Long-Term Efficacy and Safety of Dupilumab in Adolescents with Moderate-to-Severe Atopic Dermatitis: Results Through Week 52 from a Phase III Open-Label Extension Trial (LIBERTY AD PED-OLE)

Abstract

Background: For adolescent patients (aged ≥ 12 to < 18 years) with uncontrolled moderate-to-severe atopic dermatitis (AD), 16 weeks of treatment with dupilumab resulted in substantial clinical benefit compared with placebo, with an acceptable safety profile. However, long-term data on the approved dose regimens of dupilumab in adolescents with AD are lacking.

Objectives: This open-label extension study (LIBERTY AD PED-OLE, NCT02612454) reports the long-term safety, efficacy, and pharmacokinetics of dupilumab in adolescents with moderate-to-severe AD who had participated in dupilumab parent trials.

Methods: Patients enrolled under the original study protocol received subcutaneous dupilumab according to a weight-based regimen (2 or 4 mg/kg every week). Following protocol amendment, patients were switched to subcutaneous dupilumab 300 mg every 4 weeks (q4w) irrespective of weight, and newly enrolled patients were started on dupilumab 300 mg q4w. Patients with an inadequate clinical response (Investigator's Global Assessment [IGA] score of 0/1 was not reached) to the q4w regimen could be uptitrated to the approved dupilumab dose regimens of 200 or 300 mg every 2 weeks (body weight < 60 or ≥ 60 kg, respectively). Patients whose IGA score of 0/1 was maintained continuously for a 12-week period after week 40 were discontinued from dupilumab, monitored for relapse, and re-initiated on dupilumab if required.

Results: Data for 294 patients (mean age 14.7 years) were analyzed, 102 (34.7%) of whom had completed the 52-week visit at the database lock. The dupilumab long-term safety profile was comparable to that seen in adults and consistent with the known safety profile. Most treatment-emergent adverse events were mild/moderate. By week 52, 42.7% of patients had an IGA score of 0/1 (clear/almost clear), and 93.1%, 81.2%, and 56.4%, respectively, had at least a 50%, 75%, or 90% improvement in Eczema Area and Severity Index (EASI). Most (70.9%) patients required uptitration to the approved dupilumab dose regimen. The proportions of uptitrated patients with an IGA score of 0/1 or 75% improvement in EASI increased over time, reaching 35.7% and 51.9%, respectively, 48 weeks after the first uptitration visit. By week 52, 29.4% of patients had clear/almost clear skin sustained for 12 weeks and had stopped medication; 56.7% relapsed and were subsequently re-initiated on treatment, with a mean time to re-initiation of 17.5 (± standard deviation 17.3) weeks.

Conclusions: Consistent with results seen with short-term treatment, long-term treatment with dupilumab showed an acceptable safety profile while providing incremental clinical benefit with continued treatment over time. The high proportion of patients who needed uptitration because of inadequate response to q4w dosing supports the q2w dose regimen as optimal for this age group. Finally, the majority of patients who stopped medication after having clear/almost clear skin sustained over 12 weeks experienced disease recurrence, suggesting the need for continued dupilumab dosing to maintain efficacy.

Trial registration: ClinicalTrials.gov Identifiers: NCT02612454, NCT02407756, NCT03054428, and NCT03050151.

Infographic: Video abstract: What is the long-term safety and efficacy profile in adolescents with moderate-to-severe atopic dermatitis treated with the approved dupilumab dose regimen? (MP4 40,966 KB).

Conflict of interest statement

Andrew Blauvelt is a scientific advisor and clinical study investigator for AbbVie, Abcentra, Aligos, Almirall, Amgen, Arcutis, Arena, Aslan, Athenex, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Eli Lilly and Company, Evommune, Forte, Galderma, Incyte, Janssen, Landos, LEO Pharma, Novartis, Pfizer, Rapt, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, Sun Pharma, UCB Pharma, and Vibliome. Emma Guttman-Yassky has received personal fees from AbbVie, Allergan, Amgen, Asana BioSciences, Celgene, Concert, Dermavant, Dermira, DS Biopharma, Eli Lilly and Company, Escalier BioSciences, Galderma, Glenmark, Kyowa Kirin, LEO Pharma, Mitsubishi Tanabe, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi; and has received grants paid to the institution from AbbVie, Asana Biosciences, Celgene, Concert, Dermavant, Dermira, DS Biopharma, Galderma, Glenmark, Innovaderm, LEO Pharma, Novan, Novartis, Pfizer, Ralexar Therapeutics, and Regeneron Pharmaceuticals, Inc. Amy S. Paller has served as a scientific advisor, clinical study investigator, and/or data safety monitoring board member for AbbVie, Arena, Bausch, Bristol Myers Squibb, Dermavant, Eli Lilly and Company, Forte, Incyte, Janssen, LEO Pharma, Lifemax, Novartis, Pfizer, Rapt, Regeneron Pharmaceuticals, Inc., Sanofi, and UCB. Eric L. Simpson has received personal fees from AbbVie, Boehringer Ingelheim, Collective Acumen LLC, Eli Lilly and Company, Forte Bio, Incyte, Janssen, Kyowa Hakko Kirin, LEO Pharma, Novartis, Ortho Dermatologics, Pfizer, Pierre Fabre Dermo Cosmetique, Regeneron Pharmaceuticals, Inc., Roivant, Sanofi, and Valeant; and grants (or undertaken a principal investigator role) from AbbVie, Eli Lilly and Company, Incyte, Kyowa Hakko Kirin, LEO Pharma, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, Tioga, and Vanda. Michael J. Cork has been a consultant and/or advisory board member for and/or received research grants from Astellas Pharma, Atopix, Boots, Dermavant, Eli Lilly and Company, Galapagos, Galderma, Hyphens Pharma, Johnson & Johnson, Kymab, L’Oréal, LEO Pharma, Menlo, Novartis, Oxagen, Perrigo (ACO Nordic), Pfizer, Procter & Gamble, Reckitt Benckiser, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, UCB Pharma, and the National Eczema Society, UK. Jamie Weisman has been an advisory board member or participated in a speaker’s bureau for AbbVie, Eli Lilly and Company, Janssen, Regeneron Pharmaceuticals, Inc., and UCB and received research grants from AbbVie, Allergan, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Dermira, Eli Lilly and Company, Galderma, GlaxoSmithKline, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and UCB. John Browning has been an investigator for Amryt Pharma, Arcutis Biotherapeutics, Bristol Myers Squibb, Brickell Biotech, ChemoCentryx, Eli Lilly and Company, Galderma, Incyte, Lenus Pharma, LEO Pharma, Mayne Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Valeant; has been an advisor for Dermavant and LEO Pharma; and has been a speaker for Dermira, Pfizer, and Regeneron Pharmaceuticals, Inc. Weily Soong has received research funding from AbbVie, AstraZeneca, Cara, Galderma, Genentech, GlaxoSmithKline, Glenmark, Innovaderm, LEO Pharma, Mandala, Menlo, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Relaxar, Sanofi, Symbio, Teva, and Vanda Pharmaceuticals; has received speaker fees from AstraZeneca, GlaxoSmithKline, Optinose, Regeneron Pharmaceuticals, Inc., and Sanofi; and has received consulting fees from AbbVie, Genentech, and Regeneron Pharmaceuticals, Inc. Xian Sun, Zhen Chen, Matthew P. Kosloski, Mohamed A. Kamal, Dimittri Delevry, and Ashish Bansal are employees and shareholder of Regeneron Pharmaceuticals, Inc. Chien-Chia Chuang and John T. O’Malley are employees of and may hold stock and/or stock options in Sanofi.

© 2022. The Author(s).

Figures

Fig. 1

LIBERTY AD PED-OLE study schematic. a36 patients enrolled from R668-AD-1412 phase IIa study; five patients received only the weight-based dose regimen and were excluded, 31 patients from R668-AD-1412 were analyzed. bPatients enrolled from R668-AD-1412 switched from weight-based dosing to 300 mg q4w at the time of protocol amendment, with uptitration after inadequate response, whereas all patients enrolled from R668-AD-1526 and R668-AD-1607 started directly on the q4w or q2w regimen. cUptitration to 200 mg (body weight < 60 kg) or 300 mg (body weight ≥ 60 kg) q2w at week 16 upon inadequate clinical response, or prior to week 16 if deemed necessary by the investigator. AD atopic dermatitis, OLE open-label extension, qw weekly, q2w every 2 weeks, q4w every 4 weeks, sBLA supplemental Biologics License Application

Fig. 2

Patient disposition. aAlthough 102 patients completed the week 52 visit, partial data (e.g., IGA data) were available for a further single patient who was not formally considered to have completed 52 weeks; IGA data for 103 patients have been included in the efficacy analyses. IGA Investigator’s Global Assessment

Fig. 3

Efficacy outcomes from PSBL through week 52. aProportion of patients achieving (a) IGA 0/1 or (b) EASI-75, mean % change from BL through week 52 in (c) EASI, (d) total SCORAD, and (e) BSA affected, and (f) proportion of patients with ≥ 6-point improvement in CDLQIb from BL. a102 patients completed the week 52 visit at the time of database lock. Partial data (e.g., IGA data) were available for a further single patient who was not formally considered to have completed 52 weeks; IGA data for 103 patients were included in the efficacy analyses. 101, 101, 81, and 44 patients had EASI, BSA, SCORAD, and CDLQI assessment, respectively, at week 52. SCORAD data were not collected in R668-AD-1607. CDLQI data were not collected in R668-AD-1412 and R668-AD-1607. bIn adolescents with moderate-to-severe AD, a within-patient change of 6–8 points in CDLQI is considered to be a minimum clinically meaningful difference. AD atopic dermatitis, BL baseline, BSA body surface area, CDLQI Children’s Dermatology Life Quality Index (range 0–30), EASI Eczema Area and Severity Index, EASI-75, patients achieving a ≥ 75% reduction in EASI compared with PSBL, IGA Investigator’s Global Assessment, PSBL parent study baseline, SCORAD SCORing Atopic Dermatitis, SD standard deviation

Fig. 4

Efficacy outcomes from PSBL through week 52 by patient baseline weight. Proportion of patients achieving (a) IGA 0/1 or (b) EASI-75, and (c) mean % change in EASI. BL baseline, EASI Eczema Area and Severity Index, EASI-75 patients achieving a ≥ 75% reduction in EASI compared with PSBL, IGA Investigator’s Global Assessment, PSBL parent study baseline, SD standard deviation

Fig. 5

Proportion of uptitrated patients achieving (a) IGA 0/1 or (b) EASI-75, and (c) mean % change in EASI from PSBL in uptitrated patients. BL baseline, EASI Eczema Area and Severity Index, EASI-75 patients achieving a ≥ 75% reduction in EASI from PSBL, IGA Investigator’s Global Assessment, PSBL parent study baseline, SD standard deviation, U time of uptitration

Fig. 6

IGA assessment for the 11a patients who relapsed and were re-initiated on dupilumabb. a17 patients relapsed and were re-initiated on dupilumab; the data in the figure are presented for the 11 for whom another IGA assessment was performed subsequent to re-initiation. bThe blue segment depicts the period from baseline to the last dupilumab treatment before recording IGA 0/1 sustained over 12 weeks; the orange segment depicts the period from the last dupilumab treatment before achieving IGA 0/1 sustained over 12 weeks to dupilumab re-initiation; the green segment depicts the period from dupilumab re-initiation to the last IGA assessment. IGA Investigator’s Global Assessment

Fig. 7

Mean (± standard deviation) concentrations of functional dupilumab in serum at weeks 0, 16, and 52. Concentrations below the lower limit of quantification were set to 0. Patients from parent studies R668-AD-1526 or R668-AD-1607 are shown. Patients may have been eligible for uptitration during the study. Treatment group was defined by the initially administered dose in study R668-AD-1434 at week 0 and by the last dose received prior to sample collection for subsequent visits. NA not applicable, q2w every 2 weeks, q4w every 4 weeks