New paradigm in asthma management: Switching between biologics!

The nominalist definition acknowledges asthma as an abnormality of the airways, typically comprising of variable airflow limitation over short periods of time, hyperresponsiveness, and airway inflammation.1 The severity of asthma has primarily been assessed by the level of treatment required to control symptoms and exacerbations, with corticosteroids (inhaled and/or oral) as the mainstay treatment for suppressing the overall inflammatory component.2 It was not until the past decade that enough importance was given to the precise recognition, assessment, and targeted treatment of inflammation in clinical asthma management. Indeed, in today's time and age, one can no longer state that. There are four monoclonal antibody (mAb) therapies (omalizumab, mepolizumab, reslizumab, and benralizumab) that are currently approved as an adjunct therapy for targeting the inflammatory component of severe asthma. In fact, there are a few more in the pipeline for the same (dupilumab, tezepelumab, etc. (reviewed extensively in3). This paradigm shift in clinical management of targeting the underlying inflammatory component can be attributed to the identification of asthma “endotypes” from “phenotypes”4—an approach that integrated the underlying immunobiology of inflammation contributing to severity and the clinical manifestations as a consequence. Broadly, there are two endotypes of asthma characterized as Type 2 (T2) high and T2 low inflammation.3 Biologics targeting mediators associated with T2 high inflammation in asthma have been hugely successful. For instance, identifying immunoglobulin (Ig) E as the dominant mediator of T2 inflammation in early-onset allergic asthma led to the development of a targeted monoclonal antibody (mAb), omalizumab, that allows ~25% reduction in asthma exacerbation rates and substantial tapering of inhaled corticosteroid (ICS) maintenance doses. However, to date, its steroid-sparing effect in patients on daily oral corticosteroids (OCS) remains to be confirmed.5 Though omalizumab is approved for severe allergic asthma, retrospective analysis of 25 randomized controlled trials (RCTs) demonstrated greater reduction in asthma exacerbations in patients with high blood eosinophil counts and high exhaled nitric oxide levels, indicative of ongoing eosinophilic inflammation.6 Therefore, prescribing the available anti-IgE mAb to severe allergic eosinophilic asthmatics seemed justified when a targeted eosinophil-depletion strategy was unavailable to clinicians. More than a decade later, mepolizumab, an IgG1 mAb targeting the IL-5 pathway (crucial for the maintenance of the eosinophil biology), was approved for severe eosinophilic asthma (see Table 1 for clinical indications for both mAbs). RCTs reported a ~50% reduction in exacerbation rates, a decrease in total use of OCS, and complete weaning off OCS in 14% patients.3 Despite differences in the target molecule and mechanisms of drug action, both mepolizumab and omalizumab are indicated as a Step 5 GINA treatment for severe eosinophilic asthma.2 In the current study by Chapman et al7 published in this journal, promising efforts were made to investigate whether mepolizumab could optimally control a sub-set of moderate-to-severe eosinophilic asthmatics who were otherwise inadequately controlled on omalizumab. The open-label, single-arm, multicenter study was designed with a pragmatic approach of switching from one biologic (omalizumab) to another (mepolizumab) without a standard washout period (which is usually the scenario in clinical practice). The study was conducted in patients who were eligible for both biologics and had uncontrolled disease. The authors report substantial improvement in asthma control using Asthma Control Questionnaire-5 (ACQ-5) with 77% of asthmatics achieving the minimal clinically important difference (MCID, reduction by 0.5 points) at week 32, and also significant reduction of blood eosinophils and serum markers of eosinophil activation (eosinophil cationic protein). The key finding of this study that can be immediately translated into clinical practice is the direct switch from omalizumab to mepolizumab (within 2-4 weeks of the last biologic dose) with no reported adverse/tolerability issues. Subgroup analysis confirmed no additional benefit when both biologics were in the patient's system, nor a decline in benefit as omalizumab was naturally washed out in the second half of the study. It is apparent that the 111 patients (77%) who showed favorable clinical outcomes to mepolizumab had an underlying IL-5-mediated pathology, wherein curbing only the IgE component with omalizumab was inadequate. From a molecular standpoint, since IL-5 is upstream of IgE in the canonical allergic inflammatory cascade, coupled with current emerging evidence of non-IgE-mediated alternative IL-5 pathways that can maintain eosinophilia, it is reasonable to expect an anti-IL-5 mAb to be effective when an anti-IgE mAb fails to curb symptoms. However, in the current study, there is lacking information regarding strict eligibility for omalizumab in the initial phase. This may be attributed to the fact that in the era of single use of omalizumab, the eligibility process may have overlooked a strict application of the initial recommendations. With a number of mAbs currently available for treating severe asthma with a T2 high signature, it has become crucial to objectively assess biomarkers that would indicate the dominant inflammatory mediator driving disease symptoms in the target organ (ie, the airways). In this study, it may be argued that selecting patients based on blood eosinophils (with an absolute count of 150-300 cells/μL) was adequate to predict and monitor response to mepolizumab. However, discordance between blood and sputum eosinophilia with increasing asthma severity,8 and reported incidents where mepolizumab response was deemed clinically inadequate despite normalization of blood eosinophil levels9, 10 question the reliability of blood eosinophils as the biomarker of choice. In fact, in the current study, 41% patients experienced a total of 104 exacerbations within the 32-week study period, despite normalization of blood eosinophil levels by week 8. Again, the median ACQ-5 score reported at week 32 was 1.75 (ACQ-5 < 1.5 is considered to reflect asthma control), indicating that a sub-set of patients remained symptomatic. Further, we note that 5%8 of the recruited patients experienced asthma worsening. This is in tandem with a recent report of asthma worsening on low-dose mepolizumab therapy (100 mg, subcutaenous) in a prototype severe OCS-dependent asthmatic with persistent airway eosinophilia.10 It may be argued that assessing the “rate of exacerbations” would have been a more objective outcome to evaluate the optimal therapeutic effect of mepolizumab, especially in this patient set selected based on the evidence of exacerbations despite omalizumab therapy. Clinical trials as such conducted by Chapman et al in a pragmatic clinical setting are required to assess the effectiveness of novel therapies indicated for a similar/overlapping asthma population, essentially when (a) one biologic is deemed clinically inadequate to control symptoms and (b) in the absence of head-to-head inferiority/superiority trials. It may have been prudent for the authors to assess clinical parameters (vital for identifying biomarkers) that could discriminate between patients who responded to omalizumab, from those who did not, and more importantly, those who went ahead and responded to mepolizumab. The future now warrants the identification and validation of precise biomarkers that will present a better ability to predict response to mAb treatment either alone or in combination with existing therapies. In the meantime, the immediate unmet need in asthma clinical management can be summarized in one sentence: ″selecting the right patient, recognizing the right target and focusing on the right outcome.″ MM is supported by postdoctoral fellowships from Canadian Institutes of Health Research and Canadian Allergy, Asthma, and Immunology Foundation. MM and BK have nothing to disclose. SL has received honorarium for speaking fees and advisory boards from GSK and Novartis.

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