FDA News

FDA panel narrowly backs approval of inhaled mannitol for adult cystic fibrosis

The FDA’s Pulmonary-Allergy Drugs Advisory Committee today voted 9-7 in favor of approval of the inhaled dry powder formulation of mannitol for management of cystic fibrosis to improve pulmonary function in conjunction with standard therapies in adults.

Inhaled mannitol, which is marketed as Bronchitol (Chiesi) and was first approved in 2011 in Australia, is currently approved for treatment of adults with cystic fibrosis in 35 countries and is marketed in eight countries. Approximately 8,000 patients have been treated with mannitol as of December 2018, according to a briefing document issued by the FDA.

This is the second time this therapy has been discussed during an FDA advisory panel. In 2013, the Pulmonary-Allergy Drugs Advisory Committee unanimously recommended against approval of inhaled mannitol. At the time, panel members noted that the two phase 3 clinical trials (Studies 301 and 302) discussed at the meeting were not adequate to determine efficacy and raised safety concerns about increased risk for hemoptysis.

The current advisory panel meeting focused on a third trial (Study 303) that was recommended by the FDA in 2013. The primary endpoint was forced expiratory volume in 1 second (FEV1) over 6 months. Important secondary endpoints were pulmonary exacerbations and Cystic Fibrosis Questionnaire-Revised scores. Only adults were included in this trial due to concern about hemoptysis in the pediatric population.

Although Study 303 met its primary endpoint by showing a statistically significant increase in FEV1 with inhaled mannitol, the improvement was modest. Furthermore, Studies 302 and 303 did not show a benefit with inhaled mannitol with respect to reduction in pulmonary exacerbations, with some results even showing a numerical increase in the treatment arm vs. the control arm.

In light of these data, the advisory committee was split 10-6 on whether the data provided substantial evidence of inhaled mannitol’s efficacy and 10-6 on whether the data provided substantial evidence of the product’s safety.

Most panel members expressed uncertainty about how the modest improvement in FEV1 translates to clinical benefit as well as concern about the potential for increased exacerbations. Some noted, though, that exacerbations are already a part of the disease progression of cystic fibrosis, many patients experience them regularly and clinicians would stop use of the drug if it was causing harm. Others, however, were unsatisfied with that explanation and did not feel that the benefits outweighed the risks.

“I’m hoping that the FDA, if they approve this drug, has some way to transmit both in the labeling and advertising of this drug, the ambivalence — personal and collective — of this group that has been expressed in terms of the tiny effect size, questions about durability of efficacy and concern about exacerbations,” John M. Kelso, MD, staff physician in the division of allergy, asthma and immunology at Scripps Clinic in San Diego, who voted in favor of approval, said during the panel discussion. “That needs to be communicated in the advertising to reflect the internal struggle of this committee.”

The dry powder formulation of mannitol is an inhaled hyperosmotic agent designed to increase mucus clearance, which subsequently improves lung function in patients with cystic fibrosis. The treatment has two components: the drug product, which is a spray-dried mannitol powder in capsules and a dry powder inhaler. The proposed dose is 400 mg of mannitol, administered through oral inhalation of ten 40-mg hard gelatin capsules twice daily using the inhaler. Each inhaler is used for 1 week and is then discarded.

Although the FDA is not required to follow the recommendations of the advisory committees, it usually does. – by Melissa Foster

Reference:

Chiesi briefing information. Available at: https://www.fda.gov/media/124610/download. Accessed May 8, 2019.

FDA briefing information. Available at: https://www.fda.gov/media/124609/download. Accessed May 8, 2019.

The FDA’s Pulmonary-Allergy Drugs Advisory Committee today voted 9-7 in favor of approval of the inhaled dry powder formulation of mannitol for management of cystic fibrosis to improve pulmonary function in conjunction with standard therapies in adults.

Inhaled mannitol, which is marketed as Bronchitol (Chiesi) and was first approved in 2011 in Australia, is currently approved for treatment of adults with cystic fibrosis in 35 countries and is marketed in eight countries. Approximately 8,000 patients have been treated with mannitol as of December 2018, according to a briefing document issued by the FDA.

This is the second time this therapy has been discussed during an FDA advisory panel. In 2013, the Pulmonary-Allergy Drugs Advisory Committee unanimously recommended against approval of inhaled mannitol. At the time, panel members noted that the two phase 3 clinical trials (Studies 301 and 302) discussed at the meeting were not adequate to determine efficacy and raised safety concerns about increased risk for hemoptysis.

The current advisory panel meeting focused on a third trial (Study 303) that was recommended by the FDA in 2013. The primary endpoint was forced expiratory volume in 1 second (FEV1) over 6 months. Important secondary endpoints were pulmonary exacerbations and Cystic Fibrosis Questionnaire-Revised scores. Only adults were included in this trial due to concern about hemoptysis in the pediatric population.

Although Study 303 met its primary endpoint by showing a statistically significant increase in FEV1 with inhaled mannitol, the improvement was modest. Furthermore, Studies 302 and 303 did not show a benefit with inhaled mannitol with respect to reduction in pulmonary exacerbations, with some results even showing a numerical increase in the treatment arm vs. the control arm.

In light of these data, the advisory committee was split 10-6 on whether the data provided substantial evidence of inhaled mannitol’s efficacy and 10-6 on whether the data provided substantial evidence of the product’s safety.

Most panel members expressed uncertainty about how the modest improvement in FEV1 translates to clinical benefit as well as concern about the potential for increased exacerbations. Some noted, though, that exacerbations are already a part of the disease progression of cystic fibrosis, many patients experience them regularly and clinicians would stop use of the drug if it was causing harm. Others, however, were unsatisfied with that explanation and did not feel that the benefits outweighed the risks.

“I’m hoping that the FDA, if they approve this drug, has some way to transmit both in the labeling and advertising of this drug, the ambivalence — personal and collective — of this group that has been expressed in terms of the tiny effect size, questions about durability of efficacy and concern about exacerbations,” John M. Kelso, MD, staff physician in the division of allergy, asthma and immunology at Scripps Clinic in San Diego, who voted in favor of approval, said during the panel discussion. “That needs to be communicated in the advertising to reflect the internal struggle of this committee.”

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The dry powder formulation of mannitol is an inhaled hyperosmotic agent designed to increase mucus clearance, which subsequently improves lung function in patients with cystic fibrosis. The treatment has two components: the drug product, which is a spray-dried mannitol powder in capsules and a dry powder inhaler. The proposed dose is 400 mg of mannitol, administered through oral inhalation of ten 40-mg hard gelatin capsules twice daily using the inhaler. Each inhaler is used for 1 week and is then discarded.

Although the FDA is not required to follow the recommendations of the advisory committees, it usually does. – by Melissa Foster

Reference:

Chiesi briefing information. Available at: https://www.fda.gov/media/124610/download. Accessed May 8, 2019.

FDA briefing information. Available at: https://www.fda.gov/media/124609/download. Accessed May 8, 2019.