Treatment Of Severe Eosinophilic Asthma Research Articles

Reslizumab in Eosinophilic Asthma: A Review.

Reslizumab (Cinqaero®; Cinqair®) is a humanized monoclonal antibody against interleukin-5 (IL-5), a cytokine mediator of eosinophilic airway inflammation. Reslizumab is indicated as an add-on treatment for severe eosinophilic asthma in adults, on the basis of data from the BREATH phase III clinical trial programme. In three double-blind BREATH studies of up to 52weeks' duration, adding intravenous reslizumab (3mg/kg, once every 4weeks) to the current asthma therapy of patients (aged 12-75years) with eosinophilic asthma inadequately controlled with inhaled corticosteroids resulted in significant reductions in clinical asthma exacerbation frequency and significant improvements in lung function, asthma control and health-related quality of life relative to adding placebo. Pooled data from the two trials of 52weeks' duration indicated similar benefits with reslizumab across various patient subgroups, including patients with severe eosinophilic asthma. Reslizumab was generally well tolerated, with very few recipients experiencing severe or serious treatment-related adverse events. Moreover, in an open-label extension study, continued use of reslizumab for up to 2years was associated with durable lung function benefit, without any new tolerability concerns. Thus, intravenous reslizumab extends the valuable add-on treatment options for adults with severe eosinophilic asthma inadequately controlled with standard therapies.

Inhibition of interleukin-5 induced false positive anti-drug antibody responses against mepolizumab through the use of a competitive blocking antibody

Mepolizumab, a humanized IgG1 monoclonal antibody that blocks native homodimeric interleukin-5 (IL-5) from binding to the IL-5 receptor, has recently been approved for treatment of severe eosinophilic asthma. Our initial immunogenicity assay method for phase I and II studies utilized a bridging electrochemiluminescence format with biotin and ruthenium-labelled mepolizumab linked by anti-drug antibodies (ADA). We discovered that IL-5 significantly increased in dosed subjects from a phase II study and that the increased IL-5 was in the form of a drug-bound complex. We demonstrated that the elevated drug-bound IL-5 produced false-positive response in the in vitro ADA assay, in which drug-bound IL-5 dissociated and then bridged mepolizumab conjugates to yield positive signal. To eliminate the IL-5 interference, we compared two strategies: a solid-phase immunodepletion of IL-5 and an in-solution IL-5 immunocompetition. We identified the best competitive antibody for each purpose. We found both methods demonstrated similar effectiveness in reducing the false positive signal in IL-5 spiked samples; however, the in-solution immunocompetition for IL-5 had fewer false positives in study samples. Additionally, the in-solution immunocompetition method was experimentally simpler to execute. We modified the ADA assay by adding a pre-treatment step with a mepolizumab competitive anti- IL-5 antibody. Using this new method, we retested clinical samples from two phase II studies (MEA112997 and MEA114092). The confirmed ADA positive incidence was reduced from 29% and 61% to 1% and 8% with the modified in-solution immune inhibition method. Target interference is a fairly common problem facing immunogenicity testing, and target-induced false positive cannot be distinguished from true ADA response by the commonly used drug competitive confirmation assay. The approach and method used here for resolving target interference in ADA detection will be useful for differentiating between a true ADA response and target induced false positive as well as similar challenges in other programs.

Mepolizumab: A Review in Eosinophilic Asthma.

Mepolizumab (Nucala(®)) is a humanized monoclonal antibody against interleukin-5, a cytokine involved in the development, recruitment and activation of eosinophils (cellular mediators of airway inflammation, hyper-responsiveness and tissue remodelling). The drug is indicated as an add-on treatment for severe eosinophilic asthma, on the basis of its clinical benefit in this setting in the placebo-controlled DREAM, MENSA and SIRIUS trials. Based on the 52-week, phase II, DREAM study (which assessed varying intravenous mepolizumab dosages), intravenous mepolizumab 75mg every 4weeks (q4w) and the corresponding (recommended) subcutaneous dosage of 100mg q4w were studied in the 32- and 24-week phase III MENSA and SIRIUS trials. In patients aged ≥12years with severe eosinophilic asthma in the phase III studies, adding subcutaneous mepolizumab 100mg q4w to current asthma therapy significantly reduced the rate of clinically relevant asthma exacerbations and, in those dependent on oral glucocorticoids (OCSs) for asthma control, enabled the daily OCS dose to be significantly reduced, relative to adding placebo. This mepolizumab regimen also significantly improved asthma control, health-related quality of life and (in one of the two studies) lung function, and had acceptable tolerability (with headache the most common adverse event). In the MENSA and SIRIUS extension, COSMOS, mepolizumab provided durable clinical benefit over up to 84weeks' therapy with no new tolerability concerns. Thus, mepolizumab is a valuable add-on treatment option for adults and adolescents aged ≥12years who have severe eosinophilic asthma despite optimized standard therapies.

Clinical usefulness of mepolizumab in severe eosinophilic asthma.

Asthma is a chronic inflammatory disorder of the airways with variable clinical severity from very mild and occasional symptoms to recurrent critical exacerbations, at risk of fatal or near-fatal outcome, in a small percentage of patients. Within the different inflammatory cascades involved in asthma, eosinophils play a central role in the pathogenesis and largely influence disease severity. Interleukin-5 (IL-5) is the main cytokine controlling eosinophil activity and proliferation at the site of inflammation. Mepolizumab was the first biological humanized anti-IL-5 monoclonal antibody tested in randomized clinical trials on eosinophilic asthma and other eosinophilic diseases. On the basis of several positive clinical efficacy data, it has recently been approved by the US Food and Drug Administration for the treatment of severe eosinophilic asthma. Unfortunately, high costs are at present a critical issue. Future studies will probably help in the correct selection of a potential “responder phenotype”, allowing the prescription of this promising therapy to appropriate patients and best define cost-effectiveness issues.

Mepolizumab in the treatment of severe eosinophilic asthma.

IL-5 is crucial in the pathogenesis and evolution of eosinophilic asthma. Mepolizumab is a high-affinity humanized monoclonal antibody of the IgG1/k subtype that inhibits the binding of IL-5 to its receptor expressed on eosinophils, thereby inducing significant reduction in eosinophil circulation, as well as asthma exacerbations and corticosteroid treatment. This review deals with the currently available studies of mepolizumab in the treatment of patients with severe eosinophilic asthma.

Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin 5 monoclonal antibody, in healthy Japanese male subjects.

Interleukin 5 (IL‐5) and eosinophils are thought to play an important role in the pathology of asthma. This study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of mepolizumab, a humanized anti‐IL5 IgG1 monoclonal antibody, in development for the treatment of severe eosinophilic asthma. This single‐blind study randomized 35 healthy Japanese male subjects (3:1) to receive either a single mepolizumab intravenous dose (10, 75, 250, or 750 mg) or placebo. Subjects were observed for up to 151 days postdose, depending on the dose administered. Blood samples were collected to measure mepolizumab concentrations, blood eosinophils, IL‐5, and antibodies to mepolizumab. Mepolizumab exhibited dose‐proportional pharmacokinetics. The terminal phase half‐life was 19.7–34.6 days, independent of dose. Higher mepolizumab plasma concentrations were associated with lower blood eosinophil counts. Mepolizumab 75–750 mg reduced blood eosinophils for ≥3 months postdose. Mepolizumab demonstrated a favorable safety profile: of 41 reported adverse events, most were mild in severity and none were serious. No neutralizing antibodies to mepolizumab were detected. Sustained reduction in blood eosinophils after single intravenous mepolizumab doses ≥ 75 mg, along with mepolizumab pharmacokinetics and a favorable tolerability profile in healthy Japanese subjects, provides a solid foundation for future studies with mepolizumab in Japanese patients with asthma.