Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.

BACKGROUND: Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. The blockade by dupilumab of these key drivers of type 2 helper T-cell (Th2)-mediated inflammation could help in the treatment of related diseases, including atopic dermatitis. METHODS: We performed randomized, double-blind, placebo-controlled trials involving adults who had moderate-to-severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors. Dupilumab was evaluated as monotherapy in two 4-week trials and in one 12-week trial and in combination with topical glucocorticoids in another 4-week study. End points included the Eczema Area and Severity Index (EASI) score, the investigator's global assessment score, pruritus, safety assessments, serum biomarker levels, and disease transcriptome. RESULTS: In the 4-week monotherapy studies, dupilumab resulted in rapid and dose-dependent improvements in clinical indexes, biomarker levels, and the transcriptome. The results of the 12-week study of dupilumab monotherapy reproduced and extended the 4-week findings: 85% of patients in the dupilumab group, as compared with 35% of those in the placebo group, had a 50% reduction in the EASI score (EASI-50, with higher scores in the EASI indicating greater severity of eczema) (P<0.001); 40% of patients in the dupilumab group, as compared with 7% in the placebo group, had a score of 0 to 1 (indicating clearing or near-clearing of skin lesions) on the investigator's global assessment (P<0.001); and pruritus scores decreased (indicating a reduction in itch) by 55.7% in the dupilumab group versus 15.1% in the placebo group (P<0.001). In the combination study, 100% of the patients in the dupilumab group, as compared with 50% of those who received topical glucocorticoids with placebo injection, met the criterion for EASI-50 (P=0.002), despite the fact that patients who received dupilumab plus glucocorticoids used less than half the amount of topical glucocorticoids used by those who received placebo plus the topical medication (P=0.16). Adverse events, such as skin infection, occurred more frequently with placebo; nasopharyngitis and headache were the most frequent adverse events with dupilumab. CONCLUSIONS: Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity. Side-effect profiles were not dose-limiting. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01259323, NCT01385657, NCT01639040, and NCT01548404.).

Dupilumab in persistent asthma with elevated eosinophil levels.

BACKGROUND: Moderate-to-severe asthma remains poorly treated. We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels. METHODS: We enrolled patients with persistent, moderate-to-severe asthma and a blood eosinophil count of at least 300 cells per microliter or a sputum eosinophil level of at least 3% who used medium-dose to high-dose inhaled glucocorticoids plus long-acting beta-agonists (LABAs). We administered dupilumab (300 mg) or placebo subcutaneously once weekly. Patients were instructed to discontinue LABAs at week 4 and to taper and discontinue inhaled glucocorticoids during weeks 6 through 9. Patients received the study drug for 12 weeks or until a protocol-defined asthma exacerbation occurred. The primary end point was the occurrence of an asthma exacerbation; secondary end points included a range of measures of asthma control. Effects on various type 2 helper T-cell (Th2)-associated biomarkers and safety and tolerability were also evaluated. RESULTS: A total of 52 patients were assigned to the dupilumab group, and 52 patients were assigned to the placebo group. Baseline characteristics were similar in the two groups. Three patients had an asthma exacerbation with dupilumab (6%) versus 23 with placebo (44%), corresponding to an 87% reduction with dupilumab (odds ratio, 0.08; 95% confidence interval, 0.02 to 0.28; P<0.001). Significant improvements were observed for most measures of lung function and asthma control. Dupilumab reduced biomarkers associated with Th2-driven inflammation. Injection-site reactions, nasopharyngitis, nausea, and headache occurred more frequently with dupilumab than with placebo. CONCLUSIONS: In patients with persistent, moderate-to-severe asthma and elevated eosinophil levels who used inhaled glucocorticoids and LABAs, dupilumab therapy, as compared with placebo, was associated with fewer asthma exacerbations when LABAs and inhaled glucocorticoids were withdrawn, with improved lung function and reduced levels of Th2-associated inflammatory markers. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT01312961.).

Asthma, asthma medications and their effects on maternal/fetal outcomes during pregnancy.

Maternal asthma may increase the risk of adverse fetal and maternal outcomes such as low birth weight, perinatal mortality, preterm birth, preeclampsia, hypertensive disorders, maternal mortality, uterine hemorrhage, and gestational diabetes. Controlling asthma during pregnancy with appropriate medications leads to improved intrauterine growth of the fetus and fewer adverse perinatal outcomes. Prospective population or birth cohort studies have shown that the medications used to treat asthma, such as bronchodilators (short-acting ß2-agonists) and controller medications (inhaled corticosteroids, cromones, theophylline, leukotriene inhibitors), have no or minimal effects on fetal growth, and perinatal complications are reduced when maternal asthma is adequately controlled. However, taking oral corticosteroids during pregnancy may confer increased risk of lower birth weight and congenital malformations. Therefore, managing pregnant asthmatics requires a careful benefit-risk analysis, and when indicated, the benefits of a medication that may have increased risks can dictate its use in severe uncontrolled asthma.