Tezepelumab therapy: hints toward a disease-modifying effect?

An analysis of the NAVIGATOR and DESTINATION long-term extension trials revealed that both biomarkers and clinical outcomes slowly decreased over 40 weeks. However, the outcomes did not return to baseline after discontinuation of tezepelumab therapy. Further studies are now underway to explore a possible disease-modifying effect of tezepelumab.
In the phase 2b PATHWAY (NCT02054130) and the phase 3 NAVIGATOR (NCT03347279) studies, tezepelumab improved lung function before bronchodilation, measured as a percentage of forced expiratory volume in 1 second (FEV₁) target, in patients with severe, uncontrolled asthma compared with placebo [1,2]. The agent is a human monoclonal antibody that prevents thymic stromal lymphopoietin (TSLP) from interacting with its heterodimeric receptor. TSLP is involved in the inflammatory cascades of all asthma phenotypes and therefore offers the option of broadly influencing asthma pathophysiology. As Prof. Christopher Brightling (University of Leicester, UK) pointed out, tezepelumab is approved for the treatment of severe bronchial asthma as a consequence of the positive results of the phase 3 NAVIGATOR and SOURCE (NCT03406078) trials [2,3]. Following these phase 3 trials, patients had the opportunity to participate in the extension study DESTINATION (NCT03706079), a phase 3, multicentre, randomised, placebo-controlled trial. Long-term treatment of asthma with tezepelumab in DESTINATION resulted in fewer exacerbations, improvement in lung function and symptom control, and reduced inflammatory biomarkers over 104 weeks [4]. With their current study, Prof. Brightling and his co-investigators wanted to explore the effect of tezepelumab cessation after 2 years of treatment [5]. All participants had taken part in the NAVIGATOR trial and in the DESTINATION long-term extension period, and had received the last tezepelumab dose at week 100. From that time on, biomarkers and clinical outcomes were assessed in the 40-week period after the last dose. Change over time was assessed in blood eosinophil count (BEC), fractional exhaled nitric oxide (FeNO), the Asthma Control Questionnaire (ACQ)-6 score, and FEV₁ before bronchodilation (pre-BD ppFEV₁).

From week 4 onwards, both BEC and FeNO gradually increased after the last dose of tezepelumab, and pre-BD FEV₁ gradually decreased after the last dose of tezepelumab. Correspondingly, ACQ-6 scores gradually increased from this time on. However, Prof. Brightling emphasised in his conclusion that although biomarker suppression and improved clinical outcomes gradually waned in the 40 weeks after cessation of the biologic, these parameters did not return to baseline. Therefore, further studies should explore tezepelumab’s potential disease-modifying effect in certain patients, to identify which patient subgroups may achieve sustained asthma control.

1. Corren J, et al. N Engl J Med 2017 Sep 7;377(10):936-946.
2. Menzies-Gow A, et al. N Engl J Med 2021 May 13;384(19):1800-1809.
3. Wechsler ME, et al. Lancet Respir Med. 2022 Jul;10(7):650-660.
4. Menzies-Gow A, et al. Lancet Respir Med. 2023 May;11(5):425-438.
5. Brightling C. Biomarkers and clinical outcomes after cessation of tezepelumab after 2 years of treatment (DESTINATION). Abstract 1415, ERS International Congress 2023, 9–13 September, Milan, Italy.

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Posted on 29 October, 202329 October, 2023