Dupixent (dupilumab) - 3 indications

Scroll down for information on each indication:

Atopic Dermatitis; approved March 2017

Moderate-to-severe asthma; approved October 2018

Chronic Rhinosinusitis with nasal polyposis; approved June 2019

General Information

Dupixent (dupilumab) is an interleukin-4 receptor alpha antagonist.

Dupixent is specifically indicated for the following conditions:

• for the treatment of patients aged 6 years and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.
• 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.
• as an add-on maintenance treatment in adult patients with inadequately controlled chronic rhinosinusitis with nasal polyposis (CRSwNP).

Dupixent is supplied as a solution for subcutaneous administration. Scroll down to see the recommended dosing for each therapeutic condition.

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, atopic dermatitis, and CRSwNP. 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.

Side Effects

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

Atopic Dermatitis:

• injection site reactions
• conjunctivitis
• blepharitis
• oral herpes
• keratitis
• eye pruritus
• other herpes simplex virus infection
• dry eye

Asthma

• injection site reactions
• oropharyngeal pain
• eosinophilia

Chronic Rhinosinusitis with Nasal Polyposis

• injection site reactions
• eosinophilia
• insomnia
• toothache
• gastritis
• arthralgia
• conjunctivitis

Indication 1 - atopic dermatitis

Approved March 2017

Dosing/Administration

Dosing in Adults: The recommended dose of Dupixent for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week (Q2W).

Dosing in Pediatric Patients (6 to 17 Years of Age): The recommended dose of Dupixent for patients 6 to 17 years of age is specified below:

Body Weight: 15 to less than 30 kg Initial Dose: 600 mg (two 300 mg injections)  Subsequent Doses: 300 mg every 4 weeks (Q4W)

Body Weight: 30 to less than 60 kg Initial Dose: 400 mg (two 200 mg injections) Subsequent Doses: 200 mg every other week (Q2W)

Body Weight: 60 kg or more Initial Dose: 600 mg (two 300 mg injections) Subsequent Doses: 300 mg every other week (Q2W)

Clinical Trial Results

The FDA approval of Dupixent was based on three randomized, double-blind, placebo-controlled trials which enrolled subjects 18 years of age and older with moderate-to-severe atopic dermatitis (AD) not adequately controlled by topical medication(s). Disease severity was defined by an Investigator’s Global Assessment (IGA) score ≥3 in the overall assessment of AD lesions on a severity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥16 on a scale of 0 to 72, and a minimum body surface area involvement of ≥10%.  All three trials assessed the primary endpoint, the change from baseline to Week 16 in the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) and at least a 2-point improvement.

LIBERTY AD SOLO 1 and SOLO 2 enrolled 1,379 adults with moderate-to-severe AD in the identically-designed trials. Subjects were randomized into one of three treatment groups: dupilumab 300 mg subcutaneously once per week, dupilumab 300 mg subcutaneously every two weeks, or placebo for 16 weeks following an initial dupilumab loading dose of 600 mg subcutaneously, or placebo. Both trials met the primary endpoints. For SOLO 1 and SOLO 2, respectively, 37 and 36% of patients who received dupilumab 300 mg weekly, and 38 and 36% of patients who received dupilumab 300 mg every two weeks, achieved clearing or near-clearing of skin lesions (IGA 0 or 1), compared to 10 and 8.5% with placebo (p less than 0.0001).

LIBERTY AD CHRONOS enrolled 700 adults with moderate-to-severe AD. The trial was designed to demonstrate the efficacy of dupilumab when administered concomitantly with topical corticosteroids through 16 weeks. Secondary objectives of the study included the long-term safety and efficacy of dupilumab up to 52 weeks. The primary endpoints at week 16 were reached: 39% of patients who received either dupilumab 300 mg weekly with TCS or dupilumab 300 mg every two weeks with TCS achieved clearing or near-clearing of skin lesions (IGA 0 or 1), compared to 12% of patients receiving placebo with TCS (p less than 0.0001). 64% of patients who received dupilumab 300 mg weekly with TCS, and 69% of patients who received dupilumab 300 mg every two weeks with TCS achieved EASI-75, a 75 percent reduction on an index measuring eczema severity, compared to 23% of patients receiving placebo with TCS (p less than 0.0001). The secondary endpoint 52-week results were also reached and showed the following: 40% of patients who received dupilumab 300 mg weekly with TCS, and 36% of patients who received dupilumab 300 mg every two weeks with TCS achieved clearing or near-clearing of skin lesions (IGA 0 or 1), compared to 12.5% of patients receiving placebo with TCS (p less than 0.0001). 64% of patients who received 300 mg weekly with TCS, and 65% of patients who received 300 mg every two weeks with TCS achieved EASI-75, compared to 22% with placebo with TCS (p less than 0.0001).

The FDA approval of Dupixent for children with atopic dermatitis was based on data that includes pivotal Phase 3 results on the efficacy and safety of Dupixent combined with topical corticosteroids (TCS) compared to TCS alone in children with severe atopic dermatitis. In the trial, children treated with Dupixent and TCS experienced significant improvements in overall disease severity, skin clearance and itch. Results at 16 weeks showed:

• 84% improvement in average EASI (Eczema Area and Severity Index) score from baseline in patients who received Dupixent every four weeks and 80% in patients who received Dupixent every two weeks, compared to 49% and 48% for TCS alone, respectively.
• 75% of patients who received Dupixent every four weeks and 75% of patients who received Dupixent every two weeks achieved EASI-75 (Eczema Area and Severity Index-75), compared to 28% and 26% for TCS alone, respectively.
• 54% of patients who received Dupixent every four weeks and 61% of patients who received Dupixent every two weeks experienced at least a 4-point reduction in itch intensity on a 0 to 10-point scale (weekly average of daily Peak Pruritus Numerical Rating Scale), compared to 12% and 13% for TCS alone, respectively.
• 30% of patients who received Dupixent every four weeks and 39% of patients who received Dupixent every two weeks achieved clear or almost clear skin (Investigator's Global Assessment or IGA), compared to 13% and 10% for TCS alone, respectively.

Indication 2 - moderate-to-severe asthma

Approved October 2018

Dosing/Administration

The recommended dose 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, or with co-morbid moderate to-severe atopic dermatitis for which Dupixent is indicated, start with an initial dose of 600 mg followed by 300 mg given every other week.

Clinical Trial Results

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.

Indication 3 - chronic rhinosinusitis with nasal polyposis

Approved June 2019

Dosing/Administration

The recommended dose of Dupixent for adult patients is 300 mg given every other week.

Clinical Trial Results

The FDA approval of Dupixent for chronic rhinosinusitis with nasal polyposis in adults was based on two pivotal trials (the 24-week SINUS-24 and 52-week SINUS-52) that are part of the Phase 3 LIBERTY clinical trial program. These trials evaluated Dupixent 300 mg every two weeks with standard-of-care mometasone furoate nasal spray (MFNS) compared to placebo injection plus MFNS. In these trials, Dupixent significantly improved key disease measures and met all primary and secondary endpoints. At 24 weeks, patients treated with Dupixent achieved statistically significant improvements in all primary and secondary endpoints, including:

• Co-primary endpoints:
  • 57% and 51% improvement in their nasal congestion/obstruction severity compared to a 19% and 15% improvement with placebo in SINUS-24 and SINUS-52, respectively (least squares [LS] mean change from baseline of -1.34 and -1.25 for Dupixent compared to -0.45 and -0.38 for placebo; difference between Dupixent and placebo: -0.89 and -0.87).
  • 33% and 27% reduction in their nasal polyps score compared to a 7% and 4% increase with placebo in SINUS-24 and SINUS-52, respectively (LS mean change from baseline of -1.89 and -1.71 for Dupixent compared to 0.17 and 0.10 for placebo; difference between Dupixent and placebo: -2.06 and -1.80).