Outcomes improve with tezepelumab in small airways dysfunction
Key takeaways:
- Frequency-dependent heterogeneity of resistance between 5 Hz and 20 Hz and area under the resistance curve improved.
- Improvements also included eosinophils, fractional exhaled nitric oxide and total IgE.
Patients with small airways dysfunction experienced clinically and statistically significant improvements in peripheral resistance and compliance with tezepelumab, according to a study published in Annals of Allergy, Asthma & Immunology.
Type 2 biomarkers and symptoms also significantly improved, Brian J. Lipworth, MD, head of the Scottish Centre for Respiratory Research and professor of allergy and pulmonology at University of Dundee, and colleagues wrote.
The only prior data on oscillometry for these patients were a randomized controlled trial showing no significant difference between tezepelumab (Tezspire; Amgen, AstraZeneca) and placebo in peripheral resistance between 5 Hz and 20 Hz (R5-R20) and peripheral compliance as area under the reactance curve (AX), Lipworth told Healio.
“Hence, we decided to look at early data on real-life response to tezepelumab on oscillometry,” he said.
The cohort included 15 patients (men, n = 8; mean age, 53.5 years; mean BMI = 30.2 kg/m2) with severe refractory asthma and small airways disease who were taking tezepelumab for a mean of 7.1 months.
The researchers defined small airways disease by airway oscillometry, with an AX of 1 kPa/L or higher and frequency-dependent heterogeneity of R5-R20 of 0.1 kPa/L/s or higher.
The cohort had a mean AX of 3.99 kPa/L and a mean R5-R20 of 0.32 kPa/L/s at baseline, in addition to a mean forced expiratory flow between 25% and 75% of forced vital capacity (FEF25-75) of 1.2 L/s and an FEV1 of 2.06 L.
Other means at baseline included 3.4 for Asthma Control Questionnaire (ACQ-6) scores, 3.9 for prior annual exacerbation rates, 723 cells/µl for eosinophils, 44 ppb for fractional exhaled nitric oxide (FeNO), and 427 kU/L for total IgE.
With treatment, significant mean differences included 2.24 kPa/L (95% CI, 0.73-4.09) for AX, 0.17 kPa/L/s (95% CI, 0.06-0.29) for R5-R20 and 0.62 L/s (95% CI, 0.29-0.94) for FEF25-75, as well as 0.34 L (95% CI, 0.04-0.63) for FEV1.
Significant mean percentage differences included 51.2% (95% CI, 35.3%-67.2%) for AX, 52.02% (95% CI, 34.1%-69.9%) for R5-R20 and 79.9% (95% CI, 6.71%-153.1%) for FEF25-75.
These values also exceeded the minimal clinically important difference threshold, Lipworth said, with statistically significant and clinically relevant changes. Additionally, these values were of a similar magnitude to those seen with dupilumab (Dupixent; Regeneron, Sanofi) vs. placebo, he said.
“Both tezepelumab acting upstream and dupilumab acting downstream reduce signaling of IL-4 and IL-13. In this regard, IL-4 and IL-13 but not IL-5 are highly expressed in human small airway smooth muscle,” Lipworth said.
“Also, IL-13 signaling is involved in mucus plugs, so blocking IL-13 with dupilumab and tezepelumab can dissolve mucus plugs and improve peripheral lung ventilation detected by oscillometry,” he continued.
Further, 13 patients had R5-R20 totals of 0.1 kPa/L/s or higher, 11 had AX totals of 1 kPa/L or higher and 12 had FEF25-75 totals of 0.21 L/s or higher, which the researchers called biological variability thresholds.
In terms of mean differences, other significant reductions included –640 cells/µl (95% CI, –940 to –930) for eosinophils, –23.9 ppb (95% CI, –46.3 to –1.2) for FeNO, and –194.9 kU/L (95% CI, –385.2 to –4.7) for total IgE.
There also was a mean difference of –1.32 (95% CI, –2.35 to –0.29) in ACQ-6 scores. Nine patients had changes that exceeded the minimal clinically important difference of 0.5.
Lipworth noted that these changes were much bigger than those seen in the previous randomized controlled trial.
“The difference in our study is that we a priori selected patients who at baseline had oscillometry-defined small airways obstruction and, hence, room for potential improvement in response to tezepelumab,” he said.
Lipworth called this important because oscillometry as R5-20 and AX are associated with airway remodeling, but FEV1 is not, adding that physicians who follow lung function as FEV1 may miss clinically relevant improvements in small airways that are seen with oscillometry.
“Moreover, one of the reasons why biologics like tezepelumab are effective in severe asthma is that the systemic route of administration is able to reach the whole lung, including the small airways,” he said.
Based on these findings, the researchers concluded that patients experienced clinically relevant and significant improvements in small airways function with tezepelumab along with significant improvements in type 2 biomarkers and symptoms.
The researchers also noted that this was the first study to yield real-world data about tezepelumab’s impact on small airways dysfunction and recommended further studies with a larger and more diverse cohort to confirm these findings.
“We need a prospective randomized controlled trial of tezepelumab vs. placebo in patients with severe asthma — pointedly, who at baseline has oscillometry-defined small airways dysfunction — and see how this relates to outcomes such as ACQ score and [quality of life] score,” Lipworth said.
For more information:
Brian J. Lipworth, MD, can be reached at b.j.lipworth@dundee.ac.ul.
Perspective
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This study is interesting, in that it shows improvement in small airways dysfunction among a group of patients with severe asthma with significant small airways disease prior to initiation of tezepelumab. Certainly, this may help explain mechanistically as to why some asthma patients have significant symptom improvement with tezepelumab, but we would need to see this recreated likely in a substudy of a larger prospective trial.
However, this study is difficult to compare with clinical experience because oscillometry is not routinely used in clinical practice. But it does echo previous research that shows improvement in small airways disease with agents that target the IL-4 and IL-13 pathway. Also, this study should not be used to make clinical decisions regarding use of tezepelumab but it does go a ways into understanding the mechanism of symptom improvement.
I think the next step is to view this in the context of a larger clinical trial. Likely, a substudy of a larger randomized trial would go a long way to see if biologics truly improve small airways disease. Additionally, the use of functional imaging may be an interesting addition along with oscillometry to better study small airways disease in severe asthma and their response to biological therapy.
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