Kim Blakely, BSc, PhD1; Melinda Gooderham, MD, MSc, FRCPC2,4, Kim Papp, MD, PhD, FRCPC3,4
1University of Toronto, Faculty of Medicine, Toronto, ON, Canada
2Skin Centre for Dermatology, Peterborough, ON, Canada
3SK. Papp Clinical Research, Waterloo, ON, Canada
4Probity Medical Research, Waterloo, ON Canada
Conflict of interest:
Dr. Gooderham and Dr. Papp have both attended advisory board meetings and been involved in clinical research on dupilumab for Sanofi and Regeneron.
Atopic dermatitis results when aberrant barrier function and immune activation occur within the skin. Standard therapies for atopic dermatitis have fallen short, prompting efforts to discover novel therapeutics for this disease. Of these, dupilumab, a fully human monoclonal antibody that inhibits the actions of both IL-4 and IL-13, has shown the greatest promise. Clinical trials of systemic dupilumab in moderate-to-severe atopic dermatitis have demonstrated marked improvement in patient symptoms, including pruritus and clinically visible disease. Importantly, dupilumab treatment has been correlated with changes in the molecular signature of diseased skin, with reduction of both inflammatory and proliferative markers. Dupilumab recently received US FDA breakthrough therapy designation for atopic dermatitis, with ongoing trials in both adult and pediatric populations. Altogether, dupilumab has shed new light on the pathomechanisms driving atopic dermatitis and is making unprecedented advances towards highly effective control of this debilitating disease.
atopic dermatitis, dupilumab, eczema, IL-4Rα, IL-4, IL-13, monoclonal antibody, EASI-50, EASI-75, SCORAD
Atopic dermatitis (AD) is the most common chronic in ammatory skin disease, resulting from defects in skin barrier function and innate and adaptive immune responses.1,2 In its acute stages, AD presents with highly pruritic, inflamed lesions. Histologically, the epidermis of acute lesions is characterized by intracellular edema (spongiosis), and a sparse infiltrate consisting primarily of T lymphocytes. Marked perivascular inflammatory cell infiltrates with large numbers of T lymphocytes and macrophages are seen in the dermis. In its chronic stages, lesions are lichenified and plaque-like. Histologically, chronic lesions are distinguished by epidermal hyperplasia with prominent hyperkeratosis and minimal spongiosis.3-7
It is estimated that up to 30% of children and 10% of adults are affected by AD, with approximately 85% of all cases beginning within the first 5 years of life (early-onset AD).3,4,8 Although many children experience remission of their disease by adolescence, a portion will continue to be affected into adulthood.9 As well, a number of patients will have their first episode of AD diagnosed in adult life (late-onset AD), a presentation that often results in a more treatment-refractory form of the disease.4 Of those affected by AD, up to 20% have a moderate-to-severe presentation, which often manifests as a recurrent disease with remitting and relapsing phases.10 Importantly, AD impacts all aspects of patients’ lives, from their physical wellbeing to their psychological and economical quality of life by disrupting sleep, daily functioning, and requiring patients to attend frequent medical appointments.11-14
Genetics play a large role in the development of AD. Affected individuals often have a strong family history of atopy, including AD, asthma and allergic rhinitis: the atopic triad.15 Genome-wide association studies have implicated a number of genetic loci in the development of AD, including the 1q21, 3p26, 3q21, 5q31-33, 16q, 17q25, and 20p regions. These genetic loci are primarily involved in skin barrier and immune function.16-21 Importantly, interventions aimed at repairing these defects in skin barrier function and immune dysregulation hold promise for treatment, prevention and, potentially, a cure for AD.
Recent advances in our understanding of the underlying pathogenesis and risk factors for AD has resulted in two opposing theories that attempt to explain the onset and natural history of the disease: the outside-in and the inside-out hypotheses.22,23 The outside-in hypothesis proposes that genetic variations within the population result in a subpopulation of individuals that harbor defects in skin barrier function. A disrupted barrier permits allergens and microbes to cross the epithelium, which in turn triggers an in ammatory reaction. Alternatively, the inside-out hypothesis proposes that the underlying defects occur at the level of the immune system. A polarized immune response in AD patients results in immunoglobulin E (IgE) sensitization to skin pathogens and contaminants. The resultant immune response induces local inflammation and skin barrier breakdown.22,23 While debate around these theories remains, it is evident that a number of genetic and environmental factors contribute to skin barrier dysfunction and immune dysregulation in AD. The polyfactorial nature of AD accounts for the heterogeneity in severity and natural history of this disease. It is nonetheless apparent that optimal treatment of AD requires a comprehensive approach aimed at repairing defects in skin barrier function and addressing the characteristic immune abnormalities.
No currently available therapy provides complete remission or cure for affected patients. Management of AD includes patient education, optimal skin care practices, antihistamines (preferably first generation – sedating antihistamines), topical corticosteroids or topical calcineurin inhibitors (TCIs), systemic corticosteroids, systemic calcineurin inhibitors, phototherapy, and other oral immune-suppressants.7,24 These treatments work to restore skin barrier function and suppress the in ammatory response.
The availability of safe and effective treatment for moderate-to- severe AD remains a significant unmet need. Research focused on the pathophysiology of AD has identified promising targets for the treatment of this disease. One targeted therapy that has shown promise in early clinical development and is the focus of this review is dupilumab, an interleukin (IL)-4 receptor alpha (IL-4Rα) antagonist.
Immune Dysfunction in AD
Recent research has demonstrated that immune system dysfunction plays a central role in the development and persistence of AD. These cellular and cytokine targets provide potential therapeutic opportunities. AD skin has been shown to harbor increased levels of the TH2 cytokines IL-4, IL-5, IL-10, and IL-13, with a corresponding decrease in the TH1 cytokines interferon-γ and IL-2.25-30 IL-4 and IL-13 have established roles in B-cell differentiation and class switching, thus providing a plausible link to characteristic elevations of serum IgE levels in AD patients.4,31 Importantly, these TH2 cytokines have been shown to contribute to AD pathogenesis, as mice genetically engineered to over-express these cytokines develop skin barrier defects and an AD-like disease.32-35 High levels of the TH2 cytokines IL-4 and IL-13 in AD skin have been shown to act as inhibitors of both epidermal differentiation and production of antimicrobial peptides.36-38 IL-4 and IL-13 signal through a common receptor, IL-4Rα, to activate the Signal Transducer and Activator of Transcription 6 (STAT6)/Janus kinase 1 (JAK1) signalling cascade, and genetic polymorphisms in IL-4, IL-13 and IL-4Rα have all been associated with the development of AD in speci c populations.39-44 Mice that have been genetically engineered to over-express a constitutively active STAT6 display decreased expression of epidermal differentiation complex genes, including laggrin, loricrin, and involucrin, and develop an AD- like disease by allowing for enhanced penetration of allergens and pathogens across the skin barrier.45 Importantly, IL-4 deficiency was shown to be protective against the development of allergic skin inflammation in these mice, as was treatment with immune- modulators targeting either IL-4 or IL-13.45 Additionally, IL-4 and IL-13 have also been demonstrated to regulate expression of genes, such as β-defensins and cathelicidin, involved in susceptibility to skin pathogens including Staphylococcus aureus and herpes simplex virus, potentially accounting for the fact that AD patients have an increased propensity for infection by these pathogens.36-38 Together, this evidence suggests that targeting TH2 polarization in AD, including antagonism of IL-4 and IL-13, could be ef cacious in the treatment of AD.
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, significantly 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
|Trial ID||Phase||Status||N||Title of Study||Primary Outcome Measure|
|NCT01015027||I||Completed||48||A Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Phase 1 Study of the Safety and Tolerability of Intravenously Administered REGN668 in Healthy Volunteers||TEAE at 85 days (11 visits)|
|NCT01259323 (Study M4A)||I||Completed||30||A Randomized, Double-Blind, Placebo-Controlled, Sequential Ascending, Repeated-Dose Study of the Safety and Pharmacokinetics of Subcutaneous REGN668 in Patients With Moderate-to-Severe Extrinsic Atopic Dermatitis||TEAE at 12 weeks|
|NCT01385657 (Study M4B)||I/II||Completed||37||A Randomized, Double-Blind, Placebo-Controlled, Sequential Ascending, Repeated-Dose Study of the Safety, Tolerability, and Pharmacokinetics of Subcutaneous REGN668 in Patients With Moderate-to-Severe Atopic Dermatitis||TEAE at 12 weeks|
|NCT01859988||II||Completed||380||A Randomized, Double-Blind, Placebo-Controlled, Parallel- Group, Dose-Ranging Study Investigating the Efficacy, Safety, Pharmacokinetic and Biomarker Profiles of REGN668 Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis||Percent change in EASI score at 16 weeks|
|NCT01548404 (Study M12)||II||Completed||109||A Randomized, Double-Blind, Placebo-Controlled, Repeat-Dose Study of the Efficacy, Safety, Tolerability, and Pharmacodynamics of Subcutaneously-Administered REGN668 in Adult Patients With Extrinsic Moderate-to- Severe Atopic Dermatitis||Percent change in EASI score at 12 weeks|
|NCT01639040 (Study C4)||II||Completed||31||A Randomized, Double-Blind, Parallel-Group, Placebo- Controlled Study to Assess the Safety of REGN668 Administered Concomitantly With Topical Corticosteroids to Patients With Moderate-to-Severe Atopic Dermatitis||TEAE at 78 days|
|NCT01979016||II||Completed||54||A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Investigating the Efficacy, Safety, Serum Concentration and Biomarker Profile of Dupilumab Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis||Percent change in EASI score at 16 weeks|
|NCT02407756||II||Active||80||A Phase 2a Study Investigating the Safety, Pharmacokinetics, Immunogenicity, and Exploratory Efficacy of Dupilumab in Patients Aged ≥6 toPharmacokinetic parameters in pediatric patients at 12 weeks|
|NCT02277743||III||Active||600||A Phase 3 Con rmatory Study Investigating the Efficacy and Safety of Dupilumab Monotherapy Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis (SOLO-1)||Proportion of patients with both IGA 0 to 1 and a reduction from baseline of ≥2 points at 16 weeks|
|NCT02277769||III||Active||600||A Phase 3 Con rmatory Study Investigating the Efficacy and Safety of Dupilumab Monotherapy Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis (SOLO-2)||Proportion of patients with both IGA 0 to 1 and a reduction from baseline of ≥2 points at 16 weeks|
|NCT02260986||III||Active||700||A Randomized, Double-Blind, Placebo-Controlled Study|
to Demonstrate the Efficacy and Long-Term Safety of Dupilumab in Adult Patients With Moderate-to-Severe Atopic Dermatitis
|Proportion of patients with both IGA 0 to 1 and a reduction from baseline of ≥2 points at 16 weeks (Additional measures assessed up to 52 weeks)|
|NCT02395133||III||Active||440||A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Investigating the Efficacy and Safety of Multiple Dupilumab Dose Regimens Administered as Monotherapy for Maintaining Treatment Response in Patients With Atopic Dermatitis||Proportion of patients with IGA scores of 0 or 1 at 36 weeks|
|NCT01949311||III||Active||800||An Open-label Study of Dupilumab in Patients With Atopic Dermatitis Who Participated in Previous Dupilumab Clinical Trials||TEAE at 52 and 116 weeks|
|Table 1: Clinical trials of dupilumab in AD|
TEAE = treatment-emergent adverse events; EASI = Eczema Area and Severity Index; IGA = Investigator’s Global Assessment (on a 5-point scale)
The adverse event (AE) profiles 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 significant 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) (p48 The AE profile 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 inflammation (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 (p50 The safety profile 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 inflammation/ 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 efficacy 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
Over the last several years, a number of important scientific and clinical discoveries have been made regarding the pathogenesis of AD. We now understand better than ever that AD results from defects in skin barrier function and innate and adaptive immune responses, both of which have important therapeutic implications. These discoveries not only explain the limitations of currently used treatments for AD, but also provide a map forward in our discovery of novel therapeutics for this difficult-to-treat skin disorder. Dupilumab is helping to shed new light on the pathomechanisms driving atopic dermatitis, and leading the way towards highly effective control of this debilitating disease.
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