Background <p>Infants and young children with severe atopic dermatitis (AD) have a high burden of disease with a strong impact on quality of life. Here we assess long-term efficacy and safety of dupilumab in pediatric patients aged 6 months to 5 years with severe AD.</p> Methods <p>This is a subgroup analysis of patients aged 6 months to 5 years enrolled in the ongoing LIBERTY AD PED open-label extension (OLE) study of dupilumab who had previously participated in the parent study LIBERTY AD PRESCHOOL part B and had severe AD (Investigator’s Global Assessment [IGA] = 4) at parent study baseline. Patients received weight-tiered dupilumab every 4 weeks (200&#xa0;mg for patients weighing 5 to &lt; 15&#xa0;kg; 300&#xa0;mg for patients weighing 15 to &lt; 30&#xa0;kg). Key endpoints included the incidence and rate of treatment-emergent adverse events (TEAEs), the proportion of patients with a ≥ 75% improvement in Eczema Area and Severity Index (EASI-75) from parent study baseline, proportions of patients achieving IGA = 0/1 and IGA ≤ 2, and the proportion of patients with a ≥ 6-point improvement in Children’s Dermatology Life Quality Index (CDLQI) for patients aged ≥ 4 years or Infants’ Dermatitis Quality of Life (IDQoL) questionnaire for patients aged &lt; 4 years.</p> Results <p>This analysis included 121 patients, of whom 50 completed the week 104 visit. TEAEs were reported in 88% of patients; most TEAEs were mild or moderate and not related to treatment. Common TEAEs included upper respiratory tract infection, nasopharyngitis, and cough. Conjunctivitis events were reported in 19% of patients and were mild or moderate, with a median duration of 8 days. No conjunctivitis event led to treatment discontinuation, and most events resolved during the study. One drug-related event (severe urticaria) led to treatment discontinuation, but it was not serious and resolved over time. Serious TEAEs were reported in 17 patients (14%), including one drug-related pinworm event. No serious TEAE led to treatment discontinuation. By week 4 of the OLE study, patients who had received placebo in the parent study exhibited efficacy improvements comparable to patients who had received dupilumab. By week 104, 96% of patients achieved EASI-75 from parent study baseline, 27% of patients achieved an IGA score of 0/1 (clear/almost clear skin), 92% of patients achieved IGA ≤ 2 (clear skin to mild AD), and the least squares mean percent change in EASI from parent study baseline was − 89%. Additionally, 89% (23/26) of patients achieved a ≥ 6-point (clinically meaningful) improvement in CDLQI, and 100% (3/3) of patients achieved a ≥ 6-point improvement in IDQoL.</p> Conclusion <p>Long-term treatment with dupilumab for up to 2 years showed acceptable safety and sustained efficacy in signs, symptoms, and quality of life in patients aged 6 months to 5 years with severe AD, with a rapid improvement for patients who had received placebo in the parent study. Long-term safety in the OLE study was consistent with the short-term safety profile observed in the parent study, with no new safety signals detected. [Graphical abstract and plain language summary available]</p> Clinical Trial Registration <p>ClinicalTrials.gov Identifiers: NCT02612454 and NCT03346434 (part B).</p> Graphical Abstract <p></p>