Asthma Clinical Trial: Dupliumab

Antibody clinical trial for asthma; abstract;

Background Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. Its effectiveness in reducing oral glucocorticoid use in patients with severe asthma while maintaining asthma control is unknown. Methods We randomly assigned 210 patients with oral glucocorticoid-treated asthma to receive add-on dupilumab (at a dose of 300 mg) or placebo every 2 weeks for 24 weeks. After a glucocorticoid dose-adjustment period before randomization, glucocorticoid doses were adjusted in a downward trend from week 4 to week 20 and then maintained at a stable dose for 4 weeks. The primary end point was the percentage reduction in the glucocorticoid dose at week 24. Key secondary end points were the proportion of patients at week 24 with a reduction of at least 50% in the glucocorticoid dose and the proportion of patients with a reduction to a glucocorticoid dose of less than 5 mg per day. Severe exacerbation rates and the forced expiratory volume in 1 second (FEV1) before bronchodilator use were also assessed. Results The percentage change in the glucocorticoid dose was -70.1% in the dupilumab group, as compared with -41.9% in the placebo group (P<0.001); 80% versus 50% of the patients had a dose reduction of at least 50%, 69% versus 33% had a dose reduction to less than 5 mg per day, and 48% versus 25% completely discontinued oral glucocorticoid use. Despite reductions in the glucocorticoid dose, in the overall population, dupilumab treatment resulted in a severe exacerbation rate that was 59% (95% confidence interval [CI], 37 to 74) lower than that in the placebo group and resulted in an FEV1 that was 0.22 liters (95% CI, 0.09 to 0.34) higher. Injection-site reactions were more common with dupilumab than with placebo (9% vs. 4%). Transient blood eosinophilia was observed in more patients in the dupilumab group than in the placebo group (14% vs. 1%). Conclusions In patients with glucocorticoid-dependent severe asthma, dupilumab treatment reduced oral glucocorticoid use while decreasing the rate of severe exacerbations and increasing the FEV1. Transient eosinophilia was observed in approximately 1 in 7 dupilumab-treated patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA VENTURE ClinicalTrials.gov number, NCT02528214 .).

Monoclonal Antibodies For Severe Asthma

By Adenosine - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9659630

Monoclonal antibodies are being used to treat many diseases, particularly cancer, and in this paper we see their utility for treating severe asthma. Different types of antibodies can be used dependent upon asthma type and characteristics, suggesting hope for people with the more serious forms of this disease.  Abstract:

Among the monoclonal antibodies (mAbs) developed for severe asthma treatment, three have already been marketed. Omalizumab was the first, more than 10 years ago; today, mepolizumab and reslizumab are also available in the European Union and the US. Omalizumab blocks free immunoglobulin E (IgE), mepolizumab and reslizumab block an interleukin (IL-5). In the near future, dupilumab and benralizumab are expected to emerge as two new alternatives. Benralizumab blocks the receptor for IL-5 (IL5-Rα) and has a direct cytotoxic effect on eosinophils, and dupilumab blocks the α-unit of the heterodimeric receptor for IL-4 and IL-13 (IL-4Rα); as a result, dupilumab can block both IL-4 and IL-13. The purpose of this manuscript is to present the pathophysiology of some immunological aspects of severe asthma, describe the adaptive and innate immunity arms as well as their interrelations (stressing the subordination of the adaptive arm to the innate arm), outline the pharmacologic effects of these mAbs, clarify the overlapping effects of the different mAbs, and discuss the differences between mAbs based on their target molecules. Based on the data presented, I propose omalizumab for patients with an allergic phenotype regardless of their peripheral eosinophilic count, and anti-IL-5 as an alternative in allergic patients with blood eosinophilia in which omalizumab has failed; anti-IL5 for patients with an eosinophilic phenotype and omalizumab as an alternative in patients in whom anti-IL5 fails and IgE ≥30 IU/mL (compassionate use). Omalizumab is also proposed for patients with severe chronic asthma allergic to seasonal allergens.