Dataset Information

A phase 2, open-label study of single-dose dupilumab in children aged 6 months to <6 years with severe uncontrolled atopic dermatitis: pharmacokinetics, safety and efficacy.

ABSTRACT:

Background

Dupilumab has demonstrated efficacy and acceptable safety in adults and children (aged 6-17 years) with moderate-to-severe atopic dermatitis (AD), but effective systemic therapy with a favorable risk-benefit profile in younger children remains a significant unmet need.

Objectives

To determine the pharmacokinetics, safety and efficacy of single-dose dupilumab in children with severe AD aged ?6 months to <6 years.

Methods

This open-label, multicenter, phase 2, sequential, two-age cohort, two-dose level study (LIBERTY AD PRE-SCHOOL; NCT03346434) included an initial cohort of older children aged ?2 to <6 years, followed by a younger cohort aged ?6 months to <2 years. Pharmacokinetic sampling, safety monitoring and efficacy assessments were performed during the 4-week period after a single subcutaneous injection of dupilumab, in two sequential dosing groups (3 mg/kg, then 6 mg/kg). The use of standardized, low-to-medium potency topical corticosteroids was allowed.

Results

Forty patients were enrolled (20/age cohort, 10/dose level within a cohort) between December 20, 2017 and July 22, 2019. Within each age cohort, pharmacokinetic exposures after a single injection of dupilumab increased in a greater than dose-proportional manner. At week 3, treatment with 3 and 6 mg/kg dupilumab reduced scores of mean Eczema Area and Severity Index by -44.6% and -49.7% (older cohort) and -42.7% and -38.8% (younger cohort), and mean Peak Pruritus NRS scores by -22.9% and -44.7% (older cohort) and -11.1% and -18.2% (younger cohort), respectively. At week 4, improvements in most efficacy outcomes diminished in both age groups, particularly with the lower dose. The safety profile was comparable to that seen in adults, adolescents and children.

Conclusions

Single-dose dupilumab was generally well tolerated and substantially reduced clinical signs/symptoms of AD. Slightly better responses were seen in older than younger children. The pharmacokinetics of dupilumab were non-linear, consistent with previous studies in adults and adolescents.

SUBMITTER: Paller AS

PROVIDER: S-EPMC7894166 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

A phase 2, open-label study of single-dose dupilumab in children aged 6 months to <6 years with severe uncontrolled atopic dermatitis: pharmacokinetics, safety and efficacy.

Paller A S AS Siegfried E C EC Simpson E L EL Cork M J MJ Lockshin B B Kosloski M P MP Kamal M A MA Davis J D JD Sun X X Pirozzi G G Graham N M H NMH Gadkari A A Eckert L L Ruddy M M Bansal A A

Journal of the European Academy of Dermatology and Venereology : JEADV 20201108 2

<h4>Background</h4>Dupilumab has demonstrated efficacy and acceptable safety in adults and children (aged 6-17 years) with moderate-to-severe atopic dermatitis (AD), but effective systemic therapy with a favorable risk-benefit profile in younger children remains a significant unmet need.<h4>Objectives</h4>To determine the pharmacokinetics, safety and efficacy of single-dose dupilumab in children with severe AD aged ≥6 months to <6 years.<h4>Methods</h4>This open-label, multicenter, phase 2, sequ ...[more]

PMID: 32893393

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Project description:BackgroundChildren aged ≥ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16-week, randomized, placebo-controlled, phase III trial in children, dupilumab, a monoclonal antibody inhibiting interleukin (IL)-4/IL-13 signalling, significantly improved signs and symptoms with acceptable safety; longer-term safety and efficacy data are lacking.ObjectivesTo report the pharmacokinetic profile and long-term safety and efficacy of dupilumab in children (aged ≥ 6 to < 12 years) with severe AD.MethodsChildren (aged ≥ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study and subsequent open-label extension (OLE) study. Patients received single-dose dupilumab 2 or 4 mg kg-1 followed by 8-week pharmacokinetic sampling, then 2 or 4 mg kg-1 weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were dupilumab concentration-time profile and treatment-emergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PP-NRS) score.ResultsOf 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, target-mediated pharmacokinetics characterized dupilumab concentrations (week 24-48 mean serum concentrations: 2 mg kg-1 , 61-77 mg L-1 ; 4 mg kg-1 , 143-181 mg L-1 ). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kg-1 , 47%; 4 mg kg-1 , 56%) and AD exacerbation (29% and 13%, respectively). Single-dose dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PP-NRS improved by -37%/-33% and -17%/-20% at week 2 (phase IIa) and -92%/-84% and -70%/-58% at week 52 (OLE), respectively.ConclusionsThese safety and efficacy results support the use of dupilumab as a continuous long-term treatment for children aged ≥ 6 to < 12 years with severe AD.

Project description:BACKGROUND:Dupilumab (monoclonal antibody inhibiting IL-4/IL-13 signalling) is approved for use in adolescents aged ? 12 years with inadequately controlled moderate-to-severe atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16-week, randomised, placebo-controlled phase III trial in adolescents (NCT03054428). OBJECTIVES:To characterize the pharmacokinetics of dupilumab, and long-term safety and efficacy in adolescents. METHODS:This was a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study with a phase III open-label extension (OLE) in adolescents with moderate-to-severe AD. In the phase IIa study, patients received one dupilumab dose (2 mg kg-1 or 4 mg kg-1 ) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8-week safety follow-up. Patients then enrolled in the OLE, continuing 2 mg kg-1 or 4 mg kg-1 dupilumab weekly. Primary end points were dupilumab concentration-time profile and incidence of treatment-emergent adverse events (TEAEs). Secondary outcomes included Eczema Area and Severity Index (EASI). RESULTS:Forty adolescents received dupilumab in the phase IIa study; 36 enrolled in the OLE. Dupilumab showed nonlinear, target-mediated pharmacokinetics. Mean ± SD trough dupilumab concentrations in serum at week 48 (OLE) were 74 ± 19 mg L-1 and 161 ± 60 mg L-1 for 2 mg kg-1 and 4 mg kg-1 , respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kg-1 ], 47% [4 mg kg-1 ]) and AD exacerbation (29%, 42%). After one dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean ± SD reduction -34% ± 20% (2 mg kg-1 ) and -51% ± 29% (4 mg kg-1 )]. With continuing treatment, EASI scores improved further [week 52: -85% ± 12% (2 mg kg-1 ) and -84% ± 20% (4 mg kg-1 )]. CONCLUSIONS:In adolescents with moderate-to-severe AD, dupilumab's pharmacokinetic profile was similar to that in adults. These 52-week safety and efficacy data support long-term use of dupilumab in this patient population. What's already known about this topic? Adolescents with moderate-to-severe atopic dermatitis (AD) have high unmet medical need, with significant disease burden and limited treatment options. Dupilumab (monoclonal antibody against interleukin-4 receptor ?) is approved for the treatment of adolescents with moderate-to-severe AD who are inadequately responsive to standard of care (U.S.A.) or candidates for systemic therapy (European Union). A 16-week, randomized, placebo-controlled phase III trial in adolescents demonstrated significant improvements in AD signs/symptoms with an acceptable safety profile. What does this study add? These studies demonstrate the long-term safety and efficacy of dupilumab in adolescents with moderate-to-severe AD for up to 52 weeks of treatment, thus extending and reinforcing the findings from the 16-week dupilumab phase III trial. The data from these studies also support the use of dupilumab in combination with current standard of care (topical corticosteroids), which was not evaluated in the 16-week phase III monotherapy trial.

Project description:IntroductionTreatment options for children younger than 6 years with severe atopic dermatitis (AD) are limited, as systemic immunosuppressants may present safety concerns in this young age group. Dupilumab is the first systemic treatment option approved for infants and young children with severe AD in the European Union. This study reports the efficacy and safety of dupilumab with concomitant low-potency corticosteroids in children aged 6 months to 5 years with severe AD.MethodsThis was a pre-specified subgroup analysis of data for patients aged 6 months to 5 years with severe AD at baseline (Investigator's Global Assessment [IGA] = 4) from a randomised, double-blind, placebo-controlled, phase III trial of dupilumab. Patients were randomised to either subcutaneously administered dupilumab (200/300 mg) or matched placebo every 4 weeks, plus low-potency topical corticosteroids for 16 weeks. Co-primary endpoints at week 16 were the proportion of patients with IGA ≤ 1 (clear or almost clear skin) and the proportion of patients with ≥ 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Secondary endpoints at week 16 included mean changes in EASI, pruritus, skin pain, sleep loss and quality of life.ResultsThe analysis included 125 patients (63 receiving dupilumab vs. 62 placebo). At week 16, significantly more patients receiving dupilumab vs. placebo had achieved IGA ≤ 1 (14.3% vs. 1.6%; P = 0.0085) and EASI-75 (46.0% vs. 6.6%; P < 0.0001). Significant improvements with dupilumab were observed in all secondary endpoints, including a least squares mean 48.9% reduction in pruritus. The overall incidence of adverse events (AEs) was similar between the dupilumab and placebo groups (66.7% vs. 73.8%). No dupilumab-related AEs were serious or led to treatment discontinuation.ConclusionDupilumab significantly improved AD signs, symptoms and quality of life in children aged 6 months to 5 years with severe AD with acceptable safety.Trial registrationThe trial was registered with ClinicalTrials.gov with ID number NCT03346434, part B.

Project description:BackgroundFor children aged 6-11 years with uncontrolled severe atopic dermatitis (AD), 16 weeks of treatment with dupilumab resulted in substantial clinical benefit compared with placebo with an acceptable safety profile. However, longer-term safety and efficacy data are important to inform longitudinal AD management.ObjectivesThis analysis of data from an open-label extension study (LIBERTY AD PED-OLE, NCT02612454) reports the long-term safety, efficacy, and pharmacokinetics of dupilumab in children with severe AD who had participated in the pivotal dupilumab LIBERTY AD PEDS study (NCT03345914).MethodsEnrolled patients initially received subcutaneous dupilumab 300 mg every 4 weeks (q4w). The q4w regimen could be uptitrated to dupilumab dose regimens of 200 or 300 mg every 2 weeks (q2w; for body weight < 60 or ≥ 60 kg, respectively) for patients who did not achieve an Investigator's Global Assessment (IGA) score of 0/1 (clear/almost clear skin) at week 16, or prior to week 16 as rescue treatment. Additional patients were uptitrated to a weight-tiered q2w regimen following a protocol amendment. Patients who maintained an IGA score of 0/1 continuously for a 12-week period after week 40 discontinued dupilumab. They were monitored for relapse and were reinitiated on dupilumab if required.ResultsData for 321 patients (mean age 8.6 years) were analyzed, 254 (79%) of whom had completed the scheduled 52-week visit at the database lock. Most treatment-emergent adverse events were mild/moderate. By week 52, 41% of patients achieved an IGA score of 0/1, and 97%, 82%, and 50%, respectively, had at least a 50%, 75%, and 90% improvement from the parent study baseline in Eczema Area and Severity Index (EASI). By week 52, 29% of patients in the overall population had clear/almost clear skin sustained for 12 weeks and had stopped medication; of these, 40% relapsed and were subsequently reinitiated on treatment, with a mean time to reinitiation of 13.5 (standard deviation 5.2) weeks. Following reinitiation of dupilumab, 41% of the patients with evaluable data at the time of database lock had regained an IGA 0/1 clinical response.ConclusionsConsistent with results seen in adults and adolescents, long-term treatment with dupilumab in children aged 6-11 years with severe AD showed an acceptable safety profile and incremental clinical benefit. A substantial proportion of children who stopped dupilumab treatment after achieving clear/almost clear skin subsequently experienced disease recurrence, and required reinitiation of dupilumab, suggesting that continuous treatment may be necessary for maintenance of clinical benefit.Trial registrationClinicalTrials.gov Identifier NCT02612454.

Dataset Information

A phase 2, open-label study of single-dose dupilumab in children aged 6 months to <6 years with severe uncontrolled atopic dermatitis: pharmacokinetics, safety and efficacy.

Background

Objectives

Methods

Results

Conclusions

Publications

A phase 2, open-label study of single-dose dupilumab in children aged 6 months to <6 years with severe uncontrolled atopic dermatitis: pharmacokinetics, safety and efficacy.

Similar Datasets

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