Tezepelumab Reduces Exacerbations in Patients With Severe, Uncontrolled Asthma

Despite treatment with standard of care therapy, patients with severe asthma continue to experience symptoms and exacerbations. Tezepelumab (Tezspire; Amgen and AstraZeneca) is a human monoclonal antibody approved by the FDA for the treatment of severe asthma. The antibody binds to the thymic stromal lymphopoietin, which plays a key role in the initiation and persistence of processes that are associated with asthma pathophysiology, such as allergic inflammation, eosinophilic inflammation, as well as type 2-independent effects on mast cells, airway smooth muscle, and airway hyperresponsiveness.

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NAVIGATOR (NCT03347279) is a multicenter, randomized, double-blind, placebo-controlled phase 3 trial that enrolled participants with physician-diagnosed severe, uncontrolled asthma who were 12 to 80 years of age. Similar proportions of patients were included with baseline blood eosinophil count (BEC) of less than 300 cells per µl (58.4%) and 300 cells or more per µl (41.6%). Additionally, patients were receiving medium- or -high-dose inhaled corticosteroids (ICS, daily dose of ≥ 500 μg fluticasone propionate or equivalent) for at least 12 months prior to screening and at least 1 additional controller medication—with or without ICS—for at least 3 months before the date of informed consent. The enrolled participants also had to have experienced at least 2 documented asthma exacerbations—defined as a worsening of asthma symptoms leading to hospitalization, an emergency department visit resulting in the use of systemic corticosteroids for 3 or more consecutive days, or the use of systemic corticosteroids for 3 or more consecutive days—within the 12 months before the date of informed consent.

Patients were randomly assigned to receive either 210 mg of subcutaneous tezepelumab or placebo every 4 weeks for a 52-week duration. The primary efficacy end point was the annualized asthma exacerbation rate (AAER) over 52 weeks.

According to the findings, treatment with tezepelumab reduced asthma exacerbations compared with placebo over the 52-week period. Compared with placebo, reductions in AAER over 52 weeks with tezepelumab were similar in male (55%; 95% confidence interval [CI]: 37, 67) and female participants (57%; 95% CI: 45, 66). Additionally, tezepelumab reduced asthma exacerbations by approximately 48% in former smokers and 58% in those who never smoked. The treatment reduced the AAER similarly across all body mass index (BMI) subgroups, with reductions compared with placebo ranging from 54% (BMI: ≥ 30 kg/m2) to 60% (BMI: < 25 kg/m2). Further, tezepelumab reduced asthma exacerbations in patients with a very high baseline BEC (≥ 500, ≥ 750 and ≥ 1000 cells/µl), with reductions ranging from 74% (95% CI: 29, 90) in patients with a BEC of 1000 cells or more per µl to 77% (95% CI: 54, 89) in patients with a BEC of 750 cells or more per µl.

Additionally, AAER was reduced in patients treated with tezepelumab across all asthma-related comorbidity subgroups, with reductions ranging from 58% (95% CI: 47, 67) in those with rhinitis to 83% (95% CI: 66, 91) in patients with aspirin or non-steroidal anti-inflammatory drugs sensitivity. Reductions were also observed in both patients with gastroesophageal reflux disease (62%; 95% CI: 45, 74) and without (53%; 95% CI: 42, 63).

Further, compared with placebo, tezepelumab significantly reduced AAER by approximately 64% in patients eligible for dupilumab and 34% in those who were considered ineligible. Among patients with prior omalizumab use, AAER was reduced by about 51% and by 57% in those without prior use. Reductions were also seen in patients taking 1, 2, and 3 or more controller medications in addition to ICS at baseline, with decreases of approximately 41%, 68%, and 61%, respectively, in these subgroups. The greatest reductions were noted in patients on long-acting beta-agonists (LABA) and leukotriene receptor antagonists (LTRA; 78%) and those on LABA, long-acting muscarinic antagonists, and LTRA (73%). For those on other controller medications, the reduction was approximately 37%.

The investigators note that limitations include the trial’s 52-week duration and the post hoc, exploratory nature of the analyses, which means that results should be carefully interpreted until confirmed with follow-up studies. Additionally, the investigators acknowledge that some subgroups included a small number of participants. According to the authors, further studies could continue to examine the effect of tezepelumab on exacerbations defined by different asthma types, rather than individual factors alone.

Reference

Carr, TF, Moore, WC, Kraft, M, et al. Efficacy of Tezepelumab in Patients with Severe, Uncontrolled Asthma Across Multiple Clinically Relevant Subgroups in the NAVIGATOR Study. Adv Ther 41, 2978–2990 (2024) doi:10.1007/s12325-024-02889-8