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Clinical Trials of Monoclonal Antibodies for Asthma: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 3 by Jason Zhu.

Monoclonal antibodies have been developed for the treatment of severe asthma, with numerous randomised controlled trials (RCTs) conducted to define their safety and efficacy. The growing availability of biologics, which have only been available for T2-high asthma, has been further enriched by the arrival of tezepelumab. All biologic agents are effective in improving asthma control, especially with regard to reducing exacerbation rates and oral corticosteroid (OCS) use. Biologics are all effective, albeit with important differences. What fundamentally guides the choice is the patient’s clinical history, the endotype represented by biomarkers (especially blood eosinophils), and comorbidities (especially nasal polyposis).

  • severe asthma
  • biologics
  • randomised clinical trials

1. Introduction

Five biologics are currently available for the treatment of severe allergic (omalizumab), eosinophilic (mepolizumab, reslizumab, and benralizumab), and mixed asthma with atopic–eosinophilic phenotype (dupilumab), along with tezepelumab [1]. In the United States, the latter has been available since 2022. Tezepelumab has also been approved in Europe by the European Medicines Agency, and its marketing is expected in 2023. These monoclonal antibodies (mAbs) have common aspects, but also important differences regarding their inclusion criteria—baseline demographic characteristics, and biomarker levels, which are heterogeneous when carefully evaluating the different phase 3 RCTs of biologics. These aspects have great importance in the interpretation of related outcomes. Therefore, it is necessary to have a thorough understanding of these differences in biological therapies to avoid simple comparisons and considerations between the different biologics. The different biologics underwent clinical development with important pivotal phase 3 studies characterised by criteria and endpoints with sometimes significant differences, and for each of these open-label extension studies, OCS-sparing studies (except for omalizumab) and further clinical development studies for other indications have been conducted. International regulatory bodies have approved biologics for severe asthma, but regional differences and varying prescription criteria can limit the accessibility of these medicines and pose challenges for precision medicine. National prescription criteria for biologics were also evaluated by a collaborating panel of experts in the International Severe Asthma Registry [2]. The results were based on country-specific prescription criteria and the development of biological accessibility scores. These scores showed substantial differences between countries in terms of ease of access to biologics.

2. Omalizumab

Omalizumab is a recombinant humanised mAb IgG1 anti-IgE that binds to circulating IgE, preventing its binding to the receptors of mast cells and basophils, and blocking the release of histamine and other mediators [3][4]. It is used as a treatment for patients over 6 years of age with moderate severe allergic asthma (SAA), with serum IgE levels of 30–1300 IU/mL in the United States, or with SAA with serum IgE levels of 30–1500 IU/mL in Europe. The dose depends on body weight and serum IgE level, ranging from 150 mg every four weeks (Q4W) to 375 mg every two weeks (q2w) subcutaneously (SC) [5]. Omalizumab is also indicated for the treatment of chronic spontaneous urticaria, with a single dose of 300 mg Q4W [5], and for recalcitrant CRSwNP, with a dosage schedule similar to that for asthma [6]. Over nearly 20 years, numerous studies have examined the efficacy of omalizumab in patients with severe allergic asthma. In these studies, the enrolled patient populations differed somewhat in the definition of severity considered and concomitant medications used, with a trend in the most recent studies towards more severe forms of asthma and more aggressive concomitant therapies. Unlike the mAbs that arrived later, the RCTs on omalizumab did not evaluate the OCS-sparing effect at their endpoints. Data were later obtained from numerous real-life studies conducted over time [7]. In two double-blind, phase 3 RCTs conducted by Solèr et al. [8] and Busse et al. [9], patients aged >12 years with symptomatic allergic asthma were enrolled, despite doses of beclomethasone dipropionate ranging from 500 μg/day to 1200 μg/day. After 28 weeks of therapy, the reduction in inhaled corticosteroid (ICS) use was significantly greater with omalizumab than with the placebo. In these two studies, patients on active treatment had up to 58% fewer asthma exacerbations than those on placebo, and a greater likelihood of ICS dose reduction or discontinuation was observed among patients on active omalizumab treatment compared with placebo. A third pivotal trial—the Investigation of Omalizumab in Severe Asthma Treatment (INNOVATE)—evaluated the efficacy of omalizumab in patients with uncontrolled asthma, despite GINA phase 4 therapy [10]. The study included 419 subjects over 12 years of age with a proven allergy to at least one perennial allergen, a deterioration in respiratory function (predicted FEV1 of 40–80%), and a recent clinically significant history of exacerbations despite high doses of ICSs, long-acting beta-agonists (LABAs), and other control agents. The patients had received either omalizumab or a placebo for 28 weeks. During this treatment period, the rate of clinically significant exacerbations was 26% less in the active treatment arm compared with the placebo group (p = 0.0002). Severe asthma exacerbations and emergency department visits were significantly reduced, and asthma symptoms and morning peak expiratory flow were significantly improved. EXCELS was a post-marketing observational cohort study undertaken by the Food and Drug Administration (FDA) to evaluate the long-term safety of omalizumab [11]. The patient cohort included 5007 active treatment subjects and 2829 controls followed for ≤5 years. The two cohorts had similar baseline demographics, but severe asthma was more frequent in the omalizumab-treated group than in the control group (50% vs 23%). Actively treated patients had a higher rate of serious adverse CV/CBV events (13.4 per 1000 person-years (PY)) than non-omalizumab-treated patients (8.1 per 1000 PY). The differences in asthma severity between the cohorts likely contributed to this imbalance, but some increase in risk could not be ruled out. In light of these considerations, the FDA still did not recommend any changes to the prescription information, recommending only increased awareness. In a 32-week registry-based RCT of 400 patients treated with omalizumab add-on, persistence response was defined using the physician’s global evaluation of treatment efficacy (GETE) [12]. Patients on the optimised standard therapy showed less persistence of response compared with those in the omalizumab group. Good and excellent GETE scores in the omalizumab group were correlated with improvement in exacerbation rates (p < 0.001), severe exacerbations (p = 0.023), hospitalisations (p = 0.003), and overall scores on the asthma control questionnaire (ACQ) (p < 0.001). Finally, 62.7% of patients in the active treatment group had reduced or stopped using OCSs, compared with 30.4% in the control arm. The role of combined biomarkers as possible predictors of treatment response was explored in the EXTRA study, which included 850 patients with severe allergic asthma [13]. Outcomes were evaluated in relation to FeNO, blood eosinophil count (BEC), and serum periostin at baseline, and the subgroups with high and low levels of these biomarkers were analysed. During 48 weeks of treatment, the reduction in exacerbations was significant in the subgroup with high biomarkers. A 24-week RCT explored the efficacy of omalizumab on the exacerbation rate [14].

3. Mepolizumab

Mepolizumab is an anti-IL-5 IgG1k mAb approved for severe eosinophilic asthma (SEA). Numerous RCTs have confirmed its effectiveness in terms of reducing the rate of asthma exacerbations, as well as providing an OCS-sparing effect, improvement in lung function, and increase in health-related quality of life (HRQoL). The approved dose of mepolizumab (100 mg every 30 days SC) was identified based on the results of the DREAM and MENSA efficacy and safety trials [15][16], and as a steroid-sparing agent (SIRIUS) [17]. These RCTs showed that mepolizumab was more effective in patients with BEC greater than 150–300 cells/μL. In a post hoc analysis of the DREAM study, a single BEC measurement of 150/μL or greater predicted the mean of subsequent measurements to be 150/μL or greater in 85% of this population. Using an average of several measurements increased the sensitivity only marginally. Sputum eosinophils did not predict the response to mepolizumab treatment [18]. A secondary analysis of the DREAM and MENSA studies demonstrated that the reduction in exacerbation rate with mepolizumab versus placebo increased progressively from 52% in patients with a baseline BEC of at least 150 cells/μL to 70% in patients with a baseline BEC of at least 500 cells/μL [19]. Additionally, in subjects with a BEC of less than 150 cells/μL, the efficacy of mepolizumab was reduced.

4. Benralizumab

Benralizumab is an IgG1 mAb targeting the α subunit of the IL-5 receptor. It activates an antibody-mediated cellular cytotoxicity mechanism, leading to a profound depletion of eosinophils and their precursors in the blood and tissues [20]. In the Windward development programme, two phase 3 studies (CALIMA and SIROCCO) explored the efficacy of benralizumab in patients with high eosinophil levels (≥300 cells/μL) and low eosinophil levels (<300 cells/μL) [21][22]. In the CALIMA study, benralizumab reduced asthma exacerbations by 36% and 28% compared with a placebo in the high-BEC population in groups dosed every 4 and 8 weeks, respectively. SIROCCO showed superior performance, as benralizumab reduced the exacerbation rate by 45% and 51% compared with the placebo in the high-BEC population dosing every 4 (Q4W) and 8 weeks Q8W), respectively. In the low-BEC population, the reduction in the exacerbation rate was only 17% compared with placebo Q8W. A pooled analysis of the results from the SIROCCO and CALIMA studies found that the greatest improvements in the annual exacerbation rate (AER) compared with placebo were seen in patients with a combination of high BEC (≥300 or ≥450 cells/μL) and a history of more frequent exacerbations (three or more) [23]. In the phase 3 ZONDA study, the primary endpoint was the percentage change in OCS dose from baseline to treatment week 28 [24]. Benralizumab showed a 50% reduction in prednisone dose compared with the placebo. In the secondary outcomes, Q8W administration resulted in a 55% lower annual exacerbation rate compared with the rate with placebo (p = 0.003), and benralizumab Q8W resulted in a 70% lower annual exacerbation rate than placebo (p < 0.001). At the end of the study, no significant effect on FEV1 was found. A post hoc analysis evaluated the rate of patients in clinical remission among pooled patients in the SIROCCO/CALIMA or ZONDA trials [25]. In the first two trials, 14.5% (85/586) of patients treated with benralizumab and 7.7% (48/620) of those on placebo achieved clinical remission at 12 months. Examining the patients enrolled in ZONDA, 22.5% (9/40) of the active benralizumab group achieved clinical remission, compared with 7.5% of the placebo group. An interesting open-label, single-arm, multicentre study had, as its primary endpoints, a proportion of patients able to eliminate sustained daily OCS use for at least 4 weeks, and a proportion achieving weaning from OCSs or a daily dose of prednisone or prednisolone of 5 mg or less for at least 4 weeks if the reason for complete discontinuation was adrenal insufficiency (AI) [26]. Moreover, 376 (62.88%) of 598 patients eliminated OCSs, and 490 (81.94%) of 598 patients eliminated their use or achieved a dose of 5 mg or less if the reason for incomplete elimination was AI. When examining subgroups, dose reductions were achieved regardless of the BAC and baseline OCS dose or the duration of treatment with them. AI was detected in 60% of patients in the first evaluation, and in 38% three months later. This is the first and only study to date that has been able to provide useful practical information on the management of OCS tapering in patients with severe asthma treated with biologics. The long-term open-label MELTEMI extension study confirmed the high safety and efficacy of benralizumab with up to five consecutive years of treatment [27].

5. Dupilumab

Dupilumab is a fully human IgG4 mAb directed to the alpha subunit of the shared receptors of IL-4 and IL-13 (IL-4/13Rα), simultaneously blocking the IL-4/IL-13 signalling pathway [28][29]. The safety and efficacy of the subcutaneous administration of dupilumab for the treatment of moderate-to-severe asthma were primarily demonstrated in three phase 3 clinical studies. The first study enrolled patients aged 12 years and older with BEC ≥ 150 cells/μL and FeNO ≥ 25 parts per billion (ppb). Dupilumab, administered to these patients every two weeks (q2W), was effective in reducing the exacerbation rate, symptoms, and lung function compared with placebo, as well as in reducing FeNO. The second study was a 52-week phase 3 RCT (LIBERTY ASTHMA QUEST) that confirmed the efficacy of dupilumab in terms of a significant reduction in exacerbations and an improvement of FEV1 and asthma control, especially in patients with higher T2 biomarkers (BEC ≥ 300 cells/µL and FeNO ≥ 25 ppb) [30]. The third study was the LIBERTY ASTHMA VENTURE, which involved a cohort of patients with severe steroid-dependent asthma. Dupilumab at a dose of 300 mg Q2W significantly reduced the rate of severe exacerbations, with a concomitant increase in FEV1. Specifically, the mean daily dose of prednisone was reduced by 70%, compared with 42% in the placebo group [31]. In this trial, transient eosinophilia was reported in approximately 14% of patients on active therapy, with normalisation occurring by the end of the treatment period and no patients experiencing clinically relevant adverse events [31]. A recent pooled analysis of the VENTURE study showed that dupilumab significantly reduced the rate of exacerbations and improved FEV1, asthma control, and HRQoL, regardless of the presence or absence of atopy [32]. Subsequently, an open-label extension study called TRAVERSE was conducted to evaluate the safety and efficacy of dupilumab over 148 weeks of treatment [33]. As in the parent studies, an increase in BEC was observed after the initiation of dupilumab. The blood eosinophils returned to baseline by week 96, confirming that the increase was transient only, with no evidence of an increased frequency of clinically significant adverse effects compared with previous studies. A recent post hoc analysis of TRAVERSE confirmed dupilumab’s ability to sustain OCS dose reduction while maintaining a low exacerbation rate, improving lung function [34]. In another post hoc analysis of the TRAVERSE study, the long-term efficacy of dupilumab was observed in patients with asthma, both with and without CRSwNP, including the OCS-sparing effect [35]. In a post hoc analysis of 11 clinical trials of dupilumab in patients with moderate-to-severe corticosteroid-dependent asthma, transient increases in the mean blood eosinophil counts were observed in patients with dupilumab-treated asthma (mean range from studies to baseline: 349–370 cells/µL; week 4: 515–578 cells/µL) [36]. A decline was then observed from week 24 to baseline, or even below. No elevations were observed in patients with eosinophilic esophagitis or atopic dermatitis. In all studies, eosinophilia rates ranged from 0% to 13.6%. Clinical symptoms associated with this increase were rare (7 of 4666 dupilumab-treated patients, including 6 cases of eosinophilic granulomatosis with polyangiitis) and occurred only in patients with asthma or CRSwNP. Eosinophilia was not associated with decreased efficacy of dupilumab.

6. Tezepelumab

A new first-in-class biologic drug has been granted an FDA breakthrough designation for non-eosinophilic asthma: tezepelumab [37]. Tezepelumab is a fully human IgG2 mAb directed to the thymic stromal lymphopoietin—a cytokine of the alarmin family that, together with IL-25 and IL-33, is derived from epithelial cells and plays a very important role in the pathogenesis of asthma [38].
The phase 3 programme called PATHFINDER brought interesting results, but also some queries. The NAVIGATOR trial randomised 1061 patients [39]. Among the patients without type 2 inflammation (baseline BEC < 150 cells/μL and baseline FeNO < 25 ppb) enrolled in the NAVIGATOR study, the therapeutic effect of tezepelumab was positive, albeit with values generally lower than those in patients with type 2 biomarkers. However, the effect was considered clinically significant. Unfortunately, in the phase 3 RCT SOURCE, with 150 patients randomised into 210 mg tezepelumab Q4W or placebo for 48 weeks of treatment, the primary endpoint of the OCS-sparing effect compared with the control group was not met [40]. A statistically significant reduction was observed only in the subgroup of patients with BEC ≥ 150 cells/μL, and an even more marked reduction in those with ≥ 300 cells/μL. Beyond this, however, the endpoint of the reduction in the use of OCSs regardless of the status of the biomarkers was not achieved—a problem that will require further investigation to clarify whether it was due to an incorrect study design or a limitation of the biologic. In this regard, a new 28-week RCT, with the primary endpoint being the percentage of participants able to discontinue OCS use without losing asthma control, is underway (NCT05274815 WAYFINDER) [41]. In this RCT, 40 adult patients with asthma and an indirect bronchial provocation test with mannitol airway hyperresponsiveness (AHR) were randomised to receive 700 mg of tezepelumab or placebo intravenously Q4W for 12 weeks. The mean change in the mannitol challenge dose resulting in a 15% reduction in the FEV1 provocative dosage (PD15) with tezepelumab was 1.9 (95% CI 1.2–2.5) versus 1.0 (95% CI 0.3–1.6) by doubling the doses with placebo (p = 0.06). Nine (45%) subjects in the tezepelumab group and three (16%) in the placebo group had a negative PD15 test at week 12 (p = 0.04). The airway tissue eosinophil and bronchoalveolar lavage levels decreased by 74% and 75%, respectively, in the tezepelumab arm, compared with a 28% increase and 7% decrease in the placebo arm (p = 0.004 and p = 0.01), respectively. In addition, the data suggest that the primary mechanism by which tezepelumab works to improve the clinical and physiologic outcomes of asthma is airway eosinophilia suppression (not to zero), and that there may be an interaction between eosinophils and mast cell activity, which needs further investigation. A secondary analysis was also conducted among patients potentially eligible for omalizumab enrolled in NAVIGATOR [42]. In this subgroup, tezepelumab significantly reduced the annualised asthma exacerbation rate (AAER) at various levels of baseline BEC and FeNO. Tezepelumab also improved FEV1 and patient-reported outcomes (PROs) and reduced type 2 biomarkers compared with placebo in all patients, as well as in those with severe allergic asthma. DESTINATION is an ongoing phase 3 RCT involving patients who completed the NAVIGATOR and SOURCE studies [43].

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