Dupilumab in adolescents with uncontrolled moderate‐to‐severe atopic dermatitis: results from a phase II a open‐label trial and subsequent phase III open‐label extension

Abstract

Summary 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 α) 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 comb...

A Calm, Dispassionate Look at Skin Microbiota in Atopic Dermatitis: An Integrative Literature Review

“…Dupilumab, a monoclonal antibody against interleukin-4 receptor alpha, has been used in numerous allergic diseases and works by blocking signaling of interleukin-4 and interleukin-13, type 2/Th2 cytokines. It has been confirmed to be effective in patients with moderate to severe AD in several double-blind, placebocontrolled studies and in clinical practice [43][44][45]. The result showed that clinical improvement is positively correlated with increased favorable microbial community and reduced abundance of S. aureus [46].…”

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Dupilumab in Healthy Adult Subjects

“…Dupilumab is also approved in the United States as an add-on treatment in patients aged ࣙ18 years with inadequately controlled chronic rhinosinusitis with nasal polyps. Clinical trials in adults [14][15][16][17][18] and adolescent populations 19,20 with moderate to severe AD, as well as in adult patients with asthma [21][22][23][24] and chronic rhinosinusitis with nasal polyps, 25,26 or eosinophilic esophagitis, 27 have demonstrated improvements in disease outcomes during dupilumab treatment, with an acceptable safety profile.…”

Dupilumab: One therapy to treat multiple atopic diseases

“…In trials of dupilumab in moderate-to-severe AD, 60% of adults and 75% to 92% of adolescents had at least 1 comorbid allergic condition. 4 , 5 , 6 Of adolescents, 45% to 66% had comorbid AR, 35% to 61% had food allergy, 30% to 54% had asthma, and 0.4% had EoE. 4 , 5 However, nearly all trials have only evaluated the effects of dupilumab on a single disease entity per trial.…”

“… 4 , 5 , 6 Of adolescents, 45% to 66% had comorbid AR, 35% to 61% had food allergy, 30% to 54% had asthma, and 0.4% had EoE. 4 , 5 However, nearly all trials have only evaluated the effects of dupilumab on a single disease entity per trial. In these studies, dupilumab dramatically improved disease severity and quality of life in AD, 4 , 5 , 6 asthma, 1 and CRwNP 3 with minimal side effects.…”

“…It is not uncommon for AD patients to have a history of multiple allergic conditions; it is less common to have all of them coexisting (ie, active) concurrently. 4 , 5 , 6 To our knowledge, this is the first case report of a pediatric AD patient with multiple comorbid allergic conditions who experienced objective improvements in all of his conditions (AD, EoE, asthma, AR, and chronic sinusitis [CS]) with dupilumab treatment.…”