SILVER SPRING, MD. – Uncertainty over safety and efficacy data, particularly in children, moved a Food and Drug Administration advisory panel to unanimously recommend against approval of a dry powder formulation of mannitol for treating cystic fibrosis.
At a Jan. 30 meeting, the Pulmonary-Allergy Drugs Advisory Committee voted 14 to 0 against FDA approval of the product for the management of cystic fibrosis in patients aged 6 years and older, the indication under review. The proposed dose is 400 mg twice a day, administered via a breath-actuated dry powder inhaler over about 5 minutes, using ten 40-mg capsules for the total dose.
Mannitol "hydrates the lung surface, leading to improved airway clearance," according to the Australian manufacturer, Pharmaxis. Dry powder mannitol (DPM) is approved for people aged 6 years and older in Australia and for adults in the European Union.
"I wish I could have voted yes, because I think there is a place for a drug like this, but I think that further studies are necessary," said one of the panelists, Dr. Mary Cataletto, a pediatric pulmonologist and professor of clinical pediatrics at the State University of New York at Stony Brook. Like several other panelists, Dr. Jeffrey Wagener, professor of pediatrics at the University of Colorado, Aurora, said he may have voted in favor of approval if the indication had been limited to adults. "But there was no evidence DPM was effective in children, and "we need more information, more study, in children, particularly long term, looking at exacerbations and other outcomes besides FEV1 [forced expiratory volume in 1 second]," he added.
Pharmaxis presented the results of two phase III studies that enrolled 600 patients aged 6 years and older with cystic fibrosis (mean age about 20-23 years) with a baseline FEV1 of 30% or greater and less than 90% predicted. The trials compared treatment with 400 mg of DPM twice a day to treatment with 50 mg of DPM twice a day (controls). Patients continued other CF treatments, except for hypertonic saline, which, like mannitol, is considered an airway hydrator, and started treatment after passing a mannitol tolerance test.
In one of the studies, conducted outside the United States, the primary endpoint, the average change from baseline in FEV1 over 26 weeks, was significantly greater among those on treatment compared with controls (118 mL vs. 35 mL). But this study had a large amount of missing data because of patients dropping out, an issue raised by the FDA reviewers. In the second study, conducted in the United States, Canada, Argentina, and several European countries, the dropout rate was lower, but improvements in FEV1 from baseline at 26 weeks were only numerically, not significantly, greater among those on treatment compared with controls (107 mL vs. 52 mL).
The safety issue that elicited the most concern among panelists and was the main focus of the safety discussion was the higher rate of hemoptysis associated with treatment, particularly among those under age 18. In the two studies, the rate of hemoptysis (reported as an adverse event, not associated with an exacerbation), was almost 11% in adults on DPM, compared with about 8% of controls. But in those aged 6-17 years, the rate was almost 8% among those on DPM, compared with almost 2% among controls, according to the company, which agreed that hemoptysis in the pediatric age group was a safety signal that needed to be evaluated further.
Other adverse events appeared to be related to tolerability of the treatment, and more patients on DPM stopped treatment because of adverse events (11% vs. 6%), for reasons that included cough and hemoptysis.
FDA reviewers raised statistical issues regarding the data, including the impact missing data had on the primary endpoint in the two studies, particularly in the non-U.S. study, and questioned whether the results provided an accurate estimate of the treatment’s effects.
Several panelists described the efficacy data as "underwhelming," but the panel generally agreed there was some evidence the drug was probably effective in a subset of patients, who have not yet been identified. They also referred to public testimony from several adults with CF who described the benefits of DPM, particularly on their ability to cough up mucus after a treatment, as anecdotal evidence that the drug was effective in some patients.
The FDA usually follows the recommendations of its advisory panels, which are not binding. If approved, Pharmaxis plans to market DPM as Bronchitol. The company markets the Aridol bronchial hyperresponsiveness test that contains 635 mg of inhaled mannitol. A statement released by Pharmaxis after the panel meeting said that the company would continue to work with the FDA to bring the product to the United States.