Novel Drug Aids CF Kids' Lungs

The experimental ion channel-regulating drug denufosol improves children's lung function early in the course of cystic fibrosis, according to results of the first large phase III trial of the agent.

The randomized trial of more than 350 CF patients age five and older found that the mean forced expiratory volume at one second (FEV1) rose 0.048 L -- approximately 2% over baseline -- during 24 weeks on denufosol compared with 0.003 L on placebo, (P=0.047), Frank J. Accurso, MD, of the University of Colorado Denver, and colleagues reported online in the American Journal of Respiratory and Critical Care Medicine.

The novel agent also appeared to be safe without elevated adverse events or impaired growth in the young CF patients, who had normal to mildly impaired lung function -- suggesting it could be suitable as an early intervention to potentially modify the course of the disease, Accurso and co-authors wrote.

The current data follow promising phase II results from another investigational ion channel agent by the same group.

Impaired chloride ion transport and poor ciliary clearance cause the thick, sticky mucus build up in the lungs -- a central feature of CF.

While treatments are available to address these symptoms, denufosol targets the underlying defects through separate ion channels to stimulate chloride secretion, inhibit sodium absorption, and get cilia moving.

Early intervention may be critical since structural damage to the lungs and reduced lung function occur in the first few years of life for children with cystic fibrosis -- even in the absence of symptoms, Accurso's group noted.

The Transport of Ions to Generate Epithelial Rehydration (TIGER-1) trial included 352 cystic fibrosis patients age five and older (mean age 14.6) with a FEV1 at least 75% of normal (mean 92%), indicating normal to mildly impaired lung function characteristic of early cystic fibrosis.

The patients were randomized to double-blind treatment with 60 mg of inhaled denufosol three times daily or a matching placebo for 24 weeks, followed by another 24-week open-label extension phase.

In addition to the primary endpoint advantage for FEV1 in the double-blind phase, the researchers found further lung function improvement with denufosol by 0.115 L by the end of the open-label phase. Accurso and colleagues called this "a notable finding given that this improvement occurred in patients with little or no pulmonary function impairment who were treated with many concomitant medications."

Placebo group patients switched to denofusol during the open-label phase also improved by a mean 0.078 L in FEV1 by the end of the study.

Big improvements weren't expected, since denufosol was designed to prevent or delay loss of lung function, preserving the increases in FEV1 expected in a healthy growing population -- rather than to act as a rescue therapy, Accurso's group noted.

The secondary endpoints showed no significant effect on pulmonary exacerbations (P=0.088 and P=0.574 by two different definitions), although patients with exacerbations tended to have less loss of lung function if taking denufosol.

Adverse events occurred among nearly all the patients at some point in the double-blind phase with no significant differences in the most commonly reported events, aside from lower incidence of sinusitis, rhinorrhea, and headache with denufosol (P<0.05).

The researchers also found no differences in changes in height, weight, or body mass index or evidence of systemic effects on any safety parameter between the groups.

"Low potential for systemic side effects is an important consideration for early intervention therapy for cystic fibrosis, which could be administered chronically over decades beginning during the first months of life," Accurso's group concluded.

And they suggested that an investigation of the novel ion channel regulator is warranted in children younger than five.

A second, similar phase III trial, incorporating a longer placebo-controlled treatment phase, is ongoing to further investigate the effectiveness of denufosol in CF patients, Accurso added in a statement.