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Clinical Trial
. 2024 Dec 5;64(6):2400316.
doi: 10.1183/13993003.00316-2024. Print 2024 Dec.

Clinical response and on-treatment clinical remission with tezepelumab in a broad population of patients with severe, uncontrolled asthma: results over 2 years from the NAVIGATOR and DESTINATION studies

Michael E Wechsler  1 , Guy Brusselle  2 , J Christian Virchow  3 , Arnaud Bourdin  4 , Konstantinos Kostikas  5 , Jean-Pierre Llanos  6 , Stephanie L Roseti  7 , Christopher S Ambrose  8 , Gillian Hunter  9 , David J Jackson  10   11 , Mario Castro  12 , Njira Lugogo  13 , Ian D Pavord  14 , Neil Martin  15   16 , Christopher E Brightling  15
Affiliations
Clinical Trial

Clinical response and on-treatment clinical remission with tezepelumab in a broad population of patients with severe, uncontrolled asthma: results over 2 years from the NAVIGATOR and DESTINATION studies

Michael E Wechsler et al. Eur Respir J. .

Abstract

Background: In asthma, clinical response is characterised by disease improvement with treatment, whereas clinical remission is characterised by long-term disease stabilisation with or without ongoing treatment. The proportions of patients receiving tezepelumab who responded to treatment and who achieved on-treatment clinical remission were assessed in the NAVIGATOR (ClinicalTrials.gov identifier NCT03347279) and DESTINATION (ClinicalTrials.gov identifier NCT03706079) studies of severe, uncontrolled asthma.

Methods: NAVIGATOR and DESTINATION were phase 3, randomised, double-blind, placebo-controlled studies; DESTINATION was an extension of NAVIGATOR. Complete clinical response was defined as achieving all of the following: ≥50% reduction in exacerbations versus the previous year, improvements in pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV1) of ≥100 mL or ≥5%, improvements in Asthma Control Questionnaire (ACQ)-6 score of ≥0.5 and physician's assessment of asthma improvement. On-treatment clinical remission was defined as an ACQ-6 total score ≤1.5, stable lung function (pre-BD FEV1 >95% of baseline) and no exacerbations or use of oral corticosteroids during the time periods assessed.

Results: Higher proportions of tezepelumab than placebo recipients achieved complete clinical response over weeks 0-52 (46% versus 24%; OR 2.83, 95% CI 2.10-3.82) and on-treatment clinical remission over weeks 0-52 (28.5% versus 21.9%; OR 1.44, 95% CI 0.95-2.19) and weeks >52-104 (33.5% versus 26.7%; OR 1.44, 95% CI 0.97-2.14). Tezepelumab recipients who achieved on-treatment clinical remission versus complete clinical response at week 52 had better preserved lung function and lower inflammatory biomarker levels at baseline, and fewer exacerbations in the 12 months before the study.

Conclusions: Among patients with severe, uncontrolled asthma, tezepelumab treatment was associated with an increased likelihood of achieving complete clinical response and on-treatment clinical remission compared with placebo. Both are clinically important outcomes, but may be driven by different patient characteristics.

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Conflict of interest statement

Conflict of interest: M.E. Wechsler is an employee of National Jewish Health and has received consultancy fees from AstraZeneca, Equillium, Genentech, GSK, Novartis, Regeneron Pharmaceuticals, resTORbio, Sanofi and Teva Pharmaceuticals. G. Brusselle has received fees for participation in advisory boards and/or speaker fees from Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, MSD, Novartis and Sanofi. J.C. Virchow has received grants for research or clinical trials from the German Research Foundation, GSK and MSD, has received consulting fees from Avontec, Boehringer Ingelheim, Chiesi, Essex Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Regeneron Pharmaceuticals, Revotar, Roche, Sandoz-Hexal, Sanofi-Aventis, Teva Pharmaceuticals and UCB Schwarz-Pharma, has received fees for lectures from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer Ingelheim, Chiesi, Essex Schering-Plough, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed Altana, Pfizer, Revotar, Sandoz-Hexal, Stallergenes Greer, Teva Pharmaceuticals, UCB Schwarz-Pharma and Zydus Cadila, has received fees for data safety-monitoring board participation from Chiesi, and has received travel support from Boehringer Ingelheim and Sanofi. A. Bourdin has received grants from AstraZeneca, Boehringer Ingelheim, Cephalon/Teva Pharmaceuticals, GSK, Novartis and Sanofi-Regeneron, has provided consultancy for Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, MedinCell, Merck, Novartis, Roche and Sanofi-Regeneron, and has acted as an investigator or co-investigator for trials sponsored by Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, Galapagos, GSK, Merck, Novartis, Roche, Sanofi-Regeneron and Vertex Pharmaceuticals. K. Kostikas has received fees for presentations and/or consultancy fees from Alector Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, ELPEN, Gilead, GSK, Menarini, Novartis, Pfizer, Sanofi, Specialty Therapeutics and WebMD, and his department has received funding and/or grants from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, Innovis, Menarini, Novartis and NuvoAir. J-P. Llanos is an employee of Amgen and owns stock in Amgen. S.L. Roseti, C.S. Ambrose, G. Hunter and N. Martin are employees of AstraZeneca and may own stock or stock options in AstraZeneca. D.J. Jackson has received consultancy fees and speaker fees from AstraZeneca, GSK, Novartis, Sanofi and Teva Pharmaceuticals. M. Castro reports grants/research support from ALA, AstraZeneca, Gala Therapeutics, Genentech, GSK, Novartis, Patient-Centered Outcomes Research Institute, Pulmatrix, Sanofi-Aventis, Shionogi Theravance and the US National Institutes of Health, consulting fees from Allakos, Amgen, Arrowhead, AstraZeneca, Genentech, Merck, Novartis, OM Pharma, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, and has received royalties from Aer Therapeutics and Elsevier. N. Lugogo has received consultancy fees for participation in advisory boards from Amgen, AstraZeneca, Genentech, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, has received fees for non-speaker bureau presentations from AstraZeneca and GSK, has received travel support from AstraZeneca, and her institution has received research support from Amgen, AstraZeneca, Avillion, Genentech, Gossamer Bio, GSK, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals. I.D. Pavord has received speaker fees from Aerocrine AB, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, has received payments for organisation of educational events from AstraZeneca, GSK, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, has received consultancy fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Dey Pharma, Genentech, GSK, Knopp Biosciences, Merck, MSD, Napp Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, RespiVert, Sanofi, Schering-Plough and Teva Pharmaceuticals, has received international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Napp Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, and has received a research grant from Chiesi. C.E. Brightling has received grants and consultancy fees from 4D Pharma, AstraZeneca, Chiesi, Genentech, Global Access Diagnostics (formerly Mologic), GSK, Novartis, Regeneron Pharmaceuticals, Roche and Sanofi.

Figures

None
Tezepelumab treatment was associated with an increased likelihood of achieving a complete clinical response and on-treatment clinical remission versus placebo in patients with severe, uncontrolled asthma. Clinical response data are taken from the NAVIGATOR phase 3 trial (52 weeks). Clinical remission data are taken from the DESTINATION phase 3 trial (104 weeks). BD: bronchodilator; BEC: blood eosinophil count; FENO: fractional exhaled nitric oxide; FEV1: forced expiratory volume in 1 s.
FIGURE 1
FIGURE 1
Clinical response and clinical remission definitions used in this analysis and summary of clinical remission definitions from the literature. CGI-C: Clinical Global Impression of Change; ACQ: Asthma Control Questionnaire; BD: bronchodilator; FEV1: forced expiratory volume in 1 s; OCS: oral corticosteroid; BEC: blood eosinophil count; FENO: fractional exhaled nitric oxide; ACAAI: American College of Allergy, Asthma and Immunology; AAAAI: American Academy of Allergy, Asthma, and Immunology; ATS: American Thoracic Society; ACT: Asthma Control Test; AirQ: Asthma Impairment and Risk Questionnaire; ICS: inhaled corticosteroid; LABA: long-acting β2-agonist; GINA: Global Initiative for Asthma; SABA: short-acting β2-agonist. #: clinical response was measured at week 52 of NAVIGATOR; : physician's assessment of improvement was expressed as a CGI-C score and was defined as minimally improved, much improved or very much improved; +: the minimum clinically important difference in ACQ-6 score is 0.5; §: on-treatment clinical remission was measured across multiple time points over the 2 years of DESTINATION.
FIGURE 2
FIGURE 2
The proportion of patients receiving a) tezepelumab 210 mg every 4 weeks and b) placebo with individual and overlapping components of clinical response at week 52. Results are reported as n (%). ACQ: Asthma Control Questionnaire; BD: bronchodilator; FEV1: forced expiratory volume in 1 s; CGI-C: Clinical Global Impression of Change.
FIGURE 3
FIGURE 3
The proportion of patients receiving tezepelumab 210 mg every 4 weeks or placebo who achieved on-treatment clinical remission during weeks 0–52 and weeks >52–104. In this analysis, for patients who completed treatment with data missing at week 104, the next available off-treatment measurement was input at week 104 for the Asthma Control Questionnaire-6 and pre-bronchodilator forced expiratory volume in 1 s criteria. An OR of >1 favours tezepelumab. There was one patient receiving tezepelumab who stopped oral corticosteroid use in DESTINATION and did achieve on-treatment clinical remission at week 52.
FIGURE 4
FIGURE 4
The proportion of patients receiving a) tezepelumab 210 mg every 4 weeks and b) placebo who achieved on-treatment clinical remission criteria over weeks 0–24, >24–52 and >52–104. In this analysis, for patients who completed treatment with data missing at week 104, the next available off-treatment measurement was input at week 104 for the Asthma Control Questionnaire (ACQ)-6 and pre-bronchodilator forced expiratory volume in 1 s criteria. Blue shading indicates the proportion of patients over weeks 0–24, >24–52 and >52–104 who met all four remission criteria since the previous period. At baseline, the purple shading represents patients who met both the study inclusion criterion and the remission criterion for ACQ-6 score (i.e. a score of ≤1.5). There was one patient receiving tezepelumab who stopped oral corticosteroid use in DESTINATION and did achieve on-treatment clinical remission at week 52.
FIGURE 5
FIGURE 5
The proportions of patients receiving tezepelumab 210 mg every 4 weeks or placebo who achieved clinical remission in weeks 0–24, and then remained in clinical remission throughout the on-treatment period. In this analysis, for patients who completed treatment with data missing at week 104, the next available off-treatment measurement was input at week 104 for the Asthma Control Questionnaire-6 and pre-bronchodilator forced expiratory volume in 1 s criteria. There was one patient receiving tezepelumab who stopped oral corticosteroid use in DESTINATION and did achieve on-treatment clinical remission at week 52.
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