Efficacy of Dupilumab in Different Racial Subgroups of Adults With Moderate-to-Severe Atopic Dermatitis in Three Randomized, Placebo-Controlled Phase 3 Trials

August 2019 | Volume 18 | Issue 8 | Original Article | 804 | Copyright © August 2019

Andrew F. Alexis MD MPH,a Marta Rendon MD,B Jonathan I. Silverberg MD,c David M. Pariser MD,D Benjamin Lockshin MD,e Christopher E.M. Griffiths MD,f Jamie Weisman MD,g Andreas Wollenberg MD,h Zhen Chen PhD,i John D. Davis PhD,i Meng Li PhD,j Laurent Eckert PhD,k Abhijit Gadkari PhD,i Brad Shumel MD,i Ana B. Rossi MD,l Neil M.H. Graham MD,i Marius Ardeleanu MDi

ªDepartment of Dermatology, Mount Sinai West, New York, NY

BRendon Center for Dermatology and Aesthetic Medicine, Boca Raton, FL

cDepartment of Dermatology, Preventive Medicine and Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL

DDepartment of Dermatology, Eastern Virginia Medical School and Virginia Clinical Research, Inc., Norfolk, VA

EU.S. Dermatology Partners, Rockville, MD

fDermatology Centre NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester, UK

gAdvanced Medical Research, PC, Atlanta, GA

hDepartment of Dermatology and Allergy, Ludwig Maximilian University, Munich, Germany

IRegeneron Pharmaceuticals, Inc., Tarrytown, NY

jSanofi, Bridgewater, NJ

kSanofi, Chilly-Mazarin, France

lSanofi Genzyme, Cambridge, MA

presentation, and severity include differential expression of specific polymorphisms in type 2 signaling pathway genes, including those of interleukin (IL)-4 and IL-13 and their receptors, and variations in skin barrier gene mutations.6 Disease presentation can also vary among racial subgroups, with Asian patients presenting with better demarcated lesions and increased scaling and lichenification compared with White patients.6 Darker-skinned patients can have perifollicular accentuation and scattered distinct papules on the extensors and trunk, and erythema may be missed when assessing AD lesions.6 AD prevalence also varies by racial subgroup, having been reported more often in Asians and Blacks than in Whites.6,8 Therefore, diagnosis and severity assessment should consider racial differences in genetics, presentation, and prevalence. However, current guidelines do not propose any differences in the diagnosis and treatment of AD by racial subgroup,9-11 and no practical evidence exists to show that treatment should be addressed differentially by racial subgroup.

Dupilumab, a fully human VelocImmune®-derived12,13 monoclonal antibody, blocks the shared receptor subunit for IL-4 and IL-13, thus inhibiting signaling of both IL-4 and IL-13. Dupilumab is approved for subcutaneous administration every two weeks (q2w) for the treatment of patients aged 12 years and older with moderate-to-severe AD inadequately controlled with topical prescription therapies or when those therapies are not advisable in the USA,14 for the treatment of adult AD patients not adequately controlled with existing therapies in Japan, and for use in adults with moderate-to-severe AD who are candidates for systemic therapy in the EU.15 Dupilumab is also approved by the US Food and Drug Administration14 as an addon maintenance treatment in patients with moderate-to-severe asthma aged ≥12 years with an eosinophilic phenotype or with oral corticosteroid-dependent asthma regardless of eosinophilic phenotype.16-18 In clinical trials, dupilumab demonstrated significant efficacy in improving signs and symptoms of AD, and an acceptable safety profile.19-23 Efficacy and safety of dupilumab have also been shown in clinical trials in other type 2 immune diseases, including chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis, thus demonstrating the importance of IL-4 and IL-13 as drivers of multiple type 2 atopic/allergic diseases.24,25

LIBERTY AD SOLO 1 and SOLO 2 were two identically designed, pivotal, 16-week, phase 3 trials that assessed efficacy and safety of dupilumab monotherapy vs placebo,21 while the 52-week CHRONOS trial assessed dupilumab with concomitant topical corticosteroids (TCS) vs TCS alone22 in adults with moderateto- severe AD. Dupilumab significantly improved skin lesions, symptoms (including pruritus and symptoms of anxiety and depression), and QoL with an acceptable safety profile21,22 in these randomized, placebo-controlled, double-blinded trials. As the efficacy and safety of dupilumab among racial subgroups have not been assessed previously, the objective of this report is to present dupilumab efficacy, safety, and pharmacokinetics (PK) among racial subgroups of adult patients with moderateto- severe AD in an analysis of the SOLO 1, SOLO 2, and CHRONOS trials.

METHODS

Study Designs

Detailed descriptions of the study populations and methodologies of these trials have been published previously.21,22 All three studies were conducted following guidelines based on the Declaration of Helsinki, International Conference on Harmonisation-Good Clinical Practice, and local applicable regulatory requirements. All patients provided written informed consent prior to undertaking any study procedures.21,22

Briefly, in SOLO 1 (NCT02277743) and SOLO 2 (NCT02277769), patients were randomized 1:1:1 to subcutaneous dupilumab 300 mg weekly (qw), q2w, or placebo for 16 weeks. A 35-day screening and washout period preceded study drug administration. In CHRONOS (NCT02260986), patients were randomized 3:1:3 to subcutaneous dupilumab 300 mg qw, q2w, or placebo for 52 weeks with concomitant TCS; concomitant topical calcineurin inhibitors could be used on body locations where TCS were considered inadvisable. A 35-day screening period preceded the study drug administration without a washout period for TCS. In all three trials, a 600 mg loading dose was administered on day 1 to patients receiving dupilumab, while patients in the placebo group received a double dose of placebo.

Patients self-reported their racial subgroup. Due to the very low number or absence of patients of other racial subgroups (American Indian, Alaska Native, Native Hawaiian or other Pacific Islander, Others), this analysis only presented data from White, Asian, and Black/African American patients.

Outcomes

Efficacy outcomes assessed in this analysis included: mean and percent change from baseline to week 16 in Eczema Area and Severity Index (EASI), Peak Pruritus Numerical Rating Scale (NRS), Dermatology Life Quality Index (DLQI), and Patient- Oriented Eczema Measure (POEM); proportion of patients achieving Investigator’s Global Assessment (IGA) score 0 or 1 and a reduction of ≥2 points from baseline at week 16; and proportion of patients with no pain or discomfort at week 16 using the European Quality of Life-5 Dimensions 3 level (EQ-5D- 3L) questionnaire among patients with at least moderate pain or discomfort at baseline. Safety outcomes included overall incidence of treatment-emergent adverse events (TEAEs); treatment-emergent serious adverse events (TE-SAEs); TEAEs leading to treatment discontinuation;