- Email: [email protected]
Pharmacokinetics and Safety of Apremilast in Pediatric Patients With Moderate to Severe Plaque Psoriasis: Results From a Phase 2 Open-Label Study
Journal Pre-proof Pharmacokinetics and Safety of Apremilast in Pediatric Patients With Moderate to Severe Plaque Psoriasis: Results From a Phase 2 Open-Label Study Amy S. Paller, MD, Ying Hong, PhD, Emily M. Becker, MD, Raul de Lucas, MD, Maria Paris, MD, Wendy Zhang, MD, MS, Zuoshun Zhang, PhD, Claire Barcellona, BS, MS, Peter Maes, BA, Loretta Fiorillo, MD PII:
S0190-9622(19)32566-6
DOI:
https://doi.org/10.1016/j.jaad.2019.08.019
Reference:
YMJD 13739
To appear in:
Journal of the American Academy of Dermatology
Received Date: 17 January 2019 Revised Date:
26 July 2019
Accepted Date: 3 August 2019
Please cite this article as: Paller AS, Hong Y, Becker EM, de Lucas R, Paris M, Zhang W, Zhang Z, Barcellona C, Maes P, Fiorillo L, Pharmacokinetics and Safety of Apremilast in Pediatric Patients With Moderate to Severe Plaque Psoriasis: Results From a Phase 2 Open-Label Study, Journal of the American Academy of Dermatology (2019), doi: https://doi.org/10.1016/j.jaad.2019.08.019. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
1 2
Pharmacokinetics and Safety of Apremilast in Pediatric Patients With Moderate to Severe Plaque Psoriasis: Results From a Phase 2 Open-Label Study
3
Short title: Apremilast PK and Safety in Pediatric Psoriasis
4 5 6
Amy S. Paller, MD1; Ying Hong, PhD2; Emily M. Becker, MD3; Raul de Lucas, MD4; Maria Paris, MD2; Wendy Zhang, MD, MS2; Zuoshun Zhang, PhD2; Claire Barcellona, BS, MS2; Peter Maes, BA2; Loretta Fiorillo, MD5
7 8 9 10
1
Northwestern University Feinberg Medical School, Chicago, IL; 2Celgene Corporation, Summit, NJ; 3University of Texas Health Science Center – San Antonio, San Antonio TX; 4Hospital Universitario La Paz, Madrid, Spain; 5Pediatric Department, University of Alberta, Edmonton, AB, Canada
11 12 13 14 15 16 17 18
Correspondence Amy Paller, MD Northwestern University NMH Arkes Family Pavilion 676 North Saint Clair, Suite 1600 Chicago, IL 60611 Phone: 312-695-3721 Email: [email protected]
19 20 21 22 23 24 25
Word count Abstract: 216 Capsule Summary: 48 Text: 2,841 Figures: 1 (4 in supplementary appendix at http://dx.doi.org/10.17632/cm27w42ff3.1) Tables: 3 (5 in supplementary appendix at http://dx.doi.org/10.17632/cm27w42ff3.1) References: 28
26 27 28 29 30
IRB statement: This trial was conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Council for Harmonisation Harmonised Tripartite Guideline, and was approved by the Institutional Review Board or Independent Ethics Committee at each study site. All patients and/or their legally authorized representative provided written informed consent.
31
ClinicalTrials.gov: NCT02576678
32 33 34 35 36
Funding: The authors acknowledge financial support for this study from Celgene Corporation. The authors received editorial support in the preparation of this manuscript from Amy Shaberman, PhD, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, sponsored by Celgene Corporation, Summit, NJ, USA. The authors, however, directed and are fully responsible for all content and editorial decisions for this manuscript.
37 38 39 40 41 42 43 44 45 46
Conflicts of Interest Amy S. Paller has received honoraria as a consultant for Asana, Dermira, Eli Lilly, Galderma, LEO Pharma, Novartis, Pfizer, UCB, and Valeant, and has been an investigator without personal compensation for AbbVie, Celgene Corporation, Eli Lilly, Galderma, Janssen, LEO Pharma, and Novartis. Ying Hong, Maria Paris, Wendy Zhang, Zuoshun Zhang, Claire Barcellona, and Peter Maes are employees of and may have stock/stock options in Celgene Corporation. Emily M. Becker is an investigator for Celgene Corporation. Raul de Lucas has no conflicts of interest. Loretta Fiorillo has received study grants from Celgene Corporation and payment for attending advisory board meetings from Amgen, AbbVie, and Janssen.
Pediatric Phase 2
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Abstract
48
Background: No oral systemic treatments are approved for pediatric psoriasis patients.
49
Objective: To evaluate pharmacokinetics (PK) and safety of apremilast, an oral
50
phosphodiesterase 4 inhibitor, in pediatric psoriasis patients.
51
Methods: This phase 2, multicenter, open-label study enrolled pediatric patients with
52
moderate to severe plaque psoriasis. Patients received apremilast BID without titration
53
for 2 weeks (Group 1 [age 12‒17 years, weight ≥35 kg]: apremilast 20 or 30 mg; Group
54
2 [age 6‒11 years, weight ≥15 kg]: apremilast 20 mg), followed by a 48-week extension.
55
Primary endpoints were PK and safety. Other endpoints were taste/acceptability and
56
change from baseline in PASI score.
57
Results: A total of 42 enrolled patients (21 adolescents [age 12‒17 years] and 21
58
children [age 6‒11 years]) received apremilast. PK modeling and noncompartmental
59
analyses demonstrated that weight-based dosing with apremilast 20 mg BID in children
60
or apremilast 20 or 30 mg BID in adolescents provides exposure (AUC0‒12) that is
61
comparable with apremilast 30 mg BID in adults. The safety profile was generally similar
62
to that in adults. Most liked the taste of the tablet. Improvements from baseline in mean
63
PASI score were 68% for adolescents (overall) and 79% for children).
64
Limitations: No children weighing <20 kg were enrolled.
65
Conclusions: This first-time-in-children phase 2 study supports weight-based
66
apremilast dosing for future phase 3 studies of pediatric plaque psoriasis.
67
Pediatric Phase 2
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Capsule Summary
69
•
apremilast in pediatric patients with moderate to severe plaque psoriasis.
70 71
This first-time-in-children study evaluated pharmacokinetics, safety, and efficacy of
•
This study demonstrates that weight-based apremilast dosing achieved exposure
72
similar to adults, provides first evidence of potential efficacy in pediatric patients, and
73
shows safety/tolerability consistent with the adult profile.
74 75
Keywords
76
adolescent, apremilast, children, pediatric, pharmacokinetics, plaque psoriasis, safety
77
Pediatric Phase 2
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INTRODUCTION
79
Psoriasis is a chronic, systemic inflammatory disease that starts during childhood or
80
adolescence in approximately one-third of patients; annual prevalence in the United
81
States is estimated to be 128 per 100,000 pediatric individuals.1-4 Clinical features of
82
plaque psoriasis may differ between children and adults.2,5,6 Early, effective
83
management of psoriasis in children is important because the negative impact of this
84
lifelong disease on quality of life and psychological well-being may be cumulative.3,7,8
85
Most psoriasis treatments are not approved for use in children, who are often treated
86
off-label with the medications used for adults.2,9 Use of topical corticosteroids is
87
common in pediatric patients but may be associated with poor compliance, and
88
available systemic medications and phototherapy are typically reserved for severe or
89
refractory disease, as they may confer serious risks or require frequent monitoring.2,9-11
90
No oral systemic treatment for moderate to severe psoriasis is approved for pediatric
91
use. Apremilast, an oral phosphodiesterase 4 inhibitor, is approved for the treatment of
92
adults with moderate to severe plaque psoriasis or active psoriatic arthritis. This first-
93
time-in-children phase 2 study evaluated the pharmacokinetics (PK), safety of
94
apremilast, and taste of the apremilast tablet in pediatric patients with moderate to
95
severe plaque psoriasis, with the primary aim of informing the pediatric doses for a
96
phase 3 study.
97 98
METHODS
99
Patients
100
The study enrolled pediatric patients aged 6 to 17 years with moderate to severe plaque
101
psoriasis (Psoriasis Area and Severity Index [PASI] score ≥12, psoriasis-involved body Pediatric Phase 2
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102
surface area [BSA] ≥10%, static Physician Global Assessment [sPGA ] ≥3 [moderate to
103
severe]) for ≥6 months before screening and whose disease was inadequately
104
controlled by or inappropriate for topical therapy. Eligible patients were candidates for
105
systemic or phototherapy and had been exposed to ≤1 systemic agent for psoriasis with
106
sufficient washout time before initiating study treatment. Further details on inclusion
107
criteria as well as exclusion criteria for washout times are provided in the
108
Supplementary Appendix available at http://dx.doi.org/10.17632/cm27w42ff3.1.
109 110
Study Design
111
This phase 2, multicenter, open-label PK and safety study was conducted at 10 sites in
112
the United States, Canada, and Europe (NCT02576678). After a 5-week screening
113
period, patients received apremilast for 2 weeks, followed by a 48-week extension
114
treatment period and a post-treatment observational follow-up period of up to 52 weeks
115
after the last dose of apremilast (Figure S1). Dosing was weight-based using a
116
staggered, stepwise approach by age range and body weight (starting with older and
117
heavier patients). Doses for younger patients and patients with lower body weight had
118
the option for adjustment by an independent data monitoring committee based on safety
119
and PK data from older and heavier patients. In Group 1, adolescents aged 12 to 17
120
years, weighing ≥35 to <70 kg, received apremilast 20 mg BID and those weighing ≥70
121
kg received apremilast 30 mg BID (the approved dosing regimen for adults). In Group 2,
122
children aged 6 to 11 years (weight ≥15 kg) received apremilast 20 mg BID. All doses
123
administered in the clinic were given under direct supervision of trained staff. Individuals
124
responsible for dosing checked each patient’s mouth to ensure that the tablet had been
Pediatric Phase 2
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125
swallowed whole (i.e., not chewed or crushed). Compliance for outpatient administration
126
was evaluated by pill count, as outlined in the Supplementary Appendix. This trial was
127
conducted in accordance with the principles of Good Clinical Practice and the
128
Declaration of Helsinki, and was approved by the Institutional Review Board or
129
Independent Ethics Committee. All patients and/or their legally authorized
130
representatives provided written informed assent/consent.
131 132
Endpoints
133
The primary analysis assessed PK parameters using a noncompartmental analysis
134
(NCA) approach based on venous blood samples obtained on Day 1 (2 hours post-
135
morning dose, both groups) and Day 14 (Group 1: predose and 1, 2, 3, 5, 8, 12, and 24
136
hours post-morning dose [a protocol amendment later removed the 24-hour post-Day
137
14 PK sample]; Group 2: predose and 2, 5, and 12 hours post-morning dose). Plasma
138
apremilast concentrations were measured using validated liquid chromatography
139
tandem mass spectrometry. Maximal observed plasma concentration (Cmax), time to
140
Cmax (tmax), area under the curve from time 0 to 12 hours postdose (AUC0−12), AUC from
141
time 0 to the last quantifiable concentration (AUC0−t), apparent total plasma clearance
142
(CL/F), apparent total volume of distribution at steady state (Vss/F) or based on terminal
143
phase (Vz/F), and elimination half-life (t1/2) were evaluated. Safety was evaluated based
144
on treatment-emergent adverse events (TEAEs), laboratory assessments, and clinical
145
assessments.
Pediatric Phase 2
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146
The secondary endpoint was taste and acceptability of the apremilast tablet,
147
assessed using a faces Likert scale on Day 1. PASI was evaluated as an exploratory
148
endpoint at screening, baseline, and Weeks 2, 4, 8, 16, 24, 32, 40, and 50.
149 150
Statistical Analysis
151
PK analyses based on an NCA approach were performed in the PK population (patients
152
who received ≥1 dose of apremilast and had evaluable PK data). PK parameters on
153
Day 14 were calculated using plasma concentrations and actual blood sampling times
154
(Phoenix WinNonlin v.8.0), and were summarized by study group and by baseline body
155
weight category (<50 kg, 50 to <70 kg, and ≥70 kg).
156
A population PK model was developed using pooled PK data from the current
157
pediatric study and prior dose-finding studies of apremilast in adults with moderate to
158
severe psoriasis (PSOR-011 and PSOR-005).12,13 Details regarding the population PK
159
analysis are in the Supplementary Appendix. Model-based simulations were performed
160
to determine the range of body weight in pediatric patients treated with apremilast 20
161
mg BID that could achieve steady-state AUC0-12 similar to that in adults treated with
162
apremilast 30 mg BID (the recommended therapeutic dose for adults). Two hundred
163
clinical trials were simulated, with each trial having a pediatric population (patients
164
weighing 20 to <70 kg grouped in 5-kg increments) and an adult reference population.
165
The ratio of the geometric mean (GM) of AUC0‒12 for a given pediatric body weight
166
group relative to the GM of AUC0‒12 in adults was computed, and the median of the ratio
167
and its 90% predictive interval (PI) were constructed from the 200 simulated trials.
Pediatric Phase 2
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168
Safety, taste and acceptability, and mean percentage change from baseline in PASI
169
score were analyzed in the safety population (patients who received ≥1 dose of
170
apremilast) and summarized using descriptive statistics. Adverse events were classified
171
using MedDRA v.20.0 and summarized by system organ class, preferred term, severity,
172
and relationship to apremilast.
173 174
RESULTS
175
Patients
176
A total of 42 patients (21 adolescents in Group 1 and 21 children in Group 2) were
177
enrolled and treated with apremilast; 31 patients (73.8%) completed the extension
178
period and 11 (26.2%) had discontinued treatment. Primary reasons for discontinuation
179
included withdrawal by patient (n=6, 14.3%), AE (n=2, 4.8%), lost to follow-up (n=1,
180
2.4%), and other (n=2, 4.8%). One of the patients who discontinued for other reasons
181
withdrew due to patient-determined insufficient response to treatment; at the time of
182
withdrawal (Week 12), the patient had achieved a PASI-50 response. The other patient
183
who discontinued for other reasons was withdrawn from the study due to answering
184
“yes” to a Columbia-Suicide Severity Rating Scale (C-SSRS) question regarding
185
suicidal ideation. As required by the protocol, this patient was withdrawn from the study
186
and referred for psychiatric evaluation; suicidal ideation was excluded. There were no
187
withdrawals due to protocol deviation or noncompliance. Overall, 92.9% of patients
188
were compliant with study treatment. A total of 38 patients were included in the
189
noncompartmental PK analysis, and all 42 patients were included in the population PK
190
and safety analyses. Most patients were white (76.2%). At baseline, 9.5% of patients
Pediatric Phase 2
Page 8 of 25
191
were overweight, and 35.7% were obese (Table SI). Prior use of conventional systemic
192
medications (n=1, 4.8%) and biologics (n=2, 9.5%) was low in adolescents. Use of
193
conventional systemic medications was also low in children (n=2, 9.5%); no child had
194
received prior treatment with a biologic. Mean duration of psoriasis was longer for
195
adolescents (7.2 years) than children (2.8 years).
196 197
Noncompartmental PK Analysis
198
Apremilast concentration-versus-time profiles on Day 14 by dose and age group
199
(Figure 1A) showed that apremilast concentrations were lower in adolescents who
200
received apremilast 20 mg BID compared with adolescents who received apremilast 30
201
mg BID and children who received apremilast 20 mg BID. Apremilast concentrations
202
were mostly lower among patients whose body weight was 50 to <70 kg who received
203
apremilast 20 mg BID compared with those weighing ≥70 kg who received apremilast
204
30 mg BID and those weighing <50 kg who received apremilast 20 mg BID (Figure 1B).
205
Summary statistics for apremilast PK parameters are listed by age group in
206
Table I and by body weight category in Table II. Apremilast reached the maximal
207
concentration at 2 to 3 hours post-dose. Comparison of dose-normalized exposure to
208
apremilast revealed a 27% increase in Cmax in children compared with adolescents.
209
Compared to the exposure (AUC0‒12) in adolescents taking apremilast 30 mg BID
210
(2,902 ng•h/mL), similar exposure was observed in children treated with apremilast 20
211
mg BID (2,545 ng•h/mL); however, exposure decreased by 38% in adolescents taking
212
apremilast 20 mg BID (1,800 ng•h/mL) (Table I). Exposure (AUC0‒12) with apremilast 20
213
mg BID in pediatric patients weighing <50 kg (2,519 ng•h/mL) was comparable to
Pediatric Phase 2
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exposure with apremilast 30 mg BID in pediatric patients weighing ≥70 kg (2,902
215
ng•h/mL), but exposure with apremilast 20 mg BID was lower in pediatric patients
216
weighing ≥50 kg and <70 kg (1,872 ng•h/mL) (Table II).
217 218
Population PK Analysis
219
A linear one-compartment model with delayed first-order absorption and first-order
220
elimination was developed that adequately described the apremilast concentration-time
221
data in pediatric patients with moderate to severe plaque psoriasis. A detailed
222
description of the development of the population PK model and analysis results is
223
provided in the Supplementary Appendix. The model-based simulations revealed that exposure (AUC0-12) with apremilast
224 225
20 mg BID in pediatric patients weighing 20 to <50 kg was predicted to be similar to
226
exposure with apremilast 30 mg BID in adults (median of ratio within 0.8 to 1.25)
227
(Figure S2). Pediatric patients weighing 45 to <50 kg were more likely to be at the lower
228
end of the target exposure range with apremilast 20 mg BID. Pediatric patients weighing
229
≥50 kg would be considered underdosed with apremilast 20 mg BID (median of ratio
230
<0.8).
231 232
Safety
233
Most patients (95.2%) experienced ≥1 TEAE, and most TEAEs were mild to moderate
234
(Table III). One patient in Group 1 treated with apremilast 20 mg BID had 1 severe
235
TEAE each of headache and abdominal pain; both began on Day 1 and resolved the
236
next day. One patient in Group 2 (apremilast 20 mg BID) had a severe TEAE of
Pediatric Phase 2
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237
eosinophilia on Day 196; treatment was withdrawn. Nine days after the TEAE of
238
eosinophilia, a TEAE of Blastocystis hominis was reported as the cause of eosinophilia.
239
Both TEAEs resolved after an 11-day course of metronidazole and were not suspected
240
to be related to study treatment. One patient in Group 2 (apremilast 20 mg BID)
241
withdrew from the study after experiencing mild TEAEs of crying, headache, and sleep
242
disorder on Day 2. These events were suspected to be related to study treatment and
243
resolved after withdrawal of study drug. One patient in Group 2 experienced a serious
244
AE of hospitalization for moderate syncope. This event resolved and was not suspected
245
to be related to treatment, and the patient completed the study. The most frequently
246
reported AEs overall were nausea (52.4%), headache (45.2%), abdominal pain (42.9%),
247
nasopharyngitis (38.1%), diarrhea (35.7%), and vomiting (31.0%; Table III). Nausea,
248
nasopharyngitis, and diarrhea occurred more frequently in Group 1 versus Group 2, and
249
headache, abdominal pain, and vomiting occurred more frequently in Group 2 than in
250
Group 1. Onset of diarrhea, headache, and nausea mostly occurred within the first
251
month of treatment; these AEs generally resolved within 3 days (Table SII). Among
252
patients with ≥1 gastrointestinal (GI) AE, there was no trend in the occurrence of GI AEs
253
and no apparent relationship to dose. Few marked abnormalities in laboratory
254
assessments were observed (Table SIII).
255
In Group 1, 2 adolescents treated with apremilast 20 mg BID had AEs of
256
transient, moderate weight loss that resolved at study follow-up (baseline BMI: 28.8
257
kg/m2; Week 52 BMI: 29.8 kg/m2; and baseline body mass index (BMI): 18.6 kg/m2;
258
Week 52 BMI: 18.3 kg/m2). Additional details regarding the patients’ weight loss are
259
provided in Table SIV.
Pediatric Phase 2
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260
Taste and Acceptability
261
The majority of patients liked the taste of the apremilast tablet “very much” (45.2%) or “a
262
little” (14.3%) (Figure S3). A total of 3 patients indicated they disliked the taste of the
263
apremilast tablet “very much” (all in Group 2, apremilast 20 mg BID), and 2 patients
264
indicated they disliked the taste “a little” (1 patient in Group 1, apremilast 20 mg BID; 1
265
patient in Group 2, apremilast 20 mg BID).
266 267
Exploratory Efficacy
268
Improvement in PASI score was observed in patients treated with apremilast 20 mg BID
269
and apremilast 30 mg BID as early as Week 2 (Figure S4). At Week 16, mean (SD)
270
percentage change from baseline in PASI score was −69.6 (19.5) for adolescents
271
treated with apremilast 20 mg BID, −66.5 (17.1) for adolescents treated with apremilast
272
30 mg BID, and −79.3 (17.4) for children treated with apremilast 20 mg BID.
273 274
DISCUSSION
275
In this first-time-in-children phase 2 clinical study of apremilast, PK results and
276
simulations based on the population PK model support the use of weight-based dosing
277
of apremilast in children and adolescents with moderate to severe plaque psoriasis to
278
achieve exposure similar to those with apremilast 30 mg BID in adults. This bridging
279
strategy using an exposure-matching approach is in agreement with pediatric studies of
280
other systemic psoriasis treatments, in which weight-adjusted dosing ensured
281
exposures comparable to those seen in adults.14,15 Our exploratory efficacy findings
282
lend further support to the use of weight-based dosing in pediatric patients. A planned
Pediatric Phase 2
Page 12 of 25
283
phase 3 study will investigate the efficacy and safety of weight-based apremilast dosing
284
for children and adolescents with moderate to severe plaque psoriasis.
285
The safety profile of apremilast has been studied extensively in adults,
286
demonstrating an acceptable safety profile during placebo-controlled treatment (through
287
16 weeks) and with long-term exposure (through ≥156 weeks).16-18 In the current study,
288
apremilast safety in pediatric patients was generally similar to that observed in adults
289
but with a higher incidence of common AEs, particularly of diarrhea, nausea, abdominal
290
pain, viral upper respiratory tract infection, headache, and vomiting. 16,17 Dose titration
291
was not implemented in this study, which may have contributed to the higher incidence
292
of some AEs. In adult trials, dose titration was implemented to help mitigate potential GI
293
AEs, which usually occurred early in treatment. Dose titration will be implemented in the
294
phase 3 study to minimize GI AEs, as has been done in adult studies of apremilast.
295
Although 2 AEs of weight loss were reported, they were transient and resolved during
296
the study.
297
Because children with psoriasis may require treatment into adulthood, there is an
298
unmet need for effective therapies that minimize serious risks. Real-world studies have
299
demonstrated the effectiveness of conventional systemic agents, such as methotrexate,
300
cyclosporine, and acitretin, for pediatric patients with psoriasis,19-22 and these
301
conventional systemic agents are sometimes used off-label in this patient population. In
302
our study, 1 patient had received prior treatment with methotrexate (Group 1, apremilast
303
30 mg BID), and 1 with acitretin (Group 2, apremilast 20 mg BID). However, the use of
304
these agents is limited by concerns about safety and the need for frequent laboratory
305
monitoring.2,10 Biologic medications also have known safety concerns, including the
Pediatric Phase 2
Page 13 of 25
306
potential for injection-site reactions and an increased risk of opportunistic infections
307
(e.g., mycobacterial infections).2,23-25 In addition, neutralizing anti-drug antibodies can
308
form in biologic-treated patients and may be associated with reduced efficacy.26 Our
309
preliminary findings provide the first evidence of the potential efficacy of apremilast in
310
pediatric patients with plaque psoriasis, and safety was generally consistent with the
311
known safety profile of apremilast in adult patients with psoriasis.
312
Study limitations included the small sample and predominantly white study
313
population. Also, no children weighing <20 kg were enrolled. Larger studies could detect
314
rare safety events among pediatric patients. The use of PASI score as an exploratory
315
endpoint is also a limitation, as PASI is not a validated measure in pediatric patients
316
with psoriasis.
317
A review of the literature found that approximately 50% to 88% of children and
318
adolescents receiving treatment for a chronic disease do not adhere to prescription
319
medications. Pediatric patients may dislike the sticky or greasy feel of topical
320
medications or find them time-consuming to apply.27 Aversion to injections for biologics
321
and the need for frequent laboratory monitoring with conventional systemic therapies
322
may also present challenges when treating children or adolescents with psoriasis.10,27
323
For oral medications, taste is a major reason children refuse medications overall.2,3,28
324
Evaluating taste and palatability of psoriasis treatments in pediatric clinical trials may
325
help clinicians address adherence issues. In our study, most patients found the taste of
326
the apremilast tablet acceptable, and the high compliance rate observed is promising.
327
Pediatric Phase 2
Page 14 of 25
328
CONCLUSION
329
In this first-time-in children phase 2 study, PK safety and exploratory efficacy analyses
330
support the use of a weight-based apremilast dosing regimen in children and
331
adolescents with moderate to severe plaque psoriasis. Efficacy and safety of apremilast
332
in pediatric patients with psoriasis will be evaluated in a phase 3 study.
333 334
Acknowledgment
335
The authors acknowledge financial support for this study from Celgene Corporation.
336
The authors received editorial support in the preparation of this manuscript from Amy
337
Shaberman, PhD, of Peloton Advantage, LLC, an OPEN Health Company, Parsippany,
338
NJ, USA, sponsored by Celgene Corporation, Summit, NJ, USA. The authors, however,
339
directed and are fully responsible for all content and editorial decisions for this
340
manuscript.
341 342
Availability of Data and Material
343
Celgene is committed to responsible and transparent sharing of clinical trial data with
344
patients, healthcare practitioners, and independent researchers for the purpose of
345
improving scientific and medical knowledge as well as fostering innovative treatment
346
approaches. For more information, please visit: https://www.celgene.com/research-
347
development/clinical-trials/clinical-trials-data-sharing/.
348 349
Pediatric Phase 2
Page 15 of 25
350
Abbreviations and Acronyms
351
AE=adverse event
352
AUC0-12=area under the concentration-time curve from time 0 to 12 hours postdose
353
AUC0-t=AUC from time 0 to the last quantifiable concentration
354
BID=twice daily
355
BMI=body mass index
356
BSA=body surface area
357
CL/F=apparent total plasma clearance
358
Cmax=maximal observed plasma concentration
359
DMC=data monitoring committee
360
GI=gastrointestinal
361
PASI=Psoriasis Area and Severity Index
362
sPGA=static Physician Global Assessment
363
PI=predictive interval
364
PK=pharmacokinetic
365
t1/2=elimination half-life
366
TEAE=treatment-emergent adverse event
367
Vss/F=apparent total volume of distribution at steady state
368
Vz/F=apparent total volume based on terminal phase
369
Pediatric Phase 2
Page 16 of 25
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REFERENCES
371
1.
adult onset psoriasis. Pediatr Dermatol. 2000;17(3):174-178.
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Raychaudhuri SP, Gross J. A comparative study of pediatric onset psoriasis with
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Bronckers IM, Paller AS, van Geel MJ, van de Kerkhof PC, Seyger MM.
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Psoriasis in Children and Adolescents: Diagnosis, Management and
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Comorbidities. Paediatr Drugs. 2015;17(5):373-384.
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Stahle M, Atakan N, Boehncke WH, et al. Juvenile psoriasis and its clinical
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management: a European expert group consensus. Journal der Deutschen
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Dermatologischen Gesellschaft [Journal of the German Society of Dermatology:
379
JDDG]. 2010;8(10):812-818.
380
4.
Paller AS, Singh R, Cloutier M, et al. Prevalence of Psoriasis in Children and
381
Adolescents in the United States: A Claims-Based Analysis. J Drugs Dermatol.
382
2018;17(2):187-194.
383
5.
Tollefson MM, Crowson CS, McEvoy MT, Maradit Kremers H. Incidence of
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psoriasis in children: a population-based study. J Am Acad Dermatol.
385
2010;62(6):979-987.
386
6.
of 1262 cases. Pediatr Dermatol. 2001;18(3):188-198.
387 388
Morris A, Rogers M, Fischer G, Williams K. Childhood psoriasis: a clinical review
7.
Randa H, Todberg T, Skov L, Larsen LS, Zachariae R. Health-related Quality of
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Life in Children and Adolescents with Psoriasis: A Systematic Review and Meta-
390
analysis. Acta Derm Venereol. 2017;97(5):555-563.
391
8.
Remrod C, Sjostrom K, Svensson A. Psychological differences between early-
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and late-onset psoriasis: a study of personality traits, anxiety and depression in
393
psoriasis. Br J Dermatol. 2013;169(2):344-350. Pediatric Phase 2
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9.
Silverberg NB. Update on pediatric psoriasis. Cutis. 2015;95(3):147-152.
395
10.
Vogel SA, Yentzer B, Davis SA, Feldman SR, Cordoro KM. Trends in pediatric
396
psoriasis outpatient health care delivery in the United States. Arch Dermatol.
397
2012;148(1):66-71.
398
11.
Mercy K, Kwasny M, Cordoro KM, et al. Clinical manifestations of pediatric
399
psoriasis: results of a multicenter study in the United States. Pediatr Dermatol.
400
2013;30(4):424-428.
401
12.
Papp K, Cather JC, Rosoph L, et al. Efficacy of apremilast in the treatment of
402
moderate to severe psoriasis: a randomised controlled trial. Lancet.
403
2012;380:738-746.
404
13.
Ohtsuki M, Okubo Y, Komine M, et al. Apremilast, an oral phosphodiesterase 4
405
inhibitor, in the treatment of Japanese patients with moderate to severe plaque
406
psoriasis: Efficacy, safety and tolerability results from a phase 2b randomized
407
controlled trial. J Dermatol. 2017;44(8):873-884.
408
14.
Landells I, Marano C, Hsu MC, et al. Ustekinumab in adolescent patients age 12
409
to 17 years with moderate-to-severe plaque psoriasis: results of the randomized
410
phase 3 CADMUS study. J Am Acad Dermatol. 2015;73(4):594-603.
411
15.
Langley RG, Kasichayanula S, Trivedi M, et al. Pharmacokinetics,
412
Immunogenicity, and Efficacy of Etanercept in Pediatric Patients With Moderate
413
to Severe Plaque Psoriasis. J Clin Pharmacol. 2018;58(3):340-346.
414 415
16.
Papp KA, Crowley J, Paul C, et al. Apremilast, an oral phosphodiesterase 4 inhibitor: improvements in nail and scalp psoriasis and psoriasis area and
Pediatric Phase 2
Page 18 of 25
416
severity index in patients with moderate to severe plaque psoriasis [abstract
417
2889]. Arthritis Rheumatol. 2015;67(S10).
418
17.
Paul C, Cather J, Gooderham M, et al. Efficacy and safety of apremilast, an oral
419
phosphodiesterase 4 inhibitor, in patients with moderate to severe plaque
420
psoriasis over 52 weeks: a phase III, randomized, controlled trial (ESTEEM 2). Br
421
J Dermatol. 2015;173(6):1387-1399.
422
18.
Crowley J, Thaci D, Joly P, et al. Long-term safety and tolerability of apremilast in
423
patients with psoriasis: Pooled safety analysis for >/=156 weeks from 2 phase 3,
424
randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol.
425
2017;77(2):310-317.
426
19.
van Geel MJ, Oostveen AM, Hoppenreijs EP, et al. Methotrexate in pediatric
427
plaque-type psoriasis: Long-term daily clinical practice results from the Child-
428
CAPTURE registry. J Dermatol Treat. 2015;26(5):406-412.
429
20.
Di Lernia V, Bonamonte D, Lasagni C, et al. Effectiveness and Safety of Acitretin
430
in Children with Plaque Psoriasis: A Multicenter Retrospective Analysis. Pediatr
431
Dermatol. 2016;33(5):530-535.
432
21.
Di Lernia V, Stingeni L, Boccaletti V, et al. Effectiveness and safety of
433
cyclosporine in pediatric plaque psoriasis: A multicentric retrospective analysis. J
434
Dermatol Treat. 2016;27(5):395-398.
435
22.
Ergun T, Seckin Gencosmanoglu D, Alpsoy E, et al. Efficacy, safety and drug
436
survival of conventional agents in pediatric psoriasis: A multicenter, cohort study.
437
J Dermatol. 2017;44(6):630-634.
Pediatric Phase 2
Page 19 of 25
438
23.
Bronckers I, Seyger MMB, West DP, et al. Safety of Systemic Agents for the Treatment of Pediatric Psoriasis. JAMA Dermatol. 2017;153(11):1147-1157.
439 440
24.
Enbrel [package insert]. Thousand Oaks, CA: Immunex Corporation; 2017.
441
25.
Remicade (infliximab) [package insert]. Horsham, PA: Janssen Biotech, Inc.; 2018.
442 443
26.
Inflammatory Diseases: A Systematic Review. Biodrugs. 2017;31(4):299-316.
444 445
Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of Biologics in Chronic
27.
Shah KN, Cortina S, Ernst MM, Kichler JC. Psoriasis in childhood: effective
446
strategies to improve treatment adherence. Psoriasis (Auckland, NZ). 2015;5:43-
447
54.
448 449
28.
Mennella JA, Roberts KM, Mathew PS, Reed DR. Children's perceptions about medicines: individual differences and taste. BMC Pediatr. 2015;15:130.
450 451 452
Pediatric Phase 2
Page 20 of 25
453
Figure Legend
454
Figure 1. Mean (SD) Apremilast Plasma Concentration Over Time on Day 14 (A) by
455
Dose and Age Group, and (B) by Dose and Body Weight Group. Analysis was
456
performed in the PK population, which included patients who received ≥1 dose of
457
apremilast and had evaluable PK data. *Adolescents aged 12 to 17 years. §Children
458
aged 6 to 11 years. APR20=apremilast 20 mg twice daily; APR30=apremilast 30 mg
459
twice daily; SD=standard deviation.
Pediatric Phase 2
Page 21 of 25
460
Tables
461
Table I. Geometric Mean (Geometric CV%) Estimates of Apremilast Pharmacokinetic
462
Parameters at Day 14 by Group and Dose (PK Population) Group 2
PK Parameter,
Group 1
(children aged
(adolescents aged 12‒17 years)
6‒11 years)
N=20
N=18
Apremilast 20 mg
Apremilast 30 mg
Apremilast 20 mg
Geometric Mean
BID
BID
BID
(CV%)
n=12
n=8
n=18
AUC0-τ, ng•h/mL
1,795 (35.9)
2,900 (41.4)
2,368 (50.2)
AUC0-12, ng•h/mL
1,800 (36.0)
2,902 (41.2)
2,545 (40.8)
274 (34.3)
411 (39.7)
348 (47.4)
2.5 (1.0, 3.0)
3.0 (1.0, 5.0)
2.0 (1.9, 5.0)
t1/2, h
5.4 (43.1)
6.8 (50.3)
4.9 (30.2)
CL/F, L/h
11.1 (36.0)
10.3 (41.2)
7.9 (40.8)
87 (56.1)
101 (31.6)
55 (51.2)
Cmax, ng/mL Tmax, h*
Vss/F, L 463
N represents the total sample; number of patients with data available may vary. *Median
464
(range). Group 1=adolescents ages 12 to 17 years, inclusive; weight ≥35 kg. Patients
465
weighing ≥35 kg to <70 kg received APR20; patients weighing ≥70 kg received
466
apremilast 30 mg. Group 2=children ages 6 to 11 years, inclusive; weight ≥15 kg. All
467
patients in Group 2 received apremilast 20 mg. Analysis was performed in the PK
468
population, which included patients who received ≥1 dose of apremilast and had
469
evaluable PK data. AUC0-12=area under the curve from time 0 to 12 hours postdose;
470
AUC0-t=AUC from time 0 to the last quantifiable concentration; Cl/F=apparent total
471
plasma clearance; Cmax=Maximal observed plasma concentration; CV%=percent
472
coefficient of variation; PK=pharmacokinetic; t1/2=elimination half-life; Vss/F=apparent
473
total volume of distribution at steady state.
474
Pediatric Phase 2
Page 22 of 25
475
Table II. Geometric Mean (Geometric CV%) Estimates of Apremilast Pharmacokinetic
476
Parameters at Day 14 by Dose and Baseline Body Weight Group (PK Population) Apremilast 20 mg
Apremilast 20 mg
Apremilast 30 mg
PK Parameter,
BID
BID
BID
Geometric Mean
<50 kg
50 to <70 kg
≥70 kg
n=16
n=14
n=8
AUC0-τ, ng•h/mL
2,501 (41.8)
1,754 (44.5)
2,900 (41.4)
AUC0-12, ng•h/mL
2,519 (41.5)
1,872 (38.3)
2,902 (41.2)
368 (44.6)
266 (35.9)
411 (39.7)
2.0 (1.9, 5.0)
2.0 (1.0, 3.0)
3.0 (1.0, 5.0)
t1/2, h
4.5 (29.2)
5.9 (38.3)
6.8 (50.3)
CL/F, L/h
7.9 (41.5)
10.7 (38.3)
10.3 (41.2)
Vss/F, L
51.9 (50.3)
90.5 (49.0)
101.0 (31.6)
(CV%)
Cmax, ng/mL Tmax, h*
477
N represents the total sample; number of patients with data available may vary. *Median
478
(range). Analysis was performed in the PK population, which included patients who
479
received ≥1 dose of apremilast and had evaluable PK data. AUC0-12=area under the
480
curve from time 0 to 12 hours postdose; AUC0-t=AUC from time 0 to the last quantifiable
481
concentration; Cl/F=apparent total plasma clearance; Cmax=Maximal observed plasma
482
concentration; CV%=percent coefficient of variation; PK=pharmacokinetic;
483
t1/2=elimination half-life; Vss/F=apparent total volume of distribution at steady state.
484
Pediatric Phase 2
Page 23 of 25
485
Table III. Overview of AEs and AEs Occurring in ≥5% of Patients Group 2 Group 1
(children
(adolescents aged
aged 6‒11
12‒17 years)
years)
N=21
N=21
Total
Apremilast
Apremilast
Apremilast
20 mg BID
30 mg BID
20 mg BID
n=13
n=8
n=21
N=42
≥1 AE
13 (100)
7 (87.5)
20 (95.2)
40 (95.2)
≥1 Drug-related AE
11 (84.6)
6 (75.0)
17 (81.0)
34 (81.0)
≥1 Severe AE
1 (7.7)
0
1 (4.8)
2 (4.8)
≥1 Serious AE
0
0
1 (4.8)
1 (2.4)
1 (7.7)
0
4 (19.0)
5 (11.9)
0
0
2 (9.5)
2 (4.8)
0
0
0
0
Nausea
8 (61.5)
4 (50.0)
10 (47.6)
22 (52.4)
Headache
7 (53.8)
1 (12.5)
11 (52.4)
19 (45.2)
Abdominal pain
6 (46.2)
1 (12.5)
11 (52.4)
18 (42.9)
Nasopharyngitis
6 (46.2)
3 (37.5)
7 (33.3)
16 (38.1)
Diarrhea
6 (46.2)
4 (50.0)
5 (23.8)
15 (35.7)
Vomiting
4 (30.8)
1 (12.5)
8 (38.1)
13 (31.0)
Gastroenteritis
2 (15.4)
1 (12.5)
5 (23.8)
8 (19.0)
Cough
3 (23.1)
1 (12.5)
2 (9.5)
6 (14.3)
Upper abdominal pain
2 (15.4)
1 (12.5)
4 (19.0)
7 (16.7)
Oropharyngeal pain
2 (15.4)
0
3 (14.3)
5 (11.9)
Abdominal distension
1 (7.7)
1 (12.5)
3 (14.3)
5 (11.9)
Decreased appetite
2 (15.4)
1 (12.5)
1 (4.8)
4 (9.5)
Patients, n (%)
≥1 AE leading to drug interruption ≥1 AE leading to drug withdrawal ≥1 AE leading to death
Pediatric Phase 2
Page 24 of 25
Dyspepsia
2 (15.4)
1 (12.5)
1 (4.8)
4 (9.5)
Pyrexia
1 (7.7)
1 (12.5)
2 (9.5)
4 (9.5)
Arthralgia
1 (7.7)
0
2 (9.5)
3 (7.1)
Dysmenorrhea
2 (15.4)
0
1 (4.8)
3 (7.1)
increased
0
0
3 (14.3)
3 (7.1)
Influenza
2 (15.4)
0
1 (4.8)
3 (7.1)
Insomnia
2 (15.4)
0
1 (4.8)
3 (7.1)
Protein urine present
1 (7.7)
0
2 (9.5)
3 (7.1)
Urinary tract infection
1 (7.7)
2 (25.0)
0
3 (7.1)
Viral gastroenteritis
2 (15.4)
0
1 (4.8)
3 (7.1)
Eosinophil count
486
Analysis was performed in the safety population, which included patients who received
487
≥1 dose of apremilast. AE=adverse event.
488 489
Pediatric Phase 2
Page 25 of 25
S0190-9622(19)32566-6
DOI:
https://doi.org/10.1016/j.jaad.2019.08.019
Reference:
YMJD 13739
To appear in:
Journal of the American Academy of Dermatology
Received Date: 17 January 2019 Revised Date:
26 July 2019
Accepted Date: 3 August 2019
Please cite this article as: Paller AS, Hong Y, Becker EM, de Lucas R, Paris M, Zhang W, Zhang Z, Barcellona C, Maes P, Fiorillo L, Pharmacokinetics and Safety of Apremilast in Pediatric Patients With Moderate to Severe Plaque Psoriasis: Results From a Phase 2 Open-Label Study, Journal of the American Academy of Dermatology (2019), doi: https://doi.org/10.1016/j.jaad.2019.08.019. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
1 2
Pharmacokinetics and Safety of Apremilast in Pediatric Patients With Moderate to Severe Plaque Psoriasis: Results From a Phase 2 Open-Label Study
3
Short title: Apremilast PK and Safety in Pediatric Psoriasis
4 5 6
Amy S. Paller, MD1; Ying Hong, PhD2; Emily M. Becker, MD3; Raul de Lucas, MD4; Maria Paris, MD2; Wendy Zhang, MD, MS2; Zuoshun Zhang, PhD2; Claire Barcellona, BS, MS2; Peter Maes, BA2; Loretta Fiorillo, MD5
7 8 9 10
1
Northwestern University Feinberg Medical School, Chicago, IL; 2Celgene Corporation, Summit, NJ; 3University of Texas Health Science Center – San Antonio, San Antonio TX; 4Hospital Universitario La Paz, Madrid, Spain; 5Pediatric Department, University of Alberta, Edmonton, AB, Canada
11 12 13 14 15 16 17 18
Correspondence Amy Paller, MD Northwestern University NMH Arkes Family Pavilion 676 North Saint Clair, Suite 1600 Chicago, IL 60611 Phone: 312-695-3721 Email: [email protected]
19 20 21 22 23 24 25
Word count Abstract: 216 Capsule Summary: 48 Text: 2,841 Figures: 1 (4 in supplementary appendix at http://dx.doi.org/10.17632/cm27w42ff3.1) Tables: 3 (5 in supplementary appendix at http://dx.doi.org/10.17632/cm27w42ff3.1) References: 28
26 27 28 29 30
IRB statement: This trial was conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Council for Harmonisation Harmonised Tripartite Guideline, and was approved by the Institutional Review Board or Independent Ethics Committee at each study site. All patients and/or their legally authorized representative provided written informed consent.
31
ClinicalTrials.gov: NCT02576678
32 33 34 35 36
Funding: The authors acknowledge financial support for this study from Celgene Corporation. The authors received editorial support in the preparation of this manuscript from Amy Shaberman, PhD, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, sponsored by Celgene Corporation, Summit, NJ, USA. The authors, however, directed and are fully responsible for all content and editorial decisions for this manuscript.
37 38 39 40 41 42 43 44 45 46
Conflicts of Interest Amy S. Paller has received honoraria as a consultant for Asana, Dermira, Eli Lilly, Galderma, LEO Pharma, Novartis, Pfizer, UCB, and Valeant, and has been an investigator without personal compensation for AbbVie, Celgene Corporation, Eli Lilly, Galderma, Janssen, LEO Pharma, and Novartis. Ying Hong, Maria Paris, Wendy Zhang, Zuoshun Zhang, Claire Barcellona, and Peter Maes are employees of and may have stock/stock options in Celgene Corporation. Emily M. Becker is an investigator for Celgene Corporation. Raul de Lucas has no conflicts of interest. Loretta Fiorillo has received study grants from Celgene Corporation and payment for attending advisory board meetings from Amgen, AbbVie, and Janssen.
Pediatric Phase 2
Page 1 of 25
47
Abstract
48
Background: No oral systemic treatments are approved for pediatric psoriasis patients.
49
Objective: To evaluate pharmacokinetics (PK) and safety of apremilast, an oral
50
phosphodiesterase 4 inhibitor, in pediatric psoriasis patients.
51
Methods: This phase 2, multicenter, open-label study enrolled pediatric patients with
52
moderate to severe plaque psoriasis. Patients received apremilast BID without titration
53
for 2 weeks (Group 1 [age 12‒17 years, weight ≥35 kg]: apremilast 20 or 30 mg; Group
54
2 [age 6‒11 years, weight ≥15 kg]: apremilast 20 mg), followed by a 48-week extension.
55
Primary endpoints were PK and safety. Other endpoints were taste/acceptability and
56
change from baseline in PASI score.
57
Results: A total of 42 enrolled patients (21 adolescents [age 12‒17 years] and 21
58
children [age 6‒11 years]) received apremilast. PK modeling and noncompartmental
59
analyses demonstrated that weight-based dosing with apremilast 20 mg BID in children
60
or apremilast 20 or 30 mg BID in adolescents provides exposure (AUC0‒12) that is
61
comparable with apremilast 30 mg BID in adults. The safety profile was generally similar
62
to that in adults. Most liked the taste of the tablet. Improvements from baseline in mean
63
PASI score were 68% for adolescents (overall) and 79% for children).
64
Limitations: No children weighing <20 kg were enrolled.
65
Conclusions: This first-time-in-children phase 2 study supports weight-based
66
apremilast dosing for future phase 3 studies of pediatric plaque psoriasis.
67
Pediatric Phase 2
Page 2 of 25
68
Capsule Summary
69
•
apremilast in pediatric patients with moderate to severe plaque psoriasis.
70 71
This first-time-in-children study evaluated pharmacokinetics, safety, and efficacy of
•
This study demonstrates that weight-based apremilast dosing achieved exposure
72
similar to adults, provides first evidence of potential efficacy in pediatric patients, and
73
shows safety/tolerability consistent with the adult profile.
74 75
Keywords
76
adolescent, apremilast, children, pediatric, pharmacokinetics, plaque psoriasis, safety
77
Pediatric Phase 2
Page 3 of 25
78
INTRODUCTION
79
Psoriasis is a chronic, systemic inflammatory disease that starts during childhood or
80
adolescence in approximately one-third of patients; annual prevalence in the United
81
States is estimated to be 128 per 100,000 pediatric individuals.1-4 Clinical features of
82
plaque psoriasis may differ between children and adults.2,5,6 Early, effective
83
management of psoriasis in children is important because the negative impact of this
84
lifelong disease on quality of life and psychological well-being may be cumulative.3,7,8
85
Most psoriasis treatments are not approved for use in children, who are often treated
86
off-label with the medications used for adults.2,9 Use of topical corticosteroids is
87
common in pediatric patients but may be associated with poor compliance, and
88
available systemic medications and phototherapy are typically reserved for severe or
89
refractory disease, as they may confer serious risks or require frequent monitoring.2,9-11
90
No oral systemic treatment for moderate to severe psoriasis is approved for pediatric
91
use. Apremilast, an oral phosphodiesterase 4 inhibitor, is approved for the treatment of
92
adults with moderate to severe plaque psoriasis or active psoriatic arthritis. This first-
93
time-in-children phase 2 study evaluated the pharmacokinetics (PK), safety of
94
apremilast, and taste of the apremilast tablet in pediatric patients with moderate to
95
severe plaque psoriasis, with the primary aim of informing the pediatric doses for a
96
phase 3 study.
97 98
METHODS
99
Patients
100
The study enrolled pediatric patients aged 6 to 17 years with moderate to severe plaque
101
psoriasis (Psoriasis Area and Severity Index [PASI] score ≥12, psoriasis-involved body Pediatric Phase 2
Page 4 of 25
102
surface area [BSA] ≥10%, static Physician Global Assessment [sPGA ] ≥3 [moderate to
103
severe]) for ≥6 months before screening and whose disease was inadequately
104
controlled by or inappropriate for topical therapy. Eligible patients were candidates for
105
systemic or phototherapy and had been exposed to ≤1 systemic agent for psoriasis with
106
sufficient washout time before initiating study treatment. Further details on inclusion
107
criteria as well as exclusion criteria for washout times are provided in the
108
Supplementary Appendix available at http://dx.doi.org/10.17632/cm27w42ff3.1.
109 110
Study Design
111
This phase 2, multicenter, open-label PK and safety study was conducted at 10 sites in
112
the United States, Canada, and Europe (NCT02576678). After a 5-week screening
113
period, patients received apremilast for 2 weeks, followed by a 48-week extension
114
treatment period and a post-treatment observational follow-up period of up to 52 weeks
115
after the last dose of apremilast (Figure S1). Dosing was weight-based using a
116
staggered, stepwise approach by age range and body weight (starting with older and
117
heavier patients). Doses for younger patients and patients with lower body weight had
118
the option for adjustment by an independent data monitoring committee based on safety
119
and PK data from older and heavier patients. In Group 1, adolescents aged 12 to 17
120
years, weighing ≥35 to <70 kg, received apremilast 20 mg BID and those weighing ≥70
121
kg received apremilast 30 mg BID (the approved dosing regimen for adults). In Group 2,
122
children aged 6 to 11 years (weight ≥15 kg) received apremilast 20 mg BID. All doses
123
administered in the clinic were given under direct supervision of trained staff. Individuals
124
responsible for dosing checked each patient’s mouth to ensure that the tablet had been
Pediatric Phase 2
Page 5 of 25
125
swallowed whole (i.e., not chewed or crushed). Compliance for outpatient administration
126
was evaluated by pill count, as outlined in the Supplementary Appendix. This trial was
127
conducted in accordance with the principles of Good Clinical Practice and the
128
Declaration of Helsinki, and was approved by the Institutional Review Board or
129
Independent Ethics Committee. All patients and/or their legally authorized
130
representatives provided written informed assent/consent.
131 132
Endpoints
133
The primary analysis assessed PK parameters using a noncompartmental analysis
134
(NCA) approach based on venous blood samples obtained on Day 1 (2 hours post-
135
morning dose, both groups) and Day 14 (Group 1: predose and 1, 2, 3, 5, 8, 12, and 24
136
hours post-morning dose [a protocol amendment later removed the 24-hour post-Day
137
14 PK sample]; Group 2: predose and 2, 5, and 12 hours post-morning dose). Plasma
138
apremilast concentrations were measured using validated liquid chromatography
139
tandem mass spectrometry. Maximal observed plasma concentration (Cmax), time to
140
Cmax (tmax), area under the curve from time 0 to 12 hours postdose (AUC0−12), AUC from
141
time 0 to the last quantifiable concentration (AUC0−t), apparent total plasma clearance
142
(CL/F), apparent total volume of distribution at steady state (Vss/F) or based on terminal
143
phase (Vz/F), and elimination half-life (t1/2) were evaluated. Safety was evaluated based
144
on treatment-emergent adverse events (TEAEs), laboratory assessments, and clinical
145
assessments.
Pediatric Phase 2
Page 6 of 25
146
The secondary endpoint was taste and acceptability of the apremilast tablet,
147
assessed using a faces Likert scale on Day 1. PASI was evaluated as an exploratory
148
endpoint at screening, baseline, and Weeks 2, 4, 8, 16, 24, 32, 40, and 50.
149 150
Statistical Analysis
151
PK analyses based on an NCA approach were performed in the PK population (patients
152
who received ≥1 dose of apremilast and had evaluable PK data). PK parameters on
153
Day 14 were calculated using plasma concentrations and actual blood sampling times
154
(Phoenix WinNonlin v.8.0), and were summarized by study group and by baseline body
155
weight category (<50 kg, 50 to <70 kg, and ≥70 kg).
156
A population PK model was developed using pooled PK data from the current
157
pediatric study and prior dose-finding studies of apremilast in adults with moderate to
158
severe psoriasis (PSOR-011 and PSOR-005).12,13 Details regarding the population PK
159
analysis are in the Supplementary Appendix. Model-based simulations were performed
160
to determine the range of body weight in pediatric patients treated with apremilast 20
161
mg BID that could achieve steady-state AUC0-12 similar to that in adults treated with
162
apremilast 30 mg BID (the recommended therapeutic dose for adults). Two hundred
163
clinical trials were simulated, with each trial having a pediatric population (patients
164
weighing 20 to <70 kg grouped in 5-kg increments) and an adult reference population.
165
The ratio of the geometric mean (GM) of AUC0‒12 for a given pediatric body weight
166
group relative to the GM of AUC0‒12 in adults was computed, and the median of the ratio
167
and its 90% predictive interval (PI) were constructed from the 200 simulated trials.
Pediatric Phase 2
Page 7 of 25
168
Safety, taste and acceptability, and mean percentage change from baseline in PASI
169
score were analyzed in the safety population (patients who received ≥1 dose of
170
apremilast) and summarized using descriptive statistics. Adverse events were classified
171
using MedDRA v.20.0 and summarized by system organ class, preferred term, severity,
172
and relationship to apremilast.
173 174
RESULTS
175
Patients
176
A total of 42 patients (21 adolescents in Group 1 and 21 children in Group 2) were
177
enrolled and treated with apremilast; 31 patients (73.8%) completed the extension
178
period and 11 (26.2%) had discontinued treatment. Primary reasons for discontinuation
179
included withdrawal by patient (n=6, 14.3%), AE (n=2, 4.8%), lost to follow-up (n=1,
180
2.4%), and other (n=2, 4.8%). One of the patients who discontinued for other reasons
181
withdrew due to patient-determined insufficient response to treatment; at the time of
182
withdrawal (Week 12), the patient had achieved a PASI-50 response. The other patient
183
who discontinued for other reasons was withdrawn from the study due to answering
184
“yes” to a Columbia-Suicide Severity Rating Scale (C-SSRS) question regarding
185
suicidal ideation. As required by the protocol, this patient was withdrawn from the study
186
and referred for psychiatric evaluation; suicidal ideation was excluded. There were no
187
withdrawals due to protocol deviation or noncompliance. Overall, 92.9% of patients
188
were compliant with study treatment. A total of 38 patients were included in the
189
noncompartmental PK analysis, and all 42 patients were included in the population PK
190
and safety analyses. Most patients were white (76.2%). At baseline, 9.5% of patients
Pediatric Phase 2
Page 8 of 25
191
were overweight, and 35.7% were obese (Table SI). Prior use of conventional systemic
192
medications (n=1, 4.8%) and biologics (n=2, 9.5%) was low in adolescents. Use of
193
conventional systemic medications was also low in children (n=2, 9.5%); no child had
194
received prior treatment with a biologic. Mean duration of psoriasis was longer for
195
adolescents (7.2 years) than children (2.8 years).
196 197
Noncompartmental PK Analysis
198
Apremilast concentration-versus-time profiles on Day 14 by dose and age group
199
(Figure 1A) showed that apremilast concentrations were lower in adolescents who
200
received apremilast 20 mg BID compared with adolescents who received apremilast 30
201
mg BID and children who received apremilast 20 mg BID. Apremilast concentrations
202
were mostly lower among patients whose body weight was 50 to <70 kg who received
203
apremilast 20 mg BID compared with those weighing ≥70 kg who received apremilast
204
30 mg BID and those weighing <50 kg who received apremilast 20 mg BID (Figure 1B).
205
Summary statistics for apremilast PK parameters are listed by age group in
206
Table I and by body weight category in Table II. Apremilast reached the maximal
207
concentration at 2 to 3 hours post-dose. Comparison of dose-normalized exposure to
208
apremilast revealed a 27% increase in Cmax in children compared with adolescents.
209
Compared to the exposure (AUC0‒12) in adolescents taking apremilast 30 mg BID
210
(2,902 ng•h/mL), similar exposure was observed in children treated with apremilast 20
211
mg BID (2,545 ng•h/mL); however, exposure decreased by 38% in adolescents taking
212
apremilast 20 mg BID (1,800 ng•h/mL) (Table I). Exposure (AUC0‒12) with apremilast 20
213
mg BID in pediatric patients weighing <50 kg (2,519 ng•h/mL) was comparable to
Pediatric Phase 2
Page 9 of 25
214
exposure with apremilast 30 mg BID in pediatric patients weighing ≥70 kg (2,902
215
ng•h/mL), but exposure with apremilast 20 mg BID was lower in pediatric patients
216
weighing ≥50 kg and <70 kg (1,872 ng•h/mL) (Table II).
217 218
Population PK Analysis
219
A linear one-compartment model with delayed first-order absorption and first-order
220
elimination was developed that adequately described the apremilast concentration-time
221
data in pediatric patients with moderate to severe plaque psoriasis. A detailed
222
description of the development of the population PK model and analysis results is
223
provided in the Supplementary Appendix. The model-based simulations revealed that exposure (AUC0-12) with apremilast
224 225
20 mg BID in pediatric patients weighing 20 to <50 kg was predicted to be similar to
226
exposure with apremilast 30 mg BID in adults (median of ratio within 0.8 to 1.25)
227
(Figure S2). Pediatric patients weighing 45 to <50 kg were more likely to be at the lower
228
end of the target exposure range with apremilast 20 mg BID. Pediatric patients weighing
229
≥50 kg would be considered underdosed with apremilast 20 mg BID (median of ratio
230
<0.8).
231 232
Safety
233
Most patients (95.2%) experienced ≥1 TEAE, and most TEAEs were mild to moderate
234
(Table III). One patient in Group 1 treated with apremilast 20 mg BID had 1 severe
235
TEAE each of headache and abdominal pain; both began on Day 1 and resolved the
236
next day. One patient in Group 2 (apremilast 20 mg BID) had a severe TEAE of
Pediatric Phase 2
Page 10 of 25
237
eosinophilia on Day 196; treatment was withdrawn. Nine days after the TEAE of
238
eosinophilia, a TEAE of Blastocystis hominis was reported as the cause of eosinophilia.
239
Both TEAEs resolved after an 11-day course of metronidazole and were not suspected
240
to be related to study treatment. One patient in Group 2 (apremilast 20 mg BID)
241
withdrew from the study after experiencing mild TEAEs of crying, headache, and sleep
242
disorder on Day 2. These events were suspected to be related to study treatment and
243
resolved after withdrawal of study drug. One patient in Group 2 experienced a serious
244
AE of hospitalization for moderate syncope. This event resolved and was not suspected
245
to be related to treatment, and the patient completed the study. The most frequently
246
reported AEs overall were nausea (52.4%), headache (45.2%), abdominal pain (42.9%),
247
nasopharyngitis (38.1%), diarrhea (35.7%), and vomiting (31.0%; Table III). Nausea,
248
nasopharyngitis, and diarrhea occurred more frequently in Group 1 versus Group 2, and
249
headache, abdominal pain, and vomiting occurred more frequently in Group 2 than in
250
Group 1. Onset of diarrhea, headache, and nausea mostly occurred within the first
251
month of treatment; these AEs generally resolved within 3 days (Table SII). Among
252
patients with ≥1 gastrointestinal (GI) AE, there was no trend in the occurrence of GI AEs
253
and no apparent relationship to dose. Few marked abnormalities in laboratory
254
assessments were observed (Table SIII).
255
In Group 1, 2 adolescents treated with apremilast 20 mg BID had AEs of
256
transient, moderate weight loss that resolved at study follow-up (baseline BMI: 28.8
257
kg/m2; Week 52 BMI: 29.8 kg/m2; and baseline body mass index (BMI): 18.6 kg/m2;
258
Week 52 BMI: 18.3 kg/m2). Additional details regarding the patients’ weight loss are
259
provided in Table SIV.
Pediatric Phase 2
Page 11 of 25
260
Taste and Acceptability
261
The majority of patients liked the taste of the apremilast tablet “very much” (45.2%) or “a
262
little” (14.3%) (Figure S3). A total of 3 patients indicated they disliked the taste of the
263
apremilast tablet “very much” (all in Group 2, apremilast 20 mg BID), and 2 patients
264
indicated they disliked the taste “a little” (1 patient in Group 1, apremilast 20 mg BID; 1
265
patient in Group 2, apremilast 20 mg BID).
266 267
Exploratory Efficacy
268
Improvement in PASI score was observed in patients treated with apremilast 20 mg BID
269
and apremilast 30 mg BID as early as Week 2 (Figure S4). At Week 16, mean (SD)
270
percentage change from baseline in PASI score was −69.6 (19.5) for adolescents
271
treated with apremilast 20 mg BID, −66.5 (17.1) for adolescents treated with apremilast
272
30 mg BID, and −79.3 (17.4) for children treated with apremilast 20 mg BID.
273 274
DISCUSSION
275
In this first-time-in-children phase 2 clinical study of apremilast, PK results and
276
simulations based on the population PK model support the use of weight-based dosing
277
of apremilast in children and adolescents with moderate to severe plaque psoriasis to
278
achieve exposure similar to those with apremilast 30 mg BID in adults. This bridging
279
strategy using an exposure-matching approach is in agreement with pediatric studies of
280
other systemic psoriasis treatments, in which weight-adjusted dosing ensured
281
exposures comparable to those seen in adults.14,15 Our exploratory efficacy findings
282
lend further support to the use of weight-based dosing in pediatric patients. A planned
Pediatric Phase 2
Page 12 of 25
283
phase 3 study will investigate the efficacy and safety of weight-based apremilast dosing
284
for children and adolescents with moderate to severe plaque psoriasis.
285
The safety profile of apremilast has been studied extensively in adults,
286
demonstrating an acceptable safety profile during placebo-controlled treatment (through
287
16 weeks) and with long-term exposure (through ≥156 weeks).16-18 In the current study,
288
apremilast safety in pediatric patients was generally similar to that observed in adults
289
but with a higher incidence of common AEs, particularly of diarrhea, nausea, abdominal
290
pain, viral upper respiratory tract infection, headache, and vomiting. 16,17 Dose titration
291
was not implemented in this study, which may have contributed to the higher incidence
292
of some AEs. In adult trials, dose titration was implemented to help mitigate potential GI
293
AEs, which usually occurred early in treatment. Dose titration will be implemented in the
294
phase 3 study to minimize GI AEs, as has been done in adult studies of apremilast.
295
Although 2 AEs of weight loss were reported, they were transient and resolved during
296
the study.
297
Because children with psoriasis may require treatment into adulthood, there is an
298
unmet need for effective therapies that minimize serious risks. Real-world studies have
299
demonstrated the effectiveness of conventional systemic agents, such as methotrexate,
300
cyclosporine, and acitretin, for pediatric patients with psoriasis,19-22 and these
301
conventional systemic agents are sometimes used off-label in this patient population. In
302
our study, 1 patient had received prior treatment with methotrexate (Group 1, apremilast
303
30 mg BID), and 1 with acitretin (Group 2, apremilast 20 mg BID). However, the use of
304
these agents is limited by concerns about safety and the need for frequent laboratory
305
monitoring.2,10 Biologic medications also have known safety concerns, including the
Pediatric Phase 2
Page 13 of 25
306
potential for injection-site reactions and an increased risk of opportunistic infections
307
(e.g., mycobacterial infections).2,23-25 In addition, neutralizing anti-drug antibodies can
308
form in biologic-treated patients and may be associated with reduced efficacy.26 Our
309
preliminary findings provide the first evidence of the potential efficacy of apremilast in
310
pediatric patients with plaque psoriasis, and safety was generally consistent with the
311
known safety profile of apremilast in adult patients with psoriasis.
312
Study limitations included the small sample and predominantly white study
313
population. Also, no children weighing <20 kg were enrolled. Larger studies could detect
314
rare safety events among pediatric patients. The use of PASI score as an exploratory
315
endpoint is also a limitation, as PASI is not a validated measure in pediatric patients
316
with psoriasis.
317
A review of the literature found that approximately 50% to 88% of children and
318
adolescents receiving treatment for a chronic disease do not adhere to prescription
319
medications. Pediatric patients may dislike the sticky or greasy feel of topical
320
medications or find them time-consuming to apply.27 Aversion to injections for biologics
321
and the need for frequent laboratory monitoring with conventional systemic therapies
322
may also present challenges when treating children or adolescents with psoriasis.10,27
323
For oral medications, taste is a major reason children refuse medications overall.2,3,28
324
Evaluating taste and palatability of psoriasis treatments in pediatric clinical trials may
325
help clinicians address adherence issues. In our study, most patients found the taste of
326
the apremilast tablet acceptable, and the high compliance rate observed is promising.
327
Pediatric Phase 2
Page 14 of 25
328
CONCLUSION
329
In this first-time-in children phase 2 study, PK safety and exploratory efficacy analyses
330
support the use of a weight-based apremilast dosing regimen in children and
331
adolescents with moderate to severe plaque psoriasis. Efficacy and safety of apremilast
332
in pediatric patients with psoriasis will be evaluated in a phase 3 study.
333 334
Acknowledgment
335
The authors acknowledge financial support for this study from Celgene Corporation.
336
The authors received editorial support in the preparation of this manuscript from Amy
337
Shaberman, PhD, of Peloton Advantage, LLC, an OPEN Health Company, Parsippany,
338
NJ, USA, sponsored by Celgene Corporation, Summit, NJ, USA. The authors, however,
339
directed and are fully responsible for all content and editorial decisions for this
340
manuscript.
341 342
Availability of Data and Material
343
Celgene is committed to responsible and transparent sharing of clinical trial data with
344
patients, healthcare practitioners, and independent researchers for the purpose of
345
improving scientific and medical knowledge as well as fostering innovative treatment
346
approaches. For more information, please visit: https://www.celgene.com/research-
347
development/clinical-trials/clinical-trials-data-sharing/.
348 349
Pediatric Phase 2
Page 15 of 25
350
Abbreviations and Acronyms
351
AE=adverse event
352
AUC0-12=area under the concentration-time curve from time 0 to 12 hours postdose
353
AUC0-t=AUC from time 0 to the last quantifiable concentration
354
BID=twice daily
355
BMI=body mass index
356
BSA=body surface area
357
CL/F=apparent total plasma clearance
358
Cmax=maximal observed plasma concentration
359
DMC=data monitoring committee
360
GI=gastrointestinal
361
PASI=Psoriasis Area and Severity Index
362
sPGA=static Physician Global Assessment
363
PI=predictive interval
364
PK=pharmacokinetic
365
t1/2=elimination half-life
366
TEAE=treatment-emergent adverse event
367
Vss/F=apparent total volume of distribution at steady state
368
Vz/F=apparent total volume based on terminal phase
369
Pediatric Phase 2
Page 16 of 25
370
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371
1.
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Raychaudhuri SP, Gross J. A comparative study of pediatric onset psoriasis with
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Bronckers IM, Paller AS, van Geel MJ, van de Kerkhof PC, Seyger MM.
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Psoriasis in Children and Adolescents: Diagnosis, Management and
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Comorbidities. Paediatr Drugs. 2015;17(5):373-384.
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Stahle M, Atakan N, Boehncke WH, et al. Juvenile psoriasis and its clinical
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management: a European expert group consensus. Journal der Deutschen
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Dermatologischen Gesellschaft [Journal of the German Society of Dermatology:
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JDDG]. 2010;8(10):812-818.
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Paller AS, Singh R, Cloutier M, et al. Prevalence of Psoriasis in Children and
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Adolescents in the United States: A Claims-Based Analysis. J Drugs Dermatol.
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Tollefson MM, Crowson CS, McEvoy MT, Maradit Kremers H. Incidence of
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Morris A, Rogers M, Fischer G, Williams K. Childhood psoriasis: a clinical review
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Randa H, Todberg T, Skov L, Larsen LS, Zachariae R. Health-related Quality of
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Life in Children and Adolescents with Psoriasis: A Systematic Review and Meta-
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analysis. Acta Derm Venereol. 2017;97(5):555-563.
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8.
Remrod C, Sjostrom K, Svensson A. Psychological differences between early-
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and late-onset psoriasis: a study of personality traits, anxiety and depression in
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psoriasis. Br J Dermatol. 2013;169(2):344-350. Pediatric Phase 2
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Silverberg NB. Update on pediatric psoriasis. Cutis. 2015;95(3):147-152.
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10.
Vogel SA, Yentzer B, Davis SA, Feldman SR, Cordoro KM. Trends in pediatric
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psoriasis outpatient health care delivery in the United States. Arch Dermatol.
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Mercy K, Kwasny M, Cordoro KM, et al. Clinical manifestations of pediatric
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psoriasis: results of a multicenter study in the United States. Pediatr Dermatol.
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12.
Papp K, Cather JC, Rosoph L, et al. Efficacy of apremilast in the treatment of
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moderate to severe psoriasis: a randomised controlled trial. Lancet.
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2012;380:738-746.
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13.
Ohtsuki M, Okubo Y, Komine M, et al. Apremilast, an oral phosphodiesterase 4
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inhibitor, in the treatment of Japanese patients with moderate to severe plaque
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psoriasis: Efficacy, safety and tolerability results from a phase 2b randomized
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controlled trial. J Dermatol. 2017;44(8):873-884.
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14.
Landells I, Marano C, Hsu MC, et al. Ustekinumab in adolescent patients age 12
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to 17 years with moderate-to-severe plaque psoriasis: results of the randomized
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phase 3 CADMUS study. J Am Acad Dermatol. 2015;73(4):594-603.
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15.
Langley RG, Kasichayanula S, Trivedi M, et al. Pharmacokinetics,
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Immunogenicity, and Efficacy of Etanercept in Pediatric Patients With Moderate
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to Severe Plaque Psoriasis. J Clin Pharmacol. 2018;58(3):340-346.
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16.
Papp KA, Crowley J, Paul C, et al. Apremilast, an oral phosphodiesterase 4 inhibitor: improvements in nail and scalp psoriasis and psoriasis area and
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severity index in patients with moderate to severe plaque psoriasis [abstract
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2889]. Arthritis Rheumatol. 2015;67(S10).
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Paul C, Cather J, Gooderham M, et al. Efficacy and safety of apremilast, an oral
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phosphodiesterase 4 inhibitor, in patients with moderate to severe plaque
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psoriasis over 52 weeks: a phase III, randomized, controlled trial (ESTEEM 2). Br
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J Dermatol. 2015;173(6):1387-1399.
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18.
Crowley J, Thaci D, Joly P, et al. Long-term safety and tolerability of apremilast in
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patients with psoriasis: Pooled safety analysis for >/=156 weeks from 2 phase 3,
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randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol.
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19.
van Geel MJ, Oostveen AM, Hoppenreijs EP, et al. Methotrexate in pediatric
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plaque-type psoriasis: Long-term daily clinical practice results from the Child-
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20.
Di Lernia V, Bonamonte D, Lasagni C, et al. Effectiveness and Safety of Acitretin
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in Children with Plaque Psoriasis: A Multicenter Retrospective Analysis. Pediatr
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Dermatol. 2016;33(5):530-535.
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21.
Di Lernia V, Stingeni L, Boccaletti V, et al. Effectiveness and safety of
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cyclosporine in pediatric plaque psoriasis: A multicentric retrospective analysis. J
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Dermatol Treat. 2016;27(5):395-398.
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22.
Ergun T, Seckin Gencosmanoglu D, Alpsoy E, et al. Efficacy, safety and drug
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survival of conventional agents in pediatric psoriasis: A multicenter, cohort study.
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J Dermatol. 2017;44(6):630-634.
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23.
Bronckers I, Seyger MMB, West DP, et al. Safety of Systemic Agents for the Treatment of Pediatric Psoriasis. JAMA Dermatol. 2017;153(11):1147-1157.
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24.
Enbrel [package insert]. Thousand Oaks, CA: Immunex Corporation; 2017.
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25.
Remicade (infliximab) [package insert]. Horsham, PA: Janssen Biotech, Inc.; 2018.
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26.
Inflammatory Diseases: A Systematic Review. Biodrugs. 2017;31(4):299-316.
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Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of Biologics in Chronic
27.
Shah KN, Cortina S, Ernst MM, Kichler JC. Psoriasis in childhood: effective
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strategies to improve treatment adherence. Psoriasis (Auckland, NZ). 2015;5:43-
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54.
448 449
28.
Mennella JA, Roberts KM, Mathew PS, Reed DR. Children's perceptions about medicines: individual differences and taste. BMC Pediatr. 2015;15:130.
450 451 452
Pediatric Phase 2
Page 20 of 25
453
Figure Legend
454
Figure 1. Mean (SD) Apremilast Plasma Concentration Over Time on Day 14 (A) by
455
Dose and Age Group, and (B) by Dose and Body Weight Group. Analysis was
456
performed in the PK population, which included patients who received ≥1 dose of
457
apremilast and had evaluable PK data. *Adolescents aged 12 to 17 years. §Children
458
aged 6 to 11 years. APR20=apremilast 20 mg twice daily; APR30=apremilast 30 mg
459
twice daily; SD=standard deviation.
Pediatric Phase 2
Page 21 of 25
460
Tables
461
Table I. Geometric Mean (Geometric CV%) Estimates of Apremilast Pharmacokinetic
462
Parameters at Day 14 by Group and Dose (PK Population) Group 2
PK Parameter,
Group 1
(children aged
(adolescents aged 12‒17 years)
6‒11 years)
N=20
N=18
Apremilast 20 mg
Apremilast 30 mg
Apremilast 20 mg
Geometric Mean
BID
BID
BID
(CV%)
n=12
n=8
n=18
AUC0-τ, ng•h/mL
1,795 (35.9)
2,900 (41.4)
2,368 (50.2)
AUC0-12, ng•h/mL
1,800 (36.0)
2,902 (41.2)
2,545 (40.8)
274 (34.3)
411 (39.7)
348 (47.4)
2.5 (1.0, 3.0)
3.0 (1.0, 5.0)
2.0 (1.9, 5.0)
t1/2, h
5.4 (43.1)
6.8 (50.3)
4.9 (30.2)
CL/F, L/h
11.1 (36.0)
10.3 (41.2)
7.9 (40.8)
87 (56.1)
101 (31.6)
55 (51.2)
Cmax, ng/mL Tmax, h*
Vss/F, L 463
N represents the total sample; number of patients with data available may vary. *Median
464
(range). Group 1=adolescents ages 12 to 17 years, inclusive; weight ≥35 kg. Patients
465
weighing ≥35 kg to <70 kg received APR20; patients weighing ≥70 kg received
466
apremilast 30 mg. Group 2=children ages 6 to 11 years, inclusive; weight ≥15 kg. All
467
patients in Group 2 received apremilast 20 mg. Analysis was performed in the PK
468
population, which included patients who received ≥1 dose of apremilast and had
469
evaluable PK data. AUC0-12=area under the curve from time 0 to 12 hours postdose;
470
AUC0-t=AUC from time 0 to the last quantifiable concentration; Cl/F=apparent total
471
plasma clearance; Cmax=Maximal observed plasma concentration; CV%=percent
472
coefficient of variation; PK=pharmacokinetic; t1/2=elimination half-life; Vss/F=apparent
473
total volume of distribution at steady state.
474
Pediatric Phase 2
Page 22 of 25
475
Table II. Geometric Mean (Geometric CV%) Estimates of Apremilast Pharmacokinetic
476
Parameters at Day 14 by Dose and Baseline Body Weight Group (PK Population) Apremilast 20 mg
Apremilast 20 mg
Apremilast 30 mg
PK Parameter,
BID
BID
BID
Geometric Mean
<50 kg
50 to <70 kg
≥70 kg
n=16
n=14
n=8
AUC0-τ, ng•h/mL
2,501 (41.8)
1,754 (44.5)
2,900 (41.4)
AUC0-12, ng•h/mL
2,519 (41.5)
1,872 (38.3)
2,902 (41.2)
368 (44.6)
266 (35.9)
411 (39.7)
2.0 (1.9, 5.0)
2.0 (1.0, 3.0)
3.0 (1.0, 5.0)
t1/2, h
4.5 (29.2)
5.9 (38.3)
6.8 (50.3)
CL/F, L/h
7.9 (41.5)
10.7 (38.3)
10.3 (41.2)
Vss/F, L
51.9 (50.3)
90.5 (49.0)
101.0 (31.6)
(CV%)
Cmax, ng/mL Tmax, h*
477
N represents the total sample; number of patients with data available may vary. *Median
478
(range). Analysis was performed in the PK population, which included patients who
479
received ≥1 dose of apremilast and had evaluable PK data. AUC0-12=area under the
480
curve from time 0 to 12 hours postdose; AUC0-t=AUC from time 0 to the last quantifiable
481
concentration; Cl/F=apparent total plasma clearance; Cmax=Maximal observed plasma
482
concentration; CV%=percent coefficient of variation; PK=pharmacokinetic;
483
t1/2=elimination half-life; Vss/F=apparent total volume of distribution at steady state.
484
Pediatric Phase 2
Page 23 of 25
485
Table III. Overview of AEs and AEs Occurring in ≥5% of Patients Group 2 Group 1
(children
(adolescents aged
aged 6‒11
12‒17 years)
years)
N=21
N=21
Total
Apremilast
Apremilast
Apremilast
20 mg BID
30 mg BID
20 mg BID
n=13
n=8
n=21
N=42
≥1 AE
13 (100)
7 (87.5)
20 (95.2)
40 (95.2)
≥1 Drug-related AE
11 (84.6)
6 (75.0)
17 (81.0)
34 (81.0)
≥1 Severe AE
1 (7.7)
0
1 (4.8)
2 (4.8)
≥1 Serious AE
0
0
1 (4.8)
1 (2.4)
1 (7.7)
0
4 (19.0)
5 (11.9)
0
0
2 (9.5)
2 (4.8)
0
0
0
0
Nausea
8 (61.5)
4 (50.0)
10 (47.6)
22 (52.4)
Headache
7 (53.8)
1 (12.5)
11 (52.4)
19 (45.2)
Abdominal pain
6 (46.2)
1 (12.5)
11 (52.4)
18 (42.9)
Nasopharyngitis
6 (46.2)
3 (37.5)
7 (33.3)
16 (38.1)
Diarrhea
6 (46.2)
4 (50.0)
5 (23.8)
15 (35.7)
Vomiting
4 (30.8)
1 (12.5)
8 (38.1)
13 (31.0)
Gastroenteritis
2 (15.4)
1 (12.5)
5 (23.8)
8 (19.0)
Cough
3 (23.1)
1 (12.5)
2 (9.5)
6 (14.3)
Upper abdominal pain
2 (15.4)
1 (12.5)
4 (19.0)
7 (16.7)
Oropharyngeal pain
2 (15.4)
0
3 (14.3)
5 (11.9)
Abdominal distension
1 (7.7)
1 (12.5)
3 (14.3)
5 (11.9)
Decreased appetite
2 (15.4)
1 (12.5)
1 (4.8)
4 (9.5)
Patients, n (%)
≥1 AE leading to drug interruption ≥1 AE leading to drug withdrawal ≥1 AE leading to death
Pediatric Phase 2
Page 24 of 25
Dyspepsia
2 (15.4)
1 (12.5)
1 (4.8)
4 (9.5)
Pyrexia
1 (7.7)
1 (12.5)
2 (9.5)
4 (9.5)
Arthralgia
1 (7.7)
0
2 (9.5)
3 (7.1)
Dysmenorrhea
2 (15.4)
0
1 (4.8)
3 (7.1)
increased
0
0
3 (14.3)
3 (7.1)
Influenza
2 (15.4)
0
1 (4.8)
3 (7.1)
Insomnia
2 (15.4)
0
1 (4.8)
3 (7.1)
Protein urine present
1 (7.7)
0
2 (9.5)
3 (7.1)
Urinary tract infection
1 (7.7)
2 (25.0)
0
3 (7.1)
Viral gastroenteritis
2 (15.4)
0
1 (4.8)
3 (7.1)
Eosinophil count
486
Analysis was performed in the safety population, which included patients who received
487
≥1 dose of apremilast. AE=adverse event.
488 489
Pediatric Phase 2
Page 25 of 25