Unmet need in severe, uncontrolled asthma: can anti-TSLP therapy with tezepelumab provide a valuable new treatment option?

The heterogeneity of severe asthma makes management of the disease highly challenging, and intensive treatment regimens involving multiple medications are required. Global Initiative for Asthma (GINA) guidelines (treatment steps 4 and 5) recommend a combination medium-to-high-dose inhaled corticosteroid (ICS) and long-acting β₂ agonist (LABA) as maintenance therapy to prevent exacerbations and to control symptoms in these patients, with additional relief from a short-acting β₂ agonist as needed (or an ICS/LABA combination as both maintenance and reliever therapy, in the case of formoterol-containing combinations) [18]. Other controller medications recommended by GINA and European Respiratory Society/American Thoracic Society guidelines for use as potential add-on therapies are inhaled tiotropium (a long-acting muscarinic antagonist; at GINA steps 4 or 5), leukotriene receptor antagonists (at step 4) and macrolides (at step 5) [18, 19]. However, many patients have an insufficient response to these treatments and so are prescribed frequent bursts of OCS [10], although the side effect profile of OCS limits the dose and makes chronic administration non-ideal. Furthermore, some patients have steroid-refractory disease. At GINA step 5, it is recommended that patients are assessed for eligibility for biologic therapies, which are indicated as additional controllers for specific phenotypes of severe asthma [18, 19]. Eligibility for these therapies is partly determined by meeting specific inflammatory biomarker thresholds (and, by extension, phenotypes) for which efficacy of the particular biologic treatment was demonstrated in clinical trials.

Currently available biologics for severe asthma comprise anti-IgE (omalizumab), anti-IL-5 (mepolizumab, reslizumab), anti-IL-5 receptor α (benralizumab) and anti-IL-4 receptor α (dupilumab, which blocks the IL-4 and IL-13 pathways) monoclonal antibodies. These therapies are generally indicated for patients with eosinophilic or allergic asthma phenotypes; to date, there are no approved biologic treatments for patients with confirmed eosinophil-low asthma (in the absence of eosinophil-lowering systemic corticosteroid therapy). In the pivotal studies of the currently approved biologics, exacerbation rates were reduced by 48–59% with the most efficacious dose regimen versus placebo [20‐24]. Improvements in lung function and symptom scores were inconsistent, with only some individuals experiencing clinically significant improvements [25‐28]. A possible explanation for this lack of complete efficacy may be that these biologics target individual, downstream elements of the asthma inflammatory response, leaving other components untreated. Targeting an upstream initiator and mediator of the inflammatory response may, therefore, have a broader effect on airway inflammation and provide more effective asthma control, including in patients with eosinophil-low phenotypes. One such potential target is thymic stromal lymphopoietin (TSLP).

TSLP is a member of the class of cytokines known as the alarmins, which also includes IL-25 and IL-33. It is primarily expressed by the airway epithelium and released in response to environmental insults such as allergens, viruses, bacteria, pollutants and physical injury, instigating a range of downstream inflammatory processes [29, 30]. There is strong evidence that TSLP dysregulation plays an important role in the pathophysiology of asthma.

TSLP expression is increased in the airways of patients with asthma compared with healthy individuals [31‐34], correlating with disease severity and impairment of lung function [31, 33, 35, 36]. Furthermore, genome-wide association studies have identified associations between asthma risk and single-nucleotide polymorphisms in the TSLP gene [37‐40].

Following its release from the epithelium, TSLP drives allergic and non-allergic eosinophilic inflammation, leading to various features of asthma pathophysiology [41]. TSLP activates dendritic cells in response to allergen exposure, inducing differentiation of naïve T cells to Th2 cells, which produce IL-4, IL-5 and IL-13. This leads to IgE switching in B cells, degranulation of mast cells, airway eosinophilia, mucus hypersecretion from goblet cells and smooth muscle contraction resulting in airway hyperresponsiveness [42, 43]. Following exposure to viruses, bacteria, pollutants and other insults, TSLP (as well as IL-33 and IL-25) activates group 2 innate lymphoid cells (ILC2s), which produce IL-5 and IL-13 [44]. In addition to its T2-related effects, there is growing evidence that TSLP plays a role in non-T2 processes involving both immune and structural cells. TSLP is thought to play a role in neutrophilic airway inflammation by activating dendritic cells to induce polarization of naïve T cells towards a Th17 phenotype, which subsequently release IL-17 [45, 46]. TSLP also promotes airway remodelling by stimulating airway smooth muscle cell migration [47], facilitating cross-talk between mast cells and airway smooth muscle cells [48] and stimulating fibroblast cells to produce collagen [49, 50]. The myriad effects of TSLP in asthma therefore make it an attractive therapeutic target.

Tezepelumab is a human monoclonal antibody (IgG2λ) that selectively blocks TSLP from interacting with its heterodimeric receptor (Fig. 1) [51‐53]. In a phase 1b, proof-of-concept study in patients with mild allergic asthma (ClinicalTrials.gov identifier NCT01405963), tezepelumab attenuated asthmatic responses to allergen challenge and reduced biomarkers of inflammation compared with placebo [51]. In the tezepelumab group, blood eosinophil counts began to decline at 2 weeks post-dosing and reached normal levels by 4 weeks, while sputum eosinophils reached normal levels by 6 weeks (the first time point measured). FeNO levels improved significantly 1 week after the first dose. The phase 2b PATHWAY study, a multicentre, randomized, double-blind, placebo-controlled trial (NCT02054130) evaluated the efficacy and safety of tezepelumab as an add-on therapy for patients with severe, uncontrolled asthma, who were receiving medium-to-high-dose ICS and a LABA with or without OCS and additional asthma controllers [52]. Tezepelumab treatment was associated with significant reductions in annualized exacerbation rates of up to 71% versus placebo. Subgroup analyses showed that these reductions were significant irrespective of patient phenotype, as measured by baseline blood eosinophil counts (< 150 cells/µL, ≥ 150 cells/µL, < 300 cells/µL or ≥ 300 cells/µL), as well as by FeNO and IgE levels, suggesting that tezepelumab provided similar efficacy in patients across the spectrum of inflammatory phenotypes [54]. Compared with placebo, tezepelumab also reduced asthma-exacerbation-related hospitalizations and improved lung function, asthma control and patient HRQoL [52]. Further analyses of the PATHWAY data showed that tezepelumab reduced blood eosinophil counts, FeNO levels, serum IgE and cytokines including IL-5 and IL-13 [52, 55]. Of the currently approved biologics, only anti-IgE has been shown to reduce FeNO levels, serum free IgE and blood or sputum eosinophil counts, although not to the same extent as anti-TSLP therapy [56]. The safety profile of tezepelumab in PATHWAY was acceptable, with a similar overall frequency of adverse events (including serious adverse events) in patients receiving tezepelumab and those receiving placebo; the most common adverse events were consistent with those expected in a patient population with severe asthma [52]. A low incidence of anti-drug antibodies was observed in patients treated with tezepelumab, without any apparent clinical impact. The observed efficacy of tezepelumab in a broad range of patients with severe asthma in PATHWAY led to it being designated a ‘breakthrough therapy’ by the US Food and Drug Administration in 2019 for patients with severe asthma without an eosinophilic phenotype, who are receiving ICS/LABA and additional asthma controllers with or without OCS [57].

Further trials of tezepelumab in patients with asthma are underway (Table 1). NAVIGATOR (NCT03347279) [58] is a pivotal phase 3 study assessing the potential efficacy of tezepelumab in adults and adolescents with severe, uncontrolled asthma spanning a broad range of phenotypes, aiming to build on the findings of PATHWAY. The recruited participants comprise roughly equal proportions of patients with baseline blood eosinophil counts of less than 300 cells/µL and at least 300 cells/µL; approximately 25% of patients have an eosinophil count of less than 150 cells/µL or of greater than 450 cells/µL. The primary efficacy endpoint is the annualized asthma exacerbation rate during the 52-week treatment period in the overall patient population, and this will also be assessed separately in patients with baseline blood eosinophil counts below 300 cells/µL. Key secondary endpoints of NAVIGATOR assess lung function, asthma control and HRQoL. SOURCE (NCT03406078) [59] is a phase 3 study that aims to evaluate the OCS-sparing potential of tezepelumab in adults with OCS-dependent asthma. Following OCS dose optimization, the 48-week treatment period comprises: a 4-week induction phase during which tezepelumab is introduced; a 36-week OCS reduction phase during which the OCS dose is tapered (dependent on the patient continuing to meet asthma control criteria); and an 8-week maintenance phase in which patients continue on their final OCS dose. The primary endpoint is the percentage reduction from baseline to week 48 in the prescribed daily OCS maintenance dose while not losing asthma control. DESTINATION (NCT03706079) [60] is a long-term extension of NAVIGATOR and SOURCE that addresses the safety and tolerability of tezepelumab for up to 2 years’ treatment. In addition to these phase 3 studies, the phase 2 mechanistic study CASCADE (NCT03688074) [61] aims to evaluate the effect of tezepelumab on airway inflammation and airway remodelling in patients spanning the spectrum of T2 airway inflammation, as determined by epithelial molecular phenotyping. The primary endpoint is the change from baseline to week 28 in airway submucosal inflammatory cells (eosinophils, neutrophils, T cells and mast cells) from bronchoscopic biopsies. Secondary endpoints include assessments of reticular basement membrane thickening and airway epithelial integrity.