Dupilumab, a Monoclonal Antibody for Atopic Dermatitis: A Review of Current Literature

Kim Blakely, BSc, PhD; Melinda Gooderham, MD, MSc, FRCPC; Kim Papp, MD, PhD, FRCPC

Disclosures

Skin Therapy Letter. 2016;21(2) 

In This Article

Dupilumab Clinical Trials in AD

Given the importance of the TH2 in ammatory pathway in AD, it is not surprising that researchers have explored if the inhibition of IL-4 and IL-13 could provide a potential new treatment approach for this chronic, difficult-to-manage disease. Dupilumab is a fully human monoclonal antibody that binds the IL-4α receptor subunit, effectively blocking signalling from both IL-4 and IL-13. First tested for therapeutic value in asthma,[46] dupilumab has shown impressive results in trials for AD, and looks to change the management landscape for this debilitating disease. To date, several phase I and II trials have been completed, with other phase II and III trials currently underway in both adult and pediatric populations (Table 1).

Recently, a collection of phase I/II trials were published, which looked at the effects of dupilumab on moderate-to-severe AD refractory to topical glucocorticoids and calcineurin inhibitors.[47] Four trials in this publication include two phase I, 4 week monotherapy trials looking at safety as a primary endpoint (NCT01259323/study M4A and NCT01385657/study M4B) and two phase II trials, one 12 week monotherapy trial (NCT01548404/study M12) and one trial of dupilumab plus mid- high potency topical glucocorticoids with 4 weeks active treatment and 8 weeks follow-up period (NCT01639040/study C4). In the program, patients aged 18 years or older with moderate-to-severe AD and an Investigator Global Assessment (IGA) of ≥3 and a Scoring Atopic Dermatitis (SCORAD) score of ≥20 (study C4), or an Eczema Area and Severity Index (EASI) score ≥12 (studies M4A and M4B) or ≥16 (study M12), were included. Remarkably, in these phase I/II trials, patients treated with dupilumab experienced rapid improvement in AD disease activity. In study M12, the 12 week monotherapy trial, signi cantly more patients in the dupilumab arm experienced a ≥50% reduction in EASI score (EASI-50) as compared to the placebo arm (85% vs. 35%, respectively; p<0.001), near-to-complete clearance of skin lesions with an IGA of 0 or 1 (40% vs. 7%, respectively; p<0.001), and decreased pruritus with improvement on the pruritus Numerical Rating Scale (NRS) (56% vs. 15%, respectively; p<0.05).[47] When combined with topical glucocorticoids in the C4 study, all patients treated with dupilumab reached EASI-50, compared with only half of those receiving topical glucocorticoids plus placebo (p=0.002). Importantly, patients receiving dual therapy with dupilumab used less than half the glucocorticoid therapy required by those patients receiving glucocorticoid plus placebo (p=0.16).[47]

The adverse event (AE) pro les were similar between the groups receiving either dupilumab or placebo in all of the studies. Most AEs were considered mild-to-moderate in severity, transient, and more likely to result in study discontinuation in the placebo group. The most common treatment-emergent adverse events (TEAEs) were nasopharyngitis and headache, which were more frequently reported in those subjects receiving dupilumab. Serious AEs were more frequently reported in the placebo groups (9/80) compared with the dupilumab groups (2/127). Interestingly, there were four times as many skin infections reported in the placebo groups (17/80) compared to the dupilumab groups (6/127), suggesting that dupilumab might improve skin barrier function. There were more injection site reactions in the dupilumab group but these were generally mild. There were no opportunistic infections or deaths in any of these studies.[47]

When evaluating the molecular signature of genes expressed in non-lesional and lesional skin from the patients included in these trials, dupilumab-treated skin showed marked improvements with downregulation of markers of both epidermal proliferation and upregulation of genes involved in skin barrier function.[26] Dupilumab treatment also suppressed the expression of genes related to the activation of T cells and related inflammatory pathways, a major driver in AD clinical disease. After only 4 weeks of dupilumab treatment, the transcriptome of skin harvested from AD patients resembled that of non-lesional skin.[26]

Another phase II international 16 week dose-ranging study (NCT01859988) including 380 patients has been completed and recently published.[48] Patients were 18 years or older and had an EASI score of ≥12 at screening (≥16 at baseline) with an inadequate response to topical therapy. This was a dose ranging study and patients were randomized to receive dupilumab 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks or placebo once a week for 16 weeks. When compared to placebo, all dupilumab dosing regimens showed a signi cant improvement in EASI score from baseline. The least-square means improvement of EASI score was -73.7% (300 mg every week), -68.2% (300 mg every 2 weeks), -65.4% (200 mg every 2 weeks), -63.5% (300 mg every 4 weeks), -44.8% (100 mg every 4 weeks) compared to -18.1% (placebo) (p<0.0001 for all comparisons).[48] The AE pro le was similar to previously published studies with the most commonly reported AEs of nasopharyngitis, exacerbation of AD, headache and upper respiratory tract infection. There were more reports of herpes infections in the dupilumab group (8%) when compared to placebo (2%) as well as conjunctival in ammation (7% vs. 3%, respectively). The rate of injection site reactions was 7% in the dupilumab group vs. 3% in the placebo group.[48]

A summary of the burden of disease in this patient group has also been published, which showed a significant burden of disease including that on quality of life as based on a number of patient reported measures: Dermatology Life Quality Index (DLQI), EuroQoL (EQ-5D) Health Status Questionnaire, Hospital and Anxiety Depression Scale (HADS), 5-D Pruritus and Patient Oriented Eczema Measure (POEM).[49]

The pooled results of the 300 mg dupilumab group from this 16 week phase II study and the 300 mg group of the M12 study compared to placebo were presented recently.[50] Dupilumab was administered weekly as monotherapy and no additional topical steroids were allowed; the analysis included a total population of patients given placebo (n=115) or dupilumab 300 mg (n=118) with a loading dose at week 1. The improvement in SCORAD from baseline was 37 points for dupilumab (baseline score 66) and 11 for placebo (baseline score 68), respectively (p<0.0001 vs. placebo at week 12). At 12 weeks, dupilumab resulted in an EASI percent improvement of 74% vs. 23% for placebo (p<0.0001) and the absolute change (mean±SD) was -21.1±12.0 for dupilumab and -6.9±14.0 for placebo. Significantly higher proportions of dupilumab-treated patients achieved EASI-50 compared with placebo (85.6% vs. 32.2%; p<0.0001) and EASI-75 compared with placebo (61.0% vs. 13.9%; p<0.0001) at week 12. Additionally, significant improvement in pruritus was noted as dupilumab resulted in pruritus NRS mean percent improvement of 53% vs. 8% for placebo (p<0.0001) at week 12.[50] The safety pro le was similar to previous studies and between the two groups. The TEAEs occurring in ≥5% of trial participants during the 12 week placebo-controlled period for placebo vs. 300 mg dupilumab included upper respiratory tract infection (33.9% vs. 42.4%), skin infections (29.7% vs. 16.4%), conjunctival in ammation/infection (3.5% vs. 15.3%), headache (7.8% vs. 14.4%), and dermatitis (14.8% vs. 11.0%), respectively. There were more injection site reactions in the dupilumab group (13.6%) vs. placebo (6.1%). There were no deaths in either study.[48,50]

Results from these studies have been extremely encouraging and prompted the quick expansion to clinical trials to evaluate the ef cacy of dupilumab in pediatric patients, as well as the long- term safety of the drug. Currently, a phase II pharmacokinetic study in pediatric patients ≥6 and <18 years is ongoing (NCT02407756) as well as a long-term extension study for patients who participated in any trial from the phase I-III program (NCT01949311). Both members of the dermatologic community and patients affected by AD eagerly await the nal results of these clinical trials.

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