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Dupilumab provides favourable longâterm safety and efficacy in children aged â„ 6 to < 12 years with uncontrolled, severe atopic dermatitis: results from an openâlabel phase IIa study and subsequent phase III openâlabel extension study
Background
Children aged â„ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16âweek, randomized, placeboâcontrolled, phase III trial in children, dupilumab, a monoclonal antibody inhibiting interleukin (IL)â4/ILâ13 signalling, significantly improved signs and symptoms with acceptable safety; longerâterm safety and efficacy data are lacking.
Objectives
To report the pharmacokinetic profile and longâterm safety and efficacy of dupilumab in children (aged â„ 6 to < 12 years) with severe AD.
Methods
Children (aged â„ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, openâlabel, ascendingâdose, sequential cohort study and subsequent openâlabel extension (OLE) study. Patients received singleâdose dupilumab 2 or 4 mg kgâ1 followed by 8âweek pharmacokinetic sampling, then 2 or 4 mg kgâ1 weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were dupilumab concentrationâtime profile and treatmentâemergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PPâNRS) score.
Results
Of 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, targetâmediated pharmacokinetics characterized dupilumab concentrations (week 24â48 mean serum concentrations: 2 mg kgâ1, 61â77 mg Lâ1; 4 mg kgâ1, 143â181 mg Lâ1). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kgâ1, 47%; 4 mg kgâ1, 56%) and AD exacerbation (29% and 13%, respectively). Singleâdose dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PPâNRS improved by â37%/â33% and â17%/â20% at week 2 (phase IIa) and â92%/â84% and â70%/â58% at week 52 (OLE), respectively.
Conclusions
These safety and efficacy results support the use of dupilumab as a continuous longâterm treatment for children aged â„ 6 to < 12 years with severe AD
Fetal Programming of Adult Glucose Homeostasis in Mice
BACKGROUND: Emerging evidence suggests that dietary soy and phytoestrogens can have beneficial effects on lipid and glucose metabolism. We have previously shown that male mice fed from conception to adulthood with a high soy-containing diet had reduced body weight, adiposity and a decrease in glucose intolerance, an early marker of insulin resistance and diabetes. OBJECTIVES: The purpose of this study was to identify the precise periods of exposure during which phytoestrogens and dietary soy improve lipid and glucose metabolism. Since intrauterine position (IUP) has been shown to alter sensitivity to endocrine disruptors, we also investigated whether the combination of IUP and fetal exposure to dietary phytoestrogens could potentially affect adult metabolic parameters. METHODS: Male outbred mice (CD-1) were allowed ad libitum access to either a high soy-containing diet or a soy-free diet either during gestation, lactation or after weaning. Adiposity and bone mass density was assessed by dual x-ray absorptiometry. Glucose tolerance was assessed by a glucose tolerance test. Blood pressure was examined by the tail-cuff system. RESULTS: Here we show that metabolic improvements are dependent on precise windows of exposure during life. The beneficial effects of dietary soy and phytoestrogens on adiposity were apparent only in animals fed post-natally, while the improvements in glucose tolerance are restricted to animals with fetal exposure to soy. Interestingly, we observed that IUP influenced adult glucose tolerance, but not adiposity. Similar IUP trends were observed for other estrogen-related metabolic parameters such as blood pressure and bone mass density. CONCLUSION: Our results suggest that IUP and fetal exposure to estrogenic environmental disrupting compounds, such as dietary phytoestrogens, could alter metabolic and cardiovascular parameters in adult individuals independently of adipose gain
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