy demonstrates its potential as an early intervention for cystic fibrosis lung disease. NACFC Baltimore 2010. Pediatr Pulmonol 2010; Suppl 33: Abstract # 226

Patients aged 5 years or older with FEV1> 75%. Subgroup from phase 3 Tiger-1 trial on only 0-2 background therapies. Denufosol demonstrated "clinically meaningful improvement relative to placebo in patients who had minimal background therapy in FEV1, FEV1%, FEF 25-75%, QOL respiratory domain. Highlight potential as an early intervention in CF.

About the Denufosol Tetrasodium Clinical Program (from Inspire website November 2010)

TIGER-1, the first Phase 3 trial with denufosol for the treatment of CF, included a 24-week placebo-controlled portion, followed by a 24-week open-label safety extension. The placebo-controlled portion was a double-blind, randomized trial comparing 60 mg of denufosol to placebo, administered three times daily by jet nebulizer, in 352 patients with mild cystic fibrosis lung disease (baseline FEV1 = 75% of predicted normal).

Inspire is currently conducting TIGER-2, its second Phase 3 clinical trial with denufosol, and expects top-line results from this trial in the first quarter of 2011. Inspire is targeting a potential U.S. commercial launch for denufosol in the 2012 timeframe assuming the results of TIGER-2 are positive, that Inspire subsequently files a New Drug Application (NDA) for denufosol with the FDA in the second half of 2011 and that the FDA approves such NDA under a priority review timeline.

Inspire is conducting additional clinical trials in connection with its evolving denufosol franchise development plans and activities. Inspire is conducting DEFY (Denufosol Efficacy Over Four Years), a denufosol open-label clinical trial open to eligible patients that complete the year-long TIGER-2 trial. This three year trial will evaluate the potential disease-modifying impact of denufosol on rate of lung function decline. In August 2010, Inspire also initiated REACH (Researching an Early Approach to Cystic Fibrosis Health), a small safety and tolerability clinical trial of denufosol in CF patients ages 2 - 4 years old.

Press release from CF Foundation January 3, 2011

Inspire Announces Disappointing Results for CF Therapy Denufosol

Inspire Pharmaceuticals, Inc., announced today that the top-line results from a second Phase 3 clinical trial of denufosol did not demonstrate a statistically significant improvement in lung function for those on the drug as compared to the placebo after 48 weeks. Read the Inspire Pharmaceuticals, Inc. news release. Improvement in lung function was the primary outcome measure for the trial. The Phase 3 trial included 466 patients in the United States, Australia, New Zealand and Canada.If the results had been positive, the data would have served as a basis for a New Drug Application (NDA) to the U.S. Food & Drug Association.

“This is a serious disappointment to the entire CF community,” said Robert J. Beall, Ph.D., president and CEO of the Foundation. “We have long understood that drug development is not predictable, but we are always hopeful that promising therapies will prove effective for those with CF. Inspire’s latest data underscores the importance of our pursuing multiple new therapies that can control and cure CF.”

The Foundation currently has more than 30 drugs in its drug development pipeline, including several in late stage clinical trials that aim to treat the basic defect in CF. Beall noted that the Foundation is “deeply indebted to the patients who participated in the denufosol trials, the caregivers who carried out the trials and the team at Inspire Pharmaceuticals for their commitment to bringing new CF therapies to patients.”