FDA adcomm offers thumbs up on AstraZeneca’s 2-in-1 asthma inhaler — but only for adults

AstraZeneca’s experimental asthma drug cruised through an FDA advisory committee, as the panel of external experts offered an overwhelming thumbs up for its use in adults.

But when it came to adolescents and kids, the adcomm was less sure.

The mixed votes could cast a shadow on the aspirations at AstraZeneca, which had proposed a broad label in its NDA filing for PT027 that covers patients 4 years or older. In convening the adcomm, the FDA had noted that the data on pediatric patients was a big focus.

The agency is slated to make a decision in the first half of 2023. While it is not required to follow the adcomm’s advice, it often does.

PT027, an inhaler combining two existing compounds, is being positioned as a rescue treatment for asthma. While patients already have options for drugs containing either a short-acting beta2-agonist (SABA) or inhaled corticosteroid (ICS), there are no products that combine both components to marry their respective bronchodilatory and anti-inflammatory effects.

What AstraZeneca did was to create a fixed-dose formulation of albuterol, a SABA, and budesonide, an ICS.

As regulators wrote in their briefing documents, there are several unique features of this application:

(Budesonide/albuterol) would be the first ICS/SABA combination product approved in the United States. The proposed indication and use to prevent severe exacerbations is novel. […] FDA approval of an ICS-containing product as a reliever treatment for asthma (rather than as controller) would be new.

Charting new paths, the FDA and AstraZeneca agreed on a trio of studies: MANDALA, which would measure efficacy; DENALI, which would explore the contribution of each of the components; and TYREE, which focuses on a post-exercise challenge.

Members of the Pulmonary-Allergy Drugs Advisory Committee had no issue voting 16 to 1 that the data support a favorable benefit-risk assessment in patients 18 years or older, thanks to data from MANDALA suggesting PT027 significantly reduced the risk of severe exacerbations compared to albuterol alone.

However, they were divided on the two other groups they were asked to weigh in on: adolescents aged 12 to 17, and children aged 4 to 11. Among the 3,132 patients enrolled in MANDALA, there were only 100 adolescents and 83 children, precluding “meaningful statistical inference of treatment benefits,” AstraZeneca wrote. It also noted that it lowered the enrollment target for adolescents and children in DENALI owing to “additional challenges” amid the Covid-19 pandemic.

Mene Pangalos

Researchers deployed Bayesian modeling to extrapolate positive data for pediatric subpopulations. But the adcomm wasn’t convinced: For adolescents, they narrowly voted 9 to 8 that the data do not support a favorable benefit-risk assessment; they had more consensus for the children group, voting 16 to 1 against.

Many of those voting no noted that they weren’t concerned about safety, but rather didn’t see enough evidence supporting the benefit.

“There wasn’t enough heterogeneity in the data presented and potentially with past studies that made it challenging to be highly confident that we could extrapolate these results,” said Alex Kaizer, an assistant professor of biostatistics and informatics at the University of Colorado-Anschutz Medical Campus.

Even among those who voted yes in the adolescents group, there are still concerns to be worked out, said Mary Cataletto, a pediatric pulmonologist at NYU Health and clinical professor of pediatrics at NYU Grossman School of Medicine.

“I think the risk benefits pretty much speak for themselves. However, I would make one exception having worked with this population basically my whole career. It has the potential for abuse,” she said. “And I think that it requires a whole new education for kids who if they’re gonna use BDA the way they use albuterol, as premedication for exercise, there is a potential that they’re gonna abuse it. So I would be very careful with that, even though I said yes. I think the exercise-induced asthma section needs to be very carefully crafted and followed.”

For its part, AstraZeneca wrote in its documents that the FDA had suggested using the Bayesian approach to determine pediatric efficacy during meetings. The agency noted that it wanted the adcomm to discuss whether extrapolation is appropriate, or if more data are needed.

Together with development partner Avillion, AstraZeneca will discuss the next steps with the FDA, “including for adolescents and children,” said Mene Pangalos, AstraZeneca’s EVP of biopharmaceuticals R&D.

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