Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. The blockade by dupilumab of these key drivers of type 2 helper T-cell (Th2)–mediated inflammation could help in the treatment of related diseases, including atopic dermatitis.
We performed randomized, double-blind, placebo-controlled trials involving adults who had moderate-to-severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors. Dupilumab was evaluated as monotherapy in two 4-week trials and in one 12-week trial and in combination with topical glucocorticoids in another 4-week study. End points included the Eczema Area and Severity Index (EASI) score, the investigator's global assessment score, pruritus, safety assessments, serum biomarker levels, and disease transcriptome.
In the 4-week monotherapy studies, dupilumab resulted in rapid and dose-dependent improvements in clinical indexes, biomarker levels, and the transcriptome. The results of the 12-week study of dupilumab monotherapy reproduced and extended the 4-week findings: 85% of patients in the dupilumab group, as compared with 35% of those in the placebo group, had a 50% reduction in the EASI score (EASI-50, with higher scores in the EASI indicating greater severity of eczema) (P<0.001); 40% of patients in the dupilumab group, as compared with 7% in the placebo group, had a score of 0 to 1 (indicating clearing or near-clearing of skin lesions) on the investigator's global assessment (P<0.001); and pruritus scores decreased (indicating a reduction in itch) by 55.7% in the dupilumab group versus 15.1% in the placebo group (P<0.001). In the combination study, 100% of the patients in the dupilumab group, as compared with 50% of those who received topical glucocorticoids with placebo injection, met the criterion for EASI-50 (P=0.002), despite the fact that patients who received dupilumab plus glucocorticoids used less than half the amount of topical glucocorticoids used by those who received placebo plus the topical medication (P=0.16). Adverse events, such as skin infection, occurred more frequently with placebo; nasopharyngitis and headache were the most frequent adverse events with dupilumab.
Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity. Side-effect profiles were not dose-limiting. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01259323, NCT01385657, NCT01639040, and NCT01548404.)
Atopic dermatitis, which is characterized by a disturbed skin barrier, robust type 2 helper T-cell (Th2)–mediated immune responses to numerous environmental antigens, susceptibility to cutaneous infections, and intractable pruritus, is a common chronic skin condition with a worldwide prevalence of 1 to 20%.1 Approximately 20% of patients with atopic dermatitis have moderate-to-severe disease,1 and treatments approved by the Food and Drug Administration for atopic dermatitis, which include emollients, topical glucocorticoids, and calcineurin inhibitors,2,3 have limited efficacy in moderate-to-severe disease.4,5
The Th2 cytokines interleukin-4 and interleukin-13 are believed to play roles in the pathogenesis of atopic dermatitis,6,7 but the clinical effect of blocking both interleukin-4 and interleukin-13 in atopic dermatitis has not been tested in clinical trials. Recently, a clinical study of dupilumab, a fully human monoclonal antibody that is directed against the shared alpha subunit of the interleukin-4 receptors and that blocks signaling from both interleukin-4 and interleukin-13, showed efficacy in patients with moderate-to-severe asthma and elevated eosinophil levels,8 raising the possibility that blocking this signaling could benefit patients with other Th2-related diseases. To address the importance of Th2-related biologic factors in atopic dermatitis, we evaluated dupilumab in four randomized, double-blind, placebo-controlled trials involving adults with moderate-to-severe disease.
Study Design and Oversight
We conducted four separate studies, three of which were early-phase studies designed primarily to assess the safety of dupilumab, administered subcutaneously, for the treatment of patients with atopic dermatitis. However, clinical end points were part of the design of each of the four trials. Two of the trials had dose-escalation designs, and two had parallel-group designs (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). Safety was assessed by means of evaluation of the incidence of adverse events, assessment of vital signs, physical examination, clinical laboratory testing, and electrocardiography. The full protocols and statistical analysis plans are provided at NEJM.org.
The study protocols were developed by the study sponsors (Regeneron Pharmaceuticals and Sanofi) with input from three of the academic authors. Data were collected by the study investigators and analyzed by the sponsors; the study investigators had confidentiality agreements with the sponsors. All the authors take responsibility for the accuracy and completeness of the data and analyses reported and for the fidelity of the studies to the protocols. The first draft of the manuscript was written by the first author, with input from all the authors; subsequent drafts were prepared with the assistance of a medical writer paid by the sponsors. The first author made the decision to submit the manuscript for publication.
Dupilumab Monotherapy for 4 Weeks
The U.S. and multinational phase 1 studies had sequential, dose-escalation cohorts. Both trials enrolled adults with moderate-to-severe atopic dermatitis that was not adequately controlled with topical medications (glucocorticoids and calcineurin inhibitors). In the U.S. study, Study M4A, patients were randomly assigned in a 1:4 ratio to receive placebo (6 patients) or dupilumab at a dose of 75 mg (8 patients), 150 mg (8 patients), or 300 mg (8 patients), with all study drugs administered subcutaneously once a week. In the multinational study, Study M4B, patients were randomly assigned in a 1:3 ratio to receive placebo (10 patients) or dupilumab at a dose of 150 mg (14 patients) or 300 mg (13 patients), with all study drugs administered subcutaneously once a week.
Both studies were designed to assess safety as the primary end point. Prespecified exploratory efficacy end points included the proportion of patients who had an investigator's global assessment score of 0 (clear) or 1 (almost clear), the percentage reduction in the affected body-surface area, the score on the Eczema Area and Severity Index (EASI, on which scores range from 0 to 72, with higher scores indicating greater severity; a score change of 6.6 has been estimated as the minimal clinically important difference),9,10 the score on the 5-D pruritus scale (on which scores range from 5 to 25, with higher scores indicating greater itch),11 the score on the pruritus numerical-rating scale (on which scores range from 0 to 10, with higher numbers indicating worse itch),12 and levels of biomarkers (i.e., thymus and activation-regulated chemokine [TARC] and IgE).
Dupilumab Monotherapy for 12 Weeks
A monotherapy trial, Study M12, was conducted in Europe to assess the clinical efficacy (primary end point) and safety (secondary end point) of weekly subcutaneous dupilumab at a dose of 300 mg in adults who had moderate-to-severe atopic dermatitis that was poorly controlled with topical agents. A total of 109 patients were randomly assigned in a 1:1 ratio to dupilumab (55 patients) or placebo (54 patients), with stratification according to a cutoff in the baseline IgE level of 150 kU per liter (360 μg per liter), with a level of less than 150 kU per liter indicating intrinsic atopic dermatitis and a level of 150 kU per liter or more indicating extrinsic atopic dermatitis.13,14 Key efficacy end points at week 12 included the percentage change in the EASI score (primary end point), the percentage reduction in the affected body-surface area, the Scoring Atopic Dermatitis (SCORAD) score (on a scale from 0 to 103, with higher scores indicating greater severity; a score change of 8.7 has been estimated as the minimal clinically important difference),10,15 the score on the pruritus numerical-rating scale, the score on the 5-D pruritus scale, the proportion of patients with a reduction of 50% or more in the EASI score (EASI-50), and the proportion of patients with an investigator's global assessment score of 0 or 1.
Combination Therapy for 4 Weeks
Study C4, a phase 2a study conducted in Europe, evaluated dupilumab in combination with topical glucocorticoids in adults with moderate-to-severe atopic dermatitis. Patients were randomly assigned in a 2:1 ratio to receive four weekly doses of subcutaneous dupilumab at a dose of 300 mg (21 patients) or placebo (10 patients), with both groups receiving a standardized regimen of topical glucocorticoids. The primary end points were the incidence and severity of adverse events. Prespecified exploratory efficacy end points included the percentage changes in the EASI score, the investigator's global assessment score, the SCORAD score, and the score on the pruritus numerical-rating scale and the proportions of patients with an investigator's global assessment score of 0 or 1 and with EASI-50 at day 29.
In all the studies, eligible patients were 18 years of age or older, with moderate-to-severe atopic dermatitis, as defined by an investigator's global assessment score of 3 or more. The proportion of body-surface area involved with atopic dermatitis that was required for inclusion varied among the studies: 15% or higher was required in Study M4A and 10% or higher in Studies M4B, M12, and C4. Also required were a SCORAD score of more than 20 (Study C4) or an EASI score of 12 or higher (Studies M4A and M4B) or 16 or higher (Study M12). The duration of disease had to have been 3 or more years for inclusion in the monotherapy studies and 2 or more years for inclusion in the combination study (Table S1 in the Supplementary Appendix).16
Biomarker and Skin-Biopsy Evaluations
Pharmacodynamic response was based on the median percentage change from baseline in the serum levels of the Th2-associated biomarkers TARC and total IgE. Serum TARC was measured by means of an enzyme-linked immunosorbent assay (R&D Systems). Total serum IgE was measured with the use of the ImmunoCAP assay (Thermo Fisher Scientific). For microarray analyses, skin-biopsy specimens were obtained at baseline and at week 4 from the patients in Studies M4A and M4B who consented to participation in an optional substudy. Details of the methodologic evaluations of biomarker levels and microarray evaluation of skin-biopsy specimens are provided in the Supplementary Appendix.
No formal sample-size calculations were performed for Studies M4A and M4B, and observations from these two studies were pooled because the studies had a similar design and similar patient populations. In Study M12, we calculated that an enrollment of 50 patients per group would provide the study with 97% power to detect a between-group difference of 40 percentage points in the percentage change from baseline in the EASI scores, assuming a standard deviation of 50% for the percentage change from baseline to week 12, with the use of a two-sided test at the 0.049 significance level. In Study C4, categorical variables were analyzed with the use of Fisher's exact test, continuous variables with the use of analysis of covariance with treatment as the main factor and baseline values as covariates, and time-to-event variables with the use of a log-rank test. Nominal P values were estimated. Details of the statistical analyses are provided in the Supplementary Appendix.
The enrollment and disposition of the patients are shown in Table S2 in the Supplementary Appendix. Withdrawal from the study occurred approximately twice as frequently in the placebo groups as in the dupilumab groups, and were due primarily to lack of efficacy. The demographic and clinical characteristics of the patients at baseline were similar between the study groups and across the studies (Table 1, and Table S3 in the Supplementary Appendix).
Monotherapy at 4 Weeks and 12 Weeks
In Studies M4A and M4B, dupilumab was associated with rapid and dose-dependent improvements in all clinical indexes (Figure 1A and 1B and Table 2), as well as reductions in the serum levels of TARC (Fig. S2A and Table S4 in the Supplementary Appendix). Similar responses were observed at the 4-week time point in Study M12 (Figure 1C and 1D and Table 2, and Fig. S2B and Table S4 in the Supplementary Appendix). Study M12 showed that continued treatment resulted in further improvements (e.g., the proportion of patients with EASI-50 increased to 85%, and the mean score on the pruritus numerical-rating scale decreased by 55.7% at 12 weeks [Table 2]), and the number of patients with an investigator's global assessment score of 0 (clear) or 1 (almost clear) more than doubled between 4 and 12 weeks (Table 2, and Fig. S3 in the Supplementary Appendix). The percentage reduction in the EASI score over the duration of the study was consistently greater with dupilumab than with placebo, in analyses in which three different statistical methods were used to control for missing data (Fig. S4 in the Supplementary Appendix). By the end of 12 weeks, the proportions of patients with EASI-50 and EASI-75 (a 75% reduction in the EASI score) were greater in the dupilumab group than in the placebo group (Table 2).
Dupilumab monotherapy was associated with a reduction in serum levels of TARC and total IgE in all the monotherapy studies (Table S4 and Fig. S5A and S5B in the Supplementary Appendix), although the reductions in IgE occurred more slowly than the reductions in TARC, presumably owing to the longer half-life of IgE. The 300-mg dose of dupilumab was associated with the greatest clinical and biomarker responses (Figure 1, and Fig. S2A and S5A in the Supplementary Appendix).
Combination Therapy at 4 Weeks
To explore the potential benefits of dupilumab in combination with the standard of care, we compared topical glucocorticoids plus dupilumab with topical glucocorticoids plus placebo. All the patients who received dupilumab plus topical glucocorticoids met the criteria for EASI-50 by 4 weeks, as compared with only 50% of those who received topical glucocorticoids plus placebo (P=0.002) (Fig. S6A in the Supplementary Appendix). Similarly, the combination of dupilumab plus topical glucocorticoids, as compared with topical glucocorticoids plus placebo, was associated with a rapid and sustained reduction in the score on the pruritus numerical-rating scale (P=0.005) (Fig. S6B in the Supplementary Appendix) and in most other clinical and biomarker indexes (Table 2, and Table S4 and Fig. S2C and S5C in the Supplementary Appendix). These changes were observed despite consistent trends at each time point suggesting a 50% reduction in the use of topical glucocorticoids by the patients who received dupilumab, as compared with those who received placebo (P=0.16) (Fig. S7 in the Supplementary Appendix).
Skin-Biopsy Expression Profiling
The 18 patients from the two 4-week monotherapy studies who participated in the substudy of expression profiling in skin-biopsy specimens had clinical responses that were similar to those in the other patients from those studies.17 Significant dose-dependent changes in the RNA-expression profile were observed in the patients after 4 weeks of treatment with 150 mg or 300 mg of dupilumab. The gene-expression profiles of samples from lesions in dupilumab-treated patients approached the profile of samples from nonlesional sites (Figure 2A); improvements of 24% and 49% were observed in the lesional transcriptome in the samples from patients who received the 150-mg and 300-mg doses of dupilumab, respectively, as compared with an exacerbation of 21% in the lesional transcriptome in the samples from those who received placebo (P<0.001) (Figure 2B). These improvements paralleled the reductions in the EASI scores. Significant dose-dependent reductions in the expression of keratin 16 (K16), a marker of keratinocyte proliferation and regulator of innate immunity,18 suggest that dupilumab reduces the epidermal hyperplasia observed in lesions caused by atopic dermatitis (Figure 2C).
Correlations between Clinical Response and Biomarkers
The Th2 biomarker levels measured at study entry (eosinophil counts, TARC, and IgE) showed weak or no correlation with improvements in the EASI or pruritus scores (as assessed by means of the 5-D and numerical-rating scales) after dupilumab treatment (Table S5 in the Supplementary Appendix). However, significant correlations were observed between reductions in the TARC level and changes in pruritus scores (Table S6 in the Supplementary Appendix). At the end of the 12-week monotherapy study, there was a significant correlation between the percentage change in the TARC level and the percentage change in the scores on the pruritus numerical-rating scale (r=0.53; P<0.001) and the 5-D pruritus scale (r=0.40; P=0.004) (Table S6 in the Supplementary Appendix).
Adverse events occurred with a similar frequency in the placebo and dupilumab groups in all the studies (Table 3). Most adverse events were mild or moderate in severity and were transient. The most common adverse events were nasopharyngitis and headache, which were generally reported at a higher frequency among patients receiving dupilumab than among those receiving placebo. Injection-site reactions were observed at a higher frequency in the dupilumab group in the 12-week monotherapy study than in any treatment group in the other studies. Clinically significant values for clinical laboratory tests, vital signs, and electrocardiographic assessments were balanced between treatment groups in each of the studies, and no trends were observed.
There was a numerical imbalance with respect to serious adverse events, and the proportion of patients with serious adverse events was greater in the placebo group in the 12-week monotherapy study than in any other study group (Table S7 in the Supplementary Appendix). Across all studies, there were 13 serious adverse events in 9 of 80 patients in the placebo groups, as compared with 2 events in 2 of 127 patients in the dupilumab groups; excluding events related to atopic dermatitis, 7 patients in the placebo groups reported 9 serious adverse events (Table S7 in the Supplementary Appendix). A total of 5 patients in the placebo groups discontinued the study owing to adverse events, as compared with 1 in the dupilumab group.
The imbalance in serious adverse events appeared to result from a greater number of skin infections and exacerbations of atopic dermatitis in the placebo groups. A total of 17 skin infections occurred among the 80 patients in the placebo groups (0.20 infections per patient), as compared with 6 skin infections among the 127 dupilumab-treated patients (0.05 infections per patient), corresponding to a rate of skin infection in the placebo group that was 4 times as high as the rate in the dupilumab group (Table 3, and Table S7 in the Supplementary Appendix). In the 12-week monotherapy study, 14 skin infections occurred in the placebo group, as compared with 4 in the dupilumab group. Among the patients in the placebo group, 7 required hospitalization (for skin infection in 3 patients and for exacerbations of atopic dermatitis in 4), as compared with 1 in the dupilumab group (for a facial fracture). There were no opportunistic infections, serious or otherwise, reported in dupilumab-treated patients, and no deaths in either study group.
Dupilumab treatment in adults with moderate-to-severe atopic dermatitis resulted in marked reductions in signs, symptoms, and associated biomarker levels in two 4-week monotherapy trials (Studies M4A and M4B), one 12-week monotherapy trial (Study M12), and a 4-week combination study with topical glucocorticoids (Study C4). The consistency of these observations across four studies provides strong support for the pathophysiological importance of Th2 cytokines in atopic dermatitis. Dupilumab treatment — as monotherapy or as part of combination therapy — was associated not only with improvement in skin lesions but also with rapid and substantial reductions in pruritus, which is a major contributor to the reduced quality of life experienced by patients with atopic dermatitis.1
Overall, side effects and adverse events were balanced between the dupilumab and placebo groups, but the placebo groups had higher rates of study discontinuation, apparently owing to a lack of therapeutic benefit. The placebo groups also had higher rates of skin infection, supporting the possibility that dupilumab improves skin-barrier function. Injection-site reactions occurred more frequently with dupilumab than with placebo, and all were classified as mild. Nasopharyngitis and headache were reported more frequently with dupilumab than with placebo, a finding also reported in a study of dupilumab in patients with asthma and elevated eosinophil levels.8
Dupilumab was associated with a reduction in all assayed biomarker levels, as well as with improvement of the lesional transcriptome of atopic dermatitis. The dose-dependent decrease in K16, a marker of keratinocyte proliferation and innate immunity, suggests that the epidermal abnormalities associated with atopic dermatitis might be reduced with dupilumab treatment. We also found a substantial dupilumab-associated reduction in the level of TARC, a key Th2 biomarker. Both the levels of TARC and the change in the levels were significantly correlated with measures of pruritus during the study. Pretreatment levels of serum total IgE, TARC, and peripheral eosinophilia were not highly predictive of a clinical response to dupilumab.
Dupilumab blocks the actions of the Th2 cytokines interleukin-4 and interleukin-13. The results of the studies reported here extend the potential benefit of this new biologic therapy beyond asthma to a second atopic disorder, atopic dermatitis.19 Dupilumab treatment resulted in highly reproducible improvements across all clinical end points when the drug was administered as monotherapy and, even more so, when it was combined with topical glucocorticoids. Using an integrated translational approach, we found that these clinical improvements were coupled with reductions in levels of serum biomarkers and improvements in the lesional transcriptome.
Our findings provide evidence that allergic asthma and atopic dermatitis might have related drivers — in particular, interleukin-4 and interleukin-13 — and that these diseases may benefit from the same therapeutic approach. Furthermore, this commonality suggests that other atopic diseases may share these drivers, providing a rationale for studying dupilumab in such conditions.
Funding and Disclosures
Supported by Regeneron Pharmaceuticals and Sanofi.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the study patients for their participation; the members of the independent data and safety monitoring committee; Ariel Teper (clinical director), Lin Wang and Chaim Cantor (biostatistics), Rand Sutherland (global clinical lead), Scott Mellis (translational medicine and predictive medicine), Thomas DiCioccio (pharmacometrics), Pavel Belomestnov (clinical pharmacology), Usman Chaudhry (predictive medicine), Jacqueline Kuritzky (clinical trial management), Judith Cusick (therapeutic area project management), Kristen Dougherty (program management), Linda Williams (global publications), and Warren Brooks (medical); and E. Jay Bienen for assistance with the preparation of an earlier version of the manuscript.
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Citing Articles (811)
- Table 1. Demographic and Clinical Characteristics of the Participants at Baseline.
- Figure 1. Key Efficacy End Points in Studies M4A and M4B Combined and in Study M12.
- Table 2. Efficacy End Points.
- Figure 2. Molecular Changes in the Atopic Dermatitis Transcriptome in Studies M4A and M4B.
- Table 3. Adverse Events.
Original ArticleMay 15 Original ArticleMay 15 Original ArticleMay 12