--------------------------------------------------------------------------------

Dupixent (dupilumab)

The following drug information is obtained from various newswires, published medical journal articles, and medical conference presentations.

Approval Status:

Approved October 2018

Specific Treatments:

moderate-to-severe asthma

General Information

Dupixent (dupilumab) inhibits the overactive signaling of interleukin-4 (IL-4) and interleukin-13 (IL-13), two key proteins that contribute to the inflammation associated with moderate-to-severe asthma.

Dupixent is specifically indicated as an add-on maintenance treatment in patients with moderate-to-severe asthma aged 12 years and older with an eosinophilic phenotype or with oral corticosteroid dependent asthma. 

Dupixent is supplied as an injection for subcutaneous administration. The recommended dose of Dupixent for adults and adolescents (12 years of age and older) is:

• an initial dose of 400 mg (two 200 mg injections) followed by 200 mg given every other week or

• an initial dose of 600 mg (two 300 mg injections) followed by 300 mg given every other week

For patients with oral corticosteroids-dependent asthma, start with an initial dose of 600 mg followed by 300 mg given every other week 

Clinical Results

FDA Approval

The FDA approval of Dupixent for moderate-to-severe asthma was based on three randomized, placebo-controlled, multicenter trials (Trial 1, Trial 2 and Trial 3) which evaluated 2,888 adult and adolescent patients with moderate-to-severe asthma for six months to one year (24 to 52 weeks). All trials enrolled patients irrespective of minimum baseline eosinophil levels.

Trial 1 was a 24-week dose-ranging study which included 776 subjects (18 years of age and older). Dupixent compared with placebo was evaluated in adult subjects with moderate to severe asthma on a medium or high-dose inhaled corticosteroid and a long acting beta agonist. Subjects were randomized to receive either 200 mg (N=150) or 300 mg (N=157) Dupixent every other week (Q2W) or 200 mg (N=154) or 300 mg (N=157) Dupixent every 4 weeks following an initial dose of 400 mg, 600 mg or placebo (N=158), respectively. The primary endpoint was mean change from baseline to Week 12 in FEV1 (L) in subjects with baseline blood eosinophils ≥300 cells/mcL. In the subgroup with at least 300 eosinophils per μL, the greatest increases (200 mg every 2 weeks, p=0·0008; 300 mg every 2 weeks, p=0·0063) in FEV 1 compared with placebo were observed at week 12 with doses every 2 weeks in the 300 mg group (mean change 0·39 L) and in the 200 mg group (mean change 0·43 L) compared with placebo (0·18 L).

Trial 2 was a 52-week study which included 1,902 subjects (12 years of age and older). Dupixent compared with placebo was evaluated in 107 adolescent and 1,795 adult subjects with moderate-to-severe asthma on a medium or high-dose inhaled corticosteroid (ICS) and a minimum of one and up to two additional controller medications. Subjects were randomized to receive either 200 mg (N=631) or 300 mg (N=633) Dupixent Q2W (or matching placebo for either 200 mg [N=317] or 300 mg [N=321] Q2W) following an initial dose of 400 mg, 600 mg or placebo respectively. The primary endpoints were the annualized rate of severe exacerbation events during the 52-week placebo controlled period and change from baseline in pre-bronchodilator FEV1 at Week 12 in the overall population (unrestricted by minimum baseline blood eosinophils count). Dupixent reduced exacerbations and improved lung function in the overall population. Benefits in exacerbations were seen in patients with eosinophil counts greater than or equal to 150 cells/microliter, which represented 70% of the patients enrolled. Efficacy improved in patients with higher eosinophil counts. For example, in patients with blood eosinophils of 300 cells/microliter or greater, Dupixent reduced severe exacerbations by 67% compared to placebo, and improved FEV1 (lung function) by 29%-33% compared to 14%-16% for placebo. In patients with eosinophil counts less than 150 cells/microliter, there was no difference in severe exacerbation rates for Dupixent versus placebo. 

Trial 3 was a 24-week oral corticosteroid-reduction study in 210 subjects with asthma who required daily oral corticosteroids in addition to regular use of high dose inhaled corticosteroids plus an additional controller. After optimizing the OCS dose during the screening period, subjects received 300 mg Dupixent (N=103) or placebo (N=107) once Q2W for 24 weeks following an initial dose of 600 mg or placebo. Subjects continued to receive their existing asthma medicine during the study; however their OCS dose was reduced every 4 weeks during the OCS reduction phase (Week 4-20), as long as asthma control was maintained. The primary endpoint was the percent reduction of oral corticosteroid dose at Weeks 20 to 24 compared with the baseline dose, while maintaining asthma control in the overall population (unrestricted by minimum baseline blood eosinophils count). Dupixent reduced average daily oral corticosteroid use by 70% compared to 42% with placebo. More than half of patients treated with Dupixent completely eliminated use of oral corticosteroids. Effects on lung function and on oral steroid and exacerbation reduction were similar for Dupixent irrespective of baseline blood eosinophil levels.

 

Side Effects

Adverse effects associated with the use of Dupixent may include, but are not limited to, the following:

injection site reactions

conjunctivitis

blepharitis

oral herpes

keratitis

eye pruritus

other herpes simplex virus infections

dry eye

Mechanism of Action

Dupixent (dupilumab) is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. Dupilumab inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL-13 signaling through the Type II receptor. Inflammation is an important component in the pathogenesis of asthma and atopic dermatitis. Multiple cell types that express IL-4Rα (e.g., mast cells, eosinophils, macrophages, lymphocytes, epithelial cells, goblet cells) and inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines, chemokines) are involved in inflammation. Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 cytokine-induced inflammatory responses, including the release of proinflammatory cytokines, chemokines, nitric oxide, and IgE; however, the mechanism of dupilumab action in asthma has not been definitively established.

Additional Information

For additional information regarding Dupixent or asthma, please visit https://www.dupixent.com/asthma

---------------------------------------------------------------------------------

[ Home | Discussions | Article Archives | Help | Submit your Site]

Copyright 1996 - 2014 by Gelber Associates All Rights Reserved.