TYPE Brief Research Report PUBLISHED 09 May 2023 DOI 10.3389/fphar.2023.1183156 Potential impact of mepolizumab OPEN ACCESS in stepping down anti-osteporotic EDITED BY Galina Sud’ina, Lomonosov Moscow State University, treatment in corticosteroid Russia REVIEWED BY -dependent asthma Rebecca Fortescue, University of London, United Kingdom Chiara Scelfo, Christian Domingo 1,2*, Ana Sogo 1,2, Enrique Casado 3, Santa Maria Nuova Hospital, Italy Eva Martínez-Moragón 4, Marina Blanco-Aparicio 5, *CORRESPONDENCE Teresa Carrillo 6,7, David Bañas-Conejero 8 and Christian Domingo, cdomingo@tauli.cat María-Guadalupe Sánchez-Herrero 8 RECEIVED 09 March 2023 1 Servicio de Neumología, Corporació Sanitària Parc Taulí, Barcelona, Spain, 2Departamento de Medicina, ACCEPTED 26 April 2023 Universitat Autònoma de Barcelona (UAB), Barcelona, Spain, 3Servicio de Reumatología, Corporació PUBLISHED 09 May 2023 Sanitària Parc Taulí, Barcelona, Spain, 4Servicio de Neumología, Hospital Universitario Doctor Peset, CITATION Valencia, Spain, 5Servicio de Neumología, Hospital Universitario A Coruña, A Coruña, Spain, 6Servicio de Domingo C, Sogo A, Casado E, Alergología, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de GranCanaria, Spain, 7 Martínez-Moragón E, Blanco-Aparicio M, Departamento de Ciencias Médicas y Quirúrgicas, Universidad de Las Palmas Gran Canaria, Las Palmas Carrillo T, Bañas-Conejero D and de Gran Canaria, Spain, 8Departamento Médico Specialty Care, GSK, Madrid, Spain Sánchez-Herrero M-G (2023), Potential impact of mepolizumab in stepping down anti-osteporotic treatment in corticosteroid-dependent asthma. Front. Pharmacol. 14:1183156. Oral corticosteroids (OCS) are commonly used for the acute management of doi: 10.3389/fphar.2023.1183156 severe asthma exacerbations or as maintenance therapy; however, chronic use is COPYRIGHT associated with significant toxicities, e.g., osteoporosis. In the REal worlD © 2023 Domingo, Sogo, Casado, Effectiveness and Safety (REDES) study of mepolizumab in a multicentric Martínez-Moragón, Blanco-Aparicio, Spanish cohort of asthma patients, mepolizumab effectively reduced clinically Carrillo, Bañas-Conejero and Sánchez- Herrero. This is an open-access article severe asthma exacerbations and decreased OCS dependence. This post-hoc distributed under the terms of the analysis further evaluates mepolizumab’s de-escalation effect on OCS dose. Creative Commons Attribution License Patients enrolled in REDES who had OCS consumption data available for (CC BY). The use, distribution or reproduction in other forums is 12 months pre- and post-mepolizumab treatment were included in this permitted, provided the original author(s) analysis. Primary outcomes were to determine the change in the proportion of and the copyright owner(s) are credited patients eligible for anti-osteoporotic treatment due to the changes in OCS and that the original publication in this journal is cited, in accordance with consumption before and after 1 year of mepolizumab treatment. All analyses accepted academic practice. No use, are descriptive. Approximately one-third (98/318; 30.8%) of patients in REDES distribution or reproduction is permitted were on maintenance OCS at the time of mepolizumab treatment initiation. In which does not comply with these terms. REDES, mean cumulative OCS exposure decreased by 54.3% after 1 year of treatment. The proportion of patients on high-dose OCS (≥7.5 mg/day) fell from 57.1% at baseline to 28.9% after 12 months of mepolizumab treatment. Thus, 53.6% of OCS-dependent asthma patients treated with mepolizumab would cease to be candidates for anti-osteoporotic treatment according to guidelines thresholds. KEYWORDS asthma, mepolizumab, oral corticosteroid, osteoporosis treatment, anti-resorptive treatment Abbreviations: ACT, asthma control test; CS, corticosteroids; GTI, Glucocorticoid Toxicity Index; IL-5, interleukin-5; IQR, interquartile range; OCS, oral corticosteroids; REDES, REal worlD Effectiveness and Safety Study; SD, standard deviation. Frontiers in Pharmacology 01 frontiersin.org Domingo et al. 10.3389/fphar.2023.1183156 1 Introduction 2 Methods Corticosteroids (CS) have potent anti-inflammatory and 2.1 Study design and patients immunosuppressant properties and are consequently used in a variety of indications in medicine. In asthma, they are widely Details of the REDES study design have been described used in an inhaled form. The oral (or parenteral) forms are previously (Domingo Ribas et al., 2021). Briefly, REDES (GSK principally used in the acute management of severe asthma ID: 213172) was a retrospective, real-world, phase IV, multicentre, exacerbations, or as alternative maintenance therapies when observational cohort study that enrolled patients with severe preferred treatments do not provide adequate disease control eosinophilic asthma from across 24 Spanish hospitals. The (Global Initiative for Asthma, 2021). However, chronic use of observational period included 12 months pre- and post- oral corticosteroids (OCS), including intermittent use at high mepolizumab treatment. Eligibility criteria for the REDES study doses (≥7.5 mg/day), is associated with significant toxicities due included: patients ≥18 years of age with a clinical diagnosis of to the ubiquitous effects of OCS on organ systems. Toxicities include severe uncontrolled eosinophilic asthma who had initiated osteoporosis, fragility fractures, pneumonia, cardiac and mepolizumab ≥12 months before the date of study inclusion cerebrovascular diseases, cataracts, sleep apnea, renal impairment, and who had ≥12 months of relevant medical records prior to depression, anxiety, type 2 diabetes, and weight gain (Price et al., enrolment. The primary endpoint of the REDES study was the 2018). annual rate of clinically significant asthma exacerbations. Although an in-depth discussion of interventions to prevent Secondary endpoints included pre- and post-bronchodilator systemic CS-related toxicities is beyond the scope of this article, the spirometric tests, changes in blood eosinophil counts, average adverse skeletal effects of these agents deserve special mention OCS daily maintenance dose, and symptom control (assessed because of the high prevalence of bone disorders in patients with using the Asthma Control Test score) pre-to post-mepolizumab severe asthma (Weare-Regales et al., 2021). Bone-related adverse treatment. These results have been previously reported (Domingo effects are the result of OCS action in osteoblasts, osteocytes, and Ribas et al., 2021). osteoclasts. After initiating OCS or systemic CS treatment, patients The REDES study was performed in line with the guiding experience an initial bone resorption phase followed by stunted bone principles of the Declaration of Helsinki and order SAS/3470/ formation. This results in rapid deterioration of bone 2009. Approval was granted by the ethics committee of Hospital microarchitecture (bone quality), and a subsequent increase in La Princesa, Madrid, Spain. Informed consent for the aggregation, fracture risk within the first 3–6 months of treatment, often anonymization and publication of health data was obtained from all before any bone mineral density (BMD) loss is detectable participants included in the study. Separate ethics approval was not (Weare-Regales et al., 2021). Although it is dose dependent, the required for this analysis. prevalence of fragility fractures in patients receiving CS has been This post-hoc analysis of the REDES study evaluates the estimated to be between 30% and 50% (Naranjo Hernández et al., difference in the proportion of patients who would be candidates 2019). for anti-osteoporotic treatment (i.e., required ≥7.5 mg of prednisone There is a need for increased clinician awareness and foresight per day), before and after 1 year of treatment with mepolizumab. regarding downstream toxicities caused by the management of asthma via CS. Effective disease management, avoidance of 2.1.1 Criteria for anti-osteoporotic treatment systemic CS-related osteoporotic fractures, and thus To determine patient eligibility for initiation of anti- improvements in patient quality of life rely on early initiation of osteoporotic treatment (anti-resorptives or bone forming agents), equally effective, OCS-sparing treatments, e.g., biologics. this analysis uses the OCS thresholds provided by the Spanish Mepolizumab is a humanized monoclonal antibody Society of Rheumatology (Naranjo Hernández et al., 2019), which marketed for T2 eosinophilic asthma, with a high affinity for recommend initiating anti-osteoporotic treatment in individuals interleukin-5 (IL-5), a key factor regulating the eosinophil receiving more than 7.5 mg of prednisone per day (although this pathway (involved in growth, differentiation, activation, treatment can be initiated in patients receiving lower doses, recruitment, and survival processes) (Domingo Ribas et al., depending on the age, BMD, previous fractures or other risk 2021). Mepolizumab has demonstrated effectiveness in factors; Figure 1). reducing severe asthma exacerbations and improving lung function in the previously conducted REal worlD Effectiveness and Safety (REDES) study, a retrospective, real- 2.2 Post-hoc endpoints world observational study of 318 patients with severe eosinophilic asthma in Spain (Domingo Ribas et al., 2021). The aim of this post-hoc analysis was to determine the change in Here, we present a post-hoc analysis of the REDES study, which the proportion of patients eligible for anti-osteoporotic treatment aimed to evaluate whether mepolizumab treatment de-escalated (according to the OCS daily dose defined in Section 2.1.1) through OCS dose, allowing for a subsequent discontinuation of anti- the evaluation of changes in OCS consumption before and after osteoporotic treatments in patients with severe eosinophilic asthma. 1 year of mepolizumab treatment. Frontiers in Pharmacology 02 frontiersin.org Domingo et al. 10.3389/fphar.2023.1183156 FIGURE 1 Recommendations to initiate preventive or anti-osteoporosis treatment in patients receiving glucocorticoids (Naranjo Hernández et al., 2019). BMD, bone mineral density; T-score: number of standard deviations from healthy young adults; Z-score: number of standard deviations from a healthy population of the same age, race, and sex. 2.3 Statistical analysis At 12 months, nine patients (2.8%) reported 13 adverse events while on treatment with mepolizumab, none of which were severe. Continuous variables were described using the mean, median, The complete list of adverse events, which were generally mild and standard deviation (SD), and interquartile range (IQR) values, while temporary, has been previously published (Domingo Ribas et al., categorical variables were described using the number and 2021). percentage within categories. As all post-hoc analyses were descriptive, no statistical comparisons were performed. 4 Discussion 3 Results As OCS or parenteral CS therapies are likely to remain as a tool used for the management of acute severe asthma exacerbations for In the REDES study, almost one-third of patients (98/318; the foreseeable future, it is important to consider the impact of 30.8%) were on maintenance OCS at the time of initiating episodic CS courses on the risk of CS-related toxicities. Episodic mepolizumab treatment; mean (SD) OCS dose was 12.14 systemic CS courses increase CS exposure beyond that of (9.97) mg/day. Figure 2 shows changes in the patients’ OCS maintenance oral/inhaled CS. The risk of osteoporosis diagnosis exposure during the study. Cumulative OCS exposure was and fracture has been shown to increase per 1-g increase in systemic 54.3% lower after 1 year of mepolizumab treatment than in CS exposure in patients with asthma (Price et al., 2018). In the year prior to starting mepolizumab (mean [SD] cumulative recognition of this risk, anti-osteoporotic treatment is dose was reduced to 1695.01 [2262.08] mg, from recommended in adults with high cumulative CS exposure (>5 g/ 3712.50 [2983.36] mg; Figure 2C). Of the 98 patients on OCS, year) (Buckley et al., 2017; Naranjo Hernández et al., 2019). 47.8% discontinued CS treatment by 12 months (Domingo Ribas Moreover, a recent analysis found large inter-person variability in et al., 2021). the risk of oral CS-related toxicity among patients with severe Importantly, the number of patients on high-dose OCS asthma, as measured by the Glucocorticoid Toxicity Index (GTI), (≥7.5 mg/day) fell from 56/98 (57.1%) at baseline to 26/90 with only a modest correlation between recent OCS exposure and (28.9%) after 12 months of mepolizumab treatment (Figure 2D). GTI score (McDowell et al., 2021). In contrast, age and disease- Thus, 30 (53.6%) CS-dependent asthma patients treated with specific quality-of-life scores correlated more strongly with the GTI mepolizumab in the REDES study would cease to be candidates score, likely reflecting the impact of lifetime OCS exposure. for anti-osteoporotic treatment according to guidelines thresholds. Compared to CS, asthma biologics such as mepolizumab have Theoretically, anti-osteoporotic treatments could have also been shown a more favorable safety profile, which, together with the withdrawn from these patients, reducing the risk of long-term drug- efficacy of biologics, has helped position CS as a last resort choice related complications. after biologics. In the clinical studies of mepolizumab, the most Frontiers in Pharmacology 03 frontiersin.org Domingo et al. 10.3389/fphar.2023.1183156 FIGURE 2 Changes in oral corticosteroid exposure (prednisolone equivalents): (A) mean daily dose and (B) mean monthly cumulative dose during mepolizumab treatment, (C) annual cumulative dose during the year prior to mepolizumab and after 12 months of receiving mepolizumab treatment, and (D) proportion of patients receiving <7.5 mg/day or ≥7.5 mg/day at entry and after 1 year of mepolizumab. OCS, oral corticosteroids. The error bars represent standard error. commonly reported adverse drug reactions were headache, injection Despite asthma guidelines recommending mepolizumab site reactions, and back pain, up to 4.8 years after treatment and other biologics over OCS as maintenance therapies for initiation (Khurana et al., 2019; Mitchell and Leigh, 2019). severe asthma (Global Initiative for Asthma, 2021), it is Although chronic use of prednisolone-equivalent OCS doses as important to note that biologics do not completely eliminate low as 2.5 mg/day are enough to increase the risk of fractures (Zeiger the need for OCS in all patients, nor do they definitively prevent et al., 2017), this risk is significantly higher in individuals exacerbations. Physicians managing severe asthma should taking ≥7.5 mg/day (van Staa et al., 2000). Consequently, continue to remain vigilant in assessing CS-related toxicity osteoporosis prevention treatment is recommended for risk in patients receiving biologics or long-term OCS, individuals (with additional risk factors) who are particularly in patients carrying additional osteoporotic risk aged <40–50 years receiving prednisolone >7.5 mg/day (Buckley factors (Weare-Regales et al., 2021). et al., 2017; Naranjo Hernández et al., 2019) or aged >50 years This post-hoc analysis shows that mepolizumab allows the receiving ≥5 mg/day (Naranjo Hernández et al., 2019). reduction of OCS in CS-dependent asthma patients, lowering their The minimization or avoidance of chronic OCS use in asthma fracture risk and therefore allowing them to discontinue anti- treatment is pertinent in reducing osteoporosis and fracture risk and osteoporotic treatment, avoiding or reducing potential long-term lessening patient exposure to other pharmacologic interventions. In drug-related complications, such as atypical femoral fractures or this respect, the data derived from the REDES study support the osteonecrosis of the jaw. benefits mepolizumab may offer in decreasing the indication of anti- The REDES study and, therefore, this post-hoc analysis have osteoporotic treatment. some limitations. The most important limitation is that our Frontiers in Pharmacology 04 frontiersin.org Domingo et al. 10.3389/fphar.2023.1183156 calculation of the proportion of patients who were candidates for content, gave their final approval of the version to be published, anti-osteoporotic treatment discontinuation is only an estimation. and agree to be accountable for the content of the work. Another limitation is that although participating centers had dedicated asthma units for data collection, the retrospective nature of the study may have resulted in incomplete data Funding collection and/or data may have been subject to time-varying confounders. An example of this is the lack of reliable data on This post-hoc analysis, the parent study (GSK ID: 213172), and cumulative OCS dose that included all OCS courses patients had medical writing assistance for the preparation of this article were received during the study, meaning we had to limit our analysis to funded by GSK. those patients receiving a maintenance daily OCS dose. Acknowledgments 5 Conclusion We would like to thank Richard Crampton and Sarah Greig, Mepolizumab has shown a de-escalation effect in OCS PhD, of Springer Healthcare Communications, who wrote the maintenance dose, as well as a reduction in cumulative CS outline and first draft of the manuscript, respectively. exposure, in a high proportion of severe asthma patients. However, its potential effect on anti-osteoporotic treatment had not been reported. Our study quantifies for the first time that 53.6% Conflict of interest of CS-dependent severe asthma patients, would cease to be candidates for anti-osteoporotic treatment after 12 months of CD has received funding for travel or speaker fees from ALK, mepolizumab therapy. Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Esteve, Ferrer, GSK, Menarini, Novartis, Stallergenes, and Pfizer. AS has received funding for travel or speaker fees from Chiesi, GSK, Sanofi-aventis, Data availability statement AstraZeneca, Boehringer Ingelheim, ImmunoTek, Menarini, Novartis, Allergy Therapeutics, and Teva. EC has received The original contributions presented in the study are included in funding for travel or speaker fees from Lilly, Amgen, UCB, the article/Supplementary Material, further inquiries can be directed to Theramex, STADA, Gedeon-Richter, and GP-Pharm. EM has the corresponding author: Christian Domingo, cdomingo@tauli.cat. received speaker or consulting fees from ALK, AstraZeneca, BIAL, Boehringer Ingelheim, Chiesi, GSK, Novartis, Teva, and Sanofi. MB has received speaker or consulting fees from ALK, Ethics statement AstraZeneca, Chiesi, GSK, Novartis, Teva, and Zambón. TC has received speaker fees from ALK, Diater, GSK, LETI, and Novartis. The studies involving human participants were reviewed and DB is an employee of GSK and holds shares in the company. MS was approved by Ethics committee of Hospital La Princesa, Madrid. The an employee of GSK when this manuscript was written. patients/participants provided their written informed consent to participate in this study. Publisher’s note Author contributions All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated CD, EM, MB, TC, DB, and MS contributed to the design of organizations, or those of the publisher, the editors and the REDES. CD, AS, EM, MB, and TC contributed to the recruitment of reviewers. Any product that may be evaluated in this article, or patients. EC contributed to interpretation of the results. All authors claim that may be made by its manufacturer, is not guaranteed or critically reviewed and revised the manuscript for intellectual endorsed by the publisher. References Buckley, L., Guyatt, G., Fink, H. A., Cannon, M., Grossman, J., Hansen, K. E., et al. Khurana, S., Brusselle, G. G., Bel, E. H., FitzGerald, J. M., Masoli, M., Korn, S., et al. (2017). American college of rheumatology guideline for the prevention and treatment of (2019). 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