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Dupilumab in adolescents with uncontrolled moderateātoāsevere atopic dermatitis : results from a phase IIa openālabel trial and subsequent phase III openālabel extension
Background
Dupilumab (monoclonal antibody inhibiting ILā4/ILā13 signalling) is approved for use in adolescents aged ā„ 12 years with inadequately controlled moderateātoāsevere atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16āweek, randomised, placeboācontrolled phase III trial in adolescents (NCT03054428).
Objectives
To characterize the pharmacokinetics of dupilumab, and longāterm safety and efficacy in adolescents.
Methods
This was a global, multicentre, phase IIa, openālabel, ascendingādose, sequential cohort study with a phase III openālabel extension (OLE) in adolescents with moderateātoāsevere AD. In the phase IIa study, patients received one dupilumab dose (2 mg kgā1 or 4 mg kgā1) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8āweek safety followāup. Patients then enrolled in the OLE, continuing 2 mg kgā1 or 4 mg kgā1 dupilumab weekly. Primary end points were dupilumab concentrationātime profile and incidence of treatmentāemergent 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, targetāmediated pharmacokinetics. Mean Ā± SD trough dupilumab concentrations in serum at week 48 (OLE) were 74 Ā± 19 mg Lā1 and 161 Ā± 60 mg Lā1 for 2 mg kgā1 and 4 mg kgā1, respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kgā1], 47% [4 mg kgā1]) and AD exacerbation (29%, 42%). After one dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean Ā± SD reduction ā34% Ā± 20% (2 mg kgā1) and ā51% Ā± 29% (4 mg kgā1)]. With continuing treatment, EASI scores improved further [week 52: ā85% Ā± 12% (2 mg kgā1) and ā84% Ā± 20% (4 mg kgā1)].
Conclusions
In adolescents with moderateātoāsevere AD, dupilumab's pharmacokinetic profile was similar to that in adults. These 52āweek safety and efficacy data support longāterm use of dupilumab in this patient population
Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19
BACKGROUND REGEN-COV (previously known as REGN-COV2), a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to markedly reduce the risk of hospitalization or death among high-risk persons with coronavirus disease 2019 (Covid-19). Whether subcutaneous REGEN-COV prevents severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent Covid-19 in persons at high risk for infection because of household exposure to a person with SARS-CoV-2 infection is unknown. METHODS We randomly assigned, in a 1:1 ratio, participants (=12 years of age) who were enrolled within 96 hours after a household contact received a diagnosis of SARSCoV- 2 infection to receive a total dose of 1200 mg of REGEN-COV or matching placebo administered by means of subcutaneous injection. At the time of randomization, participants were stratified according to the results of the local diagnostic assay for SARS-CoV-2 and according to age. The primary efficacy end point was the development of symptomatic SARS-CoV-2 infection through day 28 in participants who did not have SARS-CoV-2 infection (as measured by reverse-transcriptase- quantitative polymerase-chain-reaction assay) or previous immunity (seronegativity). RESULTS Symptomatic SARS-CoV-2 infection developed in 11 of 753 participants in the REGEN-COV group (1.5%) and in 59 of 752 participants in the placebo group (7.8%) (relative risk reduction [1 minus the relative risk], 81.4%; P104 copies per milliliter) was shorter (0.4 weeks and 1.3 weeks, respectively). No dose-limiting toxic effects of REGEN-COV were noted. CONCLUSIONS Subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Among the participants who became infected, REGEN-COV reduced the duration of symptomatic disease and the duration of a high viral load