Members of the Pulmonary-Allergy Drugs Advisory Committee (PADAC) voted 9-7 that the risk-benefit profile of dry powder mannitol (DPM) was adequate to support approval of the drug for use in adults (≥18 years) along with standard therapies.
The panel also voted 10-6 that the data showed “substantial evidence of efficacy for DPM” for the proposed indication. Asked to weigh in on whether the safety data for Bronchitol were sufficient to support approval for use in adults with cystic fibrosis (CF), the panel again voted 10-6 that it was adequate.
Dissenters included Panel Chairman David H. Au, MD, of the University of Washington in Seattle, who was unhappy with the data on both the product’s safety and its efficacy.
“I have concerns about safety signals and I think it befalls us to consider not only the potential benefits, but the potential harms, especially in a medication that I think has limited efficacy,” said Au, who voted “no” on all three questions.
But Richard Weber, MD, of National Jewish Health in Denver, who voted that the safety data for the drug was sufficient to recommend approval, said he believes a subset of patients may emerge after approval who are more responsive than the phase III clinical trials suggest.
Bronchitol is a spray-dried form of the naturally occurring sugar alcohol mannitol, which is delivered by portable inhaler to the lungs. It is used to clear mucus from the airways. Mucus buildup, which is a characteristic of CF, is a leading cause of recurrent infections, respiratory function decline, and respiratory failure.
The drug is marketed by the Australian pharmaceutical company Pharmaxis outside the U.S. in more than 30 countries.
At Wednesday’s PADAC meeting, an official with Chiesi USA, the U.S. licensee seeking the approval, said around 8,000 CF patients have been treated with the dry powder mannitol product, primarily in Europe, Australia, and Russia.
In January 2013, the FDA advisory committee voted unanimously against recommending approval of the drug for use in children and adults with CF, due to concerns about the product’s efficacy and safety.
Two phase III studies presented at that time, which enrolled children and adults, showed signals of increased risk for hemoptysis — coughing up bloody mucus — especially in pediatric patients.
The studies also did not establish efficacy for the primary endpoint of meaningful improvement in forced expiratory volume in one second (FEV1) over 26 weeks due to a high treatment-related dropout rate in one of the trials and missing data precluding assessment of statistical significance in the other.
In May 2013, the FDA recommended that the applicant conduct a third trial limited to adults with CF. The study design was similar to the first two trials, but with certain design tweaks to address the issues encountered in the first two studies.
Unlike the previous studies, the third included follow-up data.
FDA medical officer Khalid Puthawala, MD, told the panel that the latest trial in adults was designed to minimize missing data and dropouts, with the primary endpoint of FEV1 over six months. It was also designed, Puthawala said, to be the “tie-breaker study.”
“It was noted that the primary endpoint would have to be statistically significant and clinically convincing. Along with this, the new study results would have to trend favorably for exacerbations (a secondary endpoint),” Puthawala said.
They did not.
U.S. patients enrolled in the trials tended to be sicker with a history of more exacerbations than trial patients recruited from outside the U.S.
A post hoc subgroup analysis of U.S. patients showed that those treated with Bronchitol had a numerically higher rate of exacerbations than control treated patients.
Serious exacerbations were twice as high among the DPM-treated U.S. patients than among controls (23 among 110 DPM-treated patients vs 10 among 93 control patients).
And there was no evidence in any of the phase III studies that treatment with DPM positively impacted other secondary endpoints, including time to 1st protocol-defined pulmonary exacerbation (PDPE), days in the hospital, days on antibiotics, or PDPE rate per patient per year.
“Overall in the entire phase III program, there were no secondary endpoints that provided significant support (for Bronchitol use), and in fact some concerning trends were seen,” Puthawala said.
Hemoptysis, though, was not significantly increased with Bronchitol.
“What was most concerning from a safety standpoint was that the U.S. sub-population analysis showed a striking increase in serious CF exacerbations, and the consistency of safety and efficacy results for increased CF exacerbations was of particular concern,” Puthawala said.
But CF patients, patient advocates, and clinicians who routinely treat patients with the disease largely advocated for approval of the drug. Several cited the ease of use relative to currently available mucus-clearing therapies such as hypertonic saline solutions.
The protocol for Bronchitol calls for treatment twice a day for 5 minutes each. That compares to a common protocol of twice daily 20-minute treatments with hypertonic saline solutions, which are widely prescribed for CF mucus clearance.
“My argument for the approval of inhaled mannitol comes down to adherence,” said CF nurse Ronnie Wetmore, RN, who lost two brothers to the disease. “Adherence to a demanding medication and therapy regimen with this chronic, progressive, debilitating disease is difficult. Multiple medications require an average of 2 to 3 hours daily. No vacations. No exceptions.”
But several PADAC members expressed concerns that patients would abandon an established mucus clearing therapy with proven efficacy for the potentially less efficacious treatment because it is easier to use.
The FDA is not obliged to follow recommendations of its advisory committees but often does; close votes are typically regarded as no recommendation one way or the other.