Jim Kling

May 19, 2015

DENVER — The monoclonal antibody dupilumab (Sanofi, Regeneron) improves lung function and reduces severe exacerbations in patients with asthma, according to results presented here at the American Thoracic Society 2015 International Conference that drew a standing-room-only crowd.

Delegates heard evidence suggesting that the dual inhibition of interleukin-4 and -13 represents a promising avenue for biologic-based asthma treatment.

"There is considerable improvement in important outcomes — like FEV₁, lung function, and exacerbation rate — that are probably bigger than we've seen with any new drug approach in my memory. I think that's why the excitement is there," said Sally Wenzel, MD, from the University of Pittsburgh.

Her team conducted a 24-week phase 2b study of patients with uncontrolled asthma who were using medium- or high-dose inhaled corticosteroids and a long-acting beta agonist.

The researchers categorized patients by eosinophil count; a measure of at least 300/µL was considered high and below 300/µL was considered low.

A previous phase 2a trial assessed only patients with high eosinophil counts.

Targeting Eosinophil

Patients received one of the following treatment regimens: biweekly dupilumab 200 mg or 300 mg, monthly dupilumab 200 mg or 300 mg, or placebo.

Mean age of the study cohort was 48.6 years, mean baseline predicted FEV₁ was 61%, and mean baseline score on the 5-item Asthma Control Questionnaire was 2.74.

Of the 776 patients, 63% were female, 42% had a high eosinophil count, and 58% had a low eosinophil count.

In the low-eosinophil group at week 12, improvement in FEV₁ was at least 8% in those treated with biweekly dupilumab 200 mg or 300 mg (P < .001). The reduction in the annualized rate of severe exacerbations was 68% with biweekly dupilumab 200 mg, compared with placebo (P < .01), and was 62% with biweekly dupilumab 300 mg (P < .05).

In the high-eosinophil group at week 12, improvement in FEV₁ was 12% to 15% in those treated with biweekly dupilumab 200 mg or 300 mg. The reduction in the annualized rate of severe exacerbations was 64% to 75% (P < .05)

Improvements were also seen with the two monthly regimens.

"Even though the response may have been more robust in patients with high eosinophil count, there's clearly a response in patients with lower eosinophils," Dr Wenzel reported.

That assertion drew some consternation from session moderator Wendy Moore, MD, from Wake Forest University in Winston-Salem, North Carolina. She pointed out that the data undercut Dr Wenzel's belief that eosinophil count is an effective biomarker for selecting dupilumab as a therapy.

Disputing the Biomarker

Peripheral eosinophil count is often tied to allergic asthma, which would make it a simple biomarker that could help stratify patients with moderate to severe asthma, Dr Moore explained. The fact that low-eosinophil patients responded to the drug suggests that the biomarker might be weaker than hoped.

"Eosinophil count is an easy biomarker to use. The question is whether it's the right biomarker, and that data suggest that maybe it's not perfect," she told Medscape Medical News.

Because immunomodulatory therapies are expensive, physicians like to use biomarkers or some other scheme to personalize treatment and ensure that a patient is prescribed the most effective therapy, Dr Moore added.

Still, the research was met with an enthusiastic response. Several members of the audience congratulated Dr Wenzel after the talk. "It's hard to screw up good data," she said to one well-wisher.

 
It's hard to screw up good data.
 

"This study shows a dramatic reduction in flare-ups that result in healthcare utilization," said Frank Sciurba, MD, from the University of Pittsburgh, who was enthusiastic about the findings.

"Anything that can impact exacerbations in asthma is critical," he told Medscape Medical News.

He did express a wish for a responder analysis, rather than the median values reported by Dr Wenzel. "It doesn't really matter to me how the average patient does. I want to know whether my patient will respond," Dr Sciurba said.

The study sponsors, Sanofi and Regeneron, are planning a phase 3 trial with biweekly dupilumab 200 mg.

This study was sponsored by Sanofi and Regeneron. Dr Wenzel has received research support and travel grants from both companies. Dr Sciurba and Dr Moore have disclosed no relevant financial relationships.

American Thoracic Society (ATS) 2015 International Conference: Abstract A6362. Presented May 18, 2015.

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