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Achievement of the National Psoriasis Foundation Treatment Targets With Ixekizumab: Pooled Analyses From Four Clinical Studies
Journal Pre-proof Achievement of the National Psoriasis Foundation Treatment Targets With Ixekizumab: Pooled Analyses From Four Clinical Studies April Armstrong, MD, MPH, David Amato, DO, FAAD, William Huster, PhD, Clement Ojeh, PhD, Abby S. Van Voorhees, MD. PII:
S0190-9622(19)32774-4
DOI:
https://doi.org/10.1016/j.jaad.2019.09.030
Reference:
YMJD 13841
To appear in:
Journal of the American Academy of Dermatology
Received Date: 2 July 2018 Revised Date:
13 September 2019
Accepted Date: 17 September 2019
Please cite this article as: Armstrong A, Amato D, Huster W, Ojeh C, Van Voorhees AS, Achievement of the National Psoriasis Foundation Treatment Targets With Ixekizumab: Pooled Analyses From Four Clinical Studies, Journal of the American Academy of Dermatology (2019), doi: https://doi.org/10.1016/ j.jaad.2019.09.030. 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
Achievement of the National Psoriasis Foundation Treatment Targets With
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Ixekizumab: Pooled Analyses From Four Clinical Studies
3 4
April Armstrong MD, MPH1, David Amato DO, FAAD2, William Huster PhD2,
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Clement Ojeh PhD3, Abby S Van Voorhees MD.4
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1
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Indianapolis, IN, USA; 3Lilly USA, Indianapolis, IN, USA; 4Department of Dermatology,
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Eastern Virginia Medical School, Norfolk, VA, USA
University of Southern California, Los Angeles, CA, USA; 2Eli Lilly and Company,
9 10
Corresponding author:
11
April W. Armstrong, MD MPH
12
1975 Zonal Avenue
13
Office of the Dean
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Keck School of Medicine of the USC,
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Los Angeles, CA- 90033, USA
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Phone: +11-323-442-1100
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Email: [email protected]
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Funding sources: Eli Lilly and Company
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IRB approval status: The individual studies were approved by institutional review
20
boards.
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Clinicaltrials.gov (or equivalent) listing (if applicable): I1F-MC-RHAZ:
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NCT01474512; I1F-MC-RHBA: NCT01597245; I1F-MC-RHBC: NCT01646177; I1F-MC-
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RHBS: NCT02561806 1
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Related Presentation: Achievement of the National Psoriasis Foundation Treatment
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Targets Among Patients in Ixekizumab Clinical Trials: Analysis of Pooled UNCOVER
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Results was presented at National Psoriasis Foundation - 2017 Research Symposium,
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Chicago, IL, USA.
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Conflicts of Interest:
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April Armstrong has served as an investigator and/or advisor to AbbVie, BMS,
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Celgene, Janssen, Novartis, Eli Lilly and Company, Leo Pharma, Regeneron, Sanofi,
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and Ortho Dermatologics.
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D. Amato is a shareholder and former employee of Eli Lilly and Company.
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W. Huster and C. Ojeh were employees, but retired from Eli Lilly and Company.
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Abby S. Van Voorhees has received honoraria for consulting and/or participating in the
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advisory boards for: Dermira, Novartis, Allergan, Celgene, AbbVie, DermTech, Pfizer,
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Astra Zeneca, Corrona and Valeant; she also served as an investigator for Celgene,
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Lilly, and Corrona.
38 39
Reprint requests: April Armstrong
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Manuscript word count: 1684 words [excluding capsule summary, abstract,
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references, figures, and tables]
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Abstract word count: 198
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Capsule summary word count: 50
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References: 17
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Figures: 4
2
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Tables: 1
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List of Attachments: (1) Cover Letter (2) CONSORT checklist, (3) Research protocol,
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(4) Statistical analysis plan, (5) IRB Approval Letter
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Clinical trial registration: UNCOVER-1 (I1F-MC-RHAZ: NCT01474512); UNCOVER-2 (I1F-
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MC-RHBA: NCT01597245); UNCOVER-3 (I1F-MC-RHBC: NCT01646177); IXORA-S (I1F-MC-
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RHBS: NCT02561806)
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Keywords: psoriasis; IL-17; ixekizumab; etanercept; National Psoriasis Foundation;
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treatment goals; Pooled analysis
57 58 59
Capsule Summary •
treatment goals defined by the National Psoriasis Foundation.
60 61
The majority of ixekizumab-treated psoriasis subjects achieved U.S. psoriasis
•
These results provide information regarding how psoriasis therapies such as
62
ixekizumab perform using clinically relevant endpoints established by NPF treatment
63
targets, which is critical for clinicians and patients to establish meaningful treatment
64
expectations.
65 66 67 68 69
3
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Abstract
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Background: The National Psoriasis Foundation (NPF) published treatment targets for US
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patients with plaque psoriasis. However, data are lacking on how well existing therapies
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help achieve these goals.
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Objective: We examined the ability of an IL-17 inhibitor, ixekizumab, in achieving these
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treatment targets.
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Methods: Post-hoc analysis was performed on data from four Phase III clinical trials
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assessing IXE for plaque psoriasis: pooled data from the UNCOVER-1, -2, and -3 trials,
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and data from the IXORA-S trial. Treatment response was evaluated using NPF-defined
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acceptable response (AR: BSA ≤3% or BSA improvement ≥75% at 12 weeks of treatment)
80
and target response (TR: BSA ≤1% at 12 weeks and every 6 months thereafter).
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Results: In UNCOVER studies (n=2701), AR and TR rates at Week 12 were 73.9% and
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51.8% with IXE Q2W, 35.7% and 14.9% with etanercept and 3.0% and 0.6% with placebo,
83
respectively. In IXORA-S (n=302), AR and TR rates at Week 12 were significantly higher
84
with IXE Q2W versus ustekinumab (AR: 68.4% vs 38.6%, p<.0001; TR: 50.7% vs 24.1%,
85
p<.0001).
86
Limitations: Data were from controlled studies and may not reflect real-world practice.
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Conclusion: The majority of IXE-treated subjects in four phase III clinical trials achieved
88
NPF, patient-centered treatment targets.
89
90
Introduction 4
91
The existing outcome measures used in clinical trials for psoriasis are not widely used in
92
clinical practice, well-understood, or meaningful to patients. In a pivotal effort, the National
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Psoriasis Foundation (NPF) recently defined treatment goals for patients with psoriasis in
94
the US11 which represent patient-centered outcome measures relying on improvements
95
in body surface area affected. The rationale for this effort is to establish targets to inform
96
treatment decisions, reduce disease burden and improve patient outcomes in clinical
97
practice.
98 99
To date, no published data exist on how existing therapies perform in achieving psoriasis treatment targets. These data are critical because clinicians and patients need to
100
use these data to establish treatment expectations and create meaningful response to
101
treatment.
102
In this study, we examined how ixekizumab, a high-affinity monoclonal antibody that
103
selectively targets IL-17A,12 performs in achieving established treatment targets from NPF.
104
Specifically, we evaluated the endpoint of the body surface area (BSA) data from the
105
ixekizumab phase 3 trials, against NPF treatment targets. In addition, we also evaluated
106
the concordance between the achievement of acceptable response per NPF
107
recommendations and PASI response rates from the same trials.
108 109
Methods
110
Study Design
111
UNCOVER-1, -2, -313,14, and IXORA-S15 were randomized, double-blind, Phase 3
112
studies conducted in subjects with moderate-to-severe plaque psoriasis. The study design,
113
and the efficacy and safety data from these studies have been published previously 13-16, 5
114
including the methodology for integrated data from these studies (UNCOVER-1, -2 and -3)
115
13
116
and -3 studies and the IXORA-S study were analyzed individually.
117
Study Assessments
118
. For the present study, the BSA data from the integration of the three UNCOVER-1, -2
The efficacy measures analyzed were the BSA measurements collected during the
119
UNCOVER and IXORA-S trials. BSA measurements were assessed to determine
120
response rates in accordance with the recently published NPF recommendations.
121
Response rates were classified into the proportion of subjects achieving acceptable
122
response, defined as BSA ≤3% or BSA improvement ≥75% at 12 weeks of treatment11, and
123
the proportion of subjects achieving target response, defined as BSA ≤1% at 12 weeks and
124
every 6 months thereafter11. Additionally, the percentage of subjects who achieved at least
125
90% improvement from baseline in the Psoriasis Area and Severity Index (PASI) and the
126
concordance between BSA acceptable response and PASI response were also analyzed.
127
At Week 12, data only from the placebo (PBO), etanercept (ETN) and ixekizumab 80
128
mg every 2 weeks (IXE Q2W) treatment arms were evaluated from the three UNCOVER
129
trials. For the maintenance phase (after Week 12) of the trials, target responses in
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UNCOVER-1 and -2 were evaluated based on subjects who were IXE responders (those
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achieving sPGA 0,1 at Week 12), and separate analyses were performed on all treatment
132
arms. In UNCOVER-3 study, 12 to 60 weeks results were included in subjects who were
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IXE responders to the treatment at Week 12.
134 135
For IXORA-S study, target assessments were performed for all treatment arms at Week 12, and monthly through Week 52.
6
136 137
Statistical Analysis All randomized subjects were included in the efficacy analyses; data were
138
analyzed by randomized treatment group. We calculated the percentage of subjects
139
across the pooled UNCOVER studies and in the IXORA-S study who met the NPF
140
acceptable and target response criteria. For the induction period, response rates were
141
analyzed by pair-wise comparison of the treatment groups, using a Cochran-Mantel-
142
Haenszel chi-square statistical test stratified by study. All statistical testing was
143
performed 2-sided (alpha=0.05) without adjustment for multiple comparisons. Subjects
144
who discontinued the study agent for any reason were considered nonresponders for
145
the acceptable and target responses (nonresponder imputation). No statistical testing
146
was performed for the maintenance period.
147
Results
148
A total of 3003 subjects were included from UNCOVER-1, -2, -3 (n=2701) and
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IXORA-S (n=302) studies in this analysis. Overall baseline demographics and disease
150
characteristics were similar among the treatment groups across studies included (Table 1)
151
UNCOVER-1, -2, and -3 Studies
152
During induction period (Weeks 0 to 12)
153
In the UNCOVER studies, 73.9% of subjects treated with IXE Q2W achieved the
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acceptable response (BSA ≤3% or BSA improvement ≥75%) at Week 12 versus 35.7%
155
with ENT (p<.001) and 3.0% with PBO (p<.001). (Figure 1). In subjects treated with IXE
156
Q2W, 51.8% achieved, the target response (BSA ≤1%) at Week 12 versus 14.9% with
157
etanercept (p<.001) and 0.6% with placebo (p<.001). PASI 90 was achieved in 70% 7
158
subjects with IXE Q2W versus etanercept (22.3%, p<.001), and placebo (1.1%; p<.001).
159
Additionally, the concordance between BSA acceptable response and PASI over the
160
induction period for all treatment groups was best for PASI 90 (89.8%, 86.6%, and 86.7%),
161
at Week 4 (N=3771), Week 8 (N=3732), and Week 12 (N=3683), respectively.
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Maintenance period (Week 12 to 60)
163
In the UNCOVER-1 and -2 studies (n=363), the target response (BSA ≤1%) at
164
Week 60 was 74.7% in IXE Q2W responders treated with IXE Q4W through Week 60 (IXE
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Q2W to Q4W) versus 4.7% in subjects who were re-randomized to placebo (IXE Q2W to
166
placebo) (Figure 2A). In UNCOVER-3 study, the target response was 82.1% with IXE
167
Q2W-Q4W treatment at Week 60 (Figure 2B). Comparison of BSA target responses to
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PASI 75/90 and sPGA 0,1 is shown in (Figures 3A and 3B). In the UNCOVER-1 and -2
169
studies, the concordance between BSA target response and PASI over the maintenance
170
period was best for PASI 90 (80.4%, 85.5%, and 84.2%), at Week 16 (N=1216), Week 36
171
(N=857), and Week 60 (N=595), respectively.
172
In IXE non-responders (sPGA >1 at 12 weeks) from UNCOVER-1, and -2 studies
173
who were on placebo (n=546), etanercept (n=200), or IXE Q2W (n=111) and re-treated
174
with IXE Q4W, the target response rate was achieved in 68.1% with placebo-Q4W
175
subjects, 64% with etanercept to IXE Q4W, and 34.2% with IXE Q2W to IXE Q4W at Week
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60 (Figure 2C). Similar response rates were observed in IXE non-responders from
177
UNCOVER-3 study through Week 60 (Figure 2D). Additionally, in IXE non-responders
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(UNCOVER-1, and -2), PASI 90 response rate at Week 60 was 79% in subjects treated
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with PBO to Q4W, 70% with etanercept to Q4W, and 41% with Q2W-Q4W. Similar trend
8
180
was observed with PASI 75 with IXE non-responders who participated in UNCOVER-3
181
study.
182
IXORA-S Study
183
During the induction period, acceptable response and target response rates were
184
significantly higher with IXE Q2W versus ustekinumab (acceptable response: 68.4% vs
185
38.6%, p<.0001; target response: 50.7% vs 24.1%, p<.0001; Figure 4A). During the
186
maintenance period, subjects who received Q2W for the first 12 weeks and Q4W
187
thereafter, the target response was consistently higher with IXE Q2W versus ustekinumab
188
at 52 weeks (71.3% vs 56.6%, p=.0086; Figure 4B). At Week 52, PASI 90 was achieved in
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76.5% of subjects with IXE Q2W versus ustekinumab (59.0%; p<.0014).
190
Discussion
191
The NPF established the first treatment targets for psoriasis in the US, based on an
192
expert-based consensus process 11. The NPF treatment target recommendations suggest
193
that measurement of BSA would be an appropriate outcome to measure in clinical practice.
194
To date, we have not examined how well the existing therapies can help achieve these
195
treatment targets. These data are critical to inform clinicians and patients regarding how
196
well current therapies work in achieving treatment targets and how to manage patient
197
expectations and devise future treatment plans.
198
The present study is among the first efforts to determine how a biologic therapy
199
indicated for plaque psoriasis, performs in achieving these NPF treatment targets. This
200
study leverages pooled data from the ixekizumab clinical trials program to determine how
201
well an IL-17 inhibitor can meet these treatment targets based on results from four large 9
202
clinical trials with 3428 subjects. In this population of subjects with high psoriasis disease
203
severity at baseline, 75% of all subjects achieved an acceptable response of BSA ≤3% at
204
Week 12. Nearly 80% of subjects achieved target responses of BSA ≤1% by Week 60.
205
Significantly higher proportion of ixekizumab-treated subjects per US-labeled dose
206
achieved and maintained NPF-defined psoriasis treatment goals (acceptable and target
207
response at Week 12), compared to those receiving PBO, etanercept (UNCOVER -2 and -
208
3) or ustekinumab (IXORA-S). Additionally, in subjects from 4 studies analyzed, PASI 90
209
response rates were significantly higher with ixekizumab versus etanercept or
210
ustekinumab. PASI 90 responses were generally consistent with the BSA acceptable
211
response during the induction period and consistent with the BSA target response during
212
the maintenance period.
213
These study results are critical in helping clinicians understand how current psoriasis
214
therapies perform using clinically relevant endpoints established by the NPF treatment
215
targets. The study findings show that NPF treatment targets can be achieved and
216
maintained by the majority of subjects on ixekizumab, one of several psoriasis therapies
217
with robust efficacy data from clinical trials. A limitation of the current study is that the
218
analyses were conducted using results from four clinical trials, which may not be
219
representative of all patients observed in real-world clinical settings such as patients with
220
certain comorbidities.
221
Treatment targets spark dialogs between clinicians and patients regarding
222
assessment of current therapies and need for re-evaluation. When a patient does not
223
achieve treatment targets, this provides an opportunity to ask clinically relevant questions
224
such as, “Will this patient continue to improve if enough time elapses?” or “How can I 10
225
incorporate other management options to optimize the response?”. In the present analysis,
226
one-third of nonresponders who were on ixekizumab were able to achieve treatment
227
targets when ixekizumab treatment was continued for 60 weeks. Thus, the opportunity to
228
evaluate patients against treatment targets enable a reflection point for considerations of
229
dose escalations of existing therapy, adding another agent to the existing therapy, or
230
switching to an alternative agent.
231
Conclusions
232
In this analysis from 4 studies, ixekizumab-treated subjects achieved and
233
maintained a high level of skin clearance according to the NPF treatment targets. In
234
addition, the proportion of subjects who achieved treatment targets closely aligned with
235
PASI 90 results from clinical trials. Thus, the target recommendations using BSA are
236
reflective of the PASI clinical measurement system that is used in typical psoriasis clinical
237
trials. Importantly, achieving treatment targets is possible for many psoriasis patients on
238
advanced therapies. These results highlight the importance of using clinical trial data as
239
one useful measure of how a therapy will perform in helping patients achieve treatment
240
targets in the real world.
241 242
Abbreviations
243
BSA: body surface area
244
IXE: ixekizumab 80 mg
245
NPF: National Psoriasis Foundation
11
246
PASI: Psoriasis Area and Severity Index
247
PsA: psoriatic arthritis
248
sPGA: static Physician Global Assessment
249
Q2W: every 2 weeks
250
Q4W: every 4 weeks
251 252
Acknowledgments
253
The authors would like to thank Kalyan Pulipaka and Clinton C. Bertram, Ph.D., medical writers
254
and employees of Eli Lilly and Company, for writing and editorial support.
255
12
256
Tables and Figures
257
Table 1. Baseline demographics and disease characteristics.
258
Figure 1. Plaque psoriasis. Proportion of subjects with NPF acceptable and target
259
responses at Week 12 (UNCOVER-1, -2 and -3; NRI). BSA acceptable response is BSA
260
≤3% or a reduction of ≥75% from BL. BSA target response is BSA ≤1%. ETN data is from
261
UNCOVER -2 and -3 only. PBO and IXE Q2W data is from UNCOVER-1, -2, and -3
262
studies. IXE, ixekizumab; Q2W, every 2 weeks; PBO, placebo; ETN, etanercept.
263
Figure 2. Plaque psoriasis. Proportion of IXE responders/non-responders with NPF target
264
responses during the maintenance period (Week 12 to 60; UNCOVER-1, and -2; NRI).
265
ETN data is from UNCOVER -2 and -3 only. PBO and IXE Q2W data is from
266
UNCOVER-1, -2, and -3 studies. IXE, ixekizumab; Q2W, every 2 weeks; Q4W, every 4
267
weeks; PBO, placebo; ETN, etanercept; NonR, non-responder. †Responders are those
268
who achieved sPGA 0,1 at Week 12
269
Figure 3. Plaque psoriasis. Comparison of BSA responses to PASI 75/90 and to
270
sPGA(0)/(0,1). BSA, body surface area; PASI 75, 75% improvement in Psoriasis Area
271
and Severity Index; PASI 90, 90% improvement in PASI; sPGA, static Physician Global
272
Assessment.
273
Figure 4. Plaque psoriasis. Proportion of subjects with NPF acceptable and target
274
responses (IXORA-S Study, NRI). BSA acceptable response is BSA ≤3% or a reduction of
275
≥75% from baseline. BSA target response is BSA ≤1%. BSA, body surface area; UST,
276
ustekinumab; IXE, ixekizumab.
13
277
Table 1. Baseline Demographics and Disease Characteristics UNCOVER-1, -2, and-3 a
IXORA-S b
PBO
ETN
IXE Q2W
UST
IXE Q2W
(n=792)
(n=740)
(n=1169)
(n=166)
(n=136)
Age, years
46.2 (12.8)
45.5 (13.3)
45.1 (12.9)
44.0 (13.3) 42.7 (12.7)
Male, n (%)
560 (70.7)
505 (68.2)
766 (65.5)
112 (67.5)
Race, white, n (%)
726 (91.7)
682 (92.7)
1092 (93.5)
157 (95.7) 125 (93.3)
Weight, kg
91.6 (23.5)
92.5 (23.4)
90.8 (22.7)
89.4 (24.8) 85.8 (20.3)
PASI total score
20.6 (8.5)
19.9 (7.5)
20.1 (7.9)
19.8 (9.0) 19.9 (8.2)
sPGA
3.6 (0.6)
3.5 (0.6)
3.5 (0.6)
3.6 (0.6)
% BSA
27.7 (17.8)
26.8 (16.6)
27.2 (17.1)
27.5 (16.7) 26.7 (16.5)
Duration of psoriasis (years)
19.1 (12.1)
18.5 (12.1)
18.8 (12.1)
18.2 (12.0) 18.0 (11.1)
416 (52.5)
388 (52.4)
662 (56.6)
152 (91.6) 126 (92.6)
257 (32.4)
136 (18.4)
315 (26.9)
89 (61.0)
74 (59.7)
319 (40.3)
330 (44.6)
515 (44.1)
25 (15.1)
18 (13.2)
90 (66.2)
3.6 (0.7)
≥1 Previous psoriasis treatment Nonbiologic systemic, % Phototherapy, %
c
d
Biologics, %
Abbreviations: BSA, body surface area; ETN, etanercept; IXE, ixekizumab; N, number of subjects; PBO, placebo; PUVA, psoralen and ultraviolet A; Q2W, every 2 weeks; Q4W, every 4 weeks; R, randomization; sPGA, static Physician Global Assessment; UST, ustekinumab; UVB, ultraviolet B. a
Data from UNCOVER-2 and -3 only.
b
IXE=80 mg of ixekizumab every 2 weeks from Weeks 0 to 12, then 80 mg of ixekizumab every 4 weeks from
Weeks 12 to 52. c
Nonbiologic systemic treatments include cyclosporine, methotrexate, corticosteroids, acitretin, fumaric acid
derivatives, and apremilast. d
Phototherapy includes PUVA and UVB therapy. Values are mean (standard deviation).
278 14
279
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S0190-9622(19)32774-4
DOI:
https://doi.org/10.1016/j.jaad.2019.09.030
Reference:
YMJD 13841
To appear in:
Journal of the American Academy of Dermatology
Received Date: 2 July 2018 Revised Date:
13 September 2019
Accepted Date: 17 September 2019
Please cite this article as: Armstrong A, Amato D, Huster W, Ojeh C, Van Voorhees AS, Achievement of the National Psoriasis Foundation Treatment Targets With Ixekizumab: Pooled Analyses From Four Clinical Studies, Journal of the American Academy of Dermatology (2019), doi: https://doi.org/10.1016/ j.jaad.2019.09.030. 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.
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Achievement of the National Psoriasis Foundation Treatment Targets With
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Ixekizumab: Pooled Analyses From Four Clinical Studies
3 4
April Armstrong MD, MPH1, David Amato DO, FAAD2, William Huster PhD2,
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Clement Ojeh PhD3, Abby S Van Voorhees MD.4
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1
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Indianapolis, IN, USA; 3Lilly USA, Indianapolis, IN, USA; 4Department of Dermatology,
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Eastern Virginia Medical School, Norfolk, VA, USA
University of Southern California, Los Angeles, CA, USA; 2Eli Lilly and Company,
9 10
Corresponding author:
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April W. Armstrong, MD MPH
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1975 Zonal Avenue
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Office of the Dean
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Keck School of Medicine of the USC,
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Los Angeles, CA- 90033, USA
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Phone: +11-323-442-1100
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Email: [email protected]
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Funding sources: Eli Lilly and Company
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IRB approval status: The individual studies were approved by institutional review
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boards.
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Clinicaltrials.gov (or equivalent) listing (if applicable): I1F-MC-RHAZ:
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NCT01474512; I1F-MC-RHBA: NCT01597245; I1F-MC-RHBC: NCT01646177; I1F-MC-
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RHBS: NCT02561806 1
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Related Presentation: Achievement of the National Psoriasis Foundation Treatment
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Targets Among Patients in Ixekizumab Clinical Trials: Analysis of Pooled UNCOVER
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Results was presented at National Psoriasis Foundation - 2017 Research Symposium,
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Chicago, IL, USA.
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Conflicts of Interest:
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April Armstrong has served as an investigator and/or advisor to AbbVie, BMS,
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Celgene, Janssen, Novartis, Eli Lilly and Company, Leo Pharma, Regeneron, Sanofi,
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and Ortho Dermatologics.
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D. Amato is a shareholder and former employee of Eli Lilly and Company.
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W. Huster and C. Ojeh were employees, but retired from Eli Lilly and Company.
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Abby S. Van Voorhees has received honoraria for consulting and/or participating in the
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advisory boards for: Dermira, Novartis, Allergan, Celgene, AbbVie, DermTech, Pfizer,
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Astra Zeneca, Corrona and Valeant; she also served as an investigator for Celgene,
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Lilly, and Corrona.
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Reprint requests: April Armstrong
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Manuscript word count: 1684 words [excluding capsule summary, abstract,
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references, figures, and tables]
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Abstract word count: 198
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Capsule summary word count: 50
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References: 17
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Figures: 4
2
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Tables: 1
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List of Attachments: (1) Cover Letter (2) CONSORT checklist, (3) Research protocol,
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(4) Statistical analysis plan, (5) IRB Approval Letter
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Clinical trial registration: UNCOVER-1 (I1F-MC-RHAZ: NCT01474512); UNCOVER-2 (I1F-
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MC-RHBA: NCT01597245); UNCOVER-3 (I1F-MC-RHBC: NCT01646177); IXORA-S (I1F-MC-
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RHBS: NCT02561806)
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Keywords: psoriasis; IL-17; ixekizumab; etanercept; National Psoriasis Foundation;
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treatment goals; Pooled analysis
57 58 59
Capsule Summary •
treatment goals defined by the National Psoriasis Foundation.
60 61
The majority of ixekizumab-treated psoriasis subjects achieved U.S. psoriasis
•
These results provide information regarding how psoriasis therapies such as
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ixekizumab perform using clinically relevant endpoints established by NPF treatment
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targets, which is critical for clinicians and patients to establish meaningful treatment
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expectations.
65 66 67 68 69
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Abstract
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Background: The National Psoriasis Foundation (NPF) published treatment targets for US
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patients with plaque psoriasis. However, data are lacking on how well existing therapies
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help achieve these goals.
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Objective: We examined the ability of an IL-17 inhibitor, ixekizumab, in achieving these
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treatment targets.
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Methods: Post-hoc analysis was performed on data from four Phase III clinical trials
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assessing IXE for plaque psoriasis: pooled data from the UNCOVER-1, -2, and -3 trials,
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and data from the IXORA-S trial. Treatment response was evaluated using NPF-defined
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acceptable response (AR: BSA ≤3% or BSA improvement ≥75% at 12 weeks of treatment)
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and target response (TR: BSA ≤1% at 12 weeks and every 6 months thereafter).
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Results: In UNCOVER studies (n=2701), AR and TR rates at Week 12 were 73.9% and
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51.8% with IXE Q2W, 35.7% and 14.9% with etanercept and 3.0% and 0.6% with placebo,
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respectively. In IXORA-S (n=302), AR and TR rates at Week 12 were significantly higher
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with IXE Q2W versus ustekinumab (AR: 68.4% vs 38.6%, p<.0001; TR: 50.7% vs 24.1%,
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p<.0001).
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Limitations: Data were from controlled studies and may not reflect real-world practice.
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Conclusion: The majority of IXE-treated subjects in four phase III clinical trials achieved
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NPF, patient-centered treatment targets.
89
90
Introduction 4
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The existing outcome measures used in clinical trials for psoriasis are not widely used in
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clinical practice, well-understood, or meaningful to patients. In a pivotal effort, the National
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Psoriasis Foundation (NPF) recently defined treatment goals for patients with psoriasis in
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the US11 which represent patient-centered outcome measures relying on improvements
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in body surface area affected. The rationale for this effort is to establish targets to inform
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treatment decisions, reduce disease burden and improve patient outcomes in clinical
97
practice.
98 99
To date, no published data exist on how existing therapies perform in achieving psoriasis treatment targets. These data are critical because clinicians and patients need to
100
use these data to establish treatment expectations and create meaningful response to
101
treatment.
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In this study, we examined how ixekizumab, a high-affinity monoclonal antibody that
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selectively targets IL-17A,12 performs in achieving established treatment targets from NPF.
104
Specifically, we evaluated the endpoint of the body surface area (BSA) data from the
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ixekizumab phase 3 trials, against NPF treatment targets. In addition, we also evaluated
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the concordance between the achievement of acceptable response per NPF
107
recommendations and PASI response rates from the same trials.
108 109
Methods
110
Study Design
111
UNCOVER-1, -2, -313,14, and IXORA-S15 were randomized, double-blind, Phase 3
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studies conducted in subjects with moderate-to-severe plaque psoriasis. The study design,
113
and the efficacy and safety data from these studies have been published previously 13-16, 5
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including the methodology for integrated data from these studies (UNCOVER-1, -2 and -3)
115
13
116
and -3 studies and the IXORA-S study were analyzed individually.
117
Study Assessments
118
. For the present study, the BSA data from the integration of the three UNCOVER-1, -2
The efficacy measures analyzed were the BSA measurements collected during the
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UNCOVER and IXORA-S trials. BSA measurements were assessed to determine
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response rates in accordance with the recently published NPF recommendations.
121
Response rates were classified into the proportion of subjects achieving acceptable
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response, defined as BSA ≤3% or BSA improvement ≥75% at 12 weeks of treatment11, and
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the proportion of subjects achieving target response, defined as BSA ≤1% at 12 weeks and
124
every 6 months thereafter11. Additionally, the percentage of subjects who achieved at least
125
90% improvement from baseline in the Psoriasis Area and Severity Index (PASI) and the
126
concordance between BSA acceptable response and PASI response were also analyzed.
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At Week 12, data only from the placebo (PBO), etanercept (ETN) and ixekizumab 80
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mg every 2 weeks (IXE Q2W) treatment arms were evaluated from the three UNCOVER
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trials. For the maintenance phase (after Week 12) of the trials, target responses in
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UNCOVER-1 and -2 were evaluated based on subjects who were IXE responders (those
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achieving sPGA 0,1 at Week 12), and separate analyses were performed on all treatment
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arms. In UNCOVER-3 study, 12 to 60 weeks results were included in subjects who were
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IXE responders to the treatment at Week 12.
134 135
For IXORA-S study, target assessments were performed for all treatment arms at Week 12, and monthly through Week 52.
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136 137
Statistical Analysis All randomized subjects were included in the efficacy analyses; data were
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analyzed by randomized treatment group. We calculated the percentage of subjects
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across the pooled UNCOVER studies and in the IXORA-S study who met the NPF
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acceptable and target response criteria. For the induction period, response rates were
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analyzed by pair-wise comparison of the treatment groups, using a Cochran-Mantel-
142
Haenszel chi-square statistical test stratified by study. All statistical testing was
143
performed 2-sided (alpha=0.05) without adjustment for multiple comparisons. Subjects
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who discontinued the study agent for any reason were considered nonresponders for
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the acceptable and target responses (nonresponder imputation). No statistical testing
146
was performed for the maintenance period.
147
Results
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A total of 3003 subjects were included from UNCOVER-1, -2, -3 (n=2701) and
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IXORA-S (n=302) studies in this analysis. Overall baseline demographics and disease
150
characteristics were similar among the treatment groups across studies included (Table 1)
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UNCOVER-1, -2, and -3 Studies
152
During induction period (Weeks 0 to 12)
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In the UNCOVER studies, 73.9% of subjects treated with IXE Q2W achieved the
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acceptable response (BSA ≤3% or BSA improvement ≥75%) at Week 12 versus 35.7%
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with ENT (p<.001) and 3.0% with PBO (p<.001). (Figure 1). In subjects treated with IXE
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Q2W, 51.8% achieved, the target response (BSA ≤1%) at Week 12 versus 14.9% with
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etanercept (p<.001) and 0.6% with placebo (p<.001). PASI 90 was achieved in 70% 7
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subjects with IXE Q2W versus etanercept (22.3%, p<.001), and placebo (1.1%; p<.001).
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Additionally, the concordance between BSA acceptable response and PASI over the
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induction period for all treatment groups was best for PASI 90 (89.8%, 86.6%, and 86.7%),
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at Week 4 (N=3771), Week 8 (N=3732), and Week 12 (N=3683), respectively.
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Maintenance period (Week 12 to 60)
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In the UNCOVER-1 and -2 studies (n=363), the target response (BSA ≤1%) at
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Week 60 was 74.7% in IXE Q2W responders treated with IXE Q4W through Week 60 (IXE
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Q2W to Q4W) versus 4.7% in subjects who were re-randomized to placebo (IXE Q2W to
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placebo) (Figure 2A). In UNCOVER-3 study, the target response was 82.1% with IXE
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Q2W-Q4W treatment at Week 60 (Figure 2B). Comparison of BSA target responses to
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PASI 75/90 and sPGA 0,1 is shown in (Figures 3A and 3B). In the UNCOVER-1 and -2
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studies, the concordance between BSA target response and PASI over the maintenance
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period was best for PASI 90 (80.4%, 85.5%, and 84.2%), at Week 16 (N=1216), Week 36
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(N=857), and Week 60 (N=595), respectively.
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In IXE non-responders (sPGA >1 at 12 weeks) from UNCOVER-1, and -2 studies
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who were on placebo (n=546), etanercept (n=200), or IXE Q2W (n=111) and re-treated
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with IXE Q4W, the target response rate was achieved in 68.1% with placebo-Q4W
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subjects, 64% with etanercept to IXE Q4W, and 34.2% with IXE Q2W to IXE Q4W at Week
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60 (Figure 2C). Similar response rates were observed in IXE non-responders from
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UNCOVER-3 study through Week 60 (Figure 2D). Additionally, in IXE non-responders
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(UNCOVER-1, and -2), PASI 90 response rate at Week 60 was 79% in subjects treated
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with PBO to Q4W, 70% with etanercept to Q4W, and 41% with Q2W-Q4W. Similar trend
8
180
was observed with PASI 75 with IXE non-responders who participated in UNCOVER-3
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study.
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IXORA-S Study
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During the induction period, acceptable response and target response rates were
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significantly higher with IXE Q2W versus ustekinumab (acceptable response: 68.4% vs
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38.6%, p<.0001; target response: 50.7% vs 24.1%, p<.0001; Figure 4A). During the
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maintenance period, subjects who received Q2W for the first 12 weeks and Q4W
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thereafter, the target response was consistently higher with IXE Q2W versus ustekinumab
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at 52 weeks (71.3% vs 56.6%, p=.0086; Figure 4B). At Week 52, PASI 90 was achieved in
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76.5% of subjects with IXE Q2W versus ustekinumab (59.0%; p<.0014).
190
Discussion
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The NPF established the first treatment targets for psoriasis in the US, based on an
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expert-based consensus process 11. The NPF treatment target recommendations suggest
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that measurement of BSA would be an appropriate outcome to measure in clinical practice.
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To date, we have not examined how well the existing therapies can help achieve these
195
treatment targets. These data are critical to inform clinicians and patients regarding how
196
well current therapies work in achieving treatment targets and how to manage patient
197
expectations and devise future treatment plans.
198
The present study is among the first efforts to determine how a biologic therapy
199
indicated for plaque psoriasis, performs in achieving these NPF treatment targets. This
200
study leverages pooled data from the ixekizumab clinical trials program to determine how
201
well an IL-17 inhibitor can meet these treatment targets based on results from four large 9
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clinical trials with 3428 subjects. In this population of subjects with high psoriasis disease
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severity at baseline, 75% of all subjects achieved an acceptable response of BSA ≤3% at
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Week 12. Nearly 80% of subjects achieved target responses of BSA ≤1% by Week 60.
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Significantly higher proportion of ixekizumab-treated subjects per US-labeled dose
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achieved and maintained NPF-defined psoriasis treatment goals (acceptable and target
207
response at Week 12), compared to those receiving PBO, etanercept (UNCOVER -2 and -
208
3) or ustekinumab (IXORA-S). Additionally, in subjects from 4 studies analyzed, PASI 90
209
response rates were significantly higher with ixekizumab versus etanercept or
210
ustekinumab. PASI 90 responses were generally consistent with the BSA acceptable
211
response during the induction period and consistent with the BSA target response during
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the maintenance period.
213
These study results are critical in helping clinicians understand how current psoriasis
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therapies perform using clinically relevant endpoints established by the NPF treatment
215
targets. The study findings show that NPF treatment targets can be achieved and
216
maintained by the majority of subjects on ixekizumab, one of several psoriasis therapies
217
with robust efficacy data from clinical trials. A limitation of the current study is that the
218
analyses were conducted using results from four clinical trials, which may not be
219
representative of all patients observed in real-world clinical settings such as patients with
220
certain comorbidities.
221
Treatment targets spark dialogs between clinicians and patients regarding
222
assessment of current therapies and need for re-evaluation. When a patient does not
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achieve treatment targets, this provides an opportunity to ask clinically relevant questions
224
such as, “Will this patient continue to improve if enough time elapses?” or “How can I 10
225
incorporate other management options to optimize the response?”. In the present analysis,
226
one-third of nonresponders who were on ixekizumab were able to achieve treatment
227
targets when ixekizumab treatment was continued for 60 weeks. Thus, the opportunity to
228
evaluate patients against treatment targets enable a reflection point for considerations of
229
dose escalations of existing therapy, adding another agent to the existing therapy, or
230
switching to an alternative agent.
231
Conclusions
232
In this analysis from 4 studies, ixekizumab-treated subjects achieved and
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maintained a high level of skin clearance according to the NPF treatment targets. In
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addition, the proportion of subjects who achieved treatment targets closely aligned with
235
PASI 90 results from clinical trials. Thus, the target recommendations using BSA are
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reflective of the PASI clinical measurement system that is used in typical psoriasis clinical
237
trials. Importantly, achieving treatment targets is possible for many psoriasis patients on
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advanced therapies. These results highlight the importance of using clinical trial data as
239
one useful measure of how a therapy will perform in helping patients achieve treatment
240
targets in the real world.
241 242
Abbreviations
243
BSA: body surface area
244
IXE: ixekizumab 80 mg
245
NPF: National Psoriasis Foundation
11
246
PASI: Psoriasis Area and Severity Index
247
PsA: psoriatic arthritis
248
sPGA: static Physician Global Assessment
249
Q2W: every 2 weeks
250
Q4W: every 4 weeks
251 252
Acknowledgments
253
The authors would like to thank Kalyan Pulipaka and Clinton C. Bertram, Ph.D., medical writers
254
and employees of Eli Lilly and Company, for writing and editorial support.
255
12
256
Tables and Figures
257
Table 1. Baseline demographics and disease characteristics.
258
Figure 1. Plaque psoriasis. Proportion of subjects with NPF acceptable and target
259
responses at Week 12 (UNCOVER-1, -2 and -3; NRI). BSA acceptable response is BSA
260
≤3% or a reduction of ≥75% from BL. BSA target response is BSA ≤1%. ETN data is from
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UNCOVER -2 and -3 only. PBO and IXE Q2W data is from UNCOVER-1, -2, and -3
262
studies. IXE, ixekizumab; Q2W, every 2 weeks; PBO, placebo; ETN, etanercept.
263
Figure 2. Plaque psoriasis. Proportion of IXE responders/non-responders with NPF target
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responses during the maintenance period (Week 12 to 60; UNCOVER-1, and -2; NRI).
265
ETN data is from UNCOVER -2 and -3 only. PBO and IXE Q2W data is from
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UNCOVER-1, -2, and -3 studies. IXE, ixekizumab; Q2W, every 2 weeks; Q4W, every 4
267
weeks; PBO, placebo; ETN, etanercept; NonR, non-responder. †Responders are those
268
who achieved sPGA 0,1 at Week 12
269
Figure 3. Plaque psoriasis. Comparison of BSA responses to PASI 75/90 and to
270
sPGA(0)/(0,1). BSA, body surface area; PASI 75, 75% improvement in Psoriasis Area
271
and Severity Index; PASI 90, 90% improvement in PASI; sPGA, static Physician Global
272
Assessment.
273
Figure 4. Plaque psoriasis. Proportion of subjects with NPF acceptable and target
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responses (IXORA-S Study, NRI). BSA acceptable response is BSA ≤3% or a reduction of
275
≥75% from baseline. BSA target response is BSA ≤1%. BSA, body surface area; UST,
276
ustekinumab; IXE, ixekizumab.
13
277
Table 1. Baseline Demographics and Disease Characteristics UNCOVER-1, -2, and-3 a
IXORA-S b
PBO
ETN
IXE Q2W
UST
IXE Q2W
(n=792)
(n=740)
(n=1169)
(n=166)
(n=136)
Age, years
46.2 (12.8)
45.5 (13.3)
45.1 (12.9)
44.0 (13.3) 42.7 (12.7)
Male, n (%)
560 (70.7)
505 (68.2)
766 (65.5)
112 (67.5)
Race, white, n (%)
726 (91.7)
682 (92.7)
1092 (93.5)
157 (95.7) 125 (93.3)
Weight, kg
91.6 (23.5)
92.5 (23.4)
90.8 (22.7)
89.4 (24.8) 85.8 (20.3)
PASI total score
20.6 (8.5)
19.9 (7.5)
20.1 (7.9)
19.8 (9.0) 19.9 (8.2)
sPGA
3.6 (0.6)
3.5 (0.6)
3.5 (0.6)
3.6 (0.6)
% BSA
27.7 (17.8)
26.8 (16.6)
27.2 (17.1)
27.5 (16.7) 26.7 (16.5)
Duration of psoriasis (years)
19.1 (12.1)
18.5 (12.1)
18.8 (12.1)
18.2 (12.0) 18.0 (11.1)
416 (52.5)
388 (52.4)
662 (56.6)
152 (91.6) 126 (92.6)
257 (32.4)
136 (18.4)
315 (26.9)
89 (61.0)
74 (59.7)
319 (40.3)
330 (44.6)
515 (44.1)
25 (15.1)
18 (13.2)
90 (66.2)
3.6 (0.7)
≥1 Previous psoriasis treatment Nonbiologic systemic, % Phototherapy, %
c
d
Biologics, %
Abbreviations: BSA, body surface area; ETN, etanercept; IXE, ixekizumab; N, number of subjects; PBO, placebo; PUVA, psoralen and ultraviolet A; Q2W, every 2 weeks; Q4W, every 4 weeks; R, randomization; sPGA, static Physician Global Assessment; UST, ustekinumab; UVB, ultraviolet B. a
Data from UNCOVER-2 and -3 only.
b
IXE=80 mg of ixekizumab every 2 weeks from Weeks 0 to 12, then 80 mg of ixekizumab every 4 weeks from
Weeks 12 to 52. c
Nonbiologic systemic treatments include cyclosporine, methotrexate, corticosteroids, acitretin, fumaric acid
derivatives, and apremilast. d
Phototherapy includes PUVA and UVB therapy. Values are mean (standard deviation).
278 14
279
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