FDA Advisory Panel Rejects Cystic Fibrosis Treatment

Miriam E. Tucker

January 31, 2013

A federal advisory panel has voted unanimously against the approval of dry powder mannitol (DPM) for the management of cystic fibrosis in patients aged 6 years and older to improve pulmonary function.

The US Food and Drug Administration's (FDA's) Pulmonary-Allergy Drugs Advisory Committee's 14-0 vote against the approval sought by Pharmaxis for its novel inhalation product Bronchitol was based on a lack of data for significant efficacy combined with safety concerns, particularly about an increase in hemoptysis in children younger than 18 years.

However, the panel split 3-11 on 2 additional separate votes of efficacy and safety. Several members expressed regret that the overall efficacy and safety data were insufficient to meet the FDA standards for approval, citing the unmet need. Several panelists also said that they would support the licensure of the drug for adults only.

D-Mannitol, a naturally occurring sugar alcohol, promotes mucociliary clearance via hydration of the lung surface. As an inhalation powder, it is currently licensed in the United States as a bronchoprovocation agent included in a kit (Aridol, Pharmaxis) that assesses bronchial hyperresponsiveness.

With the exception of ivacaftor (Kalydeco, Vertex Pharmaceuticals Inc), licensed in January 2012 for patients with cystic fibrosis (CF) who have a specific rare mutation, there are no drugs on the US market that treat the condition itself. All current medications used in patients with CF, including mucolytics, bronchodilators, and antibiotics, merely treat the symptoms.

Data Deemed Insufficient

Two randomized phase 3 trials for DPM were conducted sequentially, using 400 mg DPM daily compared with a 50-mg dose (deemed nonactive) as a control.

The intention-to-treat populations were 295 and 305 patients, respectively, aged 6 years and older, with forced expiratory volume at 1 second (FEV1) between 30% and 90% of that predicted in the first study and 40% to 90% of that predicted in the second. All had to pass a "mannitol tolerance test," and those with history of significant hemoptysis were excluded. Hypertonic saline use was not allowed during the trials.

The first study met its primary endpoint, with a significant improvement in FEV1 of 83.1 mL (P < .001) at 26 weeks. However, the second trial did not meet statistical significance, with an increase of just 54.1 mL in FEV1 at 26 weeks (P = .059). Secondary endpoints, including reduction in exacerbations, rescue antibiotic use, and hospitalizations, showed trends toward improvement, but none achieved statistical significance.

Moreover, the FDA reviewers pointed out, even the significance of the first study is questionable because more patients in the DPM group dropped out because of adverse events (5.1% vs 0%), thus creating a situation in which only patients who could tolerate the drug were being compared with a heterogeneous control group.

"The dropout data create an apples-to-oranges comparison of tolerators to those who may or may not be tolerators," FDA reviewer Kimberly Witzmann, MD, advised the panel.

Adverse events included significantly increased rates of cough, throat pain, vomiting, and — particularly worrisome to the FDA and the committee — a 9.4% overall rate of hemoptysis with DPM compared with just 5.4% for the control patients. The difference was particularly striking among patients younger than 18 years, at 7.8% vs 1.9% for older patients.

Support for Adult Use

In contrast to the "underwhelming" efficacy data was public testimony by 9 individuals, including patients with CF and physicians who cared for them during the trials, attesting to the efficacy of DPM and the significant effect it had on their lives. Several speakers said that in their experience, DPM worked at least as well as hypertonic saline but was far more convenient to use.

Panel member Jeffrey S. Wagener, MD, gave 1 of the 3 yes votes on efficacy.

"I think there is evidence of efficacy. It may not be based on some of the statistics that we've used historically, but in the situation where you have a life-threatening disease with no other drug in class, I would be willing as a member of this committee to stretch the definition of efficacy beyond the straightforward pure statistics," said Dr. Wagener, professor of pediatrics at the University of Colorado, Aurora.

His ultimate "no" votes on safety and approval were based on the pediatric safety concern, he said.

Panel member James M. Tracy, DO, who voted against efficacy, said he could not do so "from a regulatory standpoint," but that he did, "however, believe a subset can benefit from this drug. We just don't know who they are."

Kathryn Blake, PharmD, senior research scientist at Nemours Children's Clinic, Jacksonville, Florida, was among several panelists who said they would have supported approving DPM for adults but not overall, which is the way the FDA asked the question.

"I voted no primarily because of the pediatric safety data. I would support the sponsor's submission for adult use only. I was very moved by the stories from the patients and their clinicians, and I think this does have a place for the treatment of adults."

The FDA is expected to announce its decision regarding approval of DPM on March 18, 2013, according to a Pharmaxis statement.

FDA advisory panel members are vetted for conflicts of interest and waivers granted if necessary for participation. No waivers were granted for this meeting.