FDA panel backs new combination inhaler for asthma in adults only


An FDA advisory panel on Tuesday gave near-unanimous support for a new dual-drug combination inhaler for adults with asthma, while rejecting the product for young children.

By a margin of 16 to 1, the FDA’s Lung Allergy Drug Advisory Committee voted that the benefits of the combination inhaler outweigh the risks in adults with asthma. If ultimately approved by the agency, the combination would be the first approved product containing an inhaled corticosteroid (budesonide) and a short-acting beta-beta.2-adrenergic agonist (albuterol sulfate).

However, the outside expert panel said the data did not support the combination inhaler for children aged 4 to under 12 (by a vote of 16 to 1), and was split across teenagers aged 12 years and older, with a majority (9-8) saying there was no favorable benefit/risk profile for this population.

In explaining their positive votes for the adult population, panel members referenced efficacy and safety results from the pivotal MANDALA trial, which tested the combination versus an inhaler containing albuterol alone.

“The consensus, by a large majority, was favourable, primarily because in this older age group there was a robust signal of efficacy and there were minimal safety concerns,” the committee chair said. David Au, MD, of the University of Washington in Seattle, summarizing the views of the panel.

But, while the proposed indication for the combination of budesonide and albuterol (BDA) is “for the treatment or prevention as needed of bronchoconstriction, and for the prevention of exacerbations in patients with asthma 4 years of age and older “, panel members had questions about the effectiveness of the combination in younger age groups.

Committee members were primarily concerned that the vast majority of MANDALA patients were adults, and that data from the trial would need to be extrapolated to adolescent and pediatric patients so that the FDA could determine the benefits and risks of the drug. BDA in these populations.

“You can’t extrapolate from the adult data to this small subgroup” of younger children, said Sally Hunsberger, PhD, a mathematical statistician at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. , explaining his vote against the product in the group of children aged 4 to under 12 years. “I think we need efficacy data. You need long-term safety data, and we need to know more about how this would be used in this population.”

“There are too many uncertainties related to efficacy,” said Michelle Cloutier, MD, of the University of Connecticut School of Medicine at Farmington. “It is unclear how to use this combination in young children, especially in asthma of different severity, as well as in different indications, including exercise-induced asthma.”

The MANDALA trial included 3,132 patients with moderate to severe asthma randomized 1:1:1 to three regimens: two actuations of each of the 90/80 μg or 90/40 μg BDA combination inhalers, or two actuations of 90 μg of albuterol. Most patients (97%) were 12 years or older. The youngest group of children only received the low dose product.

The trial results showed a significant delay in time to first acute exacerbation in both BDA groups overall compared to the albuterol group:

  • Low dose BDA: HR 0.84 (95% CI 0.70-0.99)
  • High dose BDA: HR 0.74 (95% CI 0.62-0.88)

Similarly, results for the large adult subgroup also supported treatment efficacy. However, among the small subgroup of 83 children aged 4 years to less than 12 years, there was no evidence of efficacy with the low-dose BDA inhaler (HR 1.09, 95% CI 0.46-2.56).

Teen panel split

Efficacy data for the product in the 100 adolescent patients (aged 12 to less than 18 years) was mixed, with neither low-dose nor high-dose BDA inhalers showing a significant benefit over the albuterol control group.

The product developers, Avillion and AstraZeneca, offer a high-dose version of BDA for patients 12 years and older. During the meeting, ED Piper, MBBS, of AstraZeneca, explained that the efficacy results of MANDALA actually appear to favor the low-dose BDA over the high-dose regimen for adolescents, but stated that the results were probably due to “chance”:

  • Low dose BDA: HR 0.57 (95% CI 0.17-1.95)
  • High dose BDA: HR 1.44 (95% CI 0.54-3.87)

“It seems unlikely that the lower dose of BDA would perform better in adolescents given the clear dose-response in the overall population of MANDALA across all endpoints,” Piper said. “We also noted that the usage patterns were similar for both doses of BDA for adolescents.”

However, this appeared to cause some uncertainty among panel members regarding both the effectiveness of the combination and the correct dose to use.

“The risks are known and mostly manageable,” said Edward Kim, MD, of the University of North Carolina School of Medicine at Chapel Hill. “However, the benefits for me were unclear. Even if we were to assume the benefits were there by extrapolation, the correct dose I think is also unclear. I would need a sample more tall with clearer efficiency.”

Panel members who voted yes said they were reassured by the safety profile of the combination, although some said their yes votes were “soft”.

“I voted yes because of the reassuring short-term safety data that was presented, with no major safety signals identified,” said Bridgette Jones, MD, of the University of Missouri-Kansas School of Medicine. City.

“While there are variable phenotypes in children and adults, I think a full extrapolation is appropriate in this age group and you would expect similar results for a variable risk-benefit assessment like in adults,” Jones said. “I think more long-term safety data is needed to determine overall long-term exposure.”

Jones was also the only panel member to vote yes on the benefit-risk issue for younger pediatric patients. “I think there are kids in the 4 to 12 age bracket who would likely benefit from this drug and our job is to make that educated guess,” she said. “The art of medicine happens in the doctor’s office where we determine which children may benefit from the use of certain drugs.”

Although the FDA is not required to follow the advice of its advisory committees, it generally does.

  • Mike Bassett is a writer who focuses on oncology and hematology. He is based in Massachusetts.


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