Skip to main content

The new era of add-on asthma treatments: where do we stand?

Abstract

Globally, a small proportion (5–12%) of asthma patients are estimated to have severe disease. However, severe asthma accounts for disproportionately high healthcare resource utilization. The Global Initiative for Asthma (GINA) management committee recommends treating patients with asthma with inhaled corticosteroids plus long-acting β2-agonists and, when needed, adding a long-acting muscarinic receptor antagonist or biologic agent. Five biologics, targeting different effectors in the type 2 inflammatory pathway, are approved for asthma treatment. However, biologics have not been compared against each other or add-on inhaled therapies in head-to-head clinical trials. As a result, their positioning versus that of current and anticipated small-molecule strategies is largely unknown. Furthermore, with the emergence of biomarkers for predicting response to biologics, a more personalized treatment approach—currently lacking with inhaled therapies—may be possible. To gain perspective, we reviewed recent advances in asthma pathophysiology, phenotypes, and biomarkers; the place of biologics in the management and personalized treatment of severe asthma; and the future of biologics and small-molecule drugs. We propose an algorithm for the stepwise treatment of severe asthma based on recommendations in the GINA strategy document that accounts for the broad range of phenotypes targeted by inhaled therapies and the specificity of biologics. In the future, both biologics and small molecules will continue to play key roles in the individualized treatment of severe asthma. However, as targeted therapies, their application will continue to be focused on patients with certain phenotypes who meet the specific criteria for use as identified in pivotal clinical trials.

Background

Severe asthma is defined by the ERS/ATS guidelines [1] as asthma which requires treatment with high-dose inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs) or leukotriene modifier/theophylline for the previous year or systemic corticosteroids for ≥ 50% of the previous year to prevent it from becoming uncontrolled or which remains uncontrolled despite this therapy. The Global Initiative for Asthma (GINA) [2] defines severe asthma as asthma which remains uncontrolled despite optimized treatment with high-dose ICS-LABA, or that requires high-dose ICS-LABA to prevent it from becoming uncontrolled (Fig. 1). “Uncontrolled” asthma is characterized by the presence of poor symptom control, frequent severe exacerbations, serious exacerbations, or airflow limitation [1].

Fig. 1
figure 1

a GINA recommended stepwise asthma treatment. b Severe asthma definition [1, 2]. ATS American Thoracic Society, BDP budesonide propionate, CS corticosteroids, ERS European Respiratory Society, FEV1 forced expiratory volume in 1 s, GINA Global Initiative for Asthma, HDM house dust mite, ICS inhaled corticosteroids, IgE immunoglobulin E, IL interleukin, LABA long-acting β2-agonist, LAMA long-acting muscarinic antagonist; LTRA leukotriene receptor antagonist, OCS oral corticosteroids; SABA short-acting β2-agonist; SLIT sublingual immunotherapy

Of the global asthma population, approximately 5% to 12% [3,4,5] and < 4% [3, 6] are estimated to have severe asthma and severe, uncontrolled asthma, respectively; however, the true prevalence of severe uncontrolled asthma may be substantially greater as there is no consistent definition across studies. Although the proportion of patients with severe asthma may seem low, millions of individuals are afflicted, so the impact on society, associated personal and socioeconomic burdens are high [6, 7]. Persistent symptoms, frequent exacerbations, impaired quality of life (QoL), and eventual loss of lung function are common challenges faced by patients with severe asthma [7]. Furthermore, results of an observational study of patients with persistent asthma in a real-world, US managed-care setting led investigators to conclude that patients with severe asthma require more intensive therapy, greater attention to adherence and comorbidities, and more specialist care than patients with non-severe asthma [6].

Pathophysiology and inflammatory pathways in asthma

Asthma is characterized by variable obstruction, hyperresponsiveness, and inflammation of the airways. Airway obstruction results from contraction of the airway smooth muscles, mucosal inflammation, and airway remodeling involving structural changes, such as collagen deposition, airway smooth muscle hyperplasia and hypertrophy, and excess mucus production (Fig. 2). Severe asthma pathophysiology involves a greater degree of incompletely reversible airflow limitation, more severe airway remodeling, marked thickening of the airway wall, and excessive airway narrowing upon stimulation of airway smooth muscle contraction [8, 9].

Fig. 2
figure 2

a Cross-section and histology of airways in a normal person and a patient with asthma. b Pathways of inflammatory responses, biomarkers, and mechanism of action of various therapeutic agents. β2-AR β2-adrenergic receptor, CS corticosteroids, CRTH2 chemoattractant receptor-homologous molecule expressed on Th2 cells, FcεR Fcε receptor, IFN interferon, Ig immunoglobulin, IL interleukin, ILC2 innate lymphoid cell type 2, LABA long-acting β2-agonist, MMP-9 matrix metallopeptidase 9, M3R muscarinic receptor type 3, PGD2 prostaglandin D2, TCR T-cell receptor, TGF tumor growth factor, TNF tumor necrosis factor, Th T helper, TSLP thymic stromal lymphopoietin

Inflammation in asthma is heterogeneous in nature. Type 2 (T2) inflammation is characterized by the release of interleukin (IL)-4, IL-5, and IL-13 [8]. IL‐4 induces B-cell class switching to produce immunoglobulin E (IgE), which binds to high-affinity surface receptors on mast cells; degranulation occurs following IgE crosslinking with antigens. IL‐13 induces mucus hypersecretion and regulates epithelial cell function. IL-5 is associated with epithelial changes, leading to increased eotaxin expression; IL-5 promotes the proliferation, maturation, and survival of eosinophils, and is associated with airway eosinophilia [8, 10].

A T2 inflammatory response is usually initiated by type 2 cytokines, released by a subpopulation of CD4+ T cells (T-helper type 2 [Th2] cells), or innate lymphoid cells type 2 (ILC2s), which are also a major source of type 2 cytokines [11, 12]. ILC2s are activated by alarmins or epithelial cell-derived cytokines (thymic stromal lymphopoietin [TSLP], IL-33, and IL-25), which are released upon exposure to infectious agents and allergic stimuli [11]. Alarmins drive tissue inflammation by promoting type 2 cytokine release from ILC2s and development of Th2 cells. Thus, alarmins can activate both innate (ILC2s) and adaptive (Th2 cells) immune cells and are thought to be a key link between innate and adaptive immune responses in T2 inflammation [13].

The prostaglandin D2 (PGD2) pathway is also involved in T2 inflammation [14]. Mast cell activation and mast cell-derived PGD2 is increased in severe asthma, which activates mast cells and ILC2s [8].

Non-T2 (or type 1) inflammation is associated with non-T2 inflammatory pathways. Neutrophilic inflammation, as demonstrated by neutrophils in induced sputum, may be seen in a subset of patients with non-T2 asthma and is likely driven by CD4+ T cells—T-helper type 1 and type 17 cells [15]. Paucigranulocytic inflammation, characterized by the absence of increased eosinophils and neutrophils in induced sputum, is the cause of airflow limitation in the absence of cellular inflammation in the pathways and may be associated with “stable” asthma [16]. Paucigranulocytic asthma is often associated with controlled as opposed to stable asthma but there may be a small subset of patients with a phenotype whereby paucigranulocytic asthma is related to structural changes due to hyperresponsiveness [17]. Based on studies in animal models, airway obstruction in paucigranulocytic asthma has been linked to structural changes in airway smooth muscle via upregulation of asthma-specific genes [16].

Accumulating evidence, including increased neutrophilic inflammation in severe asthma [18] and increased neutrophil counts during asthma exacerbations [19], suggests that neutrophils may be associated with some types of severe asthma. This is supported by studies that showed neutrophil-generated matrix metalloprotease-9 and elastase promote airway remodeling, and the neutrophil-released cytokine, oncostatin-M, affects the epithelial barrier function in patients with severe asthma [15].

Airway hyperresponsiveness, a consistent feature of asthma, involves an exaggerated or excessive bronchoconstrictor response to stimuli. Although the mechanisms leading to airway hyperresponsiveness are poorly understood, increased activity of parasympathetic cholinergic pathways, in part, may contribute to airway hyperresponsiveness, independent of the underlying inflammation [20, 21]. Thus, anticholinergic therapies that target muscarinic receptors are effective. Sympathetic control in the airways is mediated via β2-adrenoreceptors expressed on airway smooth muscle cells and is the basis of the efficacy of short-acting β2-agonists and LABAs.

An additional video file illustrates the pathophysiology of asthma (see Additional file 1: Video S1).

Asthma phenotypes

Most early attempts to define asthma phenotypes were one dimensional and restricted to age of onset and atopy. A multidimensional approach has since been used to identify subgroups of patients with consistent patterns of clinical disease [22,23,24,25]. In a population of asthma patients receiving specialty care, four phenotypic clusters were identified: early-onset asthma, obesity-related asthma, symptom-predominant asthma with minimal eosinophilia, and the predominant eosinophilic late-onset asthma with few symptoms [23]. Because of the discordance between underlying inflammation and symptom presentation, the authors posited a role for examining underlying eosinophilic airway inflammation when deciding treatment versus the traditional approach of symptom-led ICS titration [23].

Multiple asthma phenotypes representing the spectrum of asthma severity (early-onset allergic asthma, late-onset severe asthma, and severe asthma with chronic obstructive pulmonary disease characteristics) were identified in a cohort of patients in the Severe Asthma Research Program (SARP) [22]. Among the patients who underwent sputum induction, four sputum inflammatory cellular patterns were identified based on median percentages of eosinophils (2%) and neutrophils (40%) [26]. Patients in clusters A and B (259/423 [61%]) had mild-to-moderate, early-onset asthma and either an eosinophil-predominant (≥ 2% eosinophils) or paucigranulocytic (< 2% eosinophils and < 40% neutrophils) sputum inflammatory cellular pattern. In contrast, most patients (83%) in clusters C and D (164/423 [39%]) with moderate-to-severe asthma had sputum neutrophilia, alone or with concurrent sputum eosinophilia. These results highlight the marked differences in inflammatory cell involvement across different clinical asthma phenotypes indicating that clinical heterogeneity is driven by pathobiological heterogeneity.

In a different cohort of patients from the Unbiased BIOmarkers in PREDiction of Respiratory Disease Outcomes (UBIOPRED) Consortium [27], four reproducible and stable clusters were identified: well-controlled, moderate-to-severe asthma; late-onset severe asthma in smokers and ex-smokers with chronic airflow obstruction; asthma in nonsmokers with chronic airflow obstruction; and obesity-related, uncontrolled, severe asthma in patients with increased exacerbations, but normal lung function. Although sputum neutrophil counts were similar across the clusters, sputum eosinophil counts were higher in the severe asthma clusters than in the moderate-to-severe asthma cluster.

Collectively, these studies suggest that asthma can be grouped into clinical phenotypes that are driven by several different endotypes [24]. The main inflammatory phenotypes are Th2 high (eosinophilic subtype) and Th2 low (noneosinophilic/paucigranulocytic and neutrophilic subtypes). Transcriptomic signatures may help better characterize these subtypes. Noninvasive analysis of sputum gene expression enabled identification of transcriptomic endotypes of asthma clusters that correlate with distinct clinical phenotypes of severe asthma [28]. Elucidating the underlying asthma endotypes and associated phenotypes may lead to improved precision-based medicine. Identification of patients within each phenotype using novel specific biomarkers and clinical symptoms may enable clinicians to use the right medication for the right patient.

Overview of current treatment recommendations

Established treatment options for severe asthma include small molecules such as ICSs, LABAs, the long-acting muscarinic antagonist (LAMA) tiotropium, and leukotriene receptor antagonists (LTRAs). Global guidance is provided by the GINA committee [2] and US-based guidance by the National Heart, Lung, and Blood Institute (NHLBI) [9, 29]. Per the stepwise approach outlined in the GINA strategy document [2], medium-dose maintenance ICS plus formoterol is recommended as the preferred treatment at GINA Step 4 for moderate-to-severe asthma (Fig. 1). Although LABA-based asthma medications had a black-box warning for asthma-related death for over a decade, the US Food and Drug Administration (FDA) removed the black-box warning from ICS + LABA drug labels in 2017 based on findings from four clinical trials involving 41,297 patients [30]; drug labels for single-ingredient LABA medications retain the warning. Tiotropium, the only LAMA approved for use in patients (aged ≥ 6 years) with asthma [31], may be considered as add-on therapy for children, adolescents, or adults with a history of exacerbations at GINA Step 4. Considering high-dose ICS plus formoterol, with add-on LAMA or biologics, are the preferred treatments at GINA Step 5 [2]. The NHLBI recommends daily ICS + LAMA, as early as Steps 3 and 4, as an alternative therapy, and as a preferred therapy at Step 5 for the management of persistent asthma in patients aged > 12 years [29].

However, before stepping up treatment, the presence of severe asthma—versus uncontrolled asthma caused by incorrect inhaler technique and/or poor adherence, or confounding factors and comorbidities—needs to be confirmed [1, 2]. GINA has provided general recommendations for managing severe asthma, all accompanied by caveats and limitations [32]; strategies include: optimizing the ICS + LABA dose in appropriate patients; low-dose maintenance oral corticosteroids (OCS), with strategies to minimize associated long-term side-effects; add-on treatment with tiotropium or macrolide; phenotype-guided (e.g., severe allergic, aspirin exacerbated) add-on treatments; and nonpharmacological approaches, such as bronchial thermoplasty.

Besides patient characteristics and phenotypes, patient’s preferences and practical issues (inhaler technique, adherence, and cost to patient) must also be considered while making treatment decisions.

Add-on asthma treatments

Use of LAMAs in asthma

Tiotropium reduces airflow obstruction by antagonizing muscarinic type-3 receptors on airway smooth muscles and submucosal glands, leading to bronchodilation and decreased mucus secretion (Fig. 2; see Additional file 1: Video S1) [33, 34]. Tiotropium, when added to background treatment of at least an ICS or ICS + LABA, significantly improved lung function and reduced asthma exacerbation rates (Table 1) in adult patients with moderate-to-severe asthma [35,36,37,38]. In a real-world cohort of patients with asthma initiated on ICS + LABA, compared with increasing the ICS plus LABA dose, add-on tiotropium significantly decreased all-cause and asthma-related emergency department visits and hospitalizations, the risk and rate of exacerbations, and the number of short-acting β2-agonist refills [39]. Evidence from other real-world studies supports data from randomized clinical trials and showed that add-on tiotropium resulted in improved clinical outcomes as well as reduced emergency department visits and hospitalizations in severe asthma patients [40, 41]. Of note, in a systematic review and meta-analysis of 15 randomized clinical trials (7122 patients), add-on tiotropium and ICS were associated with a significantly lower risk (risk ratio: 0.67 [95% CI 0.48, 0.92]) of asthma exacerbations than with placebo and ICS [42]; moreover, the treatment benefits from a LAMA were comparable to those from a LABA. Overall, these data suggest that treatment with ICS + LAMA can help reduce the risk of future exacerbations in patients inadequately controlled on ICS alone [43].

Table 1 Approved add-on asthma treatments

Improvements in lung function, risk of exacerbations, and symptom control with tiotropium versus placebo were independent of patients’ underlying eosinophil counts or IgE levels [44, 45]. Moreover, add-on tiotropium was considered cost-effective compared with standard of care or an anti-IgE biologic (omalizumab) at a willingness-to-pay threshold of $50,000/quality-adjusted life year in a recent US-based, cost-effectiveness study [46]. Based on the evidence, NHLBI guidelines [29], and GINA recommendations [2], tiotropium, the only LAMA approved for the treatment of asthma, should be added to ICS or ICS + LABA before considering a biologic as an add-on therapy.

Add-on biologics

FDA-approved biologics include omalizumab (anti-IgE), mepolizumab (anti-IL-5), reslizumab (anti-IL-5), benralizumab (anti-IL-5 receptor), dupilumab (anti-IL-4/IL-13 receptor), and tezepelumab (Table 1; see Additional file 1: Video S1) [47,48,49,50,51,52,53]. Tezepelumab, which targets TSLP, was recently approved by the FDA for the add-on maintenance treatment of adult and pediatric patients aged ≥ 12 years with severe asthma [53]. Tezepelumab was evaluated in phase 3 trials, such as the NAVIGATOR trial [54], which showed tezepelumab reduced exacerbations in patients with both high and low baseline blood eosinophil count, and improved asthma control, lung function, and health-related QoL in patients with severe, uncontrolled asthma. Among patients treated with medium to high doses of ICS + LABA, tezepelumab reduced rates of clinically significant asthma exacerbations compared with placebo, independent of baseline blood eosinophil counts [55].

Head-to-head clinical trials between biologics are lacking and indirect comparison of biologics has provided conflicting results, presumably because patient populations are not comparable across studies with respect to demographics and clinical characteristics, such as age, lung function, and eosinophil counts. In a network meta-analysis, benralizumab, dupilumab, mepolizumab, and reslizumab were associated with improvements in lung function (forced expiratory volume in 1 s [FEV1]), asthma control, and asthma-related QoL to varying degrees, although only reslizumab and dupilumab were found to significantly reduce asthma exacerbation rates [56]. In a global meta-analysis of randomized control trials of mepolizumab, reslizumab, and benralizumab, no clear superiority was observed [57]. However, in an indirect treatment comparison of these three biologics, where patients were stratified by baseline blood eosinophil count, mepolizumab was associated with significantly greater improvements in exacerbations and asthma control [58].

Biologics targeting IgE

Omalizumab, a monoclonal antibody that binds with IgE, is indicated for moderate-to-severe persistent asthma in patients aged ≥ 6 years with a positive skin test or in vitro reactivity to a relevant perennial aeroallergen and symptoms that are inadequately controlled with ICSs. Omalizumab treatment of patients with poorly controlled severe asthma and total serum IgE levels of 30 to 700 IU/mL improved asthma control, reduced exacerbations, and reduced or did not increase use of other medications (Table 1) [59,60,61,62,63]. Although omalizumab is indicated for use within this IgE-level range, there is some anecdotal evidence [64, 65] indicating that it can be successfully used outside of this range. Strong evidence exists for the use of omalizumab in patients with Th2-high asthma phenotype. In post hoc analyses of pooled data from phase 3 trials, omalizumab reduced exacerbations in patients with high blood eosinophil counts (≥ 260 or ≥ 300 cells/μL) [66, 67]. Furthermore, the difference in exacerbation frequency between omalizumab and placebo groups was greater in patients with moderate-to-severe persistent asthma with high blood eosinophil counts and high fractional exhaled nitric oxide (FeNO) concentrations than their low subgroup counterparts in the EXTRA study [66]. However, real-life data from the STELLAIR study suggest similar omalizumab effectiveness in patients with blood eosinophil counts of ≥ 300 cells/µL and < 300 cells/µL [68].

Biologics targeting IL-5 or IL-5 receptor

Mepolizumab and reslizumab target IL-5, which promotes the recruitment of eosinophils from the bone marrow and their subsequent proliferation [69]. Mepolizumab and reslizumab are indicated as add-on maintenance treatments for severe eosinophilic asthma in patients aged ≥ 6 years and adults aged ≥ 18 years, respectively (Table 1) [47, 48, 70,71,72,73,74,75,76]. Unlike mepolizumab, which is administered subcutaneously, reslizumab is only approved for intravenous administration [47]. The primary endpoints were not reached in phase 3 trials of subcutaneously administered reslizumab [77]. Both drugs are efficacious in eosinophilic asthma; however, the blood eosinophil count thresholds used in their respective pivotal trials were significantly different. In phase 2/3 mepolizumab trials, the thresholds used were blood eosinophil count of ≥ 150 cells/μL at screening or ≥ 300 cells/μL in the year prior to enrollment; ≥ 400 cells/μL was used in reslizumab trials [72,73,74,75,76, 78]. Of note, reslizumab has a black-box warning on anaphylaxis, which was reported in 0.3% enrolled in placebo-controlled clinical trials [47].

Benralizumab targets the IL-5 receptor α-subunit, thereby preventing binding of IL-5 to its receptor, depleting eosinophils and basophils [79]. It also enhances antibody-dependent, cell-mediated cytotoxicity as a consequence of its afucoyslation [49]. Benralizumab is indicated for the add-on maintenance treatment of patients with severe asthma aged ≥ 12 years, and with an eosinophilic inflammatory phenotype [49]. In phase 3 trials of benralizumab, efficacy was demonstrated in patients with baseline eosinophil counts of ≥ 300 cells/μL [80, 81].

Add-on biologic targeting the IL-4 and IL-13 pathways

Dupilumab inhibits the IL-4 and IL-13 pathways by binding to the IL-4 receptor α-subunit and prevents the downstream activation of effectors of these cytokines. Dupilumab is approved by the FDA as add-on maintenance treatment in patients aged ≥ 6 years with moderate-to-severe, eosinophilic asthma or with oral corticosteroid-dependent asthma, regardless of blood eosinophil count [51, 82]. Dupilumab is however most efficacious in patients with blood eosinophil counts ≥ 300 cells/μL, producing a 47.7% reduction in exacerbations and a 0.32 L increase in FEV1 in the pivotal clinical trial [82]. In addition, post hoc analyses of the phase III trial evaluating associations between T2 biomarkers and dupilumab treatment response revealed that besides blood eosinophil counts, FeNO concentration was associated with significantly reduced exacerbations and higher FEV1 [83]. Given the high prevalence in patients with chronic severe asthma of airway mucus plugs showing marked increases in IL-13 gene expression [84], dupilumab might find potential success in patients with excess mucus.

Use of biomarkers in treatment decision-making

According to the GINA strategy document, although studies are needed to identify the populations most likely to benefit from biomarker-guided treatment adjustments, such approaches may be used in patients with moderate or severe asthma managed in centers experienced in such techniques [2]. For example, a high FeNO concentration (> 50 parts per billion [ppb]) in adults is associated with ICS responsiveness [2]. FeNO is also a predictor of response to biologics; the anti-IgE biologic omalizumab yielded greater exacerbation reduction in patients with high FeNO concentration (≥ 19.5 ppb) than in patients with low FeNO (< 19.5 ppb) [66]. Further, although predictive blood eosinophil count ranges vary for different biologics, high counts are purported to predict responses to biologics targeting IL-5 and IgE [85]. Results of a meta-analysis of 16 studies of FeNO-based management and six of sputum-based management demonstrated that adjusting treatment based on FeNO levels and sputum eosinophil counts reduced the likelihood of asthma exacerbations without a significant effect on asthma control or lung function [86].

Other options

LTRAs may have limited efficacy in broad populations but select patients might warrant a short therapeutic trial to determine whether there is substantive benefit. Use of low-dose OCSs (≤ 7.5 mg/day prednisone equivalent) should be considered as a rescue medication in adults with severe asthma despite medical therapy at GINA Step 5 [32]. With bronchial thermoplasty—a nonpharmacologic, device-based treatment—thermal energy is delivered to the airways, resulting in reduction of airway smooth muscle fibers and amelioration of asthma symptoms [87]. Bronchial thermoplasty has been evaluated in a few studies, and in a meta-analysis of three randomized controlled trials and interventional nonrandomized studies, modest improvements in asthma control and QoL measures occurred after bronchial thermoplasty [88]. In addition, evaluation of long-term outcomes of bronchial thermoplasty in patients with severe asthma indicated that 3 years after the procedure, severe exacerbations, emergency department visits, and hospitalizations significantly decreased by 45%, 55%, and 40%, respectively [89].

Biologics and small molecules under investigation

IL-25 and IL-33 hold potential as upstream targets for the treatment of asthma. Although no biologics under investigation directly target IL-25, two anti-IL-33 antibodies, i.e., REGN3500 and ANB020 or etokimab, are under investigation [90, 91].

Various small molecules targeting specific inflammatory pathways (T2 or non-T2) are also being evaluated (Additional file 2: Table S1). The chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), which binds to PGD2 [92], is one potential key target. CRTH2, expressed on eosinophils, mast cells, and basophils, and PGD2 are involved in allergic inflammation [92].

Other promising targets are the STAT5/6 Src homology 2 domains. In mouse models, PM-43I—a small-molecule inhibitor of the STAT6 Src homology 2 domain that prevents recruitment to the IL-4Rα docking site and phosphorylation of Tyr641—potently inhibited STAT5- and STAT6-dependent allergic airway disease and reversed preexisting allergic airway disease [93].

Overall, these targeted therapies may play a role in individualized treatment of severe asthma; however, their application will likely be limited to patients with certain phenotypes who meet the specific criteria for use.

Algorithm for stepwise treatment of severe asthma

The assessment and management of severe asthma is a stepwise process as outlined in the GINA strategy document, with adequate checks for adherence to treatment and correct inhaler technique at every step and with all changes in treatment. Asthma management, including medication choices, should always involve a shared decision-making process between patients and physicians. Practical considerations around dosing interval, cost, number of injections, and home versus clinic dosing, may influence choice of treatment for severe asthma.

Although biologics are typically recommended for patients with severe, uncontrolled disease, high costs, parenteral administration at regular intervals, and regular monitoring may prove to be barriers to their use. In the current treatment landscape, a common dilemma that physicians face is whether to proceed to treatment with add-on biologics directly or to add a LAMA. We propose a provisional algorithm, based on available data, for the treatment of severe asthma, that builds upon the recommendations of GINA [2, 32] (Fig. 3; see Additional file 1: Video S1).

Fig. 3
figure 3

Selection of treatment options for patients with severe asthma based on clinical evaluation and biomarker levels. Biomarkers shown are not mutually exclusive. *Add-on inhaled therapy such as tiotropium may be considered before initiating biologics therapy because of the comparatively low costs associated with its use [46]. Response is defined as a reduction in exacerbations and improvement in asthma control within threshold levels. Total IgE levels should be 30–700 IU/mL. §Blood eosinophil count thresholds: reslizumab ≥ 400 µL; mepolizumab ≥ 150 cells/µL, and dupilumab and benralizumab ≥ 300 cells/µL. **Patients with high IgE levels who have blood eosinophil counts ≥ 300 cells/µL may be considered for Th2 biologic therapy. According to GINA 2021 recommendations [2], potential predictors of good asthma response include increasing baseline levels of blood eosinophils and FeNO [82]. FeNO fractional exhaled nitric oxide, FDA Food and Drug Administration, GINA Global Initiative for Asthma, ICS inhaled corticosteroids, Ig immunoglobulin, LABA long-acting β2-agonist, LTRA leukotriene receptor antagonist, OCS oral corticosteroid, Th T helper

The complete benefits of non-biologic inhaled therapies are perhaps not being fully considered before the switch to biologics. We recommend that inhaled therapies such as tiotropium should be considered before moving to a biologic therapy as they may prove efficacious and achieve control in a range of patients (i.e., of various age groups, across asthma severities, and independent of their eosinophil counts) [45]. Notably, tiotropium was approved in 2014 (2017 for ages 6–11) when most pivotal trials on biologics were conducted [71, 73,74,75,76] or a minority of patients were on LAMAs at the time of entry into these trials [70, 80, 81]. Furthermore, treatment recommendations do not strongly advocate the use of LAMAs as add-on therapy [2, 29].

If all recommended inhaled and oral therapies are ineffective, phenotyping is recommended, and biomarker screening tests should be considered to determine the most appropriate step-up therapy using a shared decision-making approach with the patient. In the absence of direct clinical comparisons of biologics, the choice of biologic may be determined by the physician based on specific biomarkers underlying patient asthma phenotypes. Bronchial thermoplasty should be considered in appropriate patients as well [32].

Conclusions

Asthma is a chronic disease comprising multiple clinical and inflammatory phenotypes. Besides medium- or high-dose ICS + LABA, tiotropium and several biologics, tailored toward specific inflammatory phenotypes, are approved as add-on therapies for treatment of severe asthma. Before considering the use of biologics, add-on inhaled therapies, such as LAMAs, may provide scope for improvement in asthma control owing to their comparatively low cost. Notably, the on-going development of new biologics and small molecules may pave the way for targeted treatments of patients with severe asthma with an appropriate phenotype.

Availability of data and materials

Not applicable.

Abbreviations

CRTH2:

Chemoattractant receptor-homologous molecule expressed on Th2 cells

FDA:

Food and Drug Administration

FeNO:

Fractional exhaled nitric oxide

FEV1 :

Forced expiratory volume in 1 s

GINA:

Global Initiative for Asthma

Ig:

Immunoglobulin

ILC2:

Innate lymphoid cell type 2

ICS:

Inhaled corticosteroids

IL:

Interleukin

LABA:

Long-acting β2-agonist

LAMA:

Long-acting muscarinic antagonist

OCS:

Oral corticosteroids

PGD2 :

Prostaglandin D2

ppb:

Parts per billion

QoL:

Quality of life

STAT:

Signal transducer and activator of transcription

Th2:

T-helper type 2

TSLP:

Thymic stromal lymphopoietin

T2:

Type 2

References

  1. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343–73 (Erratum in Eur Respir J. 2018;52:1352020).

    CAS  PubMed  Article  Google Scholar 

  2. Global Initiative for Asthma. Global strategy for asthma management and prevention; 2021. https://ginasthma.org/gina-reports/. Accessed 10 June 2021.

  3. Hekking PP, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. The prevalence of severe refractory asthma. J Allergy Clin Immunol. 2015;135:896–902.

    PubMed  Article  Google Scholar 

  4. von Bulow A, Kriegbaum M, Backer V, Porsbjerg C. The prevalence of severe asthma and low asthma control among Danish adults. J Allergy Clin Immunol Pract. 2014;2:759–67.

    Article  Google Scholar 

  5. von Bülow A, Backer V, Bodtger U, Søes-Petersen NU, Vest S, Steffensen I, et al. Differentiation of adult severe asthma from difficult-to-treat asthma—outcomes of a systematic assessment protocol. Respir Med. 2018;145:41–7.

    Article  Google Scholar 

  6. Zeiger RS, Schatz M, Dalal AA, Qian L, Chen W, Ngor EW, et al. Utilization and costs of severe uncontrolled asthma in a managed-care setting. J Allergy Clin Immunol Pract. 2016;4:120-129.e123.

    PubMed  Article  Google Scholar 

  7. Chipps BE, Zeiger RS, Borish L, Wenzel SE, Yegin A, Hayden ML, et al. Key findings and clinical implications from the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) study. J Allergy Clin Immunol. 2012;130:332-342.e310.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. King GG, James A, Harkness L, Wark PAB. Pathophysiology of severe asthma: we’ve only just started. Respirology. 2018;23:262–71.

    PubMed  Article  Google Scholar 

  9. National Asthma Education and Prevention Program, National Heart, Lung and Blood Institute. Expert panel report 3: guidelines for the diagnosis & management of asthma. 2007. http://www.ncbi.nlm.nih.gov/books/NBK7232/. Accessed 6 Feb 2020.

  10. Clutterbuck EJ, Hirst EM, Sanderson CJ. Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures: comparison and interaction with IL-1, IL-3, IL-6, and GMCSF. Blood. 1989;73:1504–12.

    CAS  PubMed  Article  Google Scholar 

  11. Lund S, Walford HH, Doherty TA. Type 2 innate lymphoid cells in allergic disease. Curr Immunol Rev. 2013;9:214–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Halim Timotheus YF, Krauß Ramona H, Sun Ann C, Takei F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity. 2012;36:451–63.

    CAS  PubMed  Article  Google Scholar 

  13. Martinez-Gonzalez I, Steer CA, Takei F. Lung ILC2s link innate and adaptive responses in allergic inflammation. Trends Immunol. 2015;36:189–95.

    CAS  PubMed  Article  Google Scholar 

  14. Fajt ML, Gelhaus SL, Freeman B, Uvalle CE, Trudeau JB, Holguin F, et al. Prostaglandin D2 pathway upregulation: relation to asthma severity, control, and TH2 inflammation. J Allergy Clin Immunol. 2013;131:1504-1512.e1512.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Ray A, Kolls JK. Neutrophilic inflammation in asthma and association with disease severity. Trends Immunol. 2017;38:942–54.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Tliba O, Panettieri RA Jr. Paucigranulocytic asthma: uncoupling of airway obstruction from inflammation. J Allergy Clin Immunol. 2019;143:1287–94.

    PubMed  Article  Google Scholar 

  17. Svenningsen S, Nair P. Asthma endotypes and an overview of targeted therapy for asthma. Front Med. 2017;4:158.

    Article  Google Scholar 

  18. Nakagome K, Matsushita S, Nagata M. Neutrophilic inflammation in severe asthma. Int Arch Allergy Immunol. 2012;158(Suppl 1):96–102.

    CAS  PubMed  Article  Google Scholar 

  19. Fahy J. Prominent neutrophilic inflammation in sputum from subjents with asthma exaceration. J Allergy Clin Immunol. 1995;95:843–852.

    CAS  PubMed  Article  Google Scholar 

  20. Goyal M, Jaseja H, Verma N. Increased parasympathetic tone as the underlying cause of asthma: a hypothesis. Med Hypotheses. 2010;74:661–4.

    PubMed  Article  Google Scholar 

  21. Price D, Fromer L, Kaplan A, van der Molen T, Roman-Rodriguez M. Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma? NPJ Prim Care Respir Med. 2014;24:14023.

    PubMed  PubMed Central  Article  Google Scholar 

  22. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the severe asthma research program. Am J Respir Crit Care Med. 2010;181:315–23.

    PubMed  Article  Google Scholar 

  23. Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008;178:218–24.

    PubMed  Article  Google Scholar 

  24. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18:716.

    CAS  PubMed  Article  Google Scholar 

  25. Siroux V, Basagaña X, Boudier A, Pin I, Garcia-Aymerich J, Vesin A, et al. Identifying adult asthma phenotypes using a clustering approach. Eur Respir J. 2011;38(2):310–7.

    CAS  PubMed  Article  Google Scholar 

  26. Moore WC, Hastie AT, Li X, Li H, Busse WW, Jarjour NN, et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol. 2014;133:1557-1563.e1555.

    PubMed  Article  Google Scholar 

  27. Lefaudeux D, De Meulder B, Loza MJ, Peffer N, Rowe A, Baribaud F, et al. U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics. J Allergy Clin Immunol. 2017;139:1797–807.

    CAS  PubMed  Article  Google Scholar 

  28. Yan X, Chu J-H, Gomez J, Koenigs M, Holm C, He X, et al. Noninvasive analysis of the sputum transcriptome discriminates clinical phenotypes of asthma. Am J Resp Critl Care Med. 2015;191:1116–25.

    CAS  Article  Google Scholar 

  29. National Asthma Education and Prevention Program, National Heart, Lung and Blood Institute. 2020 focused updates to the asthma management guidelines. 2020. https://www.nhlbi.nih.gov/health-topics/asthma-management-guidelines-2020-updates. Accessed 14 Nov 2021.

  30. FDA. FDA review finds no significant increase in risk of serious asthma outcomes with long-acting beta agonists (LABAs) used in combination with inhaled corticosteroids (ICS). 2017. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM589997.pdf. Accessed 6 Feb 2020.

  31. FDA. Spiriva® Respimat® (tiotropium bromide). Highlights of prescribing information. 2018. https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Spiriva%20Respimat/spirivarespimat.pdf. Accessed 6 Feb 2020.

  32. Global Initiative for Asthma (GINA). Pocket guide for health professionals. Difficult-to-treat and severe asthma in adolescent and adult patients: diagnosis and management. 2019. https://ginasthma.org/wp-content/uploads/2019/04/GINA-Severe-asthma-Pocket-Guide-v2.0-wms-1.pdf. Accessed 3 Dec 2019.

  33. Barnes PJ. The pharmacological properties of tiotropium. Chest. 2000;117:63S-66S.

    CAS  PubMed  Article  Google Scholar 

  34. Disse B, Speck GA, Rominger KL, Witek TJ Jr, Hammer R. Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci. 1999;64:457–64.

    CAS  PubMed  Article  Google Scholar 

  35. Hamelmann E, Bateman ED, Vogelberg C, Szefler SJ, Vandewalker M, Moroni-Zentgraf P, et al. Tiotropium add-on therapy in adolescents with moderate asthma: a 1-year randomized controlled trial. J Allergy Clin Immunol. 2016;138:441-450.e448.

    CAS  PubMed  Article  Google Scholar 

  36. Hamelmann E, Bernstein JA, Vandewalker M, Moroni-Zentgraf P, Verri D, Unseld A, et al. A randomised controlled trial of tiotropium in adolescents with severe symptomatic asthma. Eur Respir J. 2017. https://doi.org/10.1183/13993003.01100-2016.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kerstjens HA, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012;367:1198–207.

    CAS  PubMed  Article  Google Scholar 

  38. Szefler SJ, Murphy K, Harper T 3rd, Boner A, Laki I, Engel M, et al. A phase III randomized controlled trial of tiotropium add-on therapy in children with severe symptomatic asthma. J Allergy Clin Immunol. 2017;140:1277–87.

    CAS  PubMed  Article  Google Scholar 

  39. Chipps B, Mosnaim G, Mathur SK, Shaikh A, Khoury S, Gopalan G, et al. Add-on tiotropium versus step-up inhaled corticosteroid plus long-acting beta-2-agonist in real-world patients with asthma. Allergy Asthma Proc. 2020;41:248–55.

    CAS  PubMed  Article  Google Scholar 

  40. Abadoglu O, Berk S. Tiotropium may improve asthma symptoms and lung function in asthmatic patients with irreversible airway obstruction: the real-life data. Clin Respir J. 2016;10:421–7.

    CAS  PubMed  Article  Google Scholar 

  41. Price D, Kaplan A, Jones R, Freeman D, Burden A, Gould S, et al. Long-acting muscarinic antagonist use in adults with asthma: real-life prescribing and outcomes of add-on therapy with tiotropium bromide. J Asthma Allergy. 2015;8:1.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Sobieraj DM, Baker WL, Nguyen E, Weeda ER, Coleman CI, White CM, et al. Association of inhaled corticosteroids and long-acting muscarinic antagonists with asthma control in patients with uncontrolled, persistent asthma: a systematic review and meta-analysis inhaled corticosteroids and long-acting muscarinic antagonists for uncontrolled asthma inhaled corticosteroids and long-acting muscarinic antagonists for uncontrolled asthma. JAMA. 2018;319:1473–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Krishnan JA, Au DH. Time to converge FDA decisions and evidence syntheses for long-acting muscarinic antagonists and SMART in guidelines for the treatment of asthma. JAMA. 2018;319:1441–3.

    PubMed  Article  Google Scholar 

  44. Kerstjens HA, Moroni-Zentgraf P, Tashkin DP, Dahl R, Paggiaro P, Vandewalker M, et al. Tiotropium improves lung function, exacerbation rate, and asthma control, independent of baseline characteristics including age, degree of airway obstruction, and allergic status. Respir Med. 2016;117:198–206.

    PubMed  Article  Google Scholar 

  45. Casale TB, Bateman ED, Vandewalker M, Virchow JC, Schmidt H, Engel M, et al. Tiotropium respimat add-on is efficacious in symptomatic asthma, independent of T2 phenotype. J Allergy Clin Immunol Pract. 2018;6:923-935.e929.

    PubMed  Article  Google Scholar 

  46. Zafari Z, Sadatsafavi M, FitzGerald JM. Cost-effectiveness of tiotropium versus omalizumab for uncontrolled allergic asthma in US. Cost Eff Resour Alloc. 2018;16:3.

    PubMed  PubMed Central  Article  Google Scholar 

  47. FDA. Cinqair® (reslizumab). Highlights of prescribing information. 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761033lbl.pdf. Accessed 5 Feb 2020.

  48. FDA. Nucala® (mepolizumab). Highlights of prescribing information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125526s004lbl.pdf. Accessed 5 Feb 2020.

  49. FDA. Fasenra™ (benralizumab). Highlights of prescribing information. 2017. https://www.azpicentral.com/fasenra/fasenra_pi.pdf. Accessed 5 Feb 2020.

  50. FDA. Xolair® (omalizumab). Highlights of prescribing information. 2018. https://www.gene.com/download/pdf/xolair_prescribing.pdf. Accessed 5 Feb 2020.

  51. Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med. 2018;378:2475–85.

    CAS  PubMed  Article  Google Scholar 

  52. Haldar P, Pavord ID. Noneosinophilic asthma: a distinct clinical and pathologic phenotype. J Allergy Clin Immunol. 2007;119:1043–52.

    CAS  PubMed  Article  Google Scholar 

  53. FDA. TEZSPIRE™ (tezepelumab-ekko). Highlights of prescribing information 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761224s000lbl.pdf. Accessed 4 Feb 2022.

  54. Menzies-Gow A, Corren J, Bourdin A, Chupp G, Israel E, Griffiths J, et al. Efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma: results from the phase 3 NAVIGATOR study. J Allergy Clin Immunol. 2021;147:AB249.

    Google Scholar 

  55. Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017;377:936–46.

    CAS  PubMed  Article  Google Scholar 

  56. Iftikhar IH, Schimmel M, Bender W, Swenson C, Amrol D. Comparative efficacy of anti IL-4, IL-5 and IL-13 drugs for treatment of eosinophilic asthma: a network meta-analysis. Lung. 2018;196:517–30.

    CAS  PubMed  Article  Google Scholar 

  57. Cabon Y, Molinari N, Marin G, Vachier I, Gamez AS, Chanez P, et al. Comparison of anti-interleukin-5 therapies in patients with severe asthma: global and indirect meta-analyses of randomized placebo-controlled trials. Clin Exp Allergy. 2017;47:129–38.

    CAS  PubMed  Article  Google Scholar 

  58. Busse W, Chupp G, Nagase H, Albers FC, Doyle S, Shen Q, et al. Anti-IL-5 treatments in patients with severe asthma by blood eosinophil thresholds: indirect treatment comparison. J Allergy Clin Immunol. 2019;143:190-200.e120.

    CAS  PubMed  Article  Google Scholar 

  59. Bardelas J, Figliomeni M, Kianifard F, Meng X. A 26-week, randomized, double-blind, placebo-controlled, multicenter study to evaluate the effect of omalizumab on asthma control in patients with persistent allergic asthma. J Asthma. 2012;49:144–52.

    CAS  PubMed  Article  Google Scholar 

  60. Holgate ST, Chuchalin AG, Hebert J, Lötvall J, Persson GB, Chung KF, et al. Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Clin Exp Allergy. 2004;34:632–8.

    CAS  PubMed  Article  Google Scholar 

  61. Humbert M, Beasley R, Ayres J, Slavin R, Hébert J, Bousquet J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005;60:309–16.

    CAS  PubMed  Article  Google Scholar 

  62. Lanier B, Bridges T, Kulus M, Taylor AF, Berhane I, Vidaurre CF. Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. J Allergy Clin Immunol. 2009;124:1210–6.

    CAS  PubMed  Article  Google Scholar 

  63. Hanania NA, Alpan O, Hamilos DL, Condemi JJ, Reyes-Rivera I, Zhu J, et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med. 2011;154:573–82.

    PubMed  Article  Google Scholar 

  64. Ankerst J, Nopp A, Johansson SG, Adédoyin J, Oman H. Xolair is effective in allergics with a low serum IgE level. Int Arch Allergy Immunol. 2010;152:71–4.

    CAS  PubMed  Article  Google Scholar 

  65. Maselli DJ, Singh H, Diaz J, Peters JI. Efficacy of omalizumab in asthmatic patients with IgE levels above 700 IU/mL: a retrospective study. Ann Allergy Asthma Immunol. 2013;110:457–61.

    CAS  PubMed  Article  Google Scholar 

  66. Hanania NA, Wenzel S, Rosén K, Hsieh HJ, Mosesova S, Choy DF, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187:804–11.

    CAS  PubMed  Article  Google Scholar 

  67. Casale TB, Chipps BE, Rosén K, Trzaskoma B, Haselkorn T, Omachi TA, et al. Response to omalizumab using patient enrichment criteria from trials of novel biologics in asthma. Allergy. 2018;73:490–7.

    CAS  PubMed  Article  Google Scholar 

  68. Humbert M, Taillé C, Mala L, Le Gros V, Just J, Molimard M, STELLAIR investigators. Omalizumab effectiveness in patients with severe allergic asthma according to blood eosinophil count: the STELLAIR study. Eur Respir J. 2018;51:1702523.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. Pepper AN, Renz H, Casale TB, Garn H. Biologic therapy and novel molecular targets of severe asthma. J Allergy Clin Immunol Pract. 2017;5:909–16.

    PubMed  Article  Google Scholar 

  70. Chupp GL, Bradford ES, Albers FC, Bratton DJ, Wang-Jairaj J, Nelsen LM, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017;5:390–400.

    PubMed  Article  Google Scholar 

  71. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198–207.

    PubMed  Article  CAS  Google Scholar 

  72. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380:651–9.

    CAS  PubMed  Article  Google Scholar 

  73. Bjermer L, Lemiere C, Maspero J, Weiss S, Zangrilli J, Germinaro M. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016;150:789–98.

    PubMed  Article  Google Scholar 

  74. Brusselle G, Germinaro M, Weiss S, Zangrilli J. Reslizumab in patients with inadequately controlled late-onset asthma and elevated blood eosinophils. Pulm Pharmacol Ther. 2017;43:39–45.

    CAS  PubMed  Article  Google Scholar 

  75. Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3:355–66.

    CAS  PubMed  Article  Google Scholar 

  76. Corren J, Weinstein S, Janka L, Zangrilli J, Garin M. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016;150:799–810.

    PubMed  Article  Google Scholar 

  77. Teva Pharmaceuticals. Press release. 2018. Teva announces top-line results from Phase III studies of subcutaneously administered reslizumab in patients with severe eosinophilic asthma. https://www.chemdiv.com/teva-announces-top-line-results-phase-iii-studies-subcutaneously-administered-reslizumab-patients-severe-eosinophilic-asthma/. Accessed 7 Feb 2020.

  78. Ortega HG, Yancey SW, Mayer B, Gunsoy NB, Keene ON, Bleecker ER, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. 2016;4:549–56.

    CAS  PubMed  Article  Google Scholar 

  79. Kolbeck R, Kozhich A, Koike M, Peng L, Andersson CK, Damschroder MM, et al. MEDI-563, a humanized anti-IL-5 receptor α mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010;125:1344-1353.e1342.

    CAS  PubMed  Article  Google Scholar 

  80. Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388:2115–27.

    CAS  PubMed  Article  Google Scholar 

  81. FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388:2128–41.

    CAS  PubMed  Article  Google Scholar 

  82. Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378:2486–96.

    CAS  PubMed  Article  Google Scholar 

  83. Wenzel SE, Pavord I, Zhang B, Maroni J, Rowe P, Hamilton JD, et al. Type 2 biomarkers associated with dupilumab efficacy in patients with uncontrolled, moderate-to-severe asthma enrolled in the phase 3 study LIBERTY ASTHMA QUEST. C101 asthma clinical and mechanistic studies: American Thoracic Society; 2018. p. A5949.

  84. Dunican EM, Elicker BM, Gierada DS, Nagle SK, Schiebler ML, Newell JD, et al. National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP). Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. J Clin Invest. 2018;128:997–1009.

    PubMed  PubMed Central  Article  Google Scholar 

  85. Kostikas K, Brindicci C, Patalano F. Blood eosinophils as biomarkers to drive treatment choices in asthma and COPD. Curr Drug Targets. 2018;19:1882–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. Petsky HL, Cates CJ, Kew KM, Chang AB. Tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils): a systematic review and meta-analysis. Thorax. 2018;73:1110–9.

    PubMed  Article  Google Scholar 

  87. Pretolani M, Bergqvist A, Thabut G, Dombret MC, Knapp D, Hamidi F, et al. Effectiveness of bronchial thermoplasty in patients with severe refractory asthma: clinical and histopathologic correlations. J Allergy Clin Immunol. 2017;139:1176–85.

    PubMed  Article  Google Scholar 

  88. D'Anci KE, Lynch MP, Leas BF, Apter AJ, Bryant-Stephens T, Kaczmarek JL, et al. AHRQ comparative effectiveness reviews. Effectiveness and safety of bronchial thermoplasty in management of asthma. Rockville: Agency for Healthcare Research and Quality (US); 2017;18-EHC003-EF.

  89. Chupp G, Laviolette M, Cohn L, McEvoy C, Bansal S, Shifren A, et al. Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: a comparison of 3-year follow-up results from two prospective multicentre studies. Eur Respir J. 2017;50:1700017.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  90. ClinicalTrials.gov. Identifier NCT03112577, study of REGN3500 and dupilumab in patients with asthma. 2018; Bethesda: National Library of Medicine (US). https://clinicaltrials.gov/ct2/show/NCT03112577. Accessed 5 Feb 2020.

  91. ClinicalTrials.gov. Identifier NCT03469934, proof of concept study to investigate ANB020 activity in adult patients with severe eosinophilic asthma. Bethesda: National Library of Medicine (US); 2018. https://clinicaltrials.gov/ct2/show/NCT03469934. Accessed 5 Feb 2020.

  92. Hirai H, Tanaka K, Yoshie O, Ogawa K, Kenmotsu K, Takamori Y, et al. Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J Exp Med. 2001;193:255–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Knight JM, Mandal P, Morlacchi P, Mak G, Li E, Madison M, et al. Small molecule targeting of the STAT5/6 Src homology 2 (SH2) domains to inhibit allergic airway disease. J Biol Chem. 2018;293:10026–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

Writing, editorial support, and formatting assistance was provided by Michelle Rebello, Ph.D., Vidula Bhole, MD, MHSc, and Maribeth Bogush, MCI, Ph.D., of Cactus Life Sciences (part of Cactus Communications), which was contracted and compensated by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) for these services. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations.

Funding

This article was funded by Boehringer Ingelheim Pharmaceuticals, Inc. The authors received no direct compensation related to the development of the manuscript.

Author information

Authors and Affiliations

Authors

Contributions

The authors meet the criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). WJC and GLC were involved in conception and design of the review and drafting the work and revising it critically for important intellectual content. Both authors are accountable for all aspects of the work. Both authors read and approved the final manuscript.

Corresponding author

Correspondence to William J. Calhoun.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

GLC reports personal fees and other fees (consultant, speakers bureau, and clinical trial site) from GlaxoSmithKline, Boehringer Ingelheim Pharmaceuticals, Genentech, AstraZeneca, Sanofi Genzyme, and Regeneron outside the submitted work. WJC report personal fees from Genentech and grants from AstraZeneca and Sanofi, outside the submitted work.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1: Video S1. Overview of the pathophysiology of asthma, mechanism of action of available inhaled therapies and biologics, and the proposed treatment algorithm for severe asthma.

Additional file 2: Table S1.

Small molecules in asthma under investigation.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Calhoun, W.J., Chupp, G.L. The new era of add-on asthma treatments: where do we stand?. Allergy Asthma Clin Immunol 18, 42 (2022). https://doi.org/10.1186/s13223-022-00676-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13223-022-00676-0

Keywords

  • Add-on
  • Add-on therapy
  • Biological therapy
  • Severe asthma
  • Tiotropium bromide