Dupilumab associated with significant reductions in mucus plugging, volume
Click Here to Manage Email Alerts
Key takeaways:
- IL-13, which dupilumab blocks, induces nitric oxide production, which leads to mucus hypersecretion.
- At week 24, 57% of the treatment group and 11% of the placebo group had FeNO under 25 ppb.
SAN DIEGO — Patients with asthma experienced significant reductions in mucus airway plugging and mucus volume with dupilumab, according to a presentation at the American Thoracic Society International Conference.
These patients also saw reduced airway inflammation, further improving lung function, Mario Castro, MD, MPH, L.E. Phillips and Lenora Carr Phillips Professor at the University of Kansas Medical Center, and colleagues wrote.
“VESTIGE studied the effects of dupilumab [Dupixent; Regeneron, Sanofi], which is an anti-IL-4-alpha receptor, so it blocks both IL-4 and IL-13,” Castro, who also is an adjunct research professor at the University of Missouri-Kansas City School of Medicine, told Healio.
IL-13 induces nitric oxide production, which induces mucus hypersecretion. In turn, mucus plugging plays a role in airway obstruction and related chronic loss of lung function, the researchers said.
In this study, the researchers examined the biologic’s effects on lung inflammation as described by fractional exhaled nitric oxide (FeNO) as well as its effects on mucus plugging, which Castro called a remodeling measure.
The study comprised patients aged 21 to 70 years with uncontrolled moderate to severe asthma. These patients also had blood eosinophil levels of 300 cells/µL or higher and FeNO totals of 25 ppb or higher, which are elevated type 2 biomarkers.
Further, these patients had prebronchodilator percent-predicted (pre-BD pp) FEV1 totals of 80% or less, along with one or more exacerbations in the previous year.
Treatment included 300 mg of add-on dupilumab (n = 72) or matched placebo (n = 37) every 2 weeks for 24 weeks. The researchers conducted imaging at baseline, week 4 and week 24. Effects emerged by week 4 after two dupilumab injections, and these effects were sustained through 24 weeks, Castro said.
“We dropped the mucus score substantially,” Castro said.
At baseline, 67.2% of the treatment group and 73.3% of the placebo group had airway mucus scores between 4 and 18. At week 4, 50.8% of the treatment group and 73.3% of the placebo group had scores between 4 and 18. At week 24, those percentages included 32.8% of the treatment group and 76.7% of the placebo group.
Similarly, 3.3% of the treatment group and 10% of the placebo group had airway mucus scores of 0 at baseline. At week 4, these percentages included 18% of the treatment group and 3.3% of the placebo group. At week 24, they were 14.8% of the treatment group and 0% of the placebo group.
Overall, the treatment group experienced decreases in their airway mucus scores with a least square (LS) mean difference of –4.9 (standard error, 0.8) from baseline compared with the placebo group (P < .001) at week 24.
Improvements in lung function saw similar progress, Castro said.
“We dropped FeNO swiftly,” Castro said.
At baseline, only one patient in the treatment group and none of the patients in the placebo group had FeNO under 25 ppb. By week 4, 56% of the treatment group and 22% of the placebo group were under 25 ppb. By week 24, 57% of the treatment group and 11% of the placebo group were under 25 ppb.
The treatment group was 9.8 times more likely to have a FeNO under 25 ppb by week 24 compared with the placebo group, which Castro called “highly significant” (95% CI, 3.1-30.8; P < .001).
Pre-BD FEV1 was improved as well at week 24 for the treatment group, with an LS mean difference of 0.38 L (0.11; P < .001), with a strong association with decreases in airway mucus scores (Pearson’s correlation coefficient = –0.618; P < .0001).
“We think it’s an important evidence base that we’re starting to modify the disease process that correlates with patients’ improvements in symptoms and lung function afterwards,” Castro said.
The safety profile of the VESTIGE study was consistent with the safety profile of the QUEST study, with reactions largely consisting of injection site reactions and related adverse events, Castro said.
“It’s very consistent with the product label now,” he said.
Based on these findings, the researchers concluded that dupilumab led to significant reductions in mucus airway plugging, mucus volume and airway inflammation, which contributed to improved lung function.
“We believe it’s one of the key parts of the pathophysiology of asthma, severe asthmatics ... that there’s a subset that are driven by T2 inflammation that forms these mucus plugs,” Castro said. “They stay there for years.”
But if biologics can reverse this inflammation, he continued, it would be possible to turn the whole disease process back to a more normal state.
“We’re also going to look at remission acquisition here as well,” Castro said. “It’s going to be the next wave with biologics. In how many of these patients can we now induce disease remission? That’s going to be, I think, the next target. The Holy Grail.”
Castro expects research to continue too.
“Dupilumab is a wonderful drug for our patient populations. But we need to work on the low T2 space,” he said. “That’s going to be the horizon for next studies. I think this is going to help us with a lot of patients. But we need other drugs for those patients with low T2 inflammation.”