Dupilumab (Dupixent) is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and IL-13 signalling by binding to the IL-4 receptor alpha (IL-4Rα) subunit shared by the IL-4 and IL-13 receptor complexes. Multiple cell types that express IL-4Rα and inflammatory mediators are involved in inflammation.
Introduction to Atopic Dermatitis
In atopic dermatitis, IL-4 and IL-13 play a key role in the modulation of the epidermal barrier and the stimulation of dermal inflammation and remodelling. By blocking the signalling pathways, dupilumab disrupts development and progression of the allergic disorder.
Atopic dermatitis is the most common skin disorder in Singapore and represents a large clinical burden. The condition usually begins in childhood, affecting 20% of all Singaporean school children and 11% of all adults. The condition can cause intense itching, pain, loss of sleep, and mental health issues.
For decades, topical corticosteroids and general skincare by emollients and non-irritative skin preparations have been the mainstay of management. Systemic agents (e.g. immunosuppressants, oral corticosteroids) and phototherapy can be considered when topical treatments fail, although there remains no definitive cure for the disorder. There is a significant unmet need in using the conventional treatment armamentarium and extensive research has been conducted in search of safe and effective therapies.
In Singapore, the use of dupilumab is approved for the treatment of patients aged 6 years and older with moderate-to-severe atopic dermatitis who require chronic treatment, and whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. The drug is available in pre-filled syringes and is administered via subcutaneous administration at an initial dose of 600mg, followed by 300mg every other week for the treatment of atopic dermatitis in adults. Paediatric patients are dosed based on body weight. Dupilumab can be used with or without topical corticosteroids, and concomitant use of topical calcineurin inhibitors should be reserved for problem areas only.
Dupilumab: Efficacy and Safety
Regulatory approval was based on the demonstration of efficacy and safety in four randomized, double-blind, placebo-controlled trials that recruited 2,119 adult subjects and 251 adolescent subjects with moderate-to-severe atopic dermatitis.
At baseline among the three adult trials (SOLO 1 and SOLO 2; LIBERTY AD CHRONOS), 59% of the subjects were male and 48% had a baseline Investigator’s Global Assessment (IGA) score of 4 (severe). In the trial evaluating adolescents aged 12 to 17 years (LIBERTY AD ADOL), the mean age was 14.5 years, the median weight was 59.4kg, 41% of subjects were female, 54% had an IGA score of 4, and 42% had received prior systemic immunosuppressants.
In SOLO 1 and SOLO 2, the primary outcome was the proportion of patients who had both an IGA score of 0 (clear) or 1 (almost clear), and a reduction of at least 2 points in IGA score from baseline at Week 16. LIBERTY AD CHRONOS and LIBERTY AD ADOL assessed the co-primary endpoints of proportion of patients achieving IGA 0/ 1 and a 2-point or higher improvement from baseline, as well as Eczema Area and Severity Index 75% improvement from baseline (EASI 75) at Week 16. Other secondary efficacy endpoints analysed include proportion of patients with pre-specified improvements in peak scores for pruritus on a numerical rating scale (NRS), Scoring Atopic Dermatitis (SCORAD) score and Global Individual Signs Score (GISS). Improvements in Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM) and Hospital Anxiety and Depression Scale (HADS) were also studied. A summary of the trials is tabled below.
| Study | Intervention/ Comparator | Primary Outcome | Safety Findings |
| SOLO 1
N=671 |
Randomized 1:1:1 to receive for 16 weeks
Only topical rescue treatment was permitted |
Primary outcome occurred in 38% (dupilumab every other week) vs 37% (dupilumab weekly) vs 10% (placebo); P<0.001 for comparisons with placebo |
|
| SOLO 2
N=708 |
Primary outcome occurred in 36% (dupilumab every other week) vs 36% (dupilumab weekly) vs 8% (placebo); P<0.001 for comparisons with placebo | ||
| LIBERTY AD CHRONOS
N=740 |
Randomized 3:1:3 to
All groups were given concomitant topical corticosteroids with or without topical calcineurin inhibitors where inadvisable for topical corticosteroids |
IGA 0/1: 39% (dupilumab weekly) vs 39% (dupilumab every 2 weeks) vs 12% (placebo); P<0.0001
EASI 75: 64% (dupilumab weekly) vs 69% (dupilumab every 2 weeks) vs 23% (placebo); P<0.0001 |
|
| LIBERTY AD ADOL
N=251 |
Randomized 1:1:1 to
Systemic and topical rescue treatment was permitted at the discretion of the investigator |
IGA 0/1: 24.4% (dupilumab every 2 weeks) vs 17.9% (dupilumab every 4 weeks) vs 2.4% (placebo); P<0.001
EASI 75: 41.5% (dupilumab every 2 weeks) vs 38.1% (dupilumab every 4 weeks) vs 8.2% (placebo); P<0.001 |
|
From an efficacy standpoint, dupilumab treatment showed rapid and sustained improvements in the magnitude of itch symptoms, with responses progressively increasing and sustained through to the end of treatment. In a combined analysis, dupilumab produced significant rapid improvements from baseline in daily peak pruritus NRS scores versus placebo (by day 2 in adults and day 5 in adolescents). At treatment end, dupliumab versus placebo/ control had greater least-squares mean percent change from baseline in the weekly average peak pruritus NRS score: SOLO -47.5% vs -20.5%; CHRONOS -57.3% vs -30.9%; AD ADOL -47.9% vs 19.0% (p<0.0001 for all).
From a safety perspective, there were no significant concerns identified in Phase III clinical trials. The overall adverse event (AE) rates were similar between treatment and placebo groups. While dupilumab treatment is associated with headaches, injection-site reactions, conjunctivitis, and nasopharyngitis, these were mild to moderate in nature. Herpes viral infections have also been reported. Beyond the first year of treatment, longer-term open-label extension studies have also established dupilumab’s sustained safety and efficacy profile of up to 148 weeks, as demonstrated in the TRAVERSE study.
