The Posology of Dupilumab in Pediatric Patients With Atopic Dermatitis

Mohamed A Kamal, Pavel Kovalenko, Matthew P Kosloski, Kamal Srinivasan, Yi Zhang, Manoj Rajadhyaksha, Ching-Ha Lai, Vanaja Kanamaluru, Christine Xu, Xian Sun, Eric L Simpson, Amy S Paller, Elaine C Siegfried, Brad Shumel, Ashish Bansal, Nidal Al-Huniti, John D Davis, Mohamed A Kamal, Pavel Kovalenko, Matthew P Kosloski, Kamal Srinivasan, Yi Zhang, Manoj Rajadhyaksha, Ching-Ha Lai, Vanaja Kanamaluru, Christine Xu, Xian Sun, Eric L Simpson, Amy S Paller, Elaine C Siegfried, Brad Shumel, Ashish Bansal, Nidal Al-Huniti, John D Davis

Abstract

Dupilumab demonstrated efficacy with an acceptable safety profile in two randomized, double-blind, placebo-controlled, parallel-group, phase III trials in adolescents (12-17 years; LIBERTY AD ADOL) and children (6-11 years; LIBERTY AD PEDS) with atopic dermatitis (AD) treated for 16 weeks. Here, we present the pharmacokinetic profiles and exposure-response (E-R) relationships of dupilumab that guided the posology in these populations. A total of 251 adolescent patients with moderate-to-severe AD were randomized to subcutaneous dupilumab monotherapy every 2 weeks (q2w; 200 mg q2w, baseline weight < 60 kg; 300 mg q2w, ≥ 60 kg), dupilumab 300 mg every 4 weeks (q4w; non-weight tiered), or placebo; 367 children with severe AD were randomized to dupilumab q2w (100 mg q2w, baseline weight < 30 kg; 200 mg q2w, ≥ 30 kg), dupilumab 300 mg q4w, or placebo. Children received concomitant topical corticosteroids in addition to dupilumab, and loading doses were administered at the start of therapy. Mean dupilumab trough concentrations at week 16 for weight subcategories in each dosing regimen were compared with adult exposures for the approved dupilumab 300 mg q2w regimen. Positive E-R relationships were demonstrated between dupilumab trough concentrations and AD outcome measures across patient populations and regimens; no relationship was observed with treatment-emergent conjunctivitis. Based on these analyses, a weight-tiered posology was proposed for adolescents (200/300 mg q2w in patients 30-< 60 kg/≥ 60 kg) and children (300 mg q4w in patients 15-< 30 kg, 200 mg q2w in patients 30-< 60 kg) with moderate-to-severe AD.

Trial registration: ClinicalTrials.gov NCT03054428 NCT03345914.

Conflict of interest statement

M.A.K., P.K., M.P.K., K.S., Y.Z., M.R., C‐H.L., X.S., B.S., A.B., N.A‐H., and J.D.D. are employees and shareholders of Regeneron Pharmaceuticals, Inc. E.L.S. has been an advisor for Celgene and Merck; a consultant for Anacor Pharmaceuticals, Asubio, Celgene, Galderma, Genentech, Medicis Pharmaceutical, and Merck; and has received research support from Amgen, Celgene, Chugai, Galderma, and Regeneron Pharmaceuticals, Inc. A.S.P. has been a consultant for AbbVie, Abeona Therapeutics, Almirall, Asana BioSciences, Boehringer Ingelheim, BridgeBio, Dermavant, Dermira, Eli Lilly, Exicure, Forté, Incyte, InMed Pharmaceuticals, Janssen, LEO Pharma, LifeMax, Novartis, Pfizer, RAPT Therapeutics, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, Sol‐Gel, and UCB; has been on the data safety monitoring board of Bausch, Galderma, and Novan; and a Principal Investigator (funding to institution) for AbbVie, AnaptysBio, Eli Lilly, Incyte, Janssen, Lenus Pharma, LEO Pharma, Novartis, Regeneron Pharmaceuticals, Inc, and UCB. E.C.S. has been a consultant for Dermavant, Eli Lilly, Pfizer, Regeneron Pharmaceuticals, Inc., and Verrica Pharmaceuticals; has been on the data safety monitoring board of GlaxoSmithKline, LEO Pharma, and Novan; and has been the Principal Investigator in clinical trials for Eli Lilly, Janssen, Regeneron Pharmaceuticals, Inc., Stiefel, and Verrica Pharmaceuticals. V.K. and C.X. are employees of and may hold stock options in Sanofi Genzyme.

© 2021 Regeneron Pharmaceuticals, Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Mean (±SD) concentration‐time course of dupilumab by treatment‐weight group in (a) adolescents aged 12–17 and (b) children aged 6–11 years (PKAS). *US Food and Drug Administration approved doses. BLQs were set to 0. Nominal time points until week 16 were used for analysis. BLQ, below limit of quantification; PK, pharmacokinetics; PKAS, PK analysis set; q2w, every 2 weeks; q4w, every 4 weeks.
Figure 2
Figure 2
Concentrations of functional dupilumab in serum at week 16 by body weight group and dose group in adults, adolescents aged 12–17 years, and children aged 6–11 years. Mean values: adults 300 mg q2w, 74.6 mg/L; adolescents 200 mg q2w

Figure 3

Exposure‐efficacy relationships. ( a )…

Figure 3

Exposure‐efficacy relationships. ( a ) Probability of response (proportions of patients with) for…

Figure 3
Exposure‐efficacy relationships. (a) Probability of response (proportions of patients with) for IGA 0 or 1 by week 16 dupilumab concentrations. (b) Probability of response (proportions of patients with) for EASI‐75 by week 16 concentrations. (c) Percentage change in EASI from baseline to week 16 vs. trough concentration (CRAS). (d) Percentage change in Peak Pruritus Numerical Rating Scale (NRS) from baseline to week 16 vs. Ctrough (CRAS). *US Food and Drug Administration approved doses. Outliers above concentrations of 165 mg/L were removed from analysis. BLQs were set to 0. BLQ, below limit of quantification; CRAS, concentration‐response analysis set; Ctrough, trough concentration; EASI, Eczema Area and Severity Index; EASI‐75, ≥ 75% reduction from baseline in EASI; PK, pharmacokinetics; PKAS, PK analysis set; q2w, every 2 weeks; q4w, every 4 weeks. (a, b) Blue line = mean regression line, gray area = confidence area around regression line. (c, d) Blue line = locally estimated scatterplot smoothing (LOESS), gray area = 95% confidence interval.

Figure 4

Logistic regression analysis between events…

Figure 4

Logistic regression analysis between events of conjunctivitis and concentration of dupilumab. *US Food…

Figure 4
Logistic regression analysis between events of conjunctivitis and concentration of dupilumab. *US Food and Drug Administration approved doses. Outliers above concentrations of 165 mg/L were removed from analysis. BLQs were set to 0. Blue line = mean regression line, gray area = confidence area around regression line. BLQ, below limit of quantification; Ctrough, trough concentration; q2w, every 2 weeks; q4w, every 4 weeks.
Figure 3
Figure 3
Exposure‐efficacy relationships. (a) Probability of response (proportions of patients with) for IGA 0 or 1 by week 16 dupilumab concentrations. (b) Probability of response (proportions of patients with) for EASI‐75 by week 16 concentrations. (c) Percentage change in EASI from baseline to week 16 vs. trough concentration (CRAS). (d) Percentage change in Peak Pruritus Numerical Rating Scale (NRS) from baseline to week 16 vs. Ctrough (CRAS). *US Food and Drug Administration approved doses. Outliers above concentrations of 165 mg/L were removed from analysis. BLQs were set to 0. BLQ, below limit of quantification; CRAS, concentration‐response analysis set; Ctrough, trough concentration; EASI, Eczema Area and Severity Index; EASI‐75, ≥ 75% reduction from baseline in EASI; PK, pharmacokinetics; PKAS, PK analysis set; q2w, every 2 weeks; q4w, every 4 weeks. (a, b) Blue line = mean regression line, gray area = confidence area around regression line. (c, d) Blue line = locally estimated scatterplot smoothing (LOESS), gray area = 95% confidence interval.
Figure 4
Figure 4
Logistic regression analysis between events of conjunctivitis and concentration of dupilumab. *US Food and Drug Administration approved doses. Outliers above concentrations of 165 mg/L were removed from analysis. BLQs were set to 0. Blue line = mean regression line, gray area = confidence area around regression line. BLQ, below limit of quantification; Ctrough, trough concentration; q2w, every 2 weeks; q4w, every 4 weeks.

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