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IntroductionPatients with atopic dermatitis (AD) have an increased risk for infections. This open-label extension study, LIBERTY AD OLE, reports the incidence of infections in adults with moderate-to-severe AD treated with dupilumab for up to 4 years.MethodsWe evaluated infections in adults with moderate-to-severe AD treated with dupilumab 300 mg weekly (qw) or every 2 weeks (q2w; approved regimen) for up to 4 years. Topical corticosteroids (TCS) and calcineurin inhibitors (TCI) were permitted. Exposure-adjusted incidence rates (number of patients with at least one event per 100 patient-years [nP/100 PY]) are reported.ResultsOverall, 2677 patients were enrolled and treated with dupilumab: 352 (13.1%) completed up to week 204; 226 patients (8.4%) switched from qw to q2w during the trial. Rates of overall infections (71.27 nP/100 PY), serious and/or severe infections (1.39 nP/100 PY), and infections leading to discontinuation (0.34 nP/100 PY) were consistent with a previous 3-year analysis of this study and low compared with 1-year results in adults with AD treated with placebo + TCS. The cumulative number of patients with treatment-emergent serious or severe infections, non-herpetic or herpetic infections, and total skin infections decreased year-over-year. Limitations included open-label study design with no placebo arm; decreasing sample size at later time points due to sponsor decision to close sites following regulatory approval; qw dosing differs from approved q2w dosing; and patients could use TCS/TCI throughout the study, which may have impacted infection rates.ConclusionsContinuous long-term dupilumab treatment in adults with moderate-to-severe AD is not associated with an increased risk of overall systemic or cutaneous infections.Trial registrationClinicalTrials.gov Identifier: NCT01949311. Video Abstract INFOGRAPHIC.

Introduction/Background Children with moderate-to-severe atopic dermatitis (AD) are at increased risk of lower bone mineral density (BMD) and fractures. Peak bone mass achieved during prepubescence is a major determinant of lifetime risk of fractures and osteoporosis. Bone alkaline phosphatase (BALP) promotes bone mineralization and contributes to density and linear growth in children. Systemic corticosteroids (SCS) negatively impact growth and bone health. Objectives To describe the impact of dupilumab treatment on BALP in children aged 6–11 years with moderate-to-severe AD and prior history of SCS use. Methods BALP levels in sera from participants receiving dupilumab 300 mg every 4 weeks (q4w) or placebo in LIBERTY AD PEDS (NCT03345914) and dupilumab 300 mg q4w in LIBERTY AD PED-OLE (NCT02612454) were analyzed at baseline and at 8, 12, 16 (PEDS), and 52 weeks (PED-OLE). Serum BALP levels (mcg/L) were stratified by prior use (with SCS; n = 42) or with no prior use of SCS (without SCS; n = 203), as captured in PEDS patient history at baseline. Results Regardless of prior SCS use, dupilumab treatment led to significant increase in BALP levels in children with moderate-to-severe AD at Week 16 compared with the placebo group (with SCS: 300 mg q4w [n = 25] vs placebo [n = 17], mean change [standard deviation] in BALP levels of 15.1 mcg/L [16.5] vs −5.5 mcg/L [16.0], P = 0.0099; without SCS: 300 mg q4w [n = 97] vs placebo [n = 106], 11.8 mcg/L [18.8] vs 2.2 mcg/L [16.3], P = 0.0074). By Week 52, BALP levels further increased vs baseline regardless of prior SCS use and were comparable with reference intervals (with SCS: 24.5 mcg/L [16.8], P = 0.0044; without SCS: 13.4 mcg/L [19.4], P = 0.0002). Patients in the placebo group who switched to dupilumab in PED-OLE had improved to levels similar to those of patients continuing treatment by Week 52 (with SCS: 23.3 mcg/L [19.3], P = 0.0067 [vs baseline]; without SCS: 18.4 mcg/L [20.4], P < 0.0001 [vs baseline]). Conclusions Dupilumab treatment increased BALP levels in children aged 6-11 years with moderate-to-severe AD irrespective of prior history of SCS use. These results add to the body of evidence that moderate-to-severe AD can negatively impact BALP levels, and that this effect may be improved with dupilumab in this age group, regardless of history of SCS use. The increase in BALP levels suggests that dupilumab may help improve bone mineralization in children with moderate-to-severe AD when treated during prepubescence. [ABSTRACT FROM AUTHOR]

Children with atopic dermatitis (AD) are at risk for low bone mineral density (BMD), which is associated with an increased prevalence of osteopenia, osteoporosis, and fracture risk.1,2 Factors such as restricted nutrition, vitamin D deficiency, poor sleep and corticosteroid use contribute to lower bone alkaline phosphatase (BALP) levels, a marker of bone mineralization, seen in children with moderate-to-severe AD compared with healthy children.³ A major determinant for the lifetime risk of fractures and osteoporosis is the magnitude of peak bone mass achieved during prepubescent years. Low BALP and BMD in children with moderate-to-severe AD could contribute to a higher prevalence of osteopenia and osteoporosis. The objective of this analysis is to report the impact of dupilumab treatment on markers of bone formation in children aged ≥ 6 to <12 years with moderate-to-severe AD. The analysis was performed retrospectively on sera from participants in LIBERTY AD PEDS (NCT03345914) and LIBERTY AD PED-OLE (NCT02612454). In LIBERTY AD PEDS, a double-blind, 16-week, phase 3 trial, children aged 6 to <12 years were randomized 1 : 1 : 1 to 300 mg dupilumab every 4 weeks (300 mg q4w), a weight-based regimen of dupilumab every 2 weeks (100 mg q2w for patients with baseline weight <30 kg, and 200 mg q2w for those with baseline weight ≥30 kg), or placebo; with concomitant medium-potency topical corticosteroids (TCS). After the initial 16-week trial, children aged 6 to <12 years were enrolled in the open-label extension study LIBERTY AD PED-OLE. Patients received dupilumab 300 mg q4w, which could be titrated up in case of inadequate clinical response at week 16 (200 mg q2w for patients with baseline weight <60 kg, and 300 mg q2w for those with baseline weight ≥60 kg); with concomitant medium-potency TCS. Bone biomarkers including BALP, procollagen type 1 N-terminal propeptide, C-terminal crosslinking telopeptide of type 1 collagen, osteocalcin, and insulin-like growth factor 1 were analysed at baseline, 8, 12, 16 and BALP only at 52 weeks. Dupilumab treatment led to a rapid and significant increase in geometric mean (standard error) levels of BALP in children with moderate-to-severe AD at 16 weeks compared with patients in the placebo group (77.7(1.02) μgL−1 vs. 65.0(1.04) μgL−1; P<0.0001). As well as a rapid and significant increase in BALP levels in children from the placebo group once they joined the OLE trial. BALP levels increased over 52 weeks in all treated children, reaching a level of 78–84 μgL−1 which constitutes a significant improvement compared with baseline, and is comparable to healthy reference intervals. An increasing trend from baseline to 16 weeks of dupilumab treatment was observed for other biomarkers, however, there was a limited number of data points due to insufficient volumes of serum available for analysis. These placebo-controlled results show, for the first time, a rapid and significant increase in BALP, and a possible trend in other biomarkers, in children with AD during treatment with dupilumab. These results suggest increased bone mineralization during the treatment period. [ABSTRACT FROM AUTHOR]