Mepolizumab and Eosinophil-Mediated Disease

Walsh, Garry Michael

doi:10.2174/092986709789909639

Cited by 28 publications

(15 citation statements)

References 41 publications

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“…Table 1 summarises these studies and the various IL-5/IL-5R approaches [13,[34][35][36][37][38][39][40][41][42]. Although patients receiving these monoclonal antibodies have demonstrated consistent reductions in eosinophil numbers in blood and sputum, clinical responses have been quite variable [43,44]. At present, mepolizumab is the most studied anti-IL-5 in the treatment of severe asthma.…”

Section: Anti-il-5 Therapeutic Approachesmentioning

confidence: 99%

Anti-interleukin-5 therapy in severe asthma

et al. 2013

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Asthma is a chronic inflammatory disorder of the airways that leads to acute symptoms, exacerbations and sometimes, for a small part of the asthmatic population, fatal or near-fatal exacerbations.This as yet significant minority of individuals present with severe asthma and have persisting daily symptoms, and exacerbations despite compliance with high doses of inhaled steroids and additional treatment. For more than a decade, the pharmacological management of patients with severe asthma has focused on evaluating specific cytokines. The rationale of this approach is based on the distinguished key role played by eosinophils in the asthma inflammatory processes. Eosinophils are recruited from the circulation to airways where they cause airway damage via different mechanisms. Eosinophils are regulated in terms of their recruitment, activation, growth, differentiation and survival by interleukin (IL)-5. Abundant data from in vitro experiments, animal models and clinical trials has confirmed that IL-5 inhibition may be an effective approach for the treatment of asthma, especially severe asthma. Interfering with eosinophil function or reducing their numbers has been one of the most important goals of therapeutic monoclonal antibodies, which target cytokine receptor interactions in asthma, particularly IL-5. This review will consider new treatments options for severe asthma, particularly those targeting IL-5, that have already been evaluated in clinical trials in asthmatic patients. @ERSpublications Rationale, recent advances and future developments of anti-IL-5 therapy in patients with severe asthma http://ow.ly/n3viv

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Section: Anti-il-5 Therapeutic Approachesmentioning

confidence: 99%

Anti-interleukin-5 therapy in severe asthma

et al. 2013

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“…Many of the therapeutic antibodies raised against soluble antigens such as circulating TNF, vascular endothelial growth factor (VEGF), IgE, and various cytokines (e.g., interleukin (IL)-8, IL-5, IL-12/IL-23) have undergone extensive research in both various animal models and clinical studies in patients (13,(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64). For this class of compounds, application of PK-PD modeling approaches can prove highly effective for the design of successful translational strategies (4,5,9,10).…”

Section: Introductionmentioning

confidence: 99%

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Tabrizi

Funelas

Suria

2010

AAPS J

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Abstract. The advancement of therapeutic monoclonal antibodies during various stages of the drug development process can be effectively streamlined when appropriate translational strategies are applied. Design of successful translational strategies for development of monoclonal antibodies should allow for understanding of the dose-and concentration-response relationships with respect to both beneficial and toxic effects from early phases of drug development. Evaluation of relevant biomarkers during early stages of drug development should facilitate the successful design of safe and effective dosing strategies. Moreover, application of quantitative pharmacology is critical for translation of exposure-response relationships early on.

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“…This has happened following the near-demise of an antiinterleukin (IL)-5 monoclonal antibody (mepolizumab) as a candidate for asthma treatment [1] and its resurrection in trials based around using induced sputum eosinophils to identify a treatment responsive phenotype [2,3]. The improvement in outcome was spectacular.…”

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confidence: 99%

Why inflammatory phenotyping is necessary for successful drug evaluation in asthma and COPD

Gibson

2013

Eur Respir J

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@ERSpublicationsPathway specific drug trials must account for prevalence of the pathway by subject selection or by adjusting sample size http://ow.ly/nx4k9Identifying and treating the eosinophilic subtype of asthma has now achieved renewed importance for clinicians and scientists involved in clinical trials. This has happened following the near-demise of an antiinterleukin (IL)-5 monoclonal antibody (mepolizumab) as a candidate for asthma treatment [1] and its resurrection in trials based around using induced sputum eosinophils to identify a treatment responsive phenotype [2,3]. The improvement in outcome was spectacular. An effect size close to zero was converted to a massive effect size of a 50% reduction in asthma exacerbations, simply by using assessment of clinical status and eosinophils to identify a treatment responsive phenotype. The spotlight is now firmly on clinical trial design in airway diseases and how to identify disease subtypes for testing new therapies. An article by DASGUPTA et al. [4], in this issue of the European Respiratory Journal, addresses this issue by reporting a systematic review of the use of one biomarker, sputum eosinophils, in randomised controlled trials over the past 10 years, and assesses the implications for study design, analysis and sample size in particular.For a long time, asthma pharmacotherapy has been based around b 2 -agonists and corticosteroids, which are regularly reformulated to tweak their clinical efficacy. The promise of new blockbuster treatments has remained both a hope and a necessity, but elusive. Basic scientists have elucidated pathobiological pathways in asthma and, in collaboration with pharmaceutical chemists and immunobiologists, pathway specific treatments have been developed. Once a drug passes the safety hurdle, the next step has been for clinical trials to demonstrate drug efficacy in people with asthma, a phase 3 trial. While every step in this chain is critical, by the time a drug is ready for phase 3 trials, the intellectual and financial investment has been massive and an error at this stage is particularly costly. It is against this background that we need to view modern drug development in asthma and chronic obstructive pulmonary disease (COPD).What we have learnt from the mepolizumab story is that drugs designed to target a very specific pathway actually target a very specific pathway. If that pathway is not important in the people tested, then the drug has little or no effect. The logical next step is to ask how these pathways and their importance, i.e. clinical relevance, can be identified. Part of the answer lies in the use of biomarkers. The principle of this approach is to use a biomarker to identify the people in whom the pathobiological pathway is active, termed an endotype [5], and then treat them with the pathway specific therapy. We are seeing a technological revolution in biomarker discovery, with the application of 'omics technologies to this area. A recent example is the use of periostin, a serum biomarker identified using tran...

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Mepolizumab and Eosinophil-Mediated Disease

Cited by 28 publications

References 41 publications

Anti-interleukin-5 therapy in severe asthma

Anti-interleukin-5 therapy in severe asthma

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Why inflammatory phenotyping is necessary for successful drug evaluation in asthma and COPD

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