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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)

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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 98 atopic dermatitis treated with the approved dupilumab dose regimen? (MP4 40,966 KB).
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moderate-to-severe atopic dermatitis : results through week 52 from a phase III open-label
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Blauvelt, A., Guttman-Yassky, E., Paller, A.S. et al. (13 more authors) (2022) 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). American Journal of Clinical Dermatology, 23 (3). pp. 365-383. ISSN 1175-0561
https://doi.org/10.1007/s40257-022-00683-2
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American Journal of Clinical Dermatology (2022) 23:365–383
https://doi.org/10.1007/s40257-022-00683-2
ORIGINAL RESEARCH ARTICLE
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)
AndrewBlauvelt1· EmmaGuttman‑Yassky2,3· AmyS.Paller4,5· EricL.Simpson6· MichaelJ.Cork7,8·
JamieWeisman9· JohnBrowning10· WeilySoong11· XianSun12· ZhenChen12· MatthewP.Kosloski12·
MohamedA.Kamal12· DimittriDelevry12· Chien‑ChiaChuang13· JohnT.O’Malley13· AshishBansal12
Accepted: 7 March 2022 / Published online: 14 May 2022
© The Author(s) 2022, corrected publication [2022]
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, effi-
cacy, 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% improve-
ment 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 accept-
able 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.
Extended author information available on the last page of the article
366 A.Blauvelt et al.
Infographic
367Long-Term Efficacy and Safety of Dupilumab in Adolescents
Key Points
For adolescent patients with uncontrolled atopic derma-
titis (AD), short-term dupilumab treatment is efficacious
with an acceptable safety profile. However, long-term
safety and efficacy data for the approved dose regimen of
dupilumab in adolescents with AD are limited.
In this long-term open-label extension study, dupilumab
treatment every 4weeks, or uptitrated to a weight-tiered
dose regimen every 2weeks, for up to 52weeks showed
an acceptable safety profile and provided sustained and
substantial clinical benefits in AD signs and symptoms
as well as improvements in quality of life.
Most patients required uptitration of dupilumab dosing
during the study from every 4weeks to the approved
dose regimen in adolescent patients of every 2weeks.
The results also support continued use of dupilumab to
maintain efficacy, since most responding patients who
stopped medication experienced disease recurrence.
1 Introduction
Atopic dermatitis (AD) is a common chronic inflammatory
skin condition that has a substantial negative impact on the
health-related quality of life of patients. AD is characterized
by intense pruritus, disruption of skin barrier function, and
type 2 inflammation [1]. The prevalence of AD in adoles-
cents is estimated to be up to 24.6% [2, 3]. A substantial
proportion of adolescents have persistent disease [4], and
patients with higher severity of disease have been shown to
have lower rates of remission [5].
Until recently, adolescents with AD inadequately con-
trolled by topical therapies had limited treatment options.
Although systemic immunosuppressive agents are
sometimes used off label for severe AD refractory to topi-
cal therapy, the use of some of these agents, such as cyclo-
sporine, methotrexate, azathioprine, and mycophenolate
mofetil, especially in the long term, is associated with a risk
of infections, malignancies, and/or hepatic, renal, and hema-
tologic toxicities [68]. There are currently no peer-reviewed
published studies reporting long-term data on any systemic
therapy other than dupilumab for children or adolescents
with AD.
Dupilumab is a fully human VelocImmune®-derived [9,
10] monoclonal antibody that blocks interleukin (IL)-4Rα,
the shared receptor component for IL-4 and IL-13, inhibit-
ing signaling of both IL-4 and IL-13 [11, 12], which are
central and key drivers of AD and other type 2-mediated
diseases [11, 13]. Dupilumab is approved for patients with
AD, asthma, and chronic rhinosinusitis with nasal polyps
[14, 15]. The approved dupilumab dose regimen for ado-
lescents with AD is an initial dose of 400mg (for body
weight < 60kg) or 600mg (for body weight ≥ 60kg) fol-
lowed by 200mg (for body weight < 60kg) or 300mg (for
body weight ≥ 60kg) every 2weeks (q2w) [16].
Dupilumab has demonstrated significant efficacy and an
acceptable safety profile in patients with type 2 inflamma-
tory diseases [1726]. In the randomized, double-blinded,
placebo-controlled, phase III LIBERTY AD ADOL study
in adolescent patients (aged ≥ 12 to < 18years) with mod-
erate-to-severe AD, 16weeks of treatment with dupilumab
resulted in significant improvements in AD signs, symp-
toms, and quality of life compared with placebo, with an
acceptable safety profile [27]. Another analysis of a small
subset of adolescents who received dupilumab 2 or 4mg/kg
every week (qw) in a phase IIa study, and continued in an
open-label extension (OLE) study, showed early improve-
ment in signs and symptoms, with results maintained for up
to a year of therapy [28]. However, long-term data on the
approved dose regimen of dupilumab for adolescents with
AD are currently lacking. Data are also lacking on whether
the continuous use of dupilumab over a long period can
lead to sustained clear or almost clear skin (Investigator’s
Plain Language Summary
Atopic dermatitis, or eczema, is a common chronic skin disease that can cause intense and persistent itching and rashes.
Atopic dermatitis remains a problem for many adolescent patients, even if they use a number of different treatments.
Dupilumab is a newer treatment for atopic dermatitis. In short-term clinical studies, dupilumab improved the disease with
acceptable safety. In this study, adolescents with moderate-to-severe atopic dermatitis who had completed one of the short-
term studies continued dupilumab treatment for 1year. The patients started treatment with dupilumab once every 4weeks.
But if their atopic dermatitis did not improve sufficiently, they were given dupilumab every 2weeks. Through a year of
treatment, there were no unexpected side effects. The side effects that did occur were mild or moderate in severity and in
most cases did not lead to interruption of treatment. Almost half of the patients achieved skin that was clear or almost clear
of atopic dermatitis during the study. But their atopic dermatitis often returned if they stopped being treated, and about half
of them needed to start treatment again. Most patients needed to be treated every 2weeks. The positive effects of dupilumab
generally increased the longer patients were treated.
368 A.Blauvelt et al.
Global Assessment [IGA] score of 0 or 1) in adolescents
with AD.
The objective of this OLE study (LIBERTY AD PED-
OLE, NCT02612454) was to report the long-term safety
and efficacy, and pharmacokinetic profile, of dupilumab
in adolescents (aged ≥ 12 to < 18years) with moderate-to-
severe AD who had previously participated in dupilumab
trials and were subsequently enrolled in the LIBERTY AD
PED-OLE study. This analysis includes data for patients who
were initiated on dupilumab every 4weeks (q4w) and then
uptitrated to the weight-tiered q2w dose regimen, currently
approved to treat adolescents with moderate-to-severe AD,
which examined whether uptitration to the q2w regimen pro-
vided additional benefit to patients who did not respond to
the q4w regimen. Data on achievement of IGA 0/1, relapse,
and re-initiation of therapy in adolescent patients treated
with dupilumab for over 1year are also presented.
2 Methods
2.1 Study Design
LIBERTY AD PED-OLE is an ongoing OLE study in
patients aged ≥ 6months to < 18years with moderate-to-
severe AD who participated in dupilumab parent studies.
Results are presented for the cohort aged ≥ 12 to < 18years
from the study, with a data cutoff date of December 15,
2018. Previous studies (referred to as “parent studies” in
this manuscript) for this age cohort were the phase IIa study
R668-AD-1412 (NCT02407756) [28], the phase III study
LIBERTY AD ADOL (R668-AD-1526; NCT03054428)
[27], and the phase Ib R668-AD-1607 study (NCT03050151)
[29] (Fig.1).
In LIBERTY AD PED-OLE, adolescent patients with
moderate-to-severe AD who had previously participated
in dupilumab trials received dupilumab 300mg q4w, but
could be uptitrated to 200mg (for body weight < 60kg)
or 300mg (for body weight ≥ 60kg) q2w at week 16 upon
inadequate clinical response, or prior to week 16 if deemed
necessary by the investigator. The dupilumab 200/300mg
q2w weight-tiered dose regimen was intended to match the
exposure in adults receiving the approved 300mg q2w regi-
men. Adolescent patients from study R668-AD-1412 were
initially assigned to receive dupilumab 2 or 4mg/kg qw but
were switched to the q4w regimen with optional uptitra-
tion to q2w following a protocol amendment. At the time
the q4w regimen and uptitration to weight-tiered q2w regi-
mens were introduced in this study, both were under evalu-
ation for adolescents participating in LIBERTY AD ADOL.
Inadequate clinical response was defined as not having an
IGA score of 0/1 (clear/almost clear skin) during at least
16weeks from the date of initiation of treatment with the
300mg q4w regimen.
The full study designs of the parent studies
R668-AD-1412 and LIBERTY AD ADOL have been pre-
viously reported [27, 28]. Briefly, R668-AD-1412 [28] was
a phase IIa, multicenter, open-label, ascending-dose, sequen-
tial cohort study in 40 adolescents (aged ≥ 12 to < 18years)
with moderate-to-severe AD. It was conducted at multiple
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. cUp-
titration 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 derma-
titis, OLE open-label extension, qw weekly, q2w every 2 weeks, q4w
every 4 weeks, sBLA supplemental Biologics License Application
369Long-Term Efficacy and Safety of Dupilumab in Adolescents
centers in Europe (Czech Republic, Hungary, Germany,
Poland, the UK) and Canada. The study design consisted
of a screening period, a baseline visit, and two treatment
phases. In the first treatment phase, patients received a single
dose of dupilumab (2 or 4mg/kg) followed by an 8-week
sampling period for pharmacokinetic measurements. The
second phase consisted of the same dupilumab dose qw for
4weeks followed by an 8-week safety follow-up period.
Patients were then eligible to enroll in an OLE study.
LIBERTY AD ADOL (R668-AD-1526) [27] was a rand-
omized, double-blinded, placebo-controlled, parallel-group
phase III trial conducted at 45 centers in the USA and Can-
ada. A total of 251 adolescents (aged 12 to < 18years) with
moderate-to-severe AD that was inadequately controlled
with topical therapies, or for whom topical therapy was
inadvisable, were randomized (1:1:1) to receive 16weeks
of monotherapy treatment with subcutaneous dupilumab
300mg q4w, dupilumab 200/300mg q2w (200mg for
patient baseline body weight < 60kg; 300mg for baseline
bodyweight 60kg), or placebo. Following the 16-week
treatment period, patients were eligible to enter an OLE
study.
R668-AD-1607 [29] was a multicenter phase Ib study
aiming to collect actual-use data concerning the technical
performance and user interactions of the dupilumab auto-
injector device when used by patients or caregivers. Other
outcomes included safety, efficacy, and systemic exposure of
dupilumab administered using the autoinjector device ver-
sus prefilled syringe. Included patients were aged ≥ 12years
with moderate-to-severe AD inadequately controlled with
topical medications or for whom topical treatment was medi-
cally inadvisable. The study was conducted in two parts.
In part A, patients were randomized to receive subcutane-
ous dupilumab 200mg q2w using an autoinjector device
or prefilled syringe for 12weeks. When part A was fully
enrolled, in part B patients were randomized to receive sub-
cutaneous dupilumab 300 mg q2w using an autoinjector
device or prefilled syringe for 12weeks. In part A and part
B, patients were followed-up for a 12-week post-treatment
period. Patients were then eligible to enroll in an OLE study.
LIBERTY AD PED-OLE consisted of a screening period
(day − 28 to day − 1) between exit from the parent study and
entry into the OLE study, a treatment period that lasted until
regulatory approval of the product for the age group of the
patient in their geographic region, and a 12-week follow-up
period.
2.2 Main Inclusion andExclusion Criteria
Adolescents (aged 12 to < 18years at time of screening
for the OLE study) with moderate-to-severe AD were eli-
gible for inclusion in LIBERTY AD PED-OLE if they had
participated in a previous dupilumab trial and completed
all visits/assessments (for R668-AD-1412) or at least 50%
of visits and assessments (for LIBERTY AD ADOL and
R668-AD-1607). Patients from the placebo arm of the LIB-
ERTY AD ADOL trial were also allowed to participate in
LIBERTY AD PED-OLE.
Patients who had a serious adverse event (SAE) dur-
ing the parent study deemed related to the study drug, or
an adverse event (AE) related to the study drug that led to
discontinuation from the parent study, were excluded from
the OLE. See Appendix S1 in the electronic supplementary
material (ESM) for full eligibility criteria.
2.3 Treatment
According to the original LIBERTY AD PED-OLE study
protocol, patients received subcutaneous dupilumab
according to a weight-based regimen of 2 or 4mg/kg
qw. Once pharmacokinetic data from the phase II study
R668-AD-1412 became available for adolescents, the pro-
tocol was amended in the third quarter of 2017 (protocol
version R668-AD-1434.01), and patients were switched to a
regimen of dupilumab 300mg q4w. Patients enrolled in LIB-
ERTY AD PED-OLE after implementation of the amended
protocol were started directly on subcutaneous dupilumab
300mg q4w.
Patients with an inadequate clinical response to the
300 mg q4w regimen at week 16 (or 16 weeks after
switching, for patients on the original weight-based regi-
men), defined as not having an IGA score of 0/1, could be
uptitrated at the investigator’s discretion to a regimen of
dupilumab 200mg q2w (for patient body weight < 60kg)
or 300mg q2w (for patient body weight ≥ 60kg). Patients
could also be uptitrated prior to week 16 if the patient had an
IGA score of 3/4 and the investigator felt the patient needed
rescue treatment. Patients who had been uptitrated continued
on this regimen for the remainder of the study.
During the study, the use of concomitant topical corticos-
teroids and topical calcineurin inhibitors was allowed with-
out restriction, and topical crisaborole was also permitted
if approved locally for treatment of AD. However, systemic
medications for AD, including corticosteroids and nonsteroi-
dal immunosuppressants, were not permitted except as res-
cue treatment. Concomitant use of topical corticosteroids or
other AD therapies was not standardized.
Patients who had sustained remission from AD, defined
as continuous maintenance of an IGA score of 0/1 for a
12-week period after week 40, were discontinued from
dupilumab (e.g., a patient who had an IGA score of 0/1
from week 40 through week 52, inclusive, was discontinued
from study drug at week 52; similarly, a patient who had
an IGA score 0/1 from week 52 through week 64, inclu-
sive, was discontinued from study drug at week 64, etc.).
Disease activity was closely monitored in these patients
370 A.Blauvelt et al.
during the remaining study visits, and treatment with study
drug was re-initiated in patients who experienced a relapse
of disease (IGA score ≥ 2). In these cases, investigators
were encouraged to consider treatment with topical therapy
(e.g., medium potency topical corticosteroids) and to re-
initiate dupilumab only for patients who did not experience
adequate response after at least 7days of topical treatment.
Such patients were re-initiated (without a loading dose) on
the same dose regimen of dupilumab that they were on at
the time of discontinuation.
Patients who turned 18years of age during the study
and were located in a geographic region where the drug is
commercially available for the treatment of AD in adults
were treated with study drug only until the date of their 18th
birthday. These patients had an end-of-treatment visit after
their 18th birthday, followed by an end-of-study visit after
12weeks.
2.4 Outcomes
The primary outcomes of LIBERTY AD PED-OLE were the
incidence and rate (patients per 100 patient-years [100PY]
and/or events per 100PY) of treatment-emergent AEs
(TEAEs) through the last study visit.
Key secondary outcomes were incidence and rate
(patients and/or events per 100PY) of treatment-emergent
SAEs and incidence and rate (patients and/or events per
100PY) of TEAEs of special interest, such as anaphylac-
tic reactions, systemic or severe hypersensitivity reactions,
malignancies, helminthic infections, suicide-related events,
any type of (severe or serious) conjunctivitis or blepharitis,
and keratitis.
Other secondary outcomes included proportion of
patients with an IGA score of 0/1 (clear/almost clear) by
visit through week 52; proportion of patients with Eczema
Area and Severity Index (EASI)-75 (≥ 75% reduction in
EASI from baseline of parent study) by visit through week
52; percentage change from parent study baseline in EASI
and according to SCORing Atopic Dermatitis (SCORAD)
by visit through week 52; mean change in absolute EASI by
visit through week 52; change from parent study baseline in
body surface area (BSA) affected and EASI by visit through
week 52; change from parent study baseline in Children's
Dermatology Life Quality Index (CDLQI) by visit through
week 52; proportion of patients achieving EASI-50/-75/-90
(≥ 50%/≥ 75%/≥ 90% reduction, respectively, in EASI from
parent study baseline) by visit through week 52; and assess-
ment of trough concentrations of functional dupilumab in
serum after treatment with dupilumab. Post hoc analyses
were performed to evaluate the proportion of patients with
IGA 0/1 sustained over 12weeks at week 52; time to re-
initiation of dupilumab therapy following relapse after first
sustained achievement of IGA 0/1; and number of patients
regaining IGA 0/1 following treatment re-initiation. Data on
Peak Pruritus Numerical Rating Scale have been reported
in the phase II and III parent studies and for patients on 2
or 4mg/kg qw dose regimens in the current study [27, 28];
Peak Pruritus Numerical Rating Scale was not assessed in
the OLE with the dupilumab q4w or q2w dose regimens. The
proportion of patients achieving a ≥ 6-point improvement
in CDLQI was also evaluated. The improvement threshold
for CDLQI was based on the published minimal clinically
important difference in the adolescent AD population [30].
The proportion of patients who required uptitration from the
q4w to the q2w regimen was also evaluated. Furthermore,
in patients uptitrated to the q2w regimen, the efficacy of
dupilumab was evaluated according to key outcome meas-
ures such as achievement of IGA 0/1 or EASI-75 and mean
percentage change in EASI from time of uptitration.
2.5 Analyses
Based on the numbers of patients enrolled in or screened for
the parent dupilumab studies, it was anticipated that approxi-
mately 300 adolescent patients would be enrolled in this
OLE study. No formal sample size was estimated or power
calculations performed for this study.
The safety analysis set included all patients who received
one or more dose of dupilumab 300mg q4w. Efficacy and
all clinical safety variables were analyzed using the safety
analysis set. Patients who were uptitrated were analyzed
according to this regimen. All safety data were included
from the baseline of the OLE up to the database lock. For
patients enrolled from the R668-AD-1412 study, the 1-year
safety and efficacy data for the weight-based regimen of 2 or
4mg/kg qw have been previously reported [28]. This manu-
script includes longitudinal data for a dose of dupilumab
300mg q4w or from patients uptitrated to the approved
weight-tiered dose of dupilumab 200/300mg q2w for the
same patients from R668-AD-1412 and the data for patients
enrolled from the R668-AD-1526 and R668-AD-1607 par-
ent studies. For the evaluation of conjunctivitis, grouped
Medical Dictionary for Regulatory Activities (MedDRA)
Preferred Terms (PT) consistent with conjunctivitis and
selected eye disorder terms were selected for further analy-
sis. A compiled term was used, including all PTs contain-
ing the word “conjunctivitis” (conjunctivitis, conjunctivitis
allergic, conjunctivitis bacterial, conjunctivitis viral, and
atopic keratoconjunctivitis).
Efficacy outcomes were analyzed descriptively among
patients with available values at each visit (e.g., outcomes at
week 16 were evaluated among patients with data available
at the week 16 visit, etc.). All observed values were used for
analysis, regardless of whether rescue treatment was used or
data were collected after withdrawal from study treatment.
No missing values were imputed.
371Long-Term Efficacy and Safety of Dupilumab in Adolescents
The pharmacokinetic analysis included all patients
assigned to dupilumab 300mg q4w at the start of the study
and who had one or more non-missing drug concentration
result following the first dose of study drug; the pharmacoki-
netics of dupilumab in patients from R668-AD-1412 initially
assigned to 2 or 4mg/kg qw were previously reported, and
these patients were excluded. Blood samples for determi-
nation of trough concentrations of functional dupilumab in
serum (Ctrough) were collected prior to dosing at baseline,
week 16, and week 52. Treatment groups for each time point
correspond to the initially assigned treatment regimen (base-
line) or the previously administered dose (weeks 16 and 52).
For continuous variables, descriptive statistics included
the following: the number of patients reflected in the calcula-
tion (n), mean, median, Q1 (25th percentile), Q3 (75th per-
centile), standard deviation (SD), minimum, and maximum.
For categorical or ordinal data, frequencies and percentages
are displayed for each category. No formal statistical hypoth-
eses were tested.
2.6 Compliance withEthical Standards
LIBERTY AD PED-OLE and the parent studies [2729]
were conducted in accordance with the ethical principles
outlined in the Declaration of Helsinki and with the Inter-
national Council for Harmonisation guidelines for good
clinical practice and applicable regulatory requirements.
All patients provided written consent/assent, and at least
one parent or guardian for each adolescent patient provided
written informed consent. At each study site, the proto-
col, informed consent form, and patient information were
approved by an institutional review board and independent
ethics committee.
3 Results
Of the 304 patients screened, five patients did not meet the
inclusion criteria (Fig.2). At the time of the database lock,
299 patients had been enrolled in LIBERTY AD PED-
OLE and were included in the safety analysis set (36 from
R668-AD-1412, 38 from R668-AD-1607, and 225 from
LIBERTY AD ADOL). Of the 36 patients enrolled from
R668-AD-1412, five patients received only the weight-
based dose regimen and were therefore not included in this
analysis. A total of 294 patients were analyzed. Of the 294
patients, 102 (34.7%) had completed the 52-week visit at the
time of the database lock, 43 (14.6%) patients had discontin-
ued the study prematurely, and 253 patients were continuing
therapy. The most common reasons for study discontinua-
tion were withdrawal by the patient (n = 17; 5.8%), lack of
efficacy (n = 11; 3.7%), and the patient turning 18 years of
age (n = 10; 3.4%).
3.1 Patient Baseline Demographics andClinical
Characteristics
The mean age of the patients was 14.7years, and the major-
ity were White (69.0%) and male (56.8%), but the study
population included representation from other ethnici-
ties (Table1). Consistent with what has been previously
reported in the literature, a high proportion of enrolled
patients (41.2%) were overweight (body mass index ≥ 85th
percentile for age and sex). The majority of patients had
moderate-to-severe disease at baseline, with 47.3% having
IGA 3 and 24.8% having IGA 4 (Table1). This was likely
a reflection of the treatment interruption (28-day screening
period) between the parent study and the OLE study and the
inclusion of patients from the placebo arm of LIBERTY AD
ADOL. Additionally, all patients (100%) had one or more
comorbid allergic conditions at baseline, reflecting the high
type 2 burden of disease in this adolescent patient popula-
tion. Most patients (61.9%) had received one or more prior
systemic immunosuppressive medications for AD besides
dupilumab, reflecting the high unmet medical need in this
population.
3.2 Safety Assessment
The safety data for the 294 included patients are presented
from the baseline of the OLE up to the database lock. The
majority (73.8%) of patients reported one or more TEAE,
most of which were mild or moderate (Table2) and tran-
sient in duration. Of the 1131 TEAEs reported (370.2 events
per 100PY), 120 (39.3 events per 100PY) were consid-
ered related to treatment, 12 (3.9 events per 100PY) were
severe, and five (1.6 events per 100PY) were serious: one
event each of patent ductus arteriosus, injection-site edema,
food allergy, herpes simplex infection, and ankle fracture
(TableS1 in the ESM). All serious TEAEs resolved over
time, and none led to treatment discontinuation. Two adverse
events (0.7 events per 100PY) led to treatment discontinu-
ations (one event of moderate bilateral conjunctivitis [see
Appendix S2 in the ESM for a patient narrative] and one
event of moderate worsening of AD) (TableS2 in the ESM).
Six TEAEs of special interest were reported: one event (0.3
events per 100PY) each of severe viral conjunctivitis, severe
allergic conjunctivitis, mild atopic keratoconjunctivitis, mild
suicidal ideation, moderate depression, and moderate aller-
gic reaction to egg (TableS3 in the ESM).
The most frequently reported TEAEs were nasophar-
yngitis (20.4%; 23.6 patients per 100PY), AD (19.0%;
21.3 patients per 100PY), upper respiratory tract infection
(11.9%; 12.5 patients per 100PY), and headache (8.8%; 9.3
patients per 100PY). Injection-site reactions were reported
in 19 patients (6.5%; 6.6 patients per 100PY), and conjunc-
tivitis (according to descriptions given by the investigators)
372 A.Blauvelt et al.
was reported in 26 patients (8.8%; 9.2 patients per 100PY),
including conjunctivitis (12 patients; 4.1%), bacterial con-
junctivitis (six patients; 2.0%), viral conjunctivitis (two
patients; 0.7%), allergic conjunctivitis (11 patients; 3.7%),
and atopic keratoconjunctivitis (one patient; 0.3%). Herpes-
virus infections (MedDRA high-level term) were reported
in 18 patients (6.1%; 6.3 events per 100PY) (TableS4 in the
ESM). Further details of skin infections and conjunctivitis
are presented in Tables S4 and S5 in the ESM, respectively.
3.3 Efficacy Outcomes
Efficacy data for the 294 patients included in the analysis are
presented from the baseline of the parent study up to week
52 of treatment on the regimen of dupilumab 300mg q4w or
uptitrated to weight-tiered dupilumab q2w in the OLE. Clin-
ical signs showed substantial improvement over time. The
proportions of patients with an IGA score of 0/1 (Fig.3a)
or EASI-75 (Fig.3b) increased from parent study baseline
through week 52. By week 52, 42.7% of patients (44/103)
had an IGA score of 0/1, and 93.1%, 81.2%, and 56.4% of
patients had EASI-50, EASI-75, and EASI-90, respectively
(Table3). Additionally, 86.4% of patients had at least mild
disease (IGA ≤ 2) (Fig. S1a in the ESM).
The mean percent changes in EASI (Fig.3c) and SCO-
RAD (Fig.3d) showed substantial improvement from
the parent study baseline through week 52, with mean
percent ± SD change of − 83.5% ± 23.5 in EASI and
65.0% ± 21.3 in SCORAD at week 52 (Table3). At week
52, the mean EASI was 5.3, with a mean change from par-
ent study baseline of − 28.5 (Fig. S1b and S1c in the ESM).
The percentage of BSA affected decreased from the parent
study baseline through week 52 (Fig.3e), with a mean ±
SD change in percentage of BSA affected of − 42.7 ± 26.2
at week 52 (Table3).
Patients also showed improvement in health-related qual-
ity of life, with 86.4% having a ≥ 6-point improvement in
CDLQI by week 52; many experienced this improvement
as early as week 4 (Fig.3f). The mean ± SD change from
Fig. 2 Patient disposition. aAl-
though 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 analy-
ses. IGA Investigator’s Global
Assessment
373Long-Term Efficacy and Safety of Dupilumab in Adolescents
Table 1 Patient demographics and clinical characteristics at baseline of the open-label extension
Data are presented as n (%) or mean ± standard deviation unless otherwise indicated
AD atopic dermatitis, BMI body mass index, BSA body surface area, CDLQI Children’s Dermatology Life Quality Index, EASI Eczema Area and
Severity Index, IGA Investigator’s Global Assessment, SCORAD SCORing Atopic Dermatitis
Characteristic All patients (N = 294)
Age, years 14.7 ± 1.7
Sex, male 167 (56.8)
Race
White 203 (69.0)
Black or African American 30 (10.2)
Asian 42 (14.3)
American Indian or Alaska Native 2 (0.7)
Native Hawaiian or other Pacific Islander 5 (1.7)
Other 8 (2.7)
Not reported 4 (1.4)
Ethnicity
Not Hispanic or Latino 242 (82.3)
Hispanic or Latino 52 (17.7)
Weight, kg 64.8 ± 20.2
Weight group, kg
< 60 146 (49.7)
≥ 60 148 (50.3)
BMI, kg/m224.1 ± 6.0
BMI ≥ 85th percentile of population 121 (41.2)
Duration of AD, years 12.5 ± 3.2
IGA
0 4 (1.4)
1 23 (7.8)
2 55 (18.7)
3 139 (47.3)
4 73 (24.8)
EASI 19.9 ± 15.6
BSA affected by AD 34.1 ± 25.3
SCORAD 46.7 ± 21.3
CDLQI 7.0 ± 6.1
Patients with ongoing or history of allergic/atopic conditions 294 (100)
Allergic rhinitis 185 (62.9)
Food allergy 171 (58.2)
Asthma 147 (50.0)
Hives 72 (24.5)
Allergic conjunctivitis 65 (22.1)
Chronic rhinosinusitis 16 (5.4)
Nasal polyps 5 (1.7)
Aspirin sensitivity 4 (1.4)
Eosinophilic esophagitis 1 (0.3)
Other allergies 200 (68.0)
Patients receiving prior systemic medications for AD 182 (61.9)
Patients receiving prior systemic corticosteroids 124 (42.2)
Patients receiving prior systemic nonsteroidal immunosuppressants 138 (46.9)
Cyclosporine 71 (24.1)
Methotrexate 43 (14.6)
Mycophenolate mofetil 10 (3.4)
Azathioprine 7 (2.4)
374 A.Blauvelt et al.
parent study baseline in CDLQI was − 11.8 ± 6.7 at week
52 (Table3).
Patients showed clinical improvement regardless of base-
line body weight. In particular, the increase from parent
study baseline through week 52 in the proportion of patients
achieving IGA 0/1 (36.5 and 49.0% for baseline body weight
< 60 or ≥ 60kg, respectively) and EASI-75 (86.0 and 76.5%,
respectively), and the improvements in EASI (mean percent
change from baseline − 87.0 and − 80.1%, respectively),
were similar irrespective of patient baseline body weight
(Fig.4).
At the time of database lock, of the 294 patients included
in the analysis, 289 had received dupilumab q4w or q2w
regimens for at least 16 weeks in the OLE. During the course
of treatment, 70.9% (205/289) of patients required uptitra-
tion (36.3% prior to week 16, and 34.6% after week 16), with
Table 2 Safety assessment
ESM electronic supplementary material, HLT MedDRA high-level term, MedDRA Medical Dictionary for Regulatory Activities, nE number
of events, nP number of patients, PT MedDRA preferred term; 100PY 100 patient-years, SOC system organ class, TEAE treatment-emergent
adverse event
a Conjunctivitis cluster includes conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, allergic conjunctivitis, and atopic keratoconjunctivi-
tis; further details of conjunctivitis are presented in TableS4 in the ESM
b Further details of skin infections are presented in TableS5 in the ESM
TEAEs All patients (N = 294)
nE nE/100PY
Total number of TEAEs 1131 370.2
Total number of serious TEAEs 5 1.6
Total number of severe TEAEs 12 3.9
Total number of TEAEs related to treatment 120 39.3
Total number of TEAEs related to permanent treatment discontinuation 2 0.7
n (%) nP/100PY
Patients with any TEAE 217 (73.8) 194.6
Patients with any serious TEAE 5 (1.7) 1.7
Patients with any severe TEAE 11 (3.7) 3.8
Patients with any TEAEs related to treatment 53 (18.0) 20.2
Patients with any TEAEs leading to permanent discontinuation 2 (0.7) 0.7
Conjunctivitis clustera26 (8.8) 9.2
Injection-site reactions (HLT) 19 (6.5) 6.6
Skin infections and infestations (SOC)b37 (12.6) 13.9
Most common TEAEs reported in ≥3% of patients (PT)
Nasopharyngitis 60 (20.4) 23.6
Dermatitis atopic 56 (19.0) 21.3
Upper respiratory tract infection 35 (11.9) 12.5
Headache 26 (8.8) 9.3
Oropharyngeal pain 16 (5.4) 5.6
Vomiting 13 (4.4) 4.5
Influenza 13 (4.4) 4.4
Oral herpes 12 (4.1) 4.2
Conjunctivitis 12 (4.1) 4.1
Pyrexia 12 (4.1) 4.1
Acne 11 (3.7) 3.8
Conjunctivitis allergic 11 (3.7) 3.7
Diarrhea 10 (3.4) 3.5
Abdominal pain upper 10 (3.4) 3.4
Cough 9 (3.1) 3.1
Sinusitis 9 (3.1) 3.0
Viral upper respiratory tract infection 9 (3.1) 3.0
375Long-Term Efficacy and Safety of Dupilumab in Adolescents
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 improve-
ment in CDLQIb from BL. a102 patients completed the week 52 visit
at the time of database lock. Partial data (e.g., IGA data) were avail-
able 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. SCO-
RAD 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 dif-
ference. 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
376 A.Blauvelt et al.
Table 3 Efficacy assessment at week 52
Data are presented as n/N1 (%) or mean ± standard deviation
AD atopic dermatitis, BSA body surface area, CDLQI Children’s Dermatology Life Quality Index, EASI Eczema Area and Severity Index, EASI-
50/-75/-90 patients achieving a ≥ 50%/≥ 75%/≥ 90% reduction in EASI compared with parent study baseline, IGA Investigator’s Global Assess-
ment, N1 patients with non-missing EASI or IGA scores at each week, SCORAD SCORing Atopic Dermatitis
Efficacy assessment All patients (N = 294)
Proportion of patients achieving IGA 0/1 44/103 (42.7)
Proportion of patients achieving EASI-50 94/101 (93.1)
Proportion of patients achieving EASI-75 82/101 (81.2)
Proportion of patients achieving EASI-90 57/101 (56.4)
Percentage change from baseline of parent study in EASI − 83.5 ± 23.5
Change from baseline of parent study in EASI − 28.5 ± 14.9
Change from baseline of parent study in % BSA affected by AD − 42.7 ± 26.2
Percentage change from baseline of parent study SCORAD − 65.0 ± 21.3
Change from baseline of parent study in CDLQI − 11.8 ± 6.7
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% reduc-
tion in EASI compared with PSBL, IGA Investigator’s Global Assess-
ment, PSBL parent study baseline, SD standard deviation
377Long-Term Efficacy and Safety of Dupilumab in Adolescents
a mean ± SD time to uptitration of 12.5 ± 9.8weeks (median
12.0 [Q1 4.0–Q3 16.0]weeks) (Table4). The proportion of
uptitrated patients with IGA 0/1 and the proportion with
EASI-75 increased over time from the point of uptitration
(Fig.5a, b), reaching 35.7 and 51.9%, respectively, 48 weeks
after first uptitration visit. The mean ± SD percentage change
in EASI from the parent study baseline showed substan-
tial improvement from the point of uptitration in uptitrated
patients, reaching − 84.3% ± 13.7 at 48 weeks after the first
uptitration visit (Fig.5c).
By week 52, 29.4% (30/102) of patients had clear/almost
clear skin (IGA 0/1) sustained over 12weeks (Table5). Of
these, 17 patients (56.7%) had experienced relapse at the
time of the data cutoff and were re-initiated on treatment.
The mean ± SD time to dupilumab re-initiation following
relapse after first record of IGA 0/1 sustained over 12weeks
was 17.5 ± 17.3weeks. Of the 11 patients who re-initiated
the drug, and for whom another IGA assessment was per-
formed following re-initiation, ten (90.9%) regained IGA 0/1
(Table5 and Fig.6).
3.4 Dupilumab Pharmacokinetic Profile
Mean trough concentrations of functional dupilumab in the
serum of patients assigned to the regimen of dupilumab
300mg q4w at the start of the study reached a steady state
of approximately 20mg/L by week 16, and this was main-
tained through week 52 in patients who continued to receive
dupilumab 300mg q4w. Mean concentrations were higher
in patients uptitrated to a 200/300mg q2w regimen at week
16 (55.3mg/L) and week 52 (75.9mg/L) (Fig.7).
4 Discussion
In adolescents aged ≥ 12 to < 18years with inadequately
controlled moderate-to-severe AD, dupilumab treatment
for up to 52weeks in the LIBERTY AD PED-OLE study
provided incremental and substantial clinical benefit in
AD signs and symptoms, as well as improvements in qual-
ity of life. This clinical benefit was achieved irrespective
of patient baseline body weight. A trend towards further
improvement in efficacy measures over time with continued
dupilumab treatment was seen, and patients who were upti-
trated because of inadequate responses with the dupilumab
q4w regimen were shown to subsequently achieve clinically
meaningful responses with the q2w regimen. A previous
analysis demonstrated the efficacy and safety of dupilumab
in a small number of adolescents who received either 2 or
4mg/kg qw [28]. The results from LIBERTY AD PED-
OLE reinforce the long-term results shown previously.
Importantly, the analysis presented here included data for
the treatment regimen approved for treating adolescents with
moderate-to-severe AD.
The long-term safety profile was consistent with the
results previously obtained in longitudinal studies in adult
patients with AD [31] and with the short-term profile seen
in previous phase III trials of dupilumab in adolescents with
moderate-to-severe AD [27]. Only two patients discontinued
because of a TEAE, including one patient with moderate
bilateral conjunctivitis and one patient with worsening AD.
Five serious TEAEs were reported during the course of the
study. The reported events of conjunctivitis were mainly
mild or moderate, and none were categorized as SAEs. One
case of severe allergic conjunctivitis and one case of severe
viral conjunctivitis were reported, neither of which led to
treatment discontinuation.
Table 4 Proportions of patients with uptitration
Data are presented as n/N1 (%) or mean ± standard deviation unless otherwise indicated
N1 number of patients who received q4w dose for at least 16weeks, q4w every 4weeks
a One patient uptitrated to 300mg every 2weeks directly from 2mg/kg every week without receiving a q4w dose. This patient was analyzed
based on the final dose
Patients with uptitration All patients (N = 294)
Number of patients who received at least one q4w dose 293a
Number of patients who received q4w dose for at least 16 weeks 289
Number of patients with uptitration 205/289 (70.9)
Number of patients with uptitration prior to week 16 105/289 (36.3)
Number of patients with uptitration at or after week 16 100/289 (34.6)
Time in weeks from start of q4w dose to first uptitration visit 12.5 ± 9.8
Median (Q1–Q3) 12.0 (4.0–16.0)
Minimum; maximum 2.0; 52.0
378 A.Blauvelt et al.
During the study, most adolescent patients (70.9%) were
uptitrated from the dupilumab q4w to the q2w dose regi-
men, according to the study protocol, when not recording an
IGA score of 0/1 after 16weeks of treatment with the q4w
dose regimen, or prior to week 16 at the discretion of the
investigator. Mean trough concentrations of dupilumab from
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
Table 5 Proportion of patients with Investigator’s Global Assessment 0/1 sustained over 12 weeks, time to re-initiation following relapse, and
efficacy upon re-initiation
Patients who maintained an IGA score of 0 or 1 continuously for a 12-week period after week 40 were discontinued from study drug (e.g., a
patient who had an IGA score of 0 or 1 from week 40 through week 52, inclusive, was discontinued from the study drug at week 52; similarly, a
patient who had an IGA score of 0 or 1 from week 52 through week 64, inclusive, was discontinued from study drug at week 64, and so on)
IGA Investigator’s Global Assessment, N1 patients who completed treatment up to week 52, N2 patients who achieved IGA 0/1 sustained over 12
weeks at week 52, N3 patients who re-initiated study drug treatment after relapse: only includes patients for whom another IGA assessment was
performed subsequent to re-initiation, SD standard deviation
Patients All patients (N = 294)
Proportion of patients with IGA 0/1 sustained over 12weeks at week 52, n/N1 (%) 30/102 (29.4)
Patients who re-initiated treatment after relapse, n/N2 (%) 17/30 (56.7)
Time in weeks to study drug re-initiation following relapse 17.5 ± 17.3
Minimum; maximum 2.0; 64.0
Patients regaining IGA 0/1 following re-initiation, n/N3 (%) 10/11 (90.9)
Time in weeks to achievement of IGA 0/1 following re-initiation, mean ± SD 20.7 ± 18.9
Minimum; maximum 3.7; 64.0
379Long-Term Efficacy and Safety of Dupilumab in Adolescents
weeks 16 to 52 were higher for adolescent patients receiving
dupilumab 200/300mg q2w than for those receiving 300mg
q4w and were consistent with mean steady-state concentra-
tions at week 16 in the pivotal phase III study of dupilumab
in adolescents with moderate-to-severe AD receiving
dupilumab 300mg q4w (19.8mg/L) or 200/300mg q2w
(54.5mg/L) [27]. Importantly, a substantial proportion of
patients who were nonresponders to the q4w regimen in
this study may have had suboptimal exposure to dupilumab
and achieved a response following uptitration to the q2w
regimen, suggesting that the approved q2w dose regimen is
optimal for adolescents in the corresponding weight groups.
Fig. 6 IGA assessment for the 11a patients who relapsed and were
re-initiated on dupilumabb. a17 patients relapsed and were re-ini-
tiated 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
380 A.Blauvelt et al.
During the follow-up period, the majority of patients with
IGA 0/1 sustained for a continuous 12-week period who
then discontinued dupilumab experienced disease recur-
rence, suggesting the need for continuous administration of
dupilumab. Importantly, our data suggest that dupilumab can
be re-initiated in the event of a treatment interruption, and
patients can again report IGA 0/1. Of note, 13 of 30 patients
(43%) did not relapse after stopping dupilumab, with a
median follow-up period of 18.0 weeks (Q1 12.0–Q3 18.0).
This intriguing finding may suggest a potential disease-mod-
ifying role of dupilumab in some pediatric patients with AD.
However, the data are limited in terms of both the number of
patients studied and the duration of follow-up. The limited
number of patients precludes further subgroup analyses to
determine demographic and baseline disease characteris-
tics that might be predictive of long-term remission without
need for further treatment in these patients. Furthermore,
pediatric patients with AD can outgrow their disease or go
into long-term disease remission with subsequent flare-ups.
Hence, it is not possible to comment, given the current study
design, on whether the lack of relapse in these patients was
because of spontaneous remission or disease modification
by dupilumab. More investigation with a larger number of
patients, including in younger pediatric age groups, and
longer follow-up are needed to further answer this question.
A key strength of this study is that the analyses are
based on long-term (up to 1year) treatment, including the
approved dose regimen of dupilumab in a large group of
patients, thus providing data relevant to clinicians manag-
ing AD in adolescents over time. Limitations include the
open-label, nonrandomized nature of the study. Patients
were included in the study from three different parent stud-
ies, introducing some heterogeneity into the OLE patient
population. Additionally, the concomitant use of topical
corticosteroids or other AD therapies was not standardized;
the efficacy data were presented as observed analysis and did
not account for potential confounding factors resulting from
additional AD therapies.
5 Conclusions
Dupilumab treatment demonstrated acceptable safety and
sustained efficacy in adolescents aged ≥ 12 to < 18years
with inadequately controlled moderate-to-severe AD. These
results support the long-term continuous use of dupilumab
in this patient population. Additionally, the need for uptitra-
tion in most patients during the course of the study to the
approved q2w regimen suggests that this regimen is opti-
mal for adolescent patients with AD. Finally, the dupilumab
long-term safety profile was comparable to that seen in
adults, with safety consistent with the known dupilumab
safety profile.
Supplementary Information The online version contains supplemen-
tary material available at https:// doi. org/ 10. 1007/ s40257- 022- 00683-2.
Acknowledgements The authors thank the patients and their fami-
lies for their participation in these studies, their colleagues for their
support, and Linda Williams (Regeneron Pharmaceuticals, Inc.), El-
Bdaoui Haddad, Adriana Mello, and Abby Gan (Sanofi Genzyme) for
their contributions.
Declarations
Funding This research was sponsored by Sanofi and Regeneron Phar-
maceuticals, Inc. (ClinicalTrials.gov identifier: NCT03345914). The
study sponsors participated in the study design; the collection, analysis,
and interpretation of the data; the writing of the report; and the deci-
sion to submit the article for publication. Medical writing/editorial
assistance was provided by Ekaterina Semenova, PhD, of Excerpta
Medica, funded by Sanofi Genzyme and Regeneron Pharmaceuticals,
Inc., according to the Good Publication Practice Guideline.
Conflict of interest Andrew Blauvelt is a scientific advisor and clini-
cal study investigator for AbbVie, Abcentra, Aligos, Almirall, Amgen,
Arcutis, Arena, Aslan, Athenex, Boehringer Ingelheim, Bristol Myers
Squibb, Dermavant, Eli Lilly and Company, Evommune, Forte, Gal-
derma, 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 Phar-
ma, Mitsubishi Tanabe, Novartis, Pfizer, Regeneron Pharmaceuticals,
Inc., and Sanofi; and has received grants paid to the institution from
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 stud-
ies 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
381Long-Term Efficacy and Safety of Dupilumab in Adolescents
AbbVie, Asana Biosciences, Celgene, Concert, Dermavant, Dermira,
DS Biopharma, Galderma, Glenmark, Innovaderm, LEO Pharma, No-
van, Novartis, Pfizer, Ralexar Therapeutics, and Regeneron Pharma-
ceuticals, 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 In-
gelheim, 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 mem-
ber for and/or received research grants from Astellas Pharma, Atopix,
Boots, Dermavant, Eli Lilly and Company, Galapagos, Galderma, Hy-
phens Pharma, Johnson & Johnson, Kymab, L’Oréal, LEO Pharma,
Menlo, Novartis, Oxagen, Perrigo (ACO Nordic), Pfizer, Procter &
Gamble, Reckitt Benckiser, Regeneron Pharmaceuticals, Inc., Sa-
nofi 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, GlaxoS-
mithKline, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Regeneron
Pharmaceuticals, Inc., and UCB. John Browning has been an investiga-
tor 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, Genen-
tech, GlaxoSmithKline, Glenmark, Innovaderm, LEO Pharma, Man-
dala, Menlo, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Re-
laxar, Sanofi, Symbio, Teva, and Vanda Pharmaceuticals; has received
speaker fees from AstraZeneca, GlaxoSmithKline, Optinose, Regener-
on 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 Regen-
eron Pharmaceuticals, Inc. Chien-Chia Chuang and John T. O’Malley
are employees of and may hold stock and/or stock options in Sanofi.
Data availability Qualified researchers may request access to study
documents (including the clinical study report, study protocol with
any amendments, blank case report form, and statistical analysis plan)
that support the methods and findings reported in this manuscript. Indi-
vidual anonymized participant data will be considered for sharing once
the indication has been approved by a regulatory body, if there is legal
authority to share the data and there is not a reasonable likelihood of
participant re-identification. Submit requests to https:// vivli. org.
Ethics approval The study was conducted following the ethical princi-
ples derived from the Declaration of Helsinki, the International Confer-
ence on Harmonisation guidelines, Good Clinical Practice, and local
applicable regulatory requirements. Written informed consent was
obtained from all patients and the patients’ parents/guardians prior to
commencement of any study treatment.
Consent to participate All patients provided written consent/assent,
and at least one parent or guardian for each adolescent patient provided
written informed consent. All people named in the Acknowledgements
section gave written permission to be named in the manuscript.
Consent for publication Not applicable.
Author contributions Andrew Blauvelt and Ashish Bansal contributed
to the study concept and design. Andrew Blauvelt, Emma Guttman-
Yassky, Amy S. Paller, Eric L. Simpson, Michael J. Cork, Jamie Weis-
man, John Browning, and Weily Soong acquired data. Xian Sun and
Zhen Chen conducted the statistical analyses of the data. All authors
interpreted the data, provided critical feedback on the manuscript,
approved the final manuscript for submission, and are accountable for
the accuracy and integrity of the manuscript.
Open Access This article is licensed under a Creative Commons Attri-
bution-NonCommercial 4.0 International License, which permits any
non-commercial use, sharing, adaptation, distribution and reproduction
in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Com-
mons licence, and indicate if changes were made. The images or other
third party material in this article are included in the article's Creative
Commons licence, unless indicated otherwise in a credit line to the
material. If material is not included in the article's Creative Commons
licence and your intended use is not permitted by statutory regula-
tion or exceeds the permitted use, you will need to obtain permission
directly from the copyright holder. To view a copy of this licence, visit
http:// creat iveco mmons. org/ licen ses/ by- nc/4. 0/.
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Authors and Aliations
AndrewBlauvelt1· EmmaGuttman‑Yassky2,3· AmyS.Paller4,5· EricL.Simpson6· MichaelJ.Cork7,8·
JamieWeisman9· JohnBrowning10· WeilySoong11· XianSun12· ZhenChen12· MatthewP.Kosloski12·
MohamedA.Kamal12· DimittriDelevry12· Chien‑ChiaChuang13· JohnT.O’Malley13· AshishBansal12
* Ashish Bansal
ashish.bansal@regeneron.com
1 Oregon Medical Research Center, Portland, OR, USA
2 Icahn School ofMedicine atMount Sinai Medical Center,
NewYork, NY, USA
3 Rockefeller University, NewYork, NY, USA
4 Northwestern University Feinberg School ofMedicine,
Chicago, IL, USA
5 Ann andRobert H. Lurie Children’s Hospital, Chicago, IL,
USA
6 Oregon Health andScience University, Portland, OR, USA
7 Sheffield Dermatology Research, University ofSheffield,
Sheffield, UK
8 Sheffield Children’s Hospital Clinical Research Facility,
Sheffield, UK
9 Advanced Medical Research, PC, Atlanta, GA, USA
383Long-Term Efficacy and Safety of Dupilumab in Adolescents
10 University ofTexas Health San Antonio, SanAntonio, TX,
USA
11 Alabama Allergy andAsthma Center-AllerVie Health,
Birmingham, AL, USA
12 Regeneron Pharmaceuticals, Inc., 77 Old Saw Mill River
Road, Tarrytown, NY10591, USA
13 Sanofi, Cambridge, MA, USA
... 65 Most of the adverse events were mild to moderate in severity as shown in previous open label extension studies of adults and adolescents with moderate to severe atopic dermatitis. 66,67 In our systematic review, most of our included patients reported mild or no adverse events, with ocular discomfort most frequently reported. 16,32,68 The infection risk in patients under dupilumab is also a concern. ...
Article
Dupilumab greift in die Signalwege von IL-4 und IL-13 ein und wird erfolgreich zur Behandlung der atopischen Dermatitis eingesetzt. Genodermatosen wie das Netherton-Syndrom, die Epidermolysis bullosa pruriginosa und das Hyper-IgE-Syndrom sind Th2-vermittelte Erkrankungen mit Aktivierung einer Typ-2-Entzündung. In dieser systematischen Übersicht haben wir die therapeutische Rolle von Dupilumab bei der Behandlung von Genodermatosen untersucht. Dazu wurden die Datenbanken PubMed, Embase, Web of Science und Cochrane seit ihrer Einführung bis zum 13. Dezember 2021 systematisch durchsucht. Die Übersicht umfasst Studien mit relevanten Begriffen, einschließlich „Dupilumab“, „Genodermatose“, „Netherton-Syndrom“, „Ichthyose“, „Epidermolysis bullosa“ und „Hyper-IgE-Syndrom“. Die anfängliche Suche ergab 2888 Treffer; davon wurden 28 Studien und 37 Patienten mit Genodermatosen eingeschlossen. Zu den beurteilten Genodermatosen gehörten Netherton-Syndrom, Epidermolysis bullosa pruriginosa, Hyper-IgE-Syndrom, Morbus Hailey-Hailey und schwere Ekzeme im Zusammenhang mit genetischen Erkrankungen. Die meisten der beschriebenen Fälle zeigten eine signifikante klinische Verbesserung nach Einleitung der Dupilumab-Behandlung ohne wesentliche unerwünschte Ereignisse. Zudem wurden eine Verringerung der Immunglobulin-E-Spiegel und eine Normalisierung der Zytokinspiegel dokumentiert. Zusammenfassend hat Dupilumab möglicherweise eine therapeutische Rolle bei bestimmten Genodermatosen mit einer abnormal gesteigerten Typ-2-T-Helfer-Immunität (Th2), einschließlich Netherton-Syndrom, Epidermolysis bullosa pruriginosa, Hyper-IgE-Syndrom, Morbus Hailey-Hailey und schweren Ekzemen bei genetischen Erkrankungen.
... 65 Most of the adverse events were mild to moderate in severity as shown in previous open label extension studies of adults and adolescents with moderate to severe atopic dermatitis. 66,67 In our systematic review, most of our included patients reported mild or no adverse events, with ocular discomfort most frequently reported. 16,32,68 The infection risk in patients under dupilumab is also a concern. ...
Article
Dupilumab interferes with the signaling pathways of IL‐4 and IL‐13 and is effective in treating atopic dermatitis. Specific genodermatoses, including Netherton syndrome, epidermolysis bullosa pruriginosa, and hyper‐IgE syndrome, are Th2 skewed diseases with activation of type 2 inflammation. We performed this systematic review to investigate the therapeutic role of dupilumab in the treatment of genodermatosis. A systematic search was conducted of the PubMed, Embase, Web of Science, and Cochrane databases from inception to December 13, 2021. The review included studies with relevant terms including “dupilumab,” “genodermatosis”, “Netherton syndrome”, “ichthyosis”, “epidermolysis bullosa” and “hyper‐IgE syndrome”. The initial search yielded 2,888 results, of which 28 studies and 37 patients with genodermatosis were enrolled. The assessed genodermatoses included Netherton syndrome, epidermolysis bullosa pruriginosa, hyper‐IgE syndrome, Hailey‐Hailey disease, and severe eczema associated with genetic disorders. Most of the reported cases showed significant clinical improvement after the initiation of dupilumab treatment without major adverse events. Decreased immunoglobulin E levels and cytokine normalization have also been documented. In conclusion, Dupilumab may have a potential therapeutic role in certain genodermatoses skewed towards T helper 2 (Th2) immunity, including Netherton syndrome, epidermolysis bullosa pruriginosa, hyper‐IgE syndrome, Hailey‐Hailey disease, and severe eczema associated with some genetic disorders.
... Results from adolescent patients were recently published with findings relevant for a long-term safety profile consistent with the adult safety profile. Additionally, trial participants with clear/almost clear skin for 12 weeks were discontinued on DUPI with 56.7%, demonstrating recurrence and need to resume DUPI treatment to maintain AD control, which suggests a need to continue DUPI treatment to maintain efficacy [51]. With an excellent safety profile and high response rates, DUPI has become first line, when available, in refractory moderate-severe eczema. ...
Article
Full-text available
Pediatric atopic dermatitis (AD) has historically challenged dermatologists given the variable response of patients to treatment and limited available therapeutic options, often with significant potential side effects. Over the last decade, targeted treatments including dupilumab and Janus kinase (JAK) inhibitors have emerged as significant treatment advances. An updated therapeutic approach for incorporating these new practice-changing medications can help clinicians manage these challenging patients. In this review, we discuss emerging topical and systemic (oral and injectable) treatments in pediatric AD, including topical PDE4 inhibitors and tapinarof, oral JAK inhibitors, and injected biologics including IL-4Rα inhibitor dupilumab, IL-13 inhibitor tralokinumab, IL-13Rα inhibitor lebrikizumab, IL-31Rα inhibitor nemolizumab, and IL-5Rα inhibitor benralizumab. We also review experimental agents in early clinical trials, such as targeted microbiome transplant lotions/antimicrobials, which may gain relevance in AD treatment. Finally, we propose a therapeutic approach for pediatric AD that incorporates newer therapies including dupilumab and JAK inhibitors, recognizing that these agents may not be universally available or approved. Further trials that include pediatric patients, especially head-to-head studies among therapeutic classes, are needed to clarify the role of emerging treatments.
Article
Background: The treatment of chronic refractory moderate-to-severe atopic dermatitis (AD) has traditionally relied on broad-spectrum systemic anti-inflammatory agents. With the introduction of biologics and Janus kinase inhibitors (Jakinib), the step management of moderate-to-severe AD is rapidly changing; however, guidelines have yet to provide formal recommendations for how to best incorporate these agents into the treatment plan. Objective: To summarize the updated evidence-based medical treatment for AD, including a proposed position for biologics and Jakinibs in the treatment algorithm. Methods: A literature search of several medical literature data bases for guidelines, position papers, systematic reviews, and clinical trials from 2012 to 2022 on the treatment of moderate-to-severe AD was conducted to prepare this narrative review. Results: Emollients and topical corticosteroids are the mainstay for treating acute flares and for maintaining chronic control. Second-line topical agents include calcineurin inhibitors, e.g., tacrolimus and pimecrolimus; crisaborole; and ruxolitinib. For acute flares, cyclosporine is preferred over systemic corticosteroids. For chronic treatment, phototherapy should be considered before systemic anti-inflammatory agents. Of the traditional anti-inflammatory agents, cyclosporine is the first-line choice, with methotrexate and azathioprine equal secondary choices. Although abrocitinib may have better efficacy then dupilumab based on indirect comparisons, abrocitinib requires closer monitoring for adverse events. Based on package labeling, Jakinibs, e.g., abrocitinib and upadacitinib, should be used only after failure with other systemic agents, including biologics (e.g., dupilumab and tralokinumab). Biologics and Jakinibs should be considered before the traditional systemic anti-inflammatory agents. Conclusion: Clinicians should consider a modified step management for AD as they await the development of national and international guideline recommendations for how best to position the biologics and Jakinibs into the AD treatment algorithm.
Article
Resumen Introducción dupilumab es el primer fármaco biológico aprobado para el tratamiento de la dermatitis atópica en adolescentes de 12 a 18 años y niños de 6 a 11 años. Ha demostrado en sus ensayos clínicos pivotales ser eficaz y seguro; sin embargo, disponemos de pocos datos en la literatura publicada sobre su uso en la práctica clínica habitual. El objetivo de este estudio es aportar datos sobre su efectividad y seguridad en la práctica clínica habitual, así como realizar una exhaustiva revisión de la literatura publicada. Métodos se realizó un estudio observacional retrospectivo multicéntrico, incluyendo niños y adolescentes con DA moderada-grave en tratamiento con dupilumab. Se recogieron variables demográficas, clínicas, de respuesta al tratamiento y efectos secundarios. Resultados se incluyeron 8 pacientes (75% varones, mediana de edad de 12 años). El tiempo de seguimiento osciló entre 5 y 14 meses. Las medianas del Eczema Area and Severity Index (EASI) y del Investigator's Global Assessment (IGA) basales fueron de 24,8 (10–42) y 4 (3–4), respectivamente. El EASI se redujo un 81, 83 y 95,2% en las semanas 16, 24 y 52, respectivamente. Alcanzando una reducción del 75% (EASI 75) en el 75% de los pacientes en la semana 16. Se obtuvo un IGA 0 o 1 en el 50, 87,5 y 100% de los casos en las semanas 16, 24 y 52. El 25% de los pacientes sufrieron efectos adversos (conjuntivitis, reacción en el punto de inyección y cara roja). Conclusiones dupilumab ha demostrado su efectividad y el buen perfil de seguridad en la serie presentada. Estos resultados fueron concordantes con los obtenidos en las series de práctica clínica real con los niños y los adolescentes en tratamiento con dupilumab publicadas hasta la fecha.
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Importance The dupilumab regimen of 300 mg every 2 weeks is approved for uncontrolled, moderate to severe atopic dermatitis (AD). Objective To assess the efficacy and safety of different dupilumab regimens in maintaining response after 16 weeks of initial treatment. Design, Setting, and Participants The Study to Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults With Atopic Dermatitis (LIBERTY AD SOLO-CONTINUE) was a randomized, double-blind, phase 3 clinical trial conducted from March 25, 2015, to October 18, 2016, at 185 sites in North America, Europe, Asia, and Japan. Patients with moderate to severe AD who received dupilumab treatment and achieved an Investigator’s Global Assessment score of 0 or 1 or 75% improvement in Eczema Area and Severity Index scores (EASI-75) at week 16 in 2 previous dupilumab monotherapy trials (LIBERTY AD SOLO 1 and 2) were rerandomized in SOLO-CONTINUE. After completing SOLO-CONTINUE, patients were followed up for up to 12 weeks or enrolled in an open-label extension. Data were analyzed from December 5 to 12, 2016. Interventions High-responding patients treated with dupilumab in SOLO were rerandomized 2:1:1:1 to continue their original regimen of dupilumab, 300 mg, weekly or every 2 weeks or to receive dupilumab, 300 mg, every 4 or 8 weeks or placebo for 36 weeks. Main Outcomes and Measures Percentage change in EASI score from baseline during the SOLO-CONTINUE trial, percentage of patients with EASI-75 at week 36, and safety. Results Among the 422 patients (mean [SD] age, 38.2 [14.5] years; 227 [53.8%] male), continuing dupilumab treatment once weekly or every 2 weeks maintained optimal efficacy, with negligible change in percent EASI improvement from SOLO 1 and 2 baseline during the SOLO-CONTINUE trial (−0.06%; P < .001 vs placebo); percent change with the other regimens dose-dependently worsened (dupilumab every 4 weeks, −3.84%; dupilumab every 8 weeks, −6.84%; placebo, −21.67%). More patients taking dupilumab weekly or every 2 weeks (116 of 162 [71.6%]; P < .001 vs placebo) maintained EASI-75 response than those taking dupilumab every 4 weeks (49 of 84 [58.3%]) or every 8 weeks (45 of 82 [54.9%]) or those taking placebo (24 of 79 [30.4%]). Overall adverse event incidences were 70.7% in the weekly or every 2 weeks group, 73.6% in the every 4 weeks group, 75.0% in the every 8 weeks group, and 81.7% in the placebo group. Treatment groups had similar conjunctivitis rates. Treatment-emergent antidrug antibody incidence was lower with more frequent dupilumab dose regimens (11.3% in the placebo group and 11.7%, 6.0%, 4.3%, and 1.2% in the dupilumab every 8 weeks, every 4 weeks, every 2 weeks, and weekly groups, respectively). Conclusions and Relevance In this trial, continued response over time was most consistently maintained with dupilumab administered weekly or every 2 weeks. Longer dosage intervals and placebo resulted in a diminution of response for both continuous and categorical end points. No new safety signals were observed. The approved regimen of 300 mg of dupilumab every 2 weeks is recommended for long-term treatment. Trial Registration ClinicalTrials.gov identifier: NCT02395133
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Background: Dupilumab, a fully human monoclonal antibody that binds IL-4Rα and inhibits signaling of both IL-4 and IL-13, has shown efficacy across multiple diseases with underlying type 2 signatures and is approved for treatment of asthma, atopic dermatitis and chronic sinusitis with nasal polyposis. We sought to provide a comprehensive analysis of the redundant and distinct roles of IL-4 and IL-13 in type 2 inflammation and report dupilumab mechanisms of action. Methods: Using primary cell assays and a mouse model of house dust mite induced asthma, we compared IL-4 versus IL-13 versus IL-4Rα blockers. Results: Intranasal administration of either IL-4 or IL-13 confers an asthma-like phenotype in mice by inducing immune cell lung infiltration, including eosinophils, increasing cytokine/chemokine expression and mucus production, thus demonstrating redundant functions of these cytokines. We further teased out their respective contributions using human in vitro culture systems. Then, in a mouse asthma model by comparing in head to head studies, either IL-4 or IL-13 inhibition to dual IL-4/IL-13 inhibition, we demonstrate that blockade of both IL-4 and IL-13 is required to broadly block type 2 inflammation, which translates to protection from allergen-induced lung function impairment. Notably, only dual IL-4/IL-13 blockade prevented eosinophil infiltration into lung tissue without affecting circulating eosinophils, demonstrating that tissue, but not circulating eosinophils contribute to disease pathology. Conclusions: Overall, these data support IL-4 and IL-13 as key drivers of type 2 inflammation, and help provide insight into the therapeutic mechanism of dupilumab, a dual IL-4/IL-13 blocker, in multiple type 2 diseases.
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Background Atopic dermatitis is a chronic inflammatory condition with substantial burden and limited treatment options for adolescents with moderate-to-severe disease. Significantly more patients treated with dupilumab vs. placebo achieved Investigator’s Global Assessment 0/1 at week 16. Objective The objective of this study was to assess the impact of dupilumab treatment vs. placebo on the achievement of clinically meaningful improvements in atopic dermatitis signs, symptoms and quality of life. Methods R668-AD-1526 LIBERTY AD ADOL was a randomized, double-blinded, parallel-group, phase III clinical trial. Two hundred and fifty-one adolescents with moderate-to-severe atopic dermatitis received dupilumab 300 mg every 4 weeks (q4w; n = 84), dupilumab 200 or 300 mg every 2 weeks (q2w; n = 82), or placebo (n = 85). A post-hoc subgroup analysis was performed on 214 patients with Investigator’s Global Assessment > 1 at week 16. Measures of atopic dermatitis signs, symptoms, and quality of life were assessed. Clinically meaningful improvement in one or more of three domains of signs, symptoms, and quality of life was defined as an improvement of ≥ 50% in Eczema Area and Severity Index, ≥ 3 points in Peak Pruritus Numerical Rating Scale, or ≥ 6 points in the Children’s Dermatology Life Quality Index from baseline. Results Of patients receiving dupilumab q2w, 80.5% [66/82] experienced clinically meaningful improvements in atopic dermatitis signs, symptoms, or quality of life at week 16 (vs. placebo, 20/85 [23.5%], difference 57.0% [95% confidence interval 44.5–69.4]; q4w vs. placebo, 53/84 [63.1%], difference 39.6% [95% confidence interval 25.9–53.3]; both p < 0.0001). Results were similar in adolescents with Investigator’s Global Assessment > 1 at week 16 (q2w, 46/62 [74.2%] vs. placebo, 18/83 [21.7%], difference 52.5% [95% confidence interval 38.5–66.6]; q4w, 38/69 [55.1%] vs. placebo, difference 33.4% [95% confidence interval 18.7–48.1]; both p < 0.0001). Conclusions Dupilumab provided clinically meaningful improvements in signs, symptoms, and quality of life in adolescents with moderate-to-severe atopic dermatitis among patients with Investigator’s Global Assessment > 1 at week 16. Treatment responses should be interpreted in the context of such clinically relevant patient-reported outcome measures. Trial Registration ClinicalTrials.gov; NCT03054428. Video abstract Adolescents with atopic dermatitis: does dupilumab improve their signs, symptoms, and quality of life? (MP4 212916 kb)
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Abstract Introduction The Patient-Oriented Eczema Measure (POEM) assesses patient-reported frequency of atopic dermatitis (AD) symptoms, while the Children’s Dermatology Life Quality Index (CDLQI) measures the impact of skin disease on health-related quality of life (HRQoL) in children. There is currently no threshold for clinically meaningful within-person change in POEM or CDLQI scores in adolescents. Here we empirically derive within-person thresholds of meaningful within-person change in POEM and CDLQI scores in adolescents with moderate-to-severe AD. Methods Data were used from a phase 3, randomized, double-blind, placebo-controlled trial of dupilumab in adolescents (aged ≥ 12 to
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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 combination with current standard of care (topical corticosteroids), which was not evaluated in the 16-week phase III monotherapy trial.
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Background & aims: Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin 4 (IL4) receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE. Methods: We performed a phase 2 study of adults with active EoE (2 dysphagia episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015 through November 9, 2016 at 14 sites. Subjects were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg; n=23) or placebo (n=24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann dysphagia instrument patient-reported outcome (SDI-PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety. Results: The mean SDI-PRO score was 6.4 when the study began. In the dupilumab group, SDI-PRO scores were reduced by a mean value of 3.0 at week 10 compared with vs a mean reduction of 1.3 in the placebo group (P=.0304) At week 12, dupilumab reduced peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P<.0001 compared with baseline), the EoE-HSS severity score by 68.3% (P<.0001 vs baseline), and the endoscopic reference score by 1.6 (P=.0006 compared with baseline. Dupilumab increased esophageal distensibility by 18% compared with baseline (P<.0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group). Conclusions: In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features, compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov no: NCT02379052.
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Background: Significant unmet need exists for long-term treatment of moderate to severe atopic dermatitis (AD). Objective: To assess the long-term safety and efficacy of dupilumab in patients with AD. Methods: This ongoing, multicenter, open-label extension study (NCT01949311) evaluated long-term dupilumab treatment in adults who had previously participated in phase 1 through 3 clinical trials of dupilumab for AD. This analysis examined patients given 300 mg dupilumab weekly for up to 76 weeks at data cutoff (April 2016). Safety was the primary outcome; efficacy was also evaluated. Results: Of 1491 enrolled patients (1042.9 patient-years), 92.9% were receiving treatment at cutoff. The safety profile was consistent with previously reported trials (420.4 adverse events/100 patient-years and 8.5 serious adverse events/100 patient-years), with no new safety signals; common adverse events included nasopharyngitis, conjunctivitis, and injection-site reactions. Sustained improvement was seen up to 76 weeks in all efficacy outcomes, including measures of skin inflammation, pruritus, and quality of life. Limitations: Lack of control arm, limited number of patients with 76 weeks or longer of treatment (median follow-up, 24 weeks), and patients not receiving the approved dose regimen of 300 mg every 2 weeks. Conclusion: The safety and efficacy profile from this study supports the role of dupilumab as continuous long-term treatment for patients with moderate to severe AD.
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This guideline was developed as a joint interdisciplinary European project, including physicians from all relevant disciplines as well as patients. It is a consensus‐based guideline, taking available evidence from other guidelines, systematic reviews and published studies into account. This second part of the guideline covers antimicrobial therapy, systemic treatment, allergen‐specific immunotherapy, complementary medicine, psychosomatic counselling and educational interventions, whereas the first part covers methods, patient perspective, general measures and avoidance strategies, basic emollient treatment and bathing, dietary intervention, topical anti‐inflammatory therapy, phototherapy and antipruritic therapy. Management of AE must consider the individual clinical variability of the disease. Systemic immunosuppressive treatment with cyclosporine, methotrexate, azathioprine and mycophenolic acid is established option for severe refractory cases, and widely available. Biologicals targeting the T helper 2 pathway such as dupilumab may be a safe and effective, disease‐modifying alternative when available. Oral drugs such as JAK inhibitors and histamine 4 receptor antagonists are in development. Microbial colonization and superinfection may cause disease exacerbation and can require additional antimicrobial treatment. Allergen‐specific immunotherapy with aeroallergens may be considered in selected cases. Psychosomatic counselling is recommended especially in stress‐induced exacerbations. Therapeutic patient education (‘Eczema school’) is recommended for children and adult patients. General measures, basic emollient treatment, bathing, dietary intervention, topical anti‐inflammatory therapy, phototherapy and antipruritic therapy have been addressed in the first part of the guideline.
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Importance Adolescents with atopic dermatitis (AD) have high disease burden negatively affecting quality of life, with limited treatment options. The efficacy and safety of dupilumab, a monoclonal antibody, approved for treatment in adolescent patients with inadequately controlled AD, remain unknown in this patient population. Objective To assess the efficacy and safety of dupilumab monotherapy in adolescents with moderate to severe inadequately controlled AD. Design, Setting, and Participants A randomized, double-blind, parallel-group, phase 3 clinical trial was conducted at 45 US and Canadian centers between March 21, 2017, and June 5, 2018. A total of 251 adolescents with moderate to severe AD inadequately controlled by topical medications or for whom topical therapy was inadvisable were included. Interventions Patients were randomized (1:1:1; interactive-response system; stratified by severity and body weight) to 16-week treatment with dupilumab, 200 mg (n = 43; baseline weight <60 kg), or dupilumab, 300 mg (n = 39; baseline weight ≥60 kg), every 2 weeks; dupilumab, 300 mg, every 4 weeks (n = 84); or placebo (n = 85). Main Outcomes and Measures Proportion of patients with 75% or more improvement from baseline in Eczema Area and Severity Index (EASI-75) (scores range from 0 to 72, with higher scores indicating greater severity) and Investigator’s Global Assessment (IGA) 0 or 1 on a 5-point scale (scores range from 0 to 4, with higher scores indicating greater severity) at week 16. Results A total of 251 patients were randomized (mean [SD] age, 14.5 [1.7] years; 148 [59.0%] male). Of 250 patients with data available on concurrent allergic conditions, most had comorbid type 2 diseases (asthma, 134 [53.6%]; food allergies, 60.8%; allergic rhinitis, 65.6%). A total of 240 patients (95.6%) completed the study. Dupilumab achieved both coprimary end points at week 16. The proportion of patients with EASI-75 improvement from baseline increased (every 2 weeks, 41.5%; every 4 weeks, 38.1%; placebo, 8.2%) with differences vs placebo of 33.2% (95% CI, 21.1%-45.4%) for every 2 weeks and 29.9% (95% CI, 17.9%-41.8%) for every 4 weeks (P < .001). Efficacy of the every-2-week regimen was generally superior to the every-4-week regimen. Patients in the dupilumab arms had higher percentage values of conjunctivitis (every 2 weeks, 9.8%; every 4 weeks, 10.8%; placebo, 4.7%) and injection-site reactions (every 2 weeks, 8.5%; every 4 weeks, 6.0%; placebo, 3.5%), and lower nonherpetic skin infections (every 2 weeks, 9.8%; every 4 weeks, 9.6%; placebo, 18.8%). Conclusions and Relevance In this study, dupilumab significantly improved AD signs, symptoms, and quality of life in adolescents with moderate to severe AD, with an acceptable safety profile. Placebo-corrected efficacy and safety of dupilumab were similar in adolescents and adults. Trial Registration ClinicalTrials.gov identifier: NCT03054428
Article
Atopic dermatitis (also called AD or eczema) is a chronic skin disease found in up to 1 in 10 adults, causing itchy rashes that may cover most of the body. Ciclosporin, an oral treatment (taken by mouth) commonly used for AD, doesn't always work and can have significant side effects. Other broadly‐acting oral medications are sometimes used, but not approved, for AD. Dupilumab is a new medication approved in many countries for adults with inadequately controlled moderate‐to‐severe AD. Dupilumab specifically targets pathways in the body that drive AD. Researchers in Europe evaluated how well dupilumab injections improved rashes, itch, and daily lives of people whose AD required ciclosporin, but for whom ciclosporin wasn't working or caused intolerable side effects, or whose medical conditions prevented its use. Among 325 participants, 110 received 300 mg dupilumab once‐weekly, 107 received it every two weeks, and 108 received placebo (dummy drug) once‐weekly. All participants used topical (applied to the skin) corticosteroids during the 16‐week study. Dupilumab improved AD rashes: at Week 0, participants’ Eczema Area and Severity Index (EASI) scores were about 31 (scale: 0–72), but by Week 16, 59% to 62% of dupilumab‐treated participants achieved 75% or greater improvement in EASI, versus 29.6% of people on placebo. Dupilumab also improved itch, other symptoms, mood, and quality of life. Conjunctivitis and injection‐site reactions were more frequent among dupilumab‐treated patients; skin infections (excluding herpes) and AD exacerbations (worsening) were more frequent with placebo. The authors conclude that dupilumab plus topical corticosteroids significantly improved AD even in adults with AD who had previously failed treatment with or were unable to use ciclosporin.