Accepted Manuscript

Efficacy and safety of dupilumab for the treatment of adult atopic dermatitis: A meta-
analysis of randomized clinical trials

Yue Han, MD, Yuxin Chen, PhD, Xiaochun Liu, MD, Jingxi Zhang, MD, Huichun Su,
MD, He Wen, MD, Wei Li, MD, PhD, Xu Yao, MD, PhD

PII: S0091-6749(17)30687-5
DOI: 10.1016/j.jaci.2017.04.015
Reference: YMAI 12783

To appear in: Journal of Allergy and Clinical Immunology

Received Date: 28 September 2016

Revised Date: 5 April 2017
Accepted Date: 10 April 2017

Please cite this article as: Han Y, Chen Y, Liu X, Zhang J, Su H, Wen H, Li W, Yao X, Efficacy and
safety of dupilumab for the treatment of adult atopic dermatitis: A meta-analysis of randomized clinical
trials, Journal of Allergy and Clinical Immunology (2017), doi: 10.1016/j.jaci.2017.04.015.

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1 Efficacy and safety of dupilumab for the treatment of adult

2 atopic dermatitis: A meta-analysis of randomized clinical trials

4 Yue Han, MD,a,* Yuxin Chen, PhD,c,* Xiaochun Liu, MDa Jingxi Zhang, MDa

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5 Huichun Su, MDa He Wen, MDa Wei Li, MD, PhDb Xu Yao, MD, PhDa

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6

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7 Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union

8 Medical College, Nanjing, 210042, P.R. China

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9 Department of Dermatology, Huashan Hospital, Fudan University, Shanghai,
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10 200040, P. R. China
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11 Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing

12 University Medical School, Nanjing, 210008, P. R.China

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14 *These authors contributed equally to this work.

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16 Corresponding author: Dr. Xu Yao, Institute of Dermatology, Chinese Academy of

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17 Medical Sciences and Peking Union Medical College, 12 Jiangwangmiao Street,

18 Nanjing, 210042, P. R. China. Tel: 86-13512513536; Fax: 86-25-85460070. Email:

19 dryao_xu@126.com. Or Dr. Wei Li, Department of Dermatology, Huashan Hospital,

20 Fudan University, 12 Wulumuqi Middle Road, Shanghai, 200040, P. R. China. Email:

21 liweiderma@163.com.
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22

23 Funding: This work was supported by National Natural Science Foundation of China

24 (81371735, 81573045, 81573038, 81600201), Natural Science Foundation of Jiangsu

25 province (BK20151066), Open Grant of the Jiangsu provincial Key Laboratory of

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26 Molecular Biology for Skin Diseases and STIs (Grant number 2015KF14), and the

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27 Milstein Medical Asian American Partnership Foundation. All the research work was

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28 conducted in Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and

29 STIs.

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31 Capsule summary: Dupilumab is a fully human monoclonal antibody that blocks
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32 both IL-4 and IL-13. Meta-analysis of 7 randomized clinical trials showed that

33 dupilumab treatment significantly alleviated the symptoms of atopic dermatitis

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34 without serious adverse effects.

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36 Key words: dupilumab, meta-analysis, atopic dermatitis, efficacy, safety

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37
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38 Abbreviation:

39 AD atopic dermatitis

40 IL-4 interleukin-4

41 IL-4R interleukin-4 receptor

42 mAb monoclonal antibodies

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43 AE adverse event

44 EASI eczema area and severity index

45 IGA ivestigators global assessment

46 NRS pruritus numerical-rating scale

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47 SAE severe adverse events

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48 RR relative risk

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49 BSA body surface area

50 RCT randomized control trial

51 DLQI dermatology life quality index

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52 SCORAD scoring atopic dermatitis
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55 To the Editor:

56 Dupilumab is a recently commercialized human monoclonal antibody against the

57 interleukin-4 receptor (IL-4R) subunit, blocking both interleukin-4 (IL-4) and IL-13

58 that have been shown to play important roles in the pathogenesis of atopic dermatitis

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59 (AD).1-3 This study is a meta-analysis evaluating the efficacy and safety of dupilumab

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60 for the treatment of AD.

On December 1th, 2016 we conducted a systematic search of PubMed, Medline,

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62 Embase, and Web of Science databases for randomized controlled trials (RCTs)

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(published between May 1, 2000 and Dec 1, 2016; English publication only) using the
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64 search terms dupilumab and atopic dermatitis or atopic eczema. A total of 7
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65 randomized, double-blinded, placebo-controlled clinical trials (two phase I, two phase

66 IIa, one phase IIb and two phase III) including 1966 (1364/601) patients diagnosed
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67 with moderate-to-severe AD were selected from 167 publications (Supplementary Fig

68 1). In the phase I trial M4A, patients received weekly administration of 75 mg, 150
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69 mg, 300 mg dupilumab or placebo for 4 weeks, respectively; and in M4B, patients
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70 received weekly doses of 150 mg or 300 mg dupilumab for 4 weeks. In the phase IIa
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71 trial M12, patients received 300 mg dupilumab weekly for 12 weeks, 4 while in study

72 C4, patients received a combination treatment of 300 mg dupilumab and topical

73 glucocorticoids for 4 weeks. 4 In the phase IIb study, patients received dupilumab 300

74 mg once a week (300mg q1w), 300 mg every 2 weeks (300mg q2w), 200 mg every 2

75 weeks (200mg q2w), 300 mg every 4 weeks (300mg q4w), 100 mg every 4 weeks
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76 (100mg q4w), or placebo once a week (qw). 5, 6 In the two latest phase III trials,

77 SOLO1 and SOLO2, patients received 300 mg dupilumab or placebo at either weekly

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78 or bi-weekly basis for 16 weeks. All patients were adults (18 years old), had

79 eczema area and severity index (EASI) score of >16, investigators global assessment

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80 (IGA) score of >3, body surface area (BSA) affected >10%, and a diagnosis of AD

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81 for >3 years. The characteristics of the selected studies were shown in Table I. The

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82 study qualities of each RCT or subgroup were evaluated using Jadad scale, and all 7

83 studies included in the meta-analysis were considered to be of high quality

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(Supplementary Table I). 4-7 All 7 trials reported adequate randomization, none was
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85 stopped early, and M4B, phase IIb, SOLO1 and SOLO2 trials were conducted in
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86 multi-national study centers. All 7 studies showed a low risk of bias (Supplementary

87 Fig 2A). Begg funnel plot and Egger test showed there did not seem to have bias in
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88 the publication (Supplementary Fig 2B).

89 In the pooled analysis of all 7 trials, significant improvement of efficacy of

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90 dupilumab for the treatment of AD was observed in various clinical indexes.

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91 Compared with the placebo control, dupilumab treatment significantly reduced the
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92 EASI score [standardized mean difference (SMD), -0.91; 95% CI, -0.99 to -0.83; P

93 <0.001] (Fig 1A), although three studies did not show a substantial reduction in EASI

94 score, including M4, C4, and phase IIb 100 mg q4w group. A higher percentage of

95 IGA response (IGA score turned to 0 or 1) was revealed in dupilumab treatment

96 groups compared to placebo group [relative risk (RR)=4.64, 95% CI, 3.81-5.66,
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97 P<0.001] (Fig 1B). In dupilumab treatment groups, the SMD of pruritus

98 numerical-rating scale (NRS) score is -0.76 (95% CI, -0.84 to -0.68, P <0.001) (Fig

99 1C), indicating that dupilumab treatment improved the relief and the life quality of the

100 patients. The results also showed a significant decrease in the mean difference of BSA

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101 score within the dupilumab groups compared with the control group (SMD -0.77,

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102 95% CI -0.84 to -0.69, P<0.001) (Fig 1D). Furthermore, the dose-dependent efficacy

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103 of dupilumab was also showed. The results indicated that the most effective clinical

104 improvement was achieved by the doses of 300 mg qw and 300 mg q2w, and the

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doses of 300 mg q4w and 200 mg q2w also showed significant clinical improvement,
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106 but were less effective; meanwhile, the dose of 100 mg q4w was almost ineffective.
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107 Moreover, the group receiving 100mg q4w was the major source of heterogeneity in

108 this meta-analysis (Supplementary Fig 3), confirming that low dose of dupilumab was
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109 less likely to achieve satisfactory therapeutic effects as high doses of dupilumab.

110 Overall, dupilumab was well tolerated and had a favorable safety profile that was
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111 substantially better than most systemic agents. The commonly reported adverse events
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112 (AE) in patients treated with dupilumab were nasopharyngitis, headache, and injection
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113 site reaction. We found that AE occurred at a similar rate among different trials

114 without statistical significance (RR=0.99, 95%CI, 0.95-1.04, P=0.827)

115 (Supplementary Fig 4A). Dupilumab treatment was associated with lower risk of

116 severe adverse events (SAE) compared to the placebo group (RR=0.44, 95% CI,

117 0.30-0.65, P<0.001) (Supplementary Fig 4B). Indeed, the frequency of SAE in pooled
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118 dupilumab group was 2.56%, while that of the pooled control group was 6.26%. The

119 major SAE in the placebo group included skin infection, inflammatory lesion,

120 impetigo and eczema herpeticum, which possibly resulted from the exacerbation of

121 AD due to the lack of effective treatment. Of note, there was a high incidence (12%)

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122 of herpes virus infection in the 100mg dupilumab group of the phase IIb trial 5. Finally,

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123 similar risks of study discontinuation between dupilumab and placebo groups were

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124 observed (RR=0.95, 95% CI 0.61-1.50, P=0.839) (Supplementary Fig 4C).

125 To our knowledge, this is the first systematic analysis and comparison of all

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published dupilumab RCTs data for the treatment of moderate-to-severe AD. The
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127 trials included had high consistency in the patients enrolled, randomization and
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128 masking, and treatment outcomes. Dupilumab was shown to be consistently more

129 effective than placebo, with a trend of a dose-dependent effect, and had a placebo-like
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safety profile.8 Combination of dupilumab with topical glucocorticoids seemed to

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131 improve the effects.9 Limitations of this meta-analysis included the limited number of
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132 clinical trials (only 7) in this study and the risks of bias, e.g. funding from
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133 pharmaceutical industry, might exist. Our findings suggest that dupilumab is a
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134 promising anti-AD medication, due to its specific action directed at the underlying

135 mechanisms of AD, resulting in its good efficacy and safety profile in severe AD

136 patients. However, further investigations still need to be performed in future studies to

137 evaluate the long-term efficacy and safety of dupilumab for the treatment of AD.

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139 Yue Han, MDa*

140 Yuxin Chen, PhDc*

141 Xiaochun Liu, MDa

142 Jingxi Zhang, MDa

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143 Huichun Su, MDa

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144 He Wen, MDa

Wei Li, MD, PhDb

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145

146 Xu Yao, MD, PhDa

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148 From the aInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union
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149 Medical College, Nanjing, bDepartment of Dermatology, Huashan Hospital, Fudan

150 University, Shanghai, and cDepartment of Laboratory Medicine, Nanjing Drum Tower
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151 Hospital, Nanjing University Medical School, Nanjing, P. R.China. Email:

152 dryao_xu@126.com. Or: liweiderma@163.com.

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153 *These authors contributed equally to this work.

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154
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155 Acknowledgement: This work was supported by National Natural Science

156 Foundation of China (81371735, 81573045, 81573038, 81600201), Natural Science

157 Foundation of Jiangsu province (BK20151066), Open Grant of the Jiangsu provincial

158 Key Laboratory of Molecular Biology for Skin Diseases and STIs (Grant number

159 2015KF14), and the Milstein Medical Asian American Partnership Foundation. All the
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160 research work was conducted in Jiangsu Key Laboratory of Molecular Biology for

161 Skin Diseases and STIs. We thank Xiangdong Gong for help in manipulation of the

162 results.

163

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164 Disclosure of potential conflict of interest: The authors declare that they have no

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165 relevant conflicts of interest.

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166 REFERENCES

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180 Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N

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187 Dupilumab therapy provides clinically meaningful improvement in

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191 7. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et

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192 al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl

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Figure legends:

FIG1 Meta-analysis of efficacy outcomes of 7 randomized controlled trials

(RCTs) with dupilumab-and placebo-treated patients with atopic dermatitis. A,

Eczema Area and Severity Index (EASI) score. B, Investigators global

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assessment (IGA) score. C, Pruritus numerical-rating scale (NRS) score. D,

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Body surface area (BSA) score. Horizontal lines stand for 95% Cls of the

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relative risk (RR) estimates. Green dots represent the standardized mean

difference (SMD). Blue dots represent the RR and diamonds represent the

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meta-analysis summary effect estimate.
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Table I Characteristics of studies included in the meta-analysis

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Age of
Referenc Stud Countr Treatment Regimen(dose of AD severity of baseline EASI
Year Phase CTG dupilumab/placebo Outcome summary
e y y /control, n dupilumab) score, treatment/control

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group
rapid and dose-depedent
Beck et NCT0125932 75mg qw,150mg

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2012 M4A I U.S.A 24/6 42.61.9/37.44.3* 30.02.0/22.83.0* improvements in all clinical
al, 2014 3 qw,300mg qw for 4 weeks
index
rapid and dose-depedent

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Beck et Multina NCT0138565 150mg qw,300mg qw for 4
2013 M4B I 27/10 42.61.9/37.44.3* 30.02.0/22.83.0* improvements in all clinical
al, 2014 tional 7 weeks

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index
Beck et NCT0154840 improvement in all clinical
2013 M12 IIa Europe 55/54 300mg qw for 12 weeks 33.71.4/39.41.7* 28.41.8/30.81.9*
al, 2014 4 index in dupilumab group

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300mg dupilumab and associated with a rapid and
Beck et NCT0163904
2013 C4 IIa Europe 21/10 topic glucocorticoids qw 36.02.5/37.85.3* 23.12.7/24.14.0* sustained reduction in

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for 4 weeks pruritus NRS

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300mg qw, 300mg q2w, greater EASI score
Thaci et Phase Multina NCT0185998 37.0(18.0-75.0)/37.2
2014 IIb 318/61 200mg q2w, 300mg q4w, 31.70.8/32.91.8* improvements in dupilumab
al, 2016 Ilb tional 8 (18.0-69.0)
100mg q4w for 12 weeks group
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Simpson 300mg qw for 16 300mg qw:30.4(21.5-40.8),
SOL Multina NCT0227774 38.0(27.5-48.0)/39.0 clinical index improvement
et 2015 III 447/224 weeks,300mg q2w for 16 300mg q2w:29.8(22.0-41.2)
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O1 tional 3 (27.0-50.5) in dupilumab group

al,2016 weeks /31.8(22.2-43.8)
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Simpson 300mg qw for 16 300mgqw:28.6(21.0-40.1),300m

SOL Multina NCT0227776 34.0(25.0-46.0)/35.0 clinical index improvement
et 2016 III 472/236 weeks,300mg q2w for 16 g q2w: 29.0(21.2-41.8)/30.5
O2 tional 9 (25.0-47.0) in dupilumab group
al,2016 weeks (22.1-41.7)

CTG,clinicaltrials.gov identification number. * mean SE. mean (range). median (range)

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