Is Efficacy of Tezepelumab Independent of Severe Asthma Phenotype?

TSLP (thymic stromal lymphopoietin), belonging to the family of alarmins, is an epithelial cell–derived cytokine that is released upon exposure to allergens, pollutants, and bacterial or viral infections (1). Tezepelumab, a human monoclonal antibody blocking the activity of TSLP, is the first biologic in a new class of antialarmin antibodies. In the dose-finding phase IIb PATHWAY (Study to Evaluate the Efficacy and Safety of MEDI9929 [AMG 157] in Adult Subjects With Inadequately Controlled, Severe Asthma) study, treatment with tezepelumab in adults over 52 weeks significantly reduced the annualized asthma exacerbation rate (AAER) compared with placebo (2). The pivotal phase III NAVIGATOR (Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma) study in adults and adolescents confirmed the efficacy of tezepelumab 210 mg subcutaneously every 4 weeks in reducing the AAER (3). Moreover, tezepelumab reduced asthma exacerbations not only in type 2–high (eosinophilic or allergic) severe asthma but also in subjects with low blood eosinophil counts (BECs; <150/μl) or a low fractional exhaled nitric oxide (Fe_NO; <25 ppb). In December 2021, the U.S. Food and Drug Administration approved tezepelumab for the treatment of severe asthma with no biomarker or phenotypic restrictions. As severe asthma is heterogeneous and tezepelumab is the first drug in a new class, it is critical to address the following questions: 1) Is the efficacy of tezepelumab in severe asthma independent of phenotype? 2) What is the effect of tezepelumab on severe asthma exacerbations requiring hospitalization or emergency department visit? and 3) What is the safety profile of tezepelumab?

In this issue of the Journal, Corren and colleagues (pp. 13–24) provide clear answers by reporting a pooled analysis of the PATHWAY and NAVIGATOR studies (4). Pooling data from these two placebo-controlled, double-blind, randomized trials increased statistical power, enabling precise estimates of the efficacy of tezepelumab across multiple clinically relevant phenotypes. All patients (mean age 50 years, 64% women, prebronchodilator FEV₁ 62% predicted) had at least two exacerbations during the year before enrollment. In the pooled population (1,334 patients), tezepelumab reduced AAER by 60% compared with placebo. In subgroups defined by baseline type 2 biomarkers, reductions in exacerbations ranged from 37% in type 2–low (BEC < 300 cells/μl and Fe_NO < 25 ppb) to 77% in type 2–high (BEC ≤ 300 cells/μl and Fe_NO ≤ 25 ppb) severe asthma. In patients with baseline BECs ≤450 cells/μl or Fe_NO ≤50 ppb, AAER was impressively reduced by 78% and 76%, respectively. Excluding patients on maintenance oral corticosteroid treatment did not affect effect estimates but widened confidence intervals. Tezepelumab reduced AAER irrespective of allergic status (by 62% and 54% in patients with and without allergy to perennial aeroallergens, respectively), as has been shown for mepolizumab and dupilumab (5, 6). Importantly, tezepelumab reduced the annualized rate of severe exacerbations requiring emergency department visit or hospitalization by 79% in the total population and by 60–90% in type 2–low versus type 2–high subgroups. Tezepelumab also improved secondary outcomes, including lung function, asthma control, and asthma-related quality of life. Regarding safety, serious adverse events (SAEs) were reported by 13% and 9% of placebo- and tezepelumab-treated patients, respectively. The incidence of severe infections was similar in the placebo and tezepelumab groups. SAEs of cardiac disorders were reported in 0.3% and 0.8% of placebo- and tezepelumab-treated patients, respectively. These data are in line with the higher incidence of cardiac SAEs in participants receiving tezepelumab compared with placebo in the DESTINATION (Extension Study to Evaluate the Safety and Tolerability of Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma) extension study (7) and warrant further investigation.

This post hoc pooled analysis of the PATHWAY and NAVIGATOR studies thus demonstrates the efficacy of tezepelumab in a broad population with severe asthma, including patients with type 2–low asthma. Tezepelumab is the first biologic to show a significant, albeit modest, AAER in type 2–low severe asthma (8). However, the magnitude of the therapeutic response to tezepelumab significantly increases with increasing BEC or Fe_NO, suggesting that its efficacy is at least partially dependent on asthma phenotype.

How does tezepelumab reduce exacerbations in severe asthma? At least three complementary mechanisms of action of tezepelumab could be envisioned (Figure 1). First, as TSLP stimulates type 2 immune responses via dendritic cells, CD4⁺ (cluster of differentiation 4) T-helper type 2 cells, and type 2 innate lymphoid cells, tezepelumab reduces IL-5 production, decreasing BEC and eosinophilic airway inflammation and its associated risk of exacerbations. The inclusion criterion of at least two exacerbations in the previous year in PATHWAY and NAVIGATOR probably enriched for the presence of eosinophilic airway inflammation in the enrolled patients despite a low or normal BEC in a subgroup. In the CASCADE (Study to Evaluate Tezepelumab on Airway Inflammation in Adults with Uncontrolled Asthma) study, tezepelumab attenuated airway eosinophilia in asthma patients with and without increased BECs (9). Second, tezepelumab reduces IL-4 and IL-13 production by T-helper type 2 cells and type 2 innate lymphoid cells, as evidenced by a progressive gradual decrease in total serum IgE and a rapid decrease in Fe_NO, respectively. Tezepelumab inhibits IL-13–induced goblet cell hyperplasia, mucus overproduction, and mucus plugging, improving lung function and decreasing exacerbation risk. Third, TSLP is produced not only by epithelial cells but also by mast cells and airway smooth muscle cells. Infiltration of mast cells in airway smooth muscle has been linked to airway hyperresponsiveness, a hallmark of asthma irrespective of phenotype (10). Tezepelumab has been shown to attenuate airway hyperresponsiveness to direct (methacholine) and indirect (mannitol) bronchial provocation challenges (11, 12). We speculate that the relative importance of these three mechanisms of action of tezepelumab varies according to asthma phenotype, immunological endotype, and exacerbation trigger, modulating the magnitude of therapeutic response in an individual patient.

Figure 1.

Simplified scheme of postulated mechanisms by which tezepelumab might reduce asthma exacerbations: (1) reduced IL-5 driven eosinophilic inflammation, (2) decreased mucus production and mucus plugging, and (3) attenuated AHR. This illustration was created using BioRender.com. AHR = airway hyperresponsiveness; CYSLTR1 = cysteinyl leukotriene receptor 1; DC = dendritic cell; FcεRI = Fc epsilon receptor I; Fe_NO = fractional exhaled nitric oxide; ILC2 = type 2 innate lymphoid cell; iNOS = inducible nitric oxide synthase; MHC-II = major histocompatibility complex II; TCR = T cell receptor; Th2 = T-helper type 2; TSLP = thymic stromal lymphopoietin; TSLPR = thymic stromal lymphopoietin receptor.

An obvious limitation of the study is the post hoc nature of the pooled analysis. However, the results are robust and supported by sensitivity analyses, such as excluding patients on maintenance oral corticosteroid treatment. As for all recently approved drugs, many research questions still need to be addressed (13, 14). First, what is the efficacy of tezepelumab in patients with severe asthma with only a single exacerbation in the previous year? Second, what are the real-life effectiveness and long-term safety of tezepelumab in patients with multimorbidity or polypharmacy? Is it cost effective? How does tezepelumab therapy compare, ideally head to head, with anti–type 2 cytokine (receptor) antibodies in severe eosinophilic asthma? Does tezepelumab have disease-modifying effects (15)? How long is add-on treatment with tezepelumab needed? Can the dosing of tezepelumab be adapted on prolonged treatment once asthma is well controlled or in clinical remission?

In summary, the pooled analysis by Corren and colleagues (4) demonstrates that tezepelumab treatment reduces exacerbations in adults with uncontrolled severe asthma, including type 2–low asthma. Importantly, the efficacy of tezepelumab in reducing exacerbations and improving lung function increases with increasing concentrations of type 2 biomarkers. Real-world studies are warranted to further delineate the effectiveness, safety, and optimal use of tezepelumab in severe asthma.