Up‐dosing of reslizumab in severe asthmatics with persistent sputum eosinophilia: A feasibility study

Anti-IL5 biologics reduce eosinophil numbers and activity and improve asthma control. Their effect depends on the dose, route of administration, and the molecules' mechanism of action. Higher doses, intravenous (IV) dosing, and targeting IL-5Rα show greater anti-eosinophil effects than subcutaneous (SC) route and IL-5 neutralizing antibodies. This has been demonstrated through direct comparisons of three doses of IV mepolizumab,1 direct and indirect comparisons of IV vs. SC mepolizumab,2, 3 and switches from SC mepolizumab to IV reslizumab4 and from SC mepolizumab to benralizumab.5 However, there is no information on whether higher doses of IV reslizumab are associated with suppression of sputum eosinophils in patients with persistent sputum eosinophilia (>3%) despite standard dose (SD). To address this, a sequential, single-center, single-blind prospective 52-week dose-escalation study (ClinicalTrials.gov #NCT04710134) was conducted at St. Joseph's Healthcare Hamilton (Hamilton, Ontario, Canada) with approval from the local Hamilton Integrated Research Ethics Board (#12763). The trial design and methodology are provided in the Data S1. Ten (n = 10) patients with severe asthma and eosinophilia met the inclusion criteria and were initiated reslizumab at 3 mg/kg. The clinical characteristics of the overall cohort are shown in Table S1. After 4 infusions (V6), four patients (40%) achieved sputum eosinophils ≤3% and an ACQ-5 score <1.5. However, 6 patients (60%), still had persistent sputum eosinophilia and were therefore dose escalated (DE) to the 4 mg/kg dose (Figure S1). Symptoms were uncontrolled (ACQ ≥1.5) in 4 out of 6 (66.7%) with an overall median ACQ score change of −0.5 (range: −1.2 to +0.4), an FEV1 increase of +0.26 L (range: +0.1 L to +1.2 L) and a FeNO increase of +30 ppb (range: +0 to +96). Of these, one patient (orange dot, Figure 1) was unable to provide a sputum sample at V10 and thus completed the trial at the 4 mg/kg dose. Only one patient was further dose-escalated to 5 mg/kg (green dot, Figure 1). Table 1 compares the screening visit (V1) clinical characteristics of patients who normalized sputum eosinophils on SD (4 of 10, 40%) and those who DE over the course of the study (6 of 10, 60%). Notably, 4 of 6 (66.7%) in the DE group had failed previous biologics, compared to none of the SD group (p = 0.07). At V14 (end of study), reslizumab reduced overall sputum eosinophils and improved asthma control and lung function compared to V1 (Figure 1A–C). In the six patients that were DE, the ACQ score decreased by −1.0 (range: −2.2 to +0.4), and FEV1 improved by +0.31 L (range: +0.1 to +1.0). No exacerbations were recorded throughout the trial. Sputum IL-5 was significantly reduced during treatment (Figure 1F), but IL-13 and anti-eosinophil peroxidase (EPX) IgG levels remained unchanged (Figure 1G,H). Remarkably, at V14, anti-EPX IgG was elevated in five patients who required DE that significantly correlated with sputum IL-13 (Figure 1I), indicating an autoimmune-prone microenvironment. Additionally, at V14, two patients (20%) had persistent sputum eosinophils (>3%) (Figure 1A). Of those, one was biologic-naïve and had elevated IL-13 and the highest levels of anti-EPX IgG (orange dot, Figure 1A,G,H). The other patient had a suboptimal response to previous treatments with omalizumab, mepolizumab and benralizumab, required an additional DE to 5 mg/kg (green dot, Figure 1A,J), but showed no evidence of any T2-associated cytokines, including IL-5, either at V1 or V14. Instead, he had elevated IL-18 signature that remained high throughout the trial period (Figure 1J), suggesting inflammasome activation (see Data S1). In this feasibility study examining dose responses to IV reslizumab, we demonstrated that the approved dose of 3 mg/kg does not control airway eosinophils in all patients with severe eosinophilic asthma. Conversely, higher doses can lead to greater suppression of eosinophils in sputum and improved asthma control. However, there are no studies to date that estimate the pharmacokinetics of a biologic in relation to airway levels of the drug and its downstream effect on airway eosinophilia. The percentage of sputum eosinophils serves as a surrogate for the concentrations of monoclonal antibodies required to achieve optimal IL-5 neutralization in the airways and, therefore, asthma control. Despite the small sample size, we were able to highlight the underlying heterogeneity of persistent airway eosinophilia, beyond IL-5 signaling and the need to assess and endotype based on sputum cytokines. Our findings suggest that some patients with severe asthma and eosinophilia may benefit from higher doses of a neutralizing anti-IL-5 monoclonal antibody, which can normalize sputum eosinophils and IL-5 levels. This concept is also applicable to mepolizumab. In a previous study we indirectly demonstrated that patients switched from a fixed 100 mg SC dose of mepolizumab to a weight-adjusted dose of IV anti-IL-5 reslizumab had significant reduction of sputum eosinophils (otherwise uncontrolled by mepolizumab).4 However, a similar dose–response relationship does not possibly apply to benralizumab (anti-IL-5Rα). Benralizumab 30 mg SC Q8W has been shown to completely deplete airway eosinophils through antibody-dependent cellular cytotoxicity and reduction of IL-5 and IL-13.5 In cases where patients do not respond to benralizumab, the non-response is likely due to mechanisms unrelated to IL-5, particularly mucus production and IL-18/inflammasome activation.5 Remarkably, in this study a subset of patients despite dose escalation remained symptomatic, displaying evidence of persistent sputum eosinophilia associated with IL-13, the presence of anti-EPX IgG, or IL-18 (see Data S1), which have been shown to predict a suboptimal response to anti-IL-5 biologics.5, 6 Conceptualization: PN; study design: PN, MM; patient recruitment and patient management: PN, MK, BA, CVG; Clinical tests and database: MK, JB; Biomarker analysis: KR, YX, JB, SN supervised by MM. Analysis: JB, SN, MM; Manuscript draft: JB, SN, MM, PN. All authors have read and approved the submitted manuscript. PN takes the overall guarantee of the study. We acknowledge Nicola Calma, MLT from the Hargreave Sputum Laboratory and Kayla Zhang, BSc, for their assistance with sputum results. C.V.G. was supported by Frederick Hargreave Clinical Research Fellowship award. M.M. was supported by the AstraZeneca Chair in Respiratory Diseases. P.N. was supported by the Frederick E. Hargreave Teva Innovation Chair in Airway Diseases. This was an investigator-initiated study funded by Teva Canada. Teva Canada conducted a medical accuracy review. The funder had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. MM reports research grants from AstraZeneca, Sanofi, Methapharm Specialty Pharamceuticals and Mirimus, consulting fees from AstraZeneca, Sanofi, Respiplus, GSK, Mirimus. PN reports research grants from AstraZeneca, Teva, Sanofi, Foresee and consulting fees from AstraZeneca, Teva, Sanofi, Equillium, Arrowhead pharma. All other authors have no conflict of interest within the scope of the submitted work. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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