Baseline FeNO levels predict response to dupilumab among patients with asthma
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Key takeaways:
- Annualized event rates increased with increasing baseline FeNO in patients on placebo and decreased for patients on dupilumab.
- Findings were independent of blood eosinophil levels.
Fractional exhaled nitric oxide levels predicted treatment response to dupilumab among patients who had uncontrolled moderate to severe asthma, according to a study published in The Journal of Allergy and Clinical Immunology: In Practice.
Treatment also was effective in patients with type 2 inflammation as well as elevated FeNO and/or elevated eosinophils, Ian D. Pavord, MD, MA, DM, FRCP, FERS, FMedSci, professor of respiratory medicine, respiratory medicine unit, Nuffield Department of Medicine, University of Oxford, and colleagues wrote.
The randomized, double-blind, placebo-controlled phase 3 LIBERTY ASTHMA QUEST study involved 1,878 patients aged 12 years and older with asthma, including 627 on placebo and 1,251 on dupilumab (Dupixent; Sanofi Genzyme/Regeneron).
With a ratio of 2:2:1:1, patients received either 200 mg or 300 mg of subcutaneous dupilumab or 1.14 mL or 2 mL of placebo every 2 weeks for up to 52 weeks.
Among the patients on placebo, increasing levels of FeNO at baseline predicted increased estimated annualized event rates of severe exacerbations. But among the dupilumab group, these levels predicted decreased annualized severe exacerbation rates.
Also, the placebo group experienced a least square (LS) mean change from baseline in prebronchodilator FEV1 that was consistent across the continuum of baseline FeNO levels at weeks 12 and 52. In the dupilumab group, however, the magnitude of improvement in FEV1 increased with increasing baseline FeNO at weeks 12 and 52.
The researchers stratified patients by FeNO subgroups as well, including less than 25 ppb, 25 ppb to less than 50 ppb, and 50 ppb and higher. Among the dupilumab group, the patients with higher FeNO levels experienced significantly higher magnitudes of decreases in rates of severe exacerbations vs. placebo than patients with FeNO levels of less than 25 ppb.
Compared with placebo, decreases in risks for severe exacerbations among the dupilumab group included 22.3% for the less than 25 ppb subgroup, 58.3% for the 25 to less than 50 ppb subgroup and 69.2% for the 50 ppb or greater subgroup.
The researchers called all these differences between the dupilumab and placebo groups significant. Treatment-by-biomarker interactions between these three FeNO subgroups were significant as well (P < .0001), the researchers continued.
Changes in prebronchodilator FEV1 from baseline were similar, the researchers said, with the 50 ppb and higher subgroup experiencing the greatest improvements at week 12. The less than 25 ppb subgroup was the only one whose differences were not significant.
Compared with placebo, LS mean differences included 0.04 (95% CI, –0.01 to 0.09) in the less than 25 ppb subgroup, 0.15 (95% CI, 0.09-0.22) in the 25 to less than 50 ppb subgroup and 0.35 (95% CI, 0.26-0.44) in the 50 ppb or higher subgroup. Again, treatment-by-biomarker interactions among the subgroups were significant (P < .0001).
Among patients with eosinophil counts of less than 150 cells/µL, the subgroups with higher FeNO levels experienced numerical improvements in exacerbation rates with dupilumab vs. placebo, but the researchers said they did not find statistical significance among any of these subgroups.
More specifically, patients with eosinophil counts from 150 cells/µL to less than 300 cells/µL and FeNO levels of less than 25 ppb and 25 ppb to less than 50 ppb had significant improvements vs. placebo, but the patients with eosinophil counts of 150 cells/µL to less than 300 cells/µL and FeNO of 50 ppb or greater did not. The researchers attributed this difference to low exacerbation rates in the placebo arm and the small sample size.
Patients with eosinophil counts of 300 cells/µL or higher had significant improvements in all FeNO subgroups, with the greatest reductions in annualized rates of severe exacerbations among the 50 ppb or greater subgroup (80.5% dupilumab vs. placebo).
At weeks 12 and 52, patients with eosinophil counts of 300 cells/µL and higher and FeNO of 50 ppb and higher had the greatest improvements in FEV1, the researchers said. LS mean differences versus placebo included 0.42 L (95% CI, 0.31-0.53; P < .0001) at week 12 and 0.43 L (95% CI, 0.32-0.55 L; P < .0001) at week 52.
Almost all subgroups that were tested experienced improvements in FEV1 with dupilumab compared with placebo, the researchers said, although these differences were not always significant. Also, patients in the less than 25 ppb FeNO group experienced smaller improvements.
Based on these findings, the researchers called FeNO a useful biomarker in predicting how patients with uncontrolled moderate to severe asthma will respond to dupilumab, independent of eosinophil levels and other clinical characteristics.
When providers are deciding whether patients should use a biologic for severe asthma, the researchers continued, they should obtain blood eosinophil and FeNO levels since elevations in these biomarkers would identify patients who are particularly likely to respond to dupilumab.
Perspective
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Finding the correct biomarkers to truly identify the appropriate biologic treatment is still the “holy grail” in asthma therapy. We know that with the current biomarkers, we only see about 60% of patients improve on biologic therapy. Several studies have shown an increased effect of dupilumab on patients with higher FeNO, but it is not an absolute indicator of disease response.
I tend to lean toward choosing dupilumab as one of my first choices in patients with elevated FeNO, depending on other factors such as comorbidities.
As I mentioned, we still need better biomarkers. But based on this study, I think if a patient has an elevated FeNO, one should factor this into the decision-making process when choosing a biologic.
Obviously, this study was retrospective, so we truly need prospective studies to look at the current biomarkers (FeNO, eosinophils and serum IgE) and investigate other potential biomarkers to see if we can better phenotype our patients when choosing a biologic therapy.
This is an exciting time for the physician treating asthma. I would hope we will develop better biomarkers and even look at starting biologics earlier in the disease to see if we can prevent worsening rather than waiting until the patient has severe disease. Also, there are discussions related to whether biologics can cause disease remission in asthma, although the definition of remission in asthma still needs to be clarified.
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