FDA Panel Recommends Mannitol Inhalation Powder for CF

Troy Brown, RN

May 09, 2019

The US Food and Drug Administration's (FDA's) Pulmonary-Allergy Drugs Advisory Committee (PADAC) voted 9 to 7 on Wednesday to recommend mannitol inhalation powder (Bronchitol, Chiesi) for oral inhalation to improve pulmonary function in adults aged 18 years and older with cystic fibrosis (CF), together with standard therapies.

The committee voted 10 to 6 in favor of the drug's efficacy and 10 to 6 in favor of its safety.

The company says "their inhaled DPM [dry powder mannitol] product will improve mucus clearance in patients with CF due to the osmotic properties of mannitol remaining in the extracellular compartment to cause an outflow of water into surrounding tissues, and thus reduce the thickness and stickiness of CF mucus secretions," according to the FDA's briefing document.

CF is an orphan disease and effects approximately 30,000 people in the United States. There are medications to treat its symptoms and sequelae, but treatment involves multiple time-consuming therapies and treatment adherence can be a problem with some patients. No FDA-approved products work the way DPM for inhalation does; hypertonic saline may work similarly but it is not approved by the FDA.

Drug With a History

The PADAC voted against recommending mannitol inhalation powder for patients aged 6 years and older on Jan. 30, 2013, citing insufficient evidence of efficacy and safety concerns including hemoptysis in children younger than 18 years. On March 19 of that year, the FDA recommended the company (Pharmaxis) conduct an additional trial for the drug to be approved. The FDA later recommended limiting that trial to adult patients out of concern regarding hemoptysis in children.

Wednesday's vote follows discussion of that trial (study 303) as well as two earlier trials (studies 301 and 302) the FDA found lacking in 2013. The group largely limited its discussion of efficacy data to study 303 but considered pooled safety data from all three studies.

Study 303 (Long Term Administration of Inhaled Mannitol in Cystic Fibrosis —A Safety and Efficacy Trial in Adult Cystic Fibrosis Subjects) was a 26-week treatment period, double-blind, randomized, parallel group, multicenter, controlled trial in adult patients with cystic fibrosis.

The study randomly assigned 350 patients in a 1:1 ratio to receive either DPM 400 mg twice daily or a matched control for 26 weeks. Patients were allowed to continue all CF-related medications except inhaled hypertonic saline and oral nonselective beta-blockers.

Inhaled mannitol can cause bronchospasm; therefore, patients were required to pass a mannitol tolerance test to be eligible for the study.

The primary efficacy endpoint for all three studies was the mean absolute change from baseline in forced expiratory volume in 1 second (FEV1) during the 26-week treatment period, assessed at weeks 6, 14, and 26. This is a common primary endpoint measure for CF studies.

Secondary endpoints for study 303 differed from studies 301 and 302 and included forced vital capacity (FVC), time to first protocol defined pulmonary exacerbation (PDPE), number of days on antibiotics as a result of PDPE, number of days in hospital for PDPE, and rate of PDPE.

The difference in change from baseline in FEV1 during 26 weeks was significant when compared with placebo (P = 0.018), with an adjusted mean difference of 55 mL (95% confidence interval, 9 to 101 ml) between the DPM (65 mL) and placebo (10 mL) groups.

In its briefing the FDA asked the panel to discuss whether the small magnitude of the effect size was clinically meaningful, at 1.2% percent of predicted FEV1. "Given the modest treatment effect on FEV1 and the lack of support from key secondary endpoints (e.g. numerical increase in exacerbations in two of the studies), the benefit of DPM is important to discuss with the PADAC," the FDA writes in a briefing document.

"Adherence is a huge factor for these patients and if we can at least get them to use a medication, I think they're going to see benefit," voting member Loretta G. Que, MD, professor of medicine, Department of Internal Medicine Division of Pulmonary, Allergy and Critical Care Medicine, Duke University Health System, Durham, North Carolina, said of her vote in favor of the drug's efficacy.

Safety

The evaluation of the product's safety included an analysis of pooled data from studies 301, 302, and 303 (414 adult patients exposed to DPM 400 mg twice daily and 347 adult patients to control; median exposure 6 months).

Two deaths occurred in the control group and none in the DPM group. Serious adverse events were distributed fairly evenly between the groups, although numerically more CF exacerbations (condition aggravated) occurred in patients in the DPM group (55; 13%) compared with the control group (39; 11%). More patients in the DPM group than in the control group discontinued treatment (51 patients [12%] vs 30 patients [9%]), which was mainly related to cough.

Overall, the most frequently reported adverse events in the studies included condition aggravated, cough, headache, hemoptysis, URTI, nasopharyngitis, and oropharyngeal discomfort.

Que was less certain about the drug's safety than she was about its efficacy, saying, "I just need to see more data. There was a clear consistent signal showing that there might be harm, and I wanted to make sure that before moving forward, I would ... see more about which patient population might be affected."

"I really, really hope that this drug is safe, and if it is not approved, I hope that there is more work done to show us that it's safe with regard to exacerbations because I do think we need more drugs in our armamentarium for these patients," voting member David J. Lederer, MD, MS, associate professor of medicine and epidemiology, Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University Medical Center, New York City, said of his vote against recommending mannitol inhalation powder.

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