Open Respiratory Archives 5 (2023) 100231 Open Respiratory Archives www.elsevier.es/ora Review Efficacy and Potential Positioning of Tezepelumab in the Treatment of Severe Asthma Vicente Plaza a,∗ , Conxa Cañete b , Christian Domingo c , Carlos Martínez Rivera d , Xavier Muñoz e a Hospital de la Santa Creu i Sant Pau (Barcelona), Universitat Autònoma Barcelona (UAB), Spain b Consorci Sanitari Integral (L’Hospitalet de Llobregat), Spain c Corporació Sanitària Parc Taulí (Sabadell), Universitat Autònoma Barcelona (UAB), Spain d Hospital Germans Trias i Pujol (Badalona), Universitat Autònoma Barcelona (UAB), Spain e Hospital de la Vall d’Hebron (Barcelona), Universitat Autònoma Barcelona (UAB), Spain a r t i c l e i n f o a b s t r a c t Article history: The excellent results for monoclonal antibodies in the treatment of severe uncontrolled asthma (SUCA) Received 14 October 2022 represent a milestone in current treatment of asthmatic disorders. Remaining, however, are several sub- Accepted 19 December 2022 sidiary areas for improvement in which new biologics are expected to make a decisive contribution. These Available online 3 January 2023 biologics include tezepelumab, a monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP). TSLP is an epithelial-release cytokine (alarmin) that plays a key role in initiating both the innate (group Keywords: 2 innate lymphoid cell (ILC) pathway) and the acquired (T helper 2 (Th2) pathway) immune responses Phenotype by activating the type 2 (T2) asthma inflammatory pathway through both. It is also thought that it may Uncontrolled asthma Alarmin additionally intervene in the neutrophilic non-T2 inflammatory pathway (via interaction with ILC3 and Thymic stromal lymphopoietin interleukin-17). Six clinical trials that included 2187 patients with uncontrolled asthma, with 2 or more exacerbations in the previous year, on medium/high-dose inhaled corticosteroids and at least 1 other controller, have demonstrated – irrespective of T2 endotype (and possibly also non-T2 endotype) – the efficacy and safety of tezepelumab, as it significantly reduces exacerbations (61.7%–66%) and bronchial hyperresponsiveness, and improves lung function, disease control, and quality of life. Tezepelumab could be indicated for the treatment of patients with, independently of the T2 phenotype (eosinophilic and non-eosinophilic), and may even be the only biologic available for treatment of non-T2 SUCA. © 2023 Sociedad Española de Neumologı́a y Cirugı́a Torácica (SEPAR). Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). Eficacia y posible posicionamiento del tezepelumab para tratar el asma grave r e s u m e n Palabras clave: Los excelentes resultados de los anticuerpos monoclonales en el tratamiento del asma grave no con- Fenotipo trolada (AGNC) constituyen un hito en el tratamiento actual de los trastornos asmáticos. Sin embargo, Asma no controlada aún quedan varios aspectos complementarios susceptibles de mejorar para los que se esperan contribu- Alarmina ciones decisivas de los nuevos biofármacos, entre los cuales se encuentra el tezepelumab, un anticuerpo Linfopoyetina estromal tímica monoclonal que bloquea la linfopoyetina estromal tímica (TSLP). La TSLP es una citocina de liberación Abbreviations: ACQ, Asthma Control Questionnaire; APC, antigen presenting cell; AQLQ, Asthma Quality Of Life Questionnaire; BHR, bronchial hyperresponsiveness; BMI, body mass index; DC, dendritic cell; EGPA, eosinophilic granulomatosis with polyangiitis; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in the first second; GEMA, Spanish Asthma Management Guidelines; GINA, Global Initiative for Asthma; HES, idiopathic hypereosinophilic syndrome; ICS, inhaled corticosteroids; IgE, immunoglobulin E; IL, interleukin; IL-1␤, interleukin 1 beta; IL-7R␣, interleukin-7 receptor alpha; ILC, innate lymphoid cell; LABA, long-acting ␤2-adrenergic agent; LAMA, long-acting muscarinic antagonist; lfTSLP, long form TSLP; MAB, monoclonal antibody; mRNA, messenger ribonucleic acid; NKT, natural killer T (cell); OCS, oral corticosteroids; SC, subcutaneous route; SEAIC, Spanish Society of Allergy and Clinical Immunology; SEPAR, Spanish Society of Pulmonology and Thoracic Surgery; sfTSLP, short form TSLP; SNOT, Sino-Nasal Outcome Test; SUCA, severe uncontrolled asthma; T2, type 2; TH, T helper (cell); TNF␣, tumour necrosis factor alpha; TReg, regulatory T (cell); TSLP, thymic stromal lymphopoietin. ∗ Corresponding author. E-mail address: vplaza@santpau.cat (V. Plaza). https://doi.org/10.1016/j.opresp.2022.100231 2659-6636/© 2023 Sociedad Española de Neumologı́a y Cirugı́a Torácica (SEPAR). Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). V. Plaza, C. Cañete, C. Domingo et al. Open Respiratory Archives 5 (2023) 100231 epitelial (alarmina) que desempeña una función clave en el inicio de las respuestas inmunitarias tanto innata (vía de las células linfocíticas innatas [ILC] del grupo 2) como adaptativa (vía de los linfocitos T cooperadores 2 [Th2]), activando la vía inflamatoria del asma del tipo 2 (T2) mediante ambas. También se cree que puede intervenir en la vía inflamatoria neutrofílica con T2 baja (mediante la interacción con los ILC3 y la interleucina 17). En seis ensayos clínicos que incluyeron a 2.187 pacientes con asma no controlada, dos o más exacerbaciones en el año anterior, a tratamiento con corticosteroides inhalados en dosis medias o altas y con un mínimo de un tratamiento preventivo adicional, se ha demostrado la eficacia y seguridad del tezepelumab sin importar el endotipo T2 (y posiblemente tampoco el endotipo no T2), ya que reduce significativamente las exacerbaciones (61,7-66%) y la hiperreactividad bronquial y mejora la función pulmonar, el control de la enfermedad y la calidad de vida. El tezepelumab puede estar indicado para tratar a pacientes con asma grave, independientemente del fenotipo T2 (eosinofílico y no eosinofílico), y tal vez sea incluso el único biofármaco existente para el tratamiento del AGNC no T2. © 2023 Sociedad Española de Neumologı́a y Cirugı́a Torácica (SEPAR). Publicado por Elsevier España, S.L.U. Este es un artı́culo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/ licenses/by-nc-nd/4.0/). Current severe asthma management in Spain Omalizumab (Xolair). Anti-immunoglobulin E (IgE): reduces exacerbations, slightly improves forced expiratory volume in the Severe asthma, a heterogeneous syndrome that clinically first second (FEV1), and effective in treating nasal polyps.9 presents in various ways, is defined as asthma that requires Mepolizumab (Nucala). Anti-interleukin 5 (IL-5): reduces exac- treatment with multiple drugs at high doses to maintain disease erbations and OCS use, improves quality of life, slightly improves control.1,2 However, even at high doses – as outlined in therapeutic lung function, and effective in treating nasal polyps, eosinophilic steps 5–6 of the Spanish Asthma Management Guidelines (GEMA) granulomatosis with polyangiitis (EGPA), and idiopathic hypere- and 5 of the Global Initiative for Asthma (GINA) – some patients are osinophilic syndrome (HES).10 unable to manage what we know as severe uncontrolled asthma Reslizumab (Cinqaero). Anti-IL-5: reduces exacerbations, (SUCA). Spanish SUCA prevalence is estimated to be approximately improves quality of life and lung function.11 3.9% of the adult population3 and 2%–5% of the child population.4 Benralizumab (Fasenra). Anti-IL-5 receptor: reduces exacerba- Poorly controlled asthma accounts for 70% of the economic cost of tions, improves symptom control, reduces the need for OCS, and the disease.5 improves lung function.12 Managing severe asthma requires a proper understanding of Dupilumab (Dupixent). Anti-IL-4 and anti-IL-13: reduces exacer- underlying aetiopathogenic mechanisms, comorbidities, and the bations, reduces OCS use, improves symptoms and lung function natural history of the disease, as well as knowledge of the different irrespective of peripheral blood eosinophil count, and effective in drugs available and their possible side effects. In view of this com- treating nasal polyps.13 plexity, the Spanish Society of Pneumology and Thoracic Surgery No specific treatment is available for non-T2 asthma, although (SEPAR) launched an initiative to accredit specialist asthma units possibilities are azithromycin,14 bronchial thermoplastyl,15 and in hospitals,6 which was also subsequently adhered to by the Span- continuous parenteral corticosteroids. ish Society of Allergy and Clinical Immunology (SEAIC). By now there are around 100 accredited asthma units (75 corresponding to SEPAR and 25 to SEAIC of varying complexity in Spain). Justification for new biologics for severe asthma In 2018, SEPAR published an expert consensus indicating that Since the introduction of omalizumab in 2006, SUCA treatment the clinical management of patients with severe asthma should be has changed substantially, with promising new biologics gradually multidisciplinary and sequential and be carried out in specialist included in the therapeutic arsenal. The current scenario for SUCA units.7 Other recommendations were to ensure a confirmed asthma diagnosis, the exclusion of comorbidities contributing to poor is undoubtedly more favourable than 2 decades ago, when patients control, and therapeutic compliance, and to establish differential would have been practically condemned to corticosteroid depen- dence. Nonetheless, numerous areas for improvement remain: characteristics (phenotypes) and possible underlying mechanisms (endotypes) with a view to customizing treatment.7 – SUCA is an orphan disease as far as treatment is concerned. All Maintenance treatment for SUCA includes inhaled corticos- teroids (ICS) combined with a high-dose long-acting ␤2 -adrenergic currently available biologics are targeted exclusively at treating the T2 phenotype and there is no specific treatment for non-T2 agent (LABA), plus another controller drug – usually a long-acting SUCA. muscarinic antagonist (LAMA) such as tiotropium or glycopyrro- – There needs to be greater insistence on seeking full remis- nium. Patients with SUCA are also frequently treated with oral sion. The percentage of super-responders to current biologics is corticosteroids (OCS), either regularly or in cycles.8 Due to their potential long-term side effects, it is recommended to use OCS at merely – depending on the definition – 14%–35%,16,17 while only the lowest effective dose and for the shortest possible time. around 69% of patients achieve a partial response.16 The phenotypes useful for therapeutic decision-making are – Current biologics mitigate T2 asthmatic inflammation, but lit- based on the inflammatory mechanisms involved, and are as fol- tle information is available on their effectiveness in preventing lows: allergic type 2 (T2) asthma (40%–50% of severe asthma cases), bronchial remodelling, crucial in the natural history of asthma, eosinophilic T2 asthma (25% of severe asthma cases), and non-T2 as uncontrolled bronchial remodelling contributes to progressive asthma. The 2 T2 phenotypes may coexist in some patients. and accelerated bronchial obstruction. Biological therapies effective in T2 asthma are now available. – Overlap is common between the 2 T2 asthma phenotypes and These are monoclonal antibodies (MABs) directed against different has therapeutic consequences, as it affects omalizumab efficacy biomarkers identified in each of the phenotypes, for which GEMA in patients with eosinophilic asthma irrespective of IgE levels,18 and (conversely), anti-IL-5 efficacy in eosinophilic severe asthma has developed a selection algorithm. Currently available biologics irrespective of atopic state and IgE levels.19 This overlap, in real are as follows: 2 V. Plaza, C. Cañete, C. Domingo et al. Open Respiratory Archives 5 (2023) 100231 clinical practice, often determines selection of the best biologic 27,28 bacteria and fungi, mechanical injury,29 allergens,30 cigarette to administer to a specific patient. smoke,31 and tryptase32 can induce TSLP expression in different – There is a growing debate regarding the advisability of admin- cells. istering 2 biologics when response to a single biologic is only partial.20 Various endotypes coexist in the SUCA T2 phenotype. Tezepelumab mechanism of action Specific blockade of a particular metabolic step may fail to control the disease, justifying use of a second biologic that acts on another The variable heavy chain fragment, but not the variable light T2 disease mechanism. This logically increases the treatment chain fragment, of the human anti-TSLP MAB (tezepelumab) binds cost. Consequently, a drug capable of blocking the inflammatory to TSLP,33 and as a consequence, all TSLP effects are blocked via both cascade at a higher level would possibly prove more efficacious. the Th2 pathway and innate immunity. In other words, by blocking – The lack of biomarkers, in practice, affects choice of biologics, free TSLP, tezepelumab prevents TSLP from binding to its receptor and, furthermore, the available biomarkers are not useful for and so blocks the T2 pathway. evaluating efficacy.21 TSLP: tezepelumab mechanism of action Principal tezepelumab clinical trial results During the 20th century, knowledge of allergic mechanisms Six important clinical trials of 2187 patients have been con- expanded, including details of what was known as the allergic cas- ducted with tezepelumab. cade. By the early 21st century, this became known as adaptive The PATHWAY study (ClinicalTrials.gov number immunity or – since T helper 2 (Th2) lymphocytes are the main cells NCT02054130)34 was the first clinical trial to demonstrate involved – the Th2 pathway, while later on in this century, the sig- tezepelumab efficacy in patients with SUCA. This phase 2b, ran- nificance of activation of the other immunity pathway, i.e., innate domized, double-blind, placebo-controlled clinical trial analysed immunity, came to be better understood. While the Th2 path- subcutaneous (SC) administration of 3 different doses of teze- way adapts to each allergen and generates a specific response, the pelumab over a period of 52 weeks. The study, conducted in 108 innate immunity response is universal. When the bronchial ciliated centres in 12 countries, included 584 adult patients aged 18–75 epithelium is damaged, it becomes secretory, releasing molecules years, non-smokers or with <10 pack-years exposure, with SUCA called alarmins (IL-33, IL-25, and TSLP) into the medium that acti- despite medium/high-dose ICS and LABA treatment. Inclusion cri- vate innate lymphoid cells (ILC) groups 2 and 3, and natural killer teria were to have had at least 2 exacerbations and have required T (NKT) cells (Fig. 1).22 Because TSLP appears to exert antigen pre- OCS administration in the previous year. The study demonstrated senting cell (APC) control, it is thought that it not only stimulates that tezepelumab led to a significant reduction in exacerbations: innate immunity cells (especially ILC2), but also regulates Th2 path- an annual rate of 0.26, 0.19, and 0.22 for 70 mg/4 weeks, 210 mg/4 way activity. Both concepts come together in what is known as the weeks, and 280 mg/2 weeks, respectively, versus 0.67 for the T2 pathway (Fig. 1).22 placebo. Tezepelumab thus reduced exacerbations by 61.7%–66% in relation to placebo, and this occurred independently of baseline TSLP blood eosinophil count. In addition, FEV1 increased by 0.11–0.15 L for tezepelumab in relation to placebo. TSLP is a cytokine that exerts its biologic effects by binding The NAVIGATOR study (ClinicalTrials.gov number to a high-affinity heterodimeric complex composed of the lym- NCT03347279)35,36 was a phase 3, multicentre, randomized, phopoietin receptor chain and the receptor for IL-7 (IL-7R␣). TSLP is double-blind, placebo-controlled clinical trial whose primary expressed primarily in activated lung and intestinal epithelial cells, objective was to determine the annual exacerbation rate in keratinocytes, and fibroblasts. However, dendritic cells (DCs), mast patients with SUCA after SC administration of 210 mg of teze- cells, and presumably other immune cells, can also produce TSLP. pelumab every 4 weeks. Recruited in 294 centres in 18 countries There are 2 TSLP variants in human tissues: the short form (sfTSLP) were 1061 patients aged 12–80 years, non-smokers or with <10 plays a homeostatic role and is the main isoform expressed in a sta- pack-years exposure, treated with medium/high-dose ICS and at ble state,23 while concentrations of the long form (lfTSLP) increase least 1 other controller drug, irrespective of whether or not they when inflammation occurs. Note that concentrations of messen- received OCS. At baseline, patients had at least 2 exacerbations in ger ribonucleic acid (mRNA) for TSLP are increased in the cells of the previous year (40% had more than 3), all had an ACQ-6 of 1.5 patients with asthma24 and appear to be related to asthma sever- or more, and similar proportions had an eosinophil count above ity. Several cellular targets for TSLP have been identified, including or below 300/␮L (25% <150/␮L and 25% >450/␮L). The results immune cells (DCs, ILC2, T cells, B cells, NKT cells, regulatory T showed that annual exacerbation rates were 0.93 for tezepelumab (TReg) cells, eosinophils, neutrophils, basophils, monocytes, mast compared to 2.10 for placebo (p < 0.001), and for eosinophils cells, and macrophages) and non-immune cells (platelets and sen- <300/␮L, were 1.02 and 1.73, respectively (p < 0.001). This reduc- sory neurons).25 tion in exacerbations was observed, not only irrespective of the eosinophil count (the reduction occurred even for <150/␮L), but TSLP mechanism of action: binding to its receptor also of fractional exhaled nitric oxide (FeNO) (<25 ppb) and of allergenic sensitization. FEV1 improved by a statistically significant The positively charged TSLP binds to the negatively charged TSLP and clinically relevant 0.23 L for tezepelumab versus only 0.09 L receptor (TSLPR). IL-7R␣ then binds to the preformed TSLP:TSLPR for placebo, as did the ACQ score and quality of life as measured by binary complex, thus forming a ternary complex, TSLPR:TSLP:IL- the AQLQ. Of note was the significant decrease observed in total 7R␣, that initiates signalling in cells that co-express TSLPR and IL- blood IgE in patients treated with tezepelumab. 7R␣ (Fig. 2). Both those clinical trials not only determined the efficacy of tezepelumab, but also its safety, as no adverse reactions of note TSLP production activators were reported. In the PATHWAY study, only 6 patients (2 on the medium dose, 3 on the high dose, and 1 on placebo) had to dis- Various cytokines, e.g., tumour necrosis factor alpha continue the study due to adverse reactions. In the NAVIGATOR (TNF␣) and IL-1 beta (IL-1␤),26 as well as respiratory viruses, study, while the number of side effects was high, at 77% in the 3 V. Plaza, C. Cañete, C. Domingo et al. Open Respiratory Archives 5 (2023) 100231 Fig. 1. Adapted from Domingo.22 The figure, which may explain clinical results, shows how adaptive immunity (via Th2) is activated by allergens, resulting in synthesized IgE, which enters the medium to bind to effector cells. The right part of the figure shows how damage produced in the bronchial ciliated epithelium causes alarmins to be released that activate ILC2 and NKT cells. In both cases, the ILs typical of T2 asthma (IL-4, IL-5, and IL-13) are synthesized and released. Note how TSLP exerts APC control. TSLP also appears to have some effect on activation of ILC3 belonging to the non-T2 pathway. treated group and 81% in the placebo group, they were only serious in 216 patients. Results demonstrated that home self-injection in 9.8% and 13.7% of cases, respectively, while study discontinu- with a pre-filled syringe is feasible, viable, and at least as efficacious ation rates were 6.8% and 10.7%, respectively. The most frequent as hospital administration. Adverse reactions were broadly similar adverse reactions reported in both studies were nasopharyngitis, to those of previous studies and were not affected by whether the upper respiratory tract infections, headache, and asthma. drug was administered at home or in hospital. SOURCE (ClinicalTrials.gov number NCT03406078)37,38 was a Finally, DESTINATION (ClinicalTrials.gov number large clinical trial with tezepelumab, designed to assess OCS NCT03706079)43 was an extension study that reported, after sparing in corticosteroid-dependent patients with severe asthma. 2 years of tezepelumab treatment, the same findings as observed This phase 3, multicentre, randomized, double-blind, placebo- in NAVIGATOR and SOURCE in terms of both safety (low incidence controlled study, conducted in 60 centres in 7 countries, included of side effects) and efficacy (sustained reductions in exacerbations 150 patients aged 18–80 years, taking, as well as OCS, high-dose regardless of initial eosinophil count, FeNO levels, and allergic ICS and at least 1 other controller drug. Patients were random- status). ized to receive 210 mg SC tezepelumab every 4 weeks or placebo over 48 weeks. Although no significant between-group differences Tezepelumab positioning in clinical practice were observed in the percentage reduction in daily OCS dose (pri- mary endpoint), an improvement was observed in patients on The candidate to receive tezepelumab is a patient for whom effi- tezepelumab with an initial eosinophil count >150/␮L. The percent- cacy has been demonstrated in the phase 2 and 3 studies described age and characteristics of adverse reactions were similar to those above,33–35 i.e., patients with uncontrolled asthma, and a mini- reported in previous studies. mum of 2 exacerbations in the previous year despite receiving The UPSTREAM (ClinicalTrials.gov number NCT02698501)39 medium/high-dose ICS and at least 1 other controller. In the NAV- and CASCADE (ClinicalTrials.gov number NCT03688074)40,41 stud- IGATOR trial, 75% and 25% of patients used high and medium ies were designed to evaluate tezepelumab effects on bronchial ICS doses, respectively.34,35 This would specifically indicate teze- hyperresponsiveness (BHR). UPSTREAM randomized 40 patients pelumab for patients with SUCA, although it may also be effective with asthma and BHR to mannitol to receive either tezepelumab for patients with moderate asthma. (n = 20) or placebo (n = 20) every 4 weeks for 12 weeks. By the Given that the therapeutic target is located upstream in the end of the study, patients treated with tezepelumab experienced inflammatory cascade, the candidate profile for tezepelumab treat- a 50% reduction in BHR. Parallel to this, pre- and post-treatment ment is very varied and may differ from the target patient bronchoalveolar lavage performed in both groups showed a signif- for currently used biologics. Bearing in mind the different sub- icant reduction in eosinophil count in the patients on tezepelumab. phenotypes recommended by GEMA2 for biologic selection to treat Similar results were reported for the CASCADE study, which SUCA, and also the findings of pivotal clinical trials, the follow- included 116 patients who, in addition to receiving treatment for 52 ing could be considered in relation to candidates for tezepelumab weeks, underwent bronchoscopy with transbronchial biopsy, with treatment: results showing a marked reduction in eosinophils infiltrating the Eosinophilic T2 asthma. The PATHWAY and NAVIGATOR bronchial wall in patients on tezepelumab. trials34,36 confirmed a significant reduction in exacerbations The PATH-HOME study (ClinicalTrials.gov number (61.7%–66%) for SUCA, and similar favourable results for both aller- NCT03968978)42 was a phase 3 open-label, multicentre, gic and non-allergic phenotypes. A PATHWAY43 post hoc analysis randomized, parallel-group clinical trial of tezepelumab conducted found no difference in exacerbation reduction according to the 4 V. Plaza, C. Cañete, C. Domingo et al. Open Respiratory Archives 5 (2023) 100231 Fig. 2. Adapted from Varricchi et al.25 The figure shows how TSLP is produced from a bronchial ciliated epithelium damaged by triggering factors. Once produced and released into the medium, this positively charged TSLP binds to TSLPR. Signalling only occurs when TSLP binds to IL-7R␣. number of allergenic sensitizations. In both trials, tezepelumab function caused by bronchial remodelling.39–41 While this finding reduced eosinophils, FeNO, and total IgE, demonstrating its action needs to be confirmed by other medium- and long-term studies, on multiple T2 pathways including IL-5, IL-4, and IL-13. the hypothesis is nevertheless attractive, since practically no infor- Non-eosinophilic T2 asthma. Findings of the PATHWAY and mation is available on the possible beneficial effects of different NAVIGATOR trials34,36 demonstrated that tezepelumab signifi- MABs on asthma. cantly reduced exacerbation rates in patients with an eosinophil To sum up, a possible candidate to receive tezepelumab – inde- count <250/␮L (and even <150/␮L in NAVIGATOR). Note that the pendently of blood eosinophil count – is profiled as a patient improvement, although favourable, was less than that observed in aged 12–80 years, with SUCA, experiencing exacerbations despite patients with eosinophilic T2 asthma. receiving high-dose ICS/LABA treatment However, response is Non-T2 asthma. Both the PATHWAY and NAVIGATOR trials34,36 greater if eosinophils or FeNO are elevated, if there is sensitization also confirmed that tezepelumab significantly reduced exacer- to some aeroallergen, or if the patient has nasal polyps. In addi- bation rates in patients with low T2 biomarkers, specifically, tion, a favourable response is achieved regardless of body mass eosinophils <150/␮L, FeNO <25 ppb, and no allergenic sensitization. index (BMI), the number of perennial aeroallergens to which the This finding would suggest that tezepelumab may be the candidate patient is sensitized, and IgE level. Response is less strong (but molecule indicated as the first possible treatment for this pheno- also favourable) when the following 3 factors coincide: eosinophils type, which, to date, has no specific biologic treatment. <150/␮L, FeNO <25 ppb, and no sensitization to aeroallergens. Three other scenarios are as follows: Corticosteroid-dependent asthma. Although the SOURCE Conclusions study36,37 did not report a significant reduction in daily OCS dose in the tezepelumab versus placebo arms, some improvement (1) Despite the great improvement implied by biologics for the was observed in patients with eosinophils >150/␮L. However, treatment of SUCA, a number of shortcomings need to be con- significance for the between-group results remains unclear, as sidered, namely: (a) the rate of super-responders (currently possible case inclusion bias affects that study, due to uncertainty low); (b) biologic selection (given the heterogeneity of endo- as to previous adherence to OCS and given the favourable results types that make up the T2 phenotype); (c) the lack of treatment also reported for the placebo arm. Further evidence is therefore for the non-T2 asthma phenotype; and (d) the limitations of needed to determine tezepelumab efficacy for patients with current biomarkers (not valid for monitoring). corticosteroid-dependent asthma. (2) New biologics could alleviate some of those shortcomings. Asthma with nasal polyps. In asthmatic patients with nasal (3) Tezepelumab is a TSLP alarmin-blocking drug that inhibits ini- polyps, tezepelumab reduces exacerbations, improves lung func- tiation of the T2 inflammatory cascade from both the innate tion, and improves nasal symptoms as evaluated using the (via ILC2) and acquired (via Th2) immune response, and also Sino-Nasal Outcome Test (SNOT).44,45 possibly also the neutrophilic non-T2 pathway (via IL-17). Bronchial remodelling associated with SUCA. The favourable (4) Six clinical trials of 2187 patients that evaluated the efficacy and results reported for tezepelumab’s capacity to reduce BHR are safety of tezepelumab have demonstrated that tezepelumab suggestive of a capacity prevent to further deterioration of lung significantly reduces exacerbations (66%–71%) and BHR, and 5 V. Plaza, C. Cañete, C. Domingo et al. Open Respiratory Archives 5 (2023) 100231 improves lung function, disease control, and quality of life for Gebro, GlaxoSmithKline, Menarini, Mundifarma, Novartis, Sanofi, patients with previous exacerbations and uncontrolled asthma and Teva. despite medium-high doses of ICS and another controller. (5) Unlike current biologics, which are highly selective, teze- References pelumab exerts its pharmacological action, irrespective of the 1. Global Initiative for Asthma (GINA). Global strategy for asthma management T2 endotype (eosinophilia and/or high or low FeNO) – and pos- and prevention; 2022. Available from: www.ginasthma.org sibly also the non-T2 endotype – considered. 2. GEMA 5.2. Guía Española para el Manejo del Asma; 2022. Available from: (6) Tezepelumab is a safe drug, as suggested by the most frequent http://www.gemasma.com [accessed May 2022]. side effects reported in clinical trials: nasopharyngitis, upper 3. Quirce S, Plaza V, Picado C, Vennera M, Casafont J. 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