Not a great news guys, we may need to wait a little long for...

Not a great news guys, we may need to wait a little long for now.

http://www.medpagetoday.com/Pulmonology/CysticFibrosis/37062


Pharmaxis CF Drug Gets Mixed Review
By David Pittman, Washington Correspondent, MedPage Today
Published: January 29, 2013
WASHINGTON -- The FDA is questioning the effectiveness of new cystic fibrosis (CF) drug mannitol (Bronchitol) because a high number of dropouts in two 26-week trials obscured results, the agency said Monday.

One trial met its primary endpoint by increasing FEV1 by an average of 83 mL after 26 weeks of the twice-daily, 400-mg inhaled powder (P<0.001), according to FDA briefing documents released in advance of a Wednesday advisory committee meeting on the drug. The second trial showed the drug increased FEV1 by 54 mL, but that result didn't achieve statistical significance (P=0.059).

However, as the FDA noted, that analysis doesn't account for the "frequent and treatment-related early discontinuations in the Phase III studies." Therefore, the FDA also interpreted data presuming dropouts as treatment failures. Under that assumption, there was no statistically significant difference between treatment groups in either study, the agency said.

The drug's manufacturer, Sydney, Australia-based Pharmaxis, is seeking an indication of managing CF in patients age 6 and older to improve pulmonary function.

The agency's Pulmonary-Allergy Drugs Advisory Committee will meet Wednesday to discuss the trial results and vote on recommending approval. The FDA is not obligated to followed the advice of its advisory committees, but usually does.

Exactly 600 patients were involved in the two randomized, placebo-controlled studies, with ages ranging from 6 to 56. In one study, 34% of the 177 patients receiving mannitol dropped out, compared with 23% in the control group. In the second study, 85% of the 184 patients on mannitol followed the half-year-long study through, compared with 92% of control group patients.

"The primary reasons for premature discontinuation were adverse events (including CF exacerbations) and withdrawal by patient," the FDA said.

CF exacerbations occurred in 17% of mannitol patients. Hemoptysis was the second-most commonly reported severe adverse event, the FDA said. Others included systemic manifestations of CF such as diabetes, respiratory infections, and intestinal obstruction.

There was also one death -- that of a 15-year-old boy with severe CF.

Pharmaxis tried to account for a 60-mL difference in FEV1 between the baseline measurement and a separate screening visit (to assess medication tolerance) among patients in the control group in one study. The company tried to average the two values to create a new "adjusted" baseline, but the FDA noted that such post-hoc manipulations weren't generally acceptable.

Pharmaxis also tried a sub-group analysis to see if smaller sections of patients benefited more from the drug. It found in one trial that patients under age 18 appeared to show only a small benefit, with those ages 12-17 actually worsening. Meanwhile, data from the other study showed that adult patients on the drug may have a better result than children and adolescents.

It was only last January when the FDA first approved a drug to treat the underlying causes of CF -- the novel drug ivacaftor (Kalydeco). Most treatments of CF only act to alleviate symptoms and treat complications, the FDA noted Monday.

Dry powder mannitol gained orphan drug status on July 2005 and was awarded fast-track development status by the FDA in November 2006.