A Food and Drug Administration Advisory Committee voted that the benefit-risk profile of an inhaled treatment for cystic fibrosis merits approval of the drug – dry powder mannitol (DPM).
Mannitol is a naturally occurring sugar alcohol that is used as a low-calorie sweetener; it is generally recognized as safe when taken enterically. Inhaled DPM, marketed as Aridol, is currently approved as a bronchoprovocation agent. For the current indication, DPM is given as 10x40-mg capsules twice daily.
In a 9-7 vote, the FDA’s Pulmonary-Allergy Drugs Advisory Committee (PADAC) decided that DPM’s modest potential to improve pulmonary function in adults with cystic fibrosis (CF) outweighed a potential signal for increased exacerbations seen in clinical trials.
Chiesi USA Inc. is seeking approval of DPM for the management of cystic fibrosis to improve pulmonary function in patients 18 years of age and older in conjunction with standard therapies. It plans to market DPM as Bronchitol.
Some committee members who voted against approval, including PADAC chair David H. Au, MD, worried that DPM’s ease of use might prompt patients and caregivers to substitute it for inhaled hypertonic saline, a medication that’s more burdensome to use but has a longer track record for efficacy and safety. While hypertonic saline requires cumbersome equipment and cleaning regimens and takes 20-30 minutes to administer, DPM is administered over about 5 minutes via a series of capsules inserted into a small inhaler device.
“I was very impressed by conversations that we heard from the community that this will be viewed as a substitute drug [for hypertonic saline],” said Dr. Au, professor of medicine at the University of Washington, Seattle. “Before we make that leap of faith ... we have to better understand how it has to be used.” He also acknowledged that making the call for DPM was “challenging.”
Other committee members were reassured by the fact that DPM is approved for adult use in 35 countries; it’s been in use since 2011 in Australia for adults and children.
Some members also noted an unmet need in CF therapies and placed confidence in those treating CF patients to find ways to use DPM safely and effectively. “I’m really counting on the cystic fibrosis clinicians who do this for a living to figure out where to use this in their armamentarium,” said John M. Kelso, MD, an allergist at Scripps Clinic, San Diego.
In 2012, the initial new drug application submitted by Pharmaxis, which then held marketing rights to DPM, resulted in a “no” vote for approval from PADAC, and eventual FDA denial of approval. The initial submission was supported by two phase 3 clinical trials, 301 and 302, that included pediatric patients. In the pediatric population, there was concern for increased hemoptysis with DPM, so the FDA advised the drug’s marketers to consider seeking approval for an adult population only in its reapplication. The current submission followed a new double-blind, randomized, placebo-controlled trial, study 303, that included adults with CF aged 18 or over.
All three studies had similar designs, tracking change from baseline in forced expiratory volume in one second (FEV1) from baseline to the end of the 26-week study period. In addition to this primary endpoint, secondary endpoints included other pulmonary function measures, as well as the number of protocol-defined pulmonary exacerbations (PDPEs). Participants also reported quality of life and symptom measures on the Cystic Fibrosis Questionnaire–Revised (CFQ-R).
In study 301, the dropout rate approached one in three participants with higher discontinuation in the intervention than the control arm, causing significant statistical problems in dealing with missing data. Thus, said the FDA’s Robert Lim, MD, though this study had positive results for FEV1, it was not “statistically robust.”
The second study, 302, did not meet its primary endpoint, and there was “no support from secondary endpoints” for efficacy, said Dr. Lim, a clinical team leader in the FDA’s Division of Pulmonary, Allergy, and Rheumatology Products.
The current submission was also supported by a new post hoc subgroup analysis of adults in studies 301 and 302. A total of 414 patients receiving DPM and 347 receiving placebo (DPM at a nontherapeutic level) were included in the integrated analysis of patients from all three studies. Studies 301 and 302 both had open-label extension arms, allowing more patients to be included in safety data.
The problems caused by the missing data from study 301 were addressed in the design of study 303 by encouraging patients who discontinued the study drug to continue data collection efforts for the study. Dropout rates were lower overall in study 303 and balanced between arms.
Over the 26-week duration of study 303, investigators saw a statistically significant improvement in FEV1 of about 50 mL, according to the FDA’s analysis. Post hoc analyses of studies 301 and 302 showed point estimate increases of approximately 80 mL, according to Dr. Lim.
In its presentations, Chiesi USA presented its integrated analysis of adult data from the three clinical trials. The analysis showed an increase in FEV1 from baseline of 73 mL for the DPM group, compared with an increase of 7 mL for the control group, using an intention-to-treat population (P less than .001). The committee heard evidence that in adults with CF, pulmonary function typically decreases by 1%-3% annually.
The PDPE rate was slightly higher in the DPM group than in the control group in studies 302 and 303, but the differences were not statistically significant. These findings have a backdrop of an overall low rate of PDPEs ranging from 0.221 to 0.995 per year, according to Chiesi presenter Scott Donaldson, MD, a pulmonologist who directs the adult cystic fibrosis center at the University of North Carolina at Chapel Hill.
When looking at the subgroup of United States study participants, the DPM integrated cohort included more patients with a history of prior pulmonary exacerbations. In the DPM group, 45% of U.S. participants had at least one exacerbation in the prior year, and 20% had two or more exacerbations, compared with 38% and 14%, respectively, in the control group. Chiesi argued that this imbalance was likely responsible for the increased exacerbation rate.
The sponsor and the FDA used different imputation methods to account for missing data from the earlier studies, complicating interpretation of the potential signal for increased exacerbations.
Quality of life data were similar between groups across the studies.
In the end, the view of the “yes” voters was encapsulated by James M. Tracy, DO, an allergist in private practice in Omaha, Neb. “This is not a drug for everybody; but absolutely, it’s a drug for somebody. Ultimately we have to make that decision – I do think that we study populations, but we really take care of people.”
The FDA usually follows the recommendations of its advisory panels.