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Serlopitant for Psoriatic Pruritus: a Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial
Journal Pre-proof Serlopitant for Psoriatic Pruritus: a Phase 2 Randomized, Double-Blind, PlaceboControlled Clinical Trial David M. Pariser, MD, Jerry Bagel, MD, Mark Lebwohl, MD, Gil Yosipovitch, MD, Elaine Chien, MD, Mary C. Spellman, MD PII:
S0190-9622(20)30140-7
DOI:
https://doi.org/10.1016/j.jaad.2020.01.056
Reference:
YMJD 14189
To appear in:
Journal of the American Academy of Dermatology
Received Date: 15 August 2019 Revised Date:
17 January 2020
Accepted Date: 21 January 2020
Please cite this article as: Pariser DM, Bagel J, Lebwohl M, Yosipovitch G, Chien E, Spellman MC, Serlopitant for Psoriatic Pruritus: a Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial, Journal of the American Academy of Dermatology (2020), doi: https://doi.org/10.1016/ j.jaad.2020.01.056. 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. © 2020 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
CAPSULE SUMMARY •
Psoriatic pruritus can be persistent and debilitating; however, many of the treatments for psoriatic plaques do not adequately address the pruritus
•
Serlopitant reduced pruritus in patients with mild-to-moderate psoriasis, and was well tolerated; thus, serlopitant may be a viable treatment option for patients with psoriatic pruritus
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47
Serlopitant for Psoriatic Pruritus: a Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial Authors: David M. Pariser, MD1; Jerry Bagel, MD2; Mark Lebwohl, MD3; Gil Yosipovitch, MD4; Elaine Chien, MD5; Mary C. Spellman, MD6* Affiliations: 1Eastern Virginia Medical School and Virginia Clinical Research, Inc., Norfolk, VA; 2Psoriasis Treatment Center of Central New Jersey, East Windsor, NJ; 3Icahn School of Medicine at Mount Sinai, New York, NY; 4 Miami Itch Center, Department of Dermatology, University of Miami, Miller School of Medicine, Miami, FL; 5Independent Contractor, Palo Alto, CA; 6Menlo Therapeutics, Inc., Redwood City, CA *At the time the research was conducted. Corresponding author: Mary Spellman, MD email: [email protected] Manuscript word count (2500 max): 2263 Abstract word count (200 max): 200 References (no limit): 28 Tables: 3 Figures: 1 Supplementary figure: 3 (DOI: 10.17632/rcpf8hfk2d.1) Supplementary tables: 0 IRB statement: The study protocol and its amendments were approved by an institutional review board. ClinicalTrial.gov identifier: NCT03343639 Funding sources: This study was funded by Menlo Therapeutics, Inc. Medical writing and editorial support for this manuscript was provided by Meredith Rogers, MS, CMPP, of The Lockwood Group (Stamford, Connecticut, USA), which was in accordance with Good Publication Practice (GPP3) guidelines and funded by Menlo Therapeutics, Inc. Conflicts of Interest: • David M. Pariser reports being a consultant, receiving honoraria or grants/research funding, and or serving on an advisory board for Abbott, Amgen, Atacama Therapeutics, Bickel Biotechnology, Biofrontera AG, Celgene, Dermavant, Dermira, DUSA Pharmaceuticals, Eli Lilly, LEO, Menlo Therapeutics, Novartis, Ortho Dermatologics, Peplin, Pfizer, Photocure ASA, Promius, Regeneron, Sanofi, TDM SurgiTech, Stiefel, TheraVida, and Valeant. • Jerry Bagel reports speaking, serving on an advisory board, and/or serving as an investigator for Novartis, Eli Lilly, Celgene, LEO, Janssen, BMS, Boehringer-Ingelheim, AbbVie, USB, and Amgen. • Mark Lebwohl is an employee of Mount Sinai which receives research funds from: AbbVie, Amgen, AstraZeneca, Boehringer-Ingelheim, Celgene, Eli Lilly, Incyte, Janssen/ Johnson & Johnson, Kadmon, Leo Pharmaceuticals, Medimmune, Novartis, Pfizer, Sciderm, UCB, Ortho Dermatologics, and ViDac. Dr. Lebwohl is also a consultant for Allergan, Almirall, Arcutis, Avotres, Birch Biomed, BoehringerIngelheim, Bristol Myers Squibb, Cara, Castle Biosciences, Dermavant, Encore, Inozyme, LEO
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48 49 50 51 52 53 54 55 56 57 58 59 60 61 62
• • •
Pharma, Meiji, Menlo, Mitsubishi Pharma, Neuroderm LTD, Pfizer, Promius/Dr. Reddy, Theravance Biopharma, and Verrica. Gil Yosipovitch reports being a consultant, receiving honoraria or grants/research funding and serving on advisory board for Menlo Therapeutics, TREVI, Sienna, Sanofi Regeneron, Eli Lilly, Novartis, Pfizer, LEO, AbbVie, Vanda, Kiniksa, Sun Pharma, CeraVe, Galderma, Bellus. Elaine Chien reports being an independent contractor engaged by Menlo Therapeutics at the time the research was conducted. Mary Spellman was an employee of Menlo Therapeutics at the time the research was conducted.
Key words: pruritus, psoriasis, substance P, neurokinin 1 receptor (NK1R), clinical trial, serlopitant
ABSTRACT (200 words; 200 max) Background: Pruritus, a common symptom of psoriasis, negatively impacts quality of life; however,
63
treatment of lesional skin does not consistently alleviate psoriatic itch.
64
Objective: Examine the effects of serlopitant, an oral, once-daily neurokinin 1 receptor antagonist, for
65
treatment of psoriatic pruritus in a phase 2, randomized clinical trial (NCT03343639).
66
Methods: Patients (n=204) were randomized to serlopitant 5 mg or placebo daily for 8 weeks. Eligible
67
adult patients had plaque psoriasis ≥6 months, plaques covering ≤10% of body surface area, pruritus ≥4
68
weeks, and worst itch numeric rating scale (WI-NRS) score ≥7 at initial screening.
69
Results: Mean age was 47.5 years, 54.2% female, and 85.2% white. Mean baseline WI-NRS scores were
70
8.3 for serlopitant and 8.1 for placebo. WI-NRS 4-point response rate at 8 weeks (primary endpoint) was
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33.3% for serlopitant vs 21.1% for placebo (P=0.028); at 4 weeks the rates were 20.8% for serlopitant vs
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11.5% for placebo (P=0.039). Treatment-related adverse events were reported for 4.9% and 4.0% of
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serlopitant and placebo-treated patients, respectively.
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Limitations: This was a phase 2 study with a small study population. Patients with severe psoriasis were
75
excluded.
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Conclusion: Serlopitant significantly reduced pruritus associated with mild-to-moderate psoriasis,
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supporting continued development of serlopitant for this patient population.
78 79
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80 81
CAPSULE SUMMARY (47 words; 50 words max) •
82 83 84
Psoriatic pruritus can be persistent and debilitating; however, many of the treatments for psoriatic plaques do not adequately address the pruritus
•
Serlopitant reduced pruritus in patients with mild-to-moderate psoriasis, and was well tolerated; thus, serlopitant may be a viable treatment option for patients with psoriatic pruritus
85
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86
INTRODUCTION
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Pruritus, an underappreciated symptom of psoriasis, has been reported in about 60% to 90% of various
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psoriatic patient populations.1-6 Patients consider pruritus one of the most important, severe, and
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troubling symptoms of psoriasis. It has been reported that around 65% of patients with psoriasis
90
consider itching to be the most bothersome symptom of psoriasis, followed by scaling.7-9 Psoriatic itch
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impacts quality of life, with negative effects on mood, concentration, sleep, sexual desire, and appetite,
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and patients have reported missing days at work or school because of itch symptoms.1, 3, 6, 10
93 94
Common therapies that have been investigated for the treatment of psoriatic pruritus confer varying
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degrees of benefit for pruritus and for those treatments that are efficacious, the results are often short-
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lived.1, 6, 11 While newer biologic therapies are effective in reducing pruritus, they are only approved for
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patients with moderate-to-severe psoriasis. In addition, many patients forgo treatment of their psoriasis
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due to perceived inefficacy, safety concerns, and low tolerability of available treatments.8, 12-16 Thus,
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there is an unmet need for an effective therapy that addresses psoriatic itch.
100 101
Although the pathology of psoriatic pruritus has not been fully elucidated, substance P and the
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neurokinin 1 (NK1) receptor appear to play an important role. Numerous studies have found
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overexpression of substance P and the NK1 receptor in pruritic skin vs nonpruritic skin in patients with
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various dermatologic conditions, including psoriasis.5, 17-20 In addition, intensity of pruritus has been
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found to correlate with the number of substance P-positive nerve fibers.18 These studies suggest that
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substance P and the NK1 receptor are viable targets for interventions that specifically address the
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pruritus in patients with psoriasis.
108 109
The small molecule, serlopitant, is a highly potent, selective NK1 receptor antagonist developed for oral
110
administration.21 Earlier clinical studies of serlopitant have been conducted in patients with chronic
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pruritus and prurigo nodularis.22, 23 In the first of two phase 2 studies in patients with chronic pruritus,
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serlopitant 5 mg resulted in 46% of patients reporting a 4-point decrease in average-itch numeric rating
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scale (NRS) pruritus score at week 6 vs 23% of placebo recipients.22 In this study, 13 of 256 (7%) patients
114
had psoriasis.22 In the second phase 2 study that focused on patients with prurigo nodularis, 46.5% of
115
serlopitant-treated (5 mg) and 25.6% of placebo-treated patients exhibited a 4-point decrease in worst
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itch numeric rating scale (WI-NRS) at week 8 (P=0.045). The present study was conducted to evaluate
12
117
the efficacy and safety of serlopitant for the treatment of pruritus associated with plaque psoriasis in
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patients with mild-to-moderate disease.
119 120 121
METHODS
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Study design
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This phase 2, double-blind, randomized, placebo-controlled study was conducted at 39 locations across
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the United States from November 2017 through November 2018. The study consisted of a screening
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period, an 8-week treatment period, and a 2-week follow-up period. During screening, the baseline WI-
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NRS scores were established for randomization.
127 128
At baseline (day 1) patients were randomized in a 1:1 ratio to either serlopitant (5 mg; 1 tablet) or
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placebo, taken orally once daily for 8 weeks. Randomization was stratified by the patient’s reported WI-
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NRS score for the 24-hour period prior to the initial screening visit (scores of 7-8 or 9-10). On the first
131
day, patients took a loading dose of 15 mg (3 tablets) or placebo. Patients entered a 2-week follow-up
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period after the 8-week treatment period or following early discontinuation of study drug.
133 134
Patients
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Adults (18 to 80 years) with plaque psoriasis for ≥6 months prior to randomization were enrolled.
136
Patients could have had plaque psoriasis in any anatomic location, covering ≤10% total body surface
137
area (BSA) at the screening and baseline visits. Patients must also have reported pruritus of ≥4 weeks
138
duration before the initial screening visit, and throughout the screening period prior to randomization. A
139
WI-NRS score ≥7 in the 24-hour period before the initial screening visit, and average weekly WI-NRS
140
scores ≥6 for the 2 weeks immediately prior to randomization were also required. Patients were
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required to discontinue use of all psoriasis therapies other than bland emollients and coal-tar shampoos.
142 143
Patients could not have had clinical worsening of their symptoms within 12 weeks prior to
144
randomization, could not have any concurrent clearly defined medical cause of pruritus (eg, atopic
145
dermatitis, hepatic or renal disease, psychogenic pruritus, drug reaction, untreated hyperthyroidism,
146
infection), could not have documented history of parasitic infection (eg, scabies) within 12 months of
147
randomization, could not have been treated with a systemic biologic therapy within 6 months or 5 half-
148
lives (whichever was longer) prior to randomization, and could not have been treated with systemic
149
nonbiologic psoriasis therapies within 12 weeks or topical/local psoriasis therapies within 4 weeks 12
150
before randomization. Patients were not to use any treatment, systemic or topical, with known
151
antipruritic properties. Use of inhaled, intranasal, and intra-articular corticosteroids were permitted.
152 153
All patients provided written informed consent before enrollment. The trial was conducted in
154
accordance with the provisions of the Declaration of Helsinki, International Conference on
155
Harmonisation Good Clinical Practice guidelines, and applicable regulatory requirements. The study
156
protocol and its amendments were approved by an institutional review board.
157 158
Endpoints
159
The primary efficacy endpoint was the WI-NRS 4-point responder rate at week 8. The itch NRS measures
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itch intensity using an 11-point scale ranging from 0 (no itch) to 10 (worst itch imaginable).24 The worst
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itch intensity during a 24-hour recall period was captured, with patients recording their itch NRS scores
162
once daily using an eDiary at the same time daily (±3 hours) throughout the screening, treatment, and
163
follow-up periods. Responders were defined as patients who had at least a 4-point reduction in score
164
between baseline and the corresponding study week; a 3-point responder was similarly defined. Key
165
secondary efficacy endpoints were the WI-NRS 4-point responder rate at week 4 and absolute change in
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WI-NRS from baseline to days 3 and 7. Other secondary efficacy endpoints were the WI-NRS 3-point
167
responder rate at weeks 4 and 8. An ad hoc analysis examined the influence of demographic and
168
baseline characteristics on the primary efficacy endpoint.
169 170
The extent of psoriasis was examined using BSA assessment and physician global assessment (PGA) of
171
psoriasis. Using the PGA, lesions were assessed for induration, erythema, and scaling on a scale ranging
172
from clear (0), almost clear (1), mild (2), moderate (3), severe (4), to very severe (5).25
173 174
Safety was assessed as the incidence of treatment-emergent adverse events (TEAEs) and serious adverse
175
events (SAEs). Severity was graded using the National Cancer Institute Common Terminology Criteria for
176
Adverse Events v4.03.26 Changes in clinical laboratory parameters, vital signs, and electrocardiogram
177
parameters were also assessed. Plasma concentrations of serlopitant and its metabolites were
178
measured.
179 180
Statistics
12
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The primary efficacy analyses were based on the intent-to-treat population, using the full analysis set,
182
which includes all randomized patients who received at least one dose of study drug. The safety
183
population comprised all treated patients with at least one postbaseline assessment. A sample size of
184
100 per group was calculated to achieve 90% power for the primary endpoint. Endpoints were
185
summarized using descriptive statistics by treatment group and visit. SAS (version 9.3) was used for all
186
statistical analyses. One-sided P values for the primary endpoint were calculated using the decision rule
187
as presented in Fleming and Richardson (2004).27 The difference between groups in WI-NRS 4-point
188
responder rate at week 8 (primary efficacy endpoint) was tested using a Cochran-Mantel-Haenszel test
189
controlling for the “as randomized” stratification factors. Secondary endpoints were analyzed using an
190
analysis of covariance (model with treatment group and stratification factor as fixed effects and the
191
respective baseline values as a covariate). Testing of key secondary endpoints were hierarchical, with
192
testing starting with the WI-NRS week 4 responder rate, then the day 7 WI-NRS endpoint, and finally the
193
day 3 WI-NRS endpoint. Statistical analysis of the ad hoc efficacy outcomes was not performed. Missing
194
efficacy data were handled using the Markov Chain Monte Carlo multiple imputation method.
195 196
RESULTS
197
Patient population
198
A total of 204 patients were randomized 1:1 to serlopitant (n=102) or placebo (n=102) (Supplemental
199
Figure 1). A majority of patients in each group completed treatment (82.4% serlopitant; 87.3% placebo).
200
The most common reasons for discontinuation from the study were withdrawal by patient (7.4%) and
201
lost to follow-up (3.9%).
202 203
The baseline and demographic characteristics of the groups were similar (Table I). The mean age of the
204
population was 47.5 years, 54% were female, and most were white (85.2%). Plaque psoriasis covered a
205
mean BSA of 4.3% and according to the PGA of psoriasis, most patients had moderate disease. The
206
mean baseline WI-NRS (1-week average before baseline) was 8.193, and most patients considered their
207
itch severe as measured by the mean static Patient Global Assessment of itch severity. During the course
208
of the study, 1 patient in the serlopitant group used a topical corticosteroid and 5 patients (3 in the
209
serlopitant group and 2 in the placebo group) used a systemic corticosteroid.
210 211
Efficacy endpoints
12
212
The study met its primary endpoint, with 33.3% of patients treated with serlopitant achieving a 4-point
213
improvement from baseline on the WI-NRS at week 8 compared with 21.1% of placebo recipients
214
(P=0.028) (Figure 1). In addition, the study met a key secondary endpoint, with 20.8% of patients treated
215
with serlopitant achieving a 4-point improvement from baseline on the WI-NRS at week 4 vs 11.5% of
216
placebo recipients (P=0.039) (Figure 1). Other key secondary endpoints were the mean absolute change
217
in WI-NRS (standard deviation) from baseline to day 3 and day 7, which were greater for serlopitant
218
than placebo at both day 3 (–0.744 [1.464] vs –0.455 [1.318]) and day 7 (–1.338 [2.025] vs –0.780
219
[1.618]) (Supplemental Figure 3).
220 221
Greater percentages of serlopitant-treated patients versus placebo recipients also achieved a ≥3-point
222
improvement in WI-NRS at Weeks 4 and 8, but the results were not statistically significant
223
(Supplemental Figure 2).
224 225
Stratifying by demographic and baseline characteristics, differences in 4-point responder rate at week 8
226
between serlopitant and placebo, respectively, were generally maintained with some variance across
227
age groups (36.9% vs 22.1% in those <47 years; 30.5% vs 19.9% in those ≥47 years), by gender (38.2% vs
228
21.7% in females; 29.0% vs 20.0% in males), by weight (36.9% vs 19.8% for <85.7 kg; 29.6% vs 22.3% for
229
≥85.7 kg), by baseline body surface area (33.2% vs 21.2% for ≤5%; 33.5% vs 20.8% for >5), by baseline
230
WI-NRS score (32.7% vs 22.9% for <9; 34.6% vs 15.0% for ≥9), and by baseline PGA (34.8% vs 22.0% for
231
mild/moderate; 22.3% vs 15.5% for severe/very severe). Statistical significance was not calculated.
232 233
There were no significant changes to psoriasis severity from baseline to week 8 and no difference
234
between groups as measured by either BSA or PGA (data not shown).
235 236
Safety
237
The proportion of patients with TEAEs were similar between serlopitant (37.3%) and placebo (35.0%)
238
groups (Table II). The majority of TEAEs were mild or moderate in severity. No serious TEAEs were
239
reported in the serlopitant group, while 2 patients in the placebo group had a serious TEAE. Treatment-
240
related TEAEs occurred in 4.9% of the serlopitant group and 4.0% of the placebo group.
241 242
The most common TEAEs were headache, diarrhea, and nasopharyngitis (Table III). In the serlopitant
243
group, the most common treatment-related TEAEs were diarrhea and headache (2.0% each) versus 1.0% 12
244
each for placebo. Somnolence was uncommon in both groups: 0 serlopitant, 1 (1.0%) placebo. Five
245
patients in the serlopitant group (1 each of cardiac palpitations, chest pain, dizziness, headache,
246
psoriasis, rash; cardiac palpitations and dizziness were experienced by the same patient) and 1 patient in
247
the placebo group discontinued the study drug due to a TEAE (fatal drug overdose not related to study
248
drug). None of the TEAEs that led to discontinuation except headache were considered likely related to
249
study drug. Of the 2 cases of SAEs in the placebo group, 1 patient experienced a fatal (and intentional)
250
drug overdose and the other a nonfatal road traffic accident.
251 252
DISCUSSION
253
Serlopitant reduced pruritus associated with mild-to-moderate psoriasis, as demonstrated by the 4-
254
point improvements on WI-NRS at weeks 4 and 8, as well as mean absolute change from baseline in WI-
255
NRS at days 3 and 7. In addition, differences between serlopitant and placebo in WI-NRS at week 8 were
256
maintained when stratified by demographic and baseline characteristics. These data are consistent with
257
what has been observed in other studies of serlopitant for pruritic conditions.22, 23
258 259
The safety data observed in this study are consistent with the previous phase 2 studies of serlopitant.22,
260
23
261
likely related to treatment occurred with similar frequency in both groups. In contrast to H1
262
antihistamines, which can have at times a profound somnolence effect,28 somnolence was distinctly
263
uncommon with serlopitant.
In this study, no SAEs were reported in the serlopitant-treated group and adverse events considered
264 265
A limitation of the study was that it was a phase 2 study with a small patient population. The difference
266
observed between serlopitant and placebo was statistically significant but modest, which may be a
267
consequence of the small sample size. While we feel these results are clinically meaningful, the
268
response should be confirmed in larger studies. As patients with psoriasis covering >10% total BSA were
269
excluded, the effects of serlopitant in patients with severe psoriasis were not evaluated. In addition,
270
concurrent antipruritic therapy was not permitted. However, corticosteroids were occasionally initiated
271
during the study period for the treatment of psoriasis or other indications. As few patients in either
272
group used corticosteroids, this did not have a meaningful impact on the overall efficacy results.
273
12
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In conclusion, serlopitant demonstrated a statistically significant effect on psoriatic itch in this study and
275
remains an attractive drug for future study in this patient population. Serlopitant was well tolerated and
276
may be a beneficial addition to treatments directed at psoriatic lesions.
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277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302
Authorship Contributions: Mary Spellman, Gil Yosipovitch, Mark Lebwohl, and Elaine Chien were involved in the concept/design of the study. All authors were involved in the analysis and/or interpretation of the data, as well as drafting and revising the manuscript, and they all had final approval of the submitted draft.
List of Abbreviations: BSA, body surface area NK1, neurokinin 1 NRS, numeric rating scale PGA, physician global assessment SAEs, serious adverse events SD, standard deviation sPGA, static patient global assessment TEAEs, treatment-emergent adverse events WI-NRS, worst itch numeric rating scale
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trial. Journal of the American Academy of Dermatology 2018;78:882-91.e10.
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23. Ständer S, Kwon P, Hirman J, Perlman AJ, Weisshaar E, Metz M et al. Serlopitant reduced pruritus in
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patients with prurigo nodularis in a phase 2, randomized, placebo-controlled trial. Journal of the
363
American Academy of Dermatology 2019;80:1395-402.
364
24. Kimball AB, Naegeli AN, Edson-Heredia E, Lin CY, Gaich C, Nikai E et al. Psychometric properties of
365
the Itch Numeric Rating Scale in patients with moderate-to-severe plaque psoriasis. The British journal
366
of dermatology 2016;175:157-62.
367
25. European Medicines Agency. Guideline on Clinical Investigation of Medicinal Products Indicated for
368
the Treatment of Psoriasis. London, UK2004.
369
26. National Institutes of Health. Common Terminology Criteria for Adverse Events (CTCAE). 4.03
370
ed2010.
371
27. Fleming TR , Richardson BA. Some design issues in trials of microbicides for the prevention of HIV
372
infection. The Journal of infectious diseases 2004;190:666-74.
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373
28. Ozdemir PG, Karadag AS, Selvi Y, Boysan M, Bilgili SG, Aydin A et al. Assessment of the effects of
374
antihistamine drugs on mood, sleep quality, sleepiness, and dream anxiety. Int J Psychiatry Clin Pract
375
2014;18:161-8.
376 377
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378 379
380 381 382 383 384
Table I. Patient Demographics and Baseline Characteristics, Full Analysis Set Serlopitant 5 mg Placebo (N=102) (N=101) Mean age, years (SD) 48.2 (15.2) 46.7 (12.3)
Total (N=203) 47.5 (13.8)
Male, n (%) 54 (52.9) 39 (38.6) 93 (45.8) Female, n (%) 48 (47.1) 62 (61.4) 110 (54.2) Hispanic/Latino, n (%) 29 (28.4) 31 (30.7) 60 (29.6) Race, n (%) White 84 (82.4) 89 (88.1) 173 (85.2) Black/African American 12 (11.8) 6 (5.9) 18 (8.9) Asian 3 (2.9) 4 (4.0) 7 (3.4) Multiple/other 3 (2.9) 2 (2.0) 5 (2.5) Mean weight, kg (SD) 91.3 (22.6) 91.5 (23.9) 91.4 (23.2) WI-NRS (1 week average before 8.303 (1.028) 8.082 (1.059) 8.193 (1.047) baseline), mean (SD) sPGA of itch severity, n (%) None 0 0 0 Mild 1 (1.0) 0 1 (0.5) Moderate 25 (24.5) 24 (23.8) 49 (24.1) Severe 57 (55.9) 59 (58.4) 116 (57.1) Very severe 19 (18.6) 18 (17.8) 37 (18.2) BSA involving plaque psoriasis, % (SD) 4.3 (2.7) 4.3 (2.9) 4.3 (2.8) PGA of psoriasis, n (%) 0-Clear 0 0 0 1-Almost clear 0 0 0 2-Mild 25 (24.5) 22 (21.8) 47 (23.2) 3-Moderate 65 (63.7) 64 (63.4) 129 (63.5) 4-Severe 11 (10.8) 15 (14.9) 26 (12.8) 5-Very severe 1 (1.0) 0 1 (0.5) BSA, body surface area; PGA, physician global assessment; SD, standard deviation; sPGA, static patient global assessment; WI-NRS, worst itch numeric rating scale.
12
385 386
387 388 389 390 391 392
Table II. Overall Summary of Treatment-Emergent Adverse Events (TEAEs), Safety Population Serlopitant 5 mg Placebo n (%) (N=102) (N=100) Patients with any TEAE 38 (37.3) 35 (35.0) Number of TEAEs 47 65 Patients with any related TEAE 5 (4.9) 4 (4.0) Number of related TEAEs 5 5 Patients with any serious TEAE 0 2 (2.0) Number of serious TEAEs 0 2 Patients with any related serious TEAE 0 0 Number of related serious TEAEs 0 0 Patients who died 0 1 (1.0) Patients who discontinued study drug due to TEAE 5 (4.9) 1 (1.0) Patients who discontinued study due to TEAE 1 (1.0) 1 (1.0)
Table III. Summary of Patients Reporting Treatment-Emergent Adverse Events (TEAEs) by Preferred Term (≥3 Patients in Any Group) Serlopitant 5 mg Placebo TEAE, n (%) (N=102) (N=100) Total 38 (37.3) 35 (35.0) Headache 3 (2.9) 5 (5.0) Diarrhea
3 (2.9)
3 (3.0)
Nasopharyngitis
2 (2.0)
6 (6.0)
Upper respiratory tract infection
1 (1.0)
4 (4.0)
393 394
12
395
Figure 1. 4-Point Reduction from Baseline Responder Rate for Worst Itch Numeric Rating Scale (WI-NRS),
396
Full Analysis Set at Week 8 (Primary Endpoint) and Week 4 (Secondary Endpoint)
397
398 399
a
400
randomization stratification. Value has been adjusted for multiple imputation.
One-sided P value from a Cochran-Mantel-Haenszel test stratified by baseline WI-NRS used for
401 402
12
S0190-9622(20)30140-7
DOI:
https://doi.org/10.1016/j.jaad.2020.01.056
Reference:
YMJD 14189
To appear in:
Journal of the American Academy of Dermatology
Received Date: 15 August 2019 Revised Date:
17 January 2020
Accepted Date: 21 January 2020
Please cite this article as: Pariser DM, Bagel J, Lebwohl M, Yosipovitch G, Chien E, Spellman MC, Serlopitant for Psoriatic Pruritus: a Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial, Journal of the American Academy of Dermatology (2020), doi: https://doi.org/10.1016/ j.jaad.2020.01.056. 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. © 2020 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
CAPSULE SUMMARY •
Psoriatic pruritus can be persistent and debilitating; however, many of the treatments for psoriatic plaques do not adequately address the pruritus
•
Serlopitant reduced pruritus in patients with mild-to-moderate psoriasis, and was well tolerated; thus, serlopitant may be a viable treatment option for patients with psoriatic pruritus
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47
Serlopitant for Psoriatic Pruritus: a Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial Authors: David M. Pariser, MD1; Jerry Bagel, MD2; Mark Lebwohl, MD3; Gil Yosipovitch, MD4; Elaine Chien, MD5; Mary C. Spellman, MD6* Affiliations: 1Eastern Virginia Medical School and Virginia Clinical Research, Inc., Norfolk, VA; 2Psoriasis Treatment Center of Central New Jersey, East Windsor, NJ; 3Icahn School of Medicine at Mount Sinai, New York, NY; 4 Miami Itch Center, Department of Dermatology, University of Miami, Miller School of Medicine, Miami, FL; 5Independent Contractor, Palo Alto, CA; 6Menlo Therapeutics, Inc., Redwood City, CA *At the time the research was conducted. Corresponding author: Mary Spellman, MD email: [email protected] Manuscript word count (2500 max): 2263 Abstract word count (200 max): 200 References (no limit): 28 Tables: 3 Figures: 1 Supplementary figure: 3 (DOI: 10.17632/rcpf8hfk2d.1) Supplementary tables: 0 IRB statement: The study protocol and its amendments were approved by an institutional review board. ClinicalTrial.gov identifier: NCT03343639 Funding sources: This study was funded by Menlo Therapeutics, Inc. Medical writing and editorial support for this manuscript was provided by Meredith Rogers, MS, CMPP, of The Lockwood Group (Stamford, Connecticut, USA), which was in accordance with Good Publication Practice (GPP3) guidelines and funded by Menlo Therapeutics, Inc. Conflicts of Interest: • David M. Pariser reports being a consultant, receiving honoraria or grants/research funding, and or serving on an advisory board for Abbott, Amgen, Atacama Therapeutics, Bickel Biotechnology, Biofrontera AG, Celgene, Dermavant, Dermira, DUSA Pharmaceuticals, Eli Lilly, LEO, Menlo Therapeutics, Novartis, Ortho Dermatologics, Peplin, Pfizer, Photocure ASA, Promius, Regeneron, Sanofi, TDM SurgiTech, Stiefel, TheraVida, and Valeant. • Jerry Bagel reports speaking, serving on an advisory board, and/or serving as an investigator for Novartis, Eli Lilly, Celgene, LEO, Janssen, BMS, Boehringer-Ingelheim, AbbVie, USB, and Amgen. • Mark Lebwohl is an employee of Mount Sinai which receives research funds from: AbbVie, Amgen, AstraZeneca, Boehringer-Ingelheim, Celgene, Eli Lilly, Incyte, Janssen/ Johnson & Johnson, Kadmon, Leo Pharmaceuticals, Medimmune, Novartis, Pfizer, Sciderm, UCB, Ortho Dermatologics, and ViDac. Dr. Lebwohl is also a consultant for Allergan, Almirall, Arcutis, Avotres, Birch Biomed, BoehringerIngelheim, Bristol Myers Squibb, Cara, Castle Biosciences, Dermavant, Encore, Inozyme, LEO
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48 49 50 51 52 53 54 55 56 57 58 59 60 61 62
• • •
Pharma, Meiji, Menlo, Mitsubishi Pharma, Neuroderm LTD, Pfizer, Promius/Dr. Reddy, Theravance Biopharma, and Verrica. Gil Yosipovitch reports being a consultant, receiving honoraria or grants/research funding and serving on advisory board for Menlo Therapeutics, TREVI, Sienna, Sanofi Regeneron, Eli Lilly, Novartis, Pfizer, LEO, AbbVie, Vanda, Kiniksa, Sun Pharma, CeraVe, Galderma, Bellus. Elaine Chien reports being an independent contractor engaged by Menlo Therapeutics at the time the research was conducted. Mary Spellman was an employee of Menlo Therapeutics at the time the research was conducted.
Key words: pruritus, psoriasis, substance P, neurokinin 1 receptor (NK1R), clinical trial, serlopitant
ABSTRACT (200 words; 200 max) Background: Pruritus, a common symptom of psoriasis, negatively impacts quality of life; however,
63
treatment of lesional skin does not consistently alleviate psoriatic itch.
64
Objective: Examine the effects of serlopitant, an oral, once-daily neurokinin 1 receptor antagonist, for
65
treatment of psoriatic pruritus in a phase 2, randomized clinical trial (NCT03343639).
66
Methods: Patients (n=204) were randomized to serlopitant 5 mg or placebo daily for 8 weeks. Eligible
67
adult patients had plaque psoriasis ≥6 months, plaques covering ≤10% of body surface area, pruritus ≥4
68
weeks, and worst itch numeric rating scale (WI-NRS) score ≥7 at initial screening.
69
Results: Mean age was 47.5 years, 54.2% female, and 85.2% white. Mean baseline WI-NRS scores were
70
8.3 for serlopitant and 8.1 for placebo. WI-NRS 4-point response rate at 8 weeks (primary endpoint) was
71
33.3% for serlopitant vs 21.1% for placebo (P=0.028); at 4 weeks the rates were 20.8% for serlopitant vs
72
11.5% for placebo (P=0.039). Treatment-related adverse events were reported for 4.9% and 4.0% of
73
serlopitant and placebo-treated patients, respectively.
74
Limitations: This was a phase 2 study with a small study population. Patients with severe psoriasis were
75
excluded.
76
Conclusion: Serlopitant significantly reduced pruritus associated with mild-to-moderate psoriasis,
77
supporting continued development of serlopitant for this patient population.
78 79
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80 81
CAPSULE SUMMARY (47 words; 50 words max) •
82 83 84
Psoriatic pruritus can be persistent and debilitating; however, many of the treatments for psoriatic plaques do not adequately address the pruritus
•
Serlopitant reduced pruritus in patients with mild-to-moderate psoriasis, and was well tolerated; thus, serlopitant may be a viable treatment option for patients with psoriatic pruritus
85
12
86
INTRODUCTION
87
Pruritus, an underappreciated symptom of psoriasis, has been reported in about 60% to 90% of various
88
psoriatic patient populations.1-6 Patients consider pruritus one of the most important, severe, and
89
troubling symptoms of psoriasis. It has been reported that around 65% of patients with psoriasis
90
consider itching to be the most bothersome symptom of psoriasis, followed by scaling.7-9 Psoriatic itch
91
impacts quality of life, with negative effects on mood, concentration, sleep, sexual desire, and appetite,
92
and patients have reported missing days at work or school because of itch symptoms.1, 3, 6, 10
93 94
Common therapies that have been investigated for the treatment of psoriatic pruritus confer varying
95
degrees of benefit for pruritus and for those treatments that are efficacious, the results are often short-
96
lived.1, 6, 11 While newer biologic therapies are effective in reducing pruritus, they are only approved for
97
patients with moderate-to-severe psoriasis. In addition, many patients forgo treatment of their psoriasis
98
due to perceived inefficacy, safety concerns, and low tolerability of available treatments.8, 12-16 Thus,
99
there is an unmet need for an effective therapy that addresses psoriatic itch.
100 101
Although the pathology of psoriatic pruritus has not been fully elucidated, substance P and the
102
neurokinin 1 (NK1) receptor appear to play an important role. Numerous studies have found
103
overexpression of substance P and the NK1 receptor in pruritic skin vs nonpruritic skin in patients with
104
various dermatologic conditions, including psoriasis.5, 17-20 In addition, intensity of pruritus has been
105
found to correlate with the number of substance P-positive nerve fibers.18 These studies suggest that
106
substance P and the NK1 receptor are viable targets for interventions that specifically address the
107
pruritus in patients with psoriasis.
108 109
The small molecule, serlopitant, is a highly potent, selective NK1 receptor antagonist developed for oral
110
administration.21 Earlier clinical studies of serlopitant have been conducted in patients with chronic
111
pruritus and prurigo nodularis.22, 23 In the first of two phase 2 studies in patients with chronic pruritus,
112
serlopitant 5 mg resulted in 46% of patients reporting a 4-point decrease in average-itch numeric rating
113
scale (NRS) pruritus score at week 6 vs 23% of placebo recipients.22 In this study, 13 of 256 (7%) patients
114
had psoriasis.22 In the second phase 2 study that focused on patients with prurigo nodularis, 46.5% of
115
serlopitant-treated (5 mg) and 25.6% of placebo-treated patients exhibited a 4-point decrease in worst
116
itch numeric rating scale (WI-NRS) at week 8 (P=0.045). The present study was conducted to evaluate
12
117
the efficacy and safety of serlopitant for the treatment of pruritus associated with plaque psoriasis in
118
patients with mild-to-moderate disease.
119 120 121
METHODS
122
Study design
123
This phase 2, double-blind, randomized, placebo-controlled study was conducted at 39 locations across
124
the United States from November 2017 through November 2018. The study consisted of a screening
125
period, an 8-week treatment period, and a 2-week follow-up period. During screening, the baseline WI-
126
NRS scores were established for randomization.
127 128
At baseline (day 1) patients were randomized in a 1:1 ratio to either serlopitant (5 mg; 1 tablet) or
129
placebo, taken orally once daily for 8 weeks. Randomization was stratified by the patient’s reported WI-
130
NRS score for the 24-hour period prior to the initial screening visit (scores of 7-8 or 9-10). On the first
131
day, patients took a loading dose of 15 mg (3 tablets) or placebo. Patients entered a 2-week follow-up
132
period after the 8-week treatment period or following early discontinuation of study drug.
133 134
Patients
135
Adults (18 to 80 years) with plaque psoriasis for ≥6 months prior to randomization were enrolled.
136
Patients could have had plaque psoriasis in any anatomic location, covering ≤10% total body surface
137
area (BSA) at the screening and baseline visits. Patients must also have reported pruritus of ≥4 weeks
138
duration before the initial screening visit, and throughout the screening period prior to randomization. A
139
WI-NRS score ≥7 in the 24-hour period before the initial screening visit, and average weekly WI-NRS
140
scores ≥6 for the 2 weeks immediately prior to randomization were also required. Patients were
141
required to discontinue use of all psoriasis therapies other than bland emollients and coal-tar shampoos.
142 143
Patients could not have had clinical worsening of their symptoms within 12 weeks prior to
144
randomization, could not have any concurrent clearly defined medical cause of pruritus (eg, atopic
145
dermatitis, hepatic or renal disease, psychogenic pruritus, drug reaction, untreated hyperthyroidism,
146
infection), could not have documented history of parasitic infection (eg, scabies) within 12 months of
147
randomization, could not have been treated with a systemic biologic therapy within 6 months or 5 half-
148
lives (whichever was longer) prior to randomization, and could not have been treated with systemic
149
nonbiologic psoriasis therapies within 12 weeks or topical/local psoriasis therapies within 4 weeks 12
150
before randomization. Patients were not to use any treatment, systemic or topical, with known
151
antipruritic properties. Use of inhaled, intranasal, and intra-articular corticosteroids were permitted.
152 153
All patients provided written informed consent before enrollment. The trial was conducted in
154
accordance with the provisions of the Declaration of Helsinki, International Conference on
155
Harmonisation Good Clinical Practice guidelines, and applicable regulatory requirements. The study
156
protocol and its amendments were approved by an institutional review board.
157 158
Endpoints
159
The primary efficacy endpoint was the WI-NRS 4-point responder rate at week 8. The itch NRS measures
160
itch intensity using an 11-point scale ranging from 0 (no itch) to 10 (worst itch imaginable).24 The worst
161
itch intensity during a 24-hour recall period was captured, with patients recording their itch NRS scores
162
once daily using an eDiary at the same time daily (±3 hours) throughout the screening, treatment, and
163
follow-up periods. Responders were defined as patients who had at least a 4-point reduction in score
164
between baseline and the corresponding study week; a 3-point responder was similarly defined. Key
165
secondary efficacy endpoints were the WI-NRS 4-point responder rate at week 4 and absolute change in
166
WI-NRS from baseline to days 3 and 7. Other secondary efficacy endpoints were the WI-NRS 3-point
167
responder rate at weeks 4 and 8. An ad hoc analysis examined the influence of demographic and
168
baseline characteristics on the primary efficacy endpoint.
169 170
The extent of psoriasis was examined using BSA assessment and physician global assessment (PGA) of
171
psoriasis. Using the PGA, lesions were assessed for induration, erythema, and scaling on a scale ranging
172
from clear (0), almost clear (1), mild (2), moderate (3), severe (4), to very severe (5).25
173 174
Safety was assessed as the incidence of treatment-emergent adverse events (TEAEs) and serious adverse
175
events (SAEs). Severity was graded using the National Cancer Institute Common Terminology Criteria for
176
Adverse Events v4.03.26 Changes in clinical laboratory parameters, vital signs, and electrocardiogram
177
parameters were also assessed. Plasma concentrations of serlopitant and its metabolites were
178
measured.
179 180
Statistics
12
181
The primary efficacy analyses were based on the intent-to-treat population, using the full analysis set,
182
which includes all randomized patients who received at least one dose of study drug. The safety
183
population comprised all treated patients with at least one postbaseline assessment. A sample size of
184
100 per group was calculated to achieve 90% power for the primary endpoint. Endpoints were
185
summarized using descriptive statistics by treatment group and visit. SAS (version 9.3) was used for all
186
statistical analyses. One-sided P values for the primary endpoint were calculated using the decision rule
187
as presented in Fleming and Richardson (2004).27 The difference between groups in WI-NRS 4-point
188
responder rate at week 8 (primary efficacy endpoint) was tested using a Cochran-Mantel-Haenszel test
189
controlling for the “as randomized” stratification factors. Secondary endpoints were analyzed using an
190
analysis of covariance (model with treatment group and stratification factor as fixed effects and the
191
respective baseline values as a covariate). Testing of key secondary endpoints were hierarchical, with
192
testing starting with the WI-NRS week 4 responder rate, then the day 7 WI-NRS endpoint, and finally the
193
day 3 WI-NRS endpoint. Statistical analysis of the ad hoc efficacy outcomes was not performed. Missing
194
efficacy data were handled using the Markov Chain Monte Carlo multiple imputation method.
195 196
RESULTS
197
Patient population
198
A total of 204 patients were randomized 1:1 to serlopitant (n=102) or placebo (n=102) (Supplemental
199
Figure 1). A majority of patients in each group completed treatment (82.4% serlopitant; 87.3% placebo).
200
The most common reasons for discontinuation from the study were withdrawal by patient (7.4%) and
201
lost to follow-up (3.9%).
202 203
The baseline and demographic characteristics of the groups were similar (Table I). The mean age of the
204
population was 47.5 years, 54% were female, and most were white (85.2%). Plaque psoriasis covered a
205
mean BSA of 4.3% and according to the PGA of psoriasis, most patients had moderate disease. The
206
mean baseline WI-NRS (1-week average before baseline) was 8.193, and most patients considered their
207
itch severe as measured by the mean static Patient Global Assessment of itch severity. During the course
208
of the study, 1 patient in the serlopitant group used a topical corticosteroid and 5 patients (3 in the
209
serlopitant group and 2 in the placebo group) used a systemic corticosteroid.
210 211
Efficacy endpoints
12
212
The study met its primary endpoint, with 33.3% of patients treated with serlopitant achieving a 4-point
213
improvement from baseline on the WI-NRS at week 8 compared with 21.1% of placebo recipients
214
(P=0.028) (Figure 1). In addition, the study met a key secondary endpoint, with 20.8% of patients treated
215
with serlopitant achieving a 4-point improvement from baseline on the WI-NRS at week 4 vs 11.5% of
216
placebo recipients (P=0.039) (Figure 1). Other key secondary endpoints were the mean absolute change
217
in WI-NRS (standard deviation) from baseline to day 3 and day 7, which were greater for serlopitant
218
than placebo at both day 3 (–0.744 [1.464] vs –0.455 [1.318]) and day 7 (–1.338 [2.025] vs –0.780
219
[1.618]) (Supplemental Figure 3).
220 221
Greater percentages of serlopitant-treated patients versus placebo recipients also achieved a ≥3-point
222
improvement in WI-NRS at Weeks 4 and 8, but the results were not statistically significant
223
(Supplemental Figure 2).
224 225
Stratifying by demographic and baseline characteristics, differences in 4-point responder rate at week 8
226
between serlopitant and placebo, respectively, were generally maintained with some variance across
227
age groups (36.9% vs 22.1% in those <47 years; 30.5% vs 19.9% in those ≥47 years), by gender (38.2% vs
228
21.7% in females; 29.0% vs 20.0% in males), by weight (36.9% vs 19.8% for <85.7 kg; 29.6% vs 22.3% for
229
≥85.7 kg), by baseline body surface area (33.2% vs 21.2% for ≤5%; 33.5% vs 20.8% for >5), by baseline
230
WI-NRS score (32.7% vs 22.9% for <9; 34.6% vs 15.0% for ≥9), and by baseline PGA (34.8% vs 22.0% for
231
mild/moderate; 22.3% vs 15.5% for severe/very severe). Statistical significance was not calculated.
232 233
There were no significant changes to psoriasis severity from baseline to week 8 and no difference
234
between groups as measured by either BSA or PGA (data not shown).
235 236
Safety
237
The proportion of patients with TEAEs were similar between serlopitant (37.3%) and placebo (35.0%)
238
groups (Table II). The majority of TEAEs were mild or moderate in severity. No serious TEAEs were
239
reported in the serlopitant group, while 2 patients in the placebo group had a serious TEAE. Treatment-
240
related TEAEs occurred in 4.9% of the serlopitant group and 4.0% of the placebo group.
241 242
The most common TEAEs were headache, diarrhea, and nasopharyngitis (Table III). In the serlopitant
243
group, the most common treatment-related TEAEs were diarrhea and headache (2.0% each) versus 1.0% 12
244
each for placebo. Somnolence was uncommon in both groups: 0 serlopitant, 1 (1.0%) placebo. Five
245
patients in the serlopitant group (1 each of cardiac palpitations, chest pain, dizziness, headache,
246
psoriasis, rash; cardiac palpitations and dizziness were experienced by the same patient) and 1 patient in
247
the placebo group discontinued the study drug due to a TEAE (fatal drug overdose not related to study
248
drug). None of the TEAEs that led to discontinuation except headache were considered likely related to
249
study drug. Of the 2 cases of SAEs in the placebo group, 1 patient experienced a fatal (and intentional)
250
drug overdose and the other a nonfatal road traffic accident.
251 252
DISCUSSION
253
Serlopitant reduced pruritus associated with mild-to-moderate psoriasis, as demonstrated by the 4-
254
point improvements on WI-NRS at weeks 4 and 8, as well as mean absolute change from baseline in WI-
255
NRS at days 3 and 7. In addition, differences between serlopitant and placebo in WI-NRS at week 8 were
256
maintained when stratified by demographic and baseline characteristics. These data are consistent with
257
what has been observed in other studies of serlopitant for pruritic conditions.22, 23
258 259
The safety data observed in this study are consistent with the previous phase 2 studies of serlopitant.22,
260
23
261
likely related to treatment occurred with similar frequency in both groups. In contrast to H1
262
antihistamines, which can have at times a profound somnolence effect,28 somnolence was distinctly
263
uncommon with serlopitant.
In this study, no SAEs were reported in the serlopitant-treated group and adverse events considered
264 265
A limitation of the study was that it was a phase 2 study with a small patient population. The difference
266
observed between serlopitant and placebo was statistically significant but modest, which may be a
267
consequence of the small sample size. While we feel these results are clinically meaningful, the
268
response should be confirmed in larger studies. As patients with psoriasis covering >10% total BSA were
269
excluded, the effects of serlopitant in patients with severe psoriasis were not evaluated. In addition,
270
concurrent antipruritic therapy was not permitted. However, corticosteroids were occasionally initiated
271
during the study period for the treatment of psoriasis or other indications. As few patients in either
272
group used corticosteroids, this did not have a meaningful impact on the overall efficacy results.
273
12
274
In conclusion, serlopitant demonstrated a statistically significant effect on psoriatic itch in this study and
275
remains an attractive drug for future study in this patient population. Serlopitant was well tolerated and
276
may be a beneficial addition to treatments directed at psoriatic lesions.
12
277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302
Authorship Contributions: Mary Spellman, Gil Yosipovitch, Mark Lebwohl, and Elaine Chien were involved in the concept/design of the study. All authors were involved in the analysis and/or interpretation of the data, as well as drafting and revising the manuscript, and they all had final approval of the submitted draft.
List of Abbreviations: BSA, body surface area NK1, neurokinin 1 NRS, numeric rating scale PGA, physician global assessment SAEs, serious adverse events SD, standard deviation sPGA, static patient global assessment TEAEs, treatment-emergent adverse events WI-NRS, worst itch numeric rating scale
12
303 304 305
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306
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5. Chang SE, Han SS, Jung HJ , Choi JH. Neuropeptides and their receptors in psoriatic skin in relation to
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Table I. Patient Demographics and Baseline Characteristics, Full Analysis Set Serlopitant 5 mg Placebo (N=102) (N=101) Mean age, years (SD) 48.2 (15.2) 46.7 (12.3)
Total (N=203) 47.5 (13.8)
Male, n (%) 54 (52.9) 39 (38.6) 93 (45.8) Female, n (%) 48 (47.1) 62 (61.4) 110 (54.2) Hispanic/Latino, n (%) 29 (28.4) 31 (30.7) 60 (29.6) Race, n (%) White 84 (82.4) 89 (88.1) 173 (85.2) Black/African American 12 (11.8) 6 (5.9) 18 (8.9) Asian 3 (2.9) 4 (4.0) 7 (3.4) Multiple/other 3 (2.9) 2 (2.0) 5 (2.5) Mean weight, kg (SD) 91.3 (22.6) 91.5 (23.9) 91.4 (23.2) WI-NRS (1 week average before 8.303 (1.028) 8.082 (1.059) 8.193 (1.047) baseline), mean (SD) sPGA of itch severity, n (%) None 0 0 0 Mild 1 (1.0) 0 1 (0.5) Moderate 25 (24.5) 24 (23.8) 49 (24.1) Severe 57 (55.9) 59 (58.4) 116 (57.1) Very severe 19 (18.6) 18 (17.8) 37 (18.2) BSA involving plaque psoriasis, % (SD) 4.3 (2.7) 4.3 (2.9) 4.3 (2.8) PGA of psoriasis, n (%) 0-Clear 0 0 0 1-Almost clear 0 0 0 2-Mild 25 (24.5) 22 (21.8) 47 (23.2) 3-Moderate 65 (63.7) 64 (63.4) 129 (63.5) 4-Severe 11 (10.8) 15 (14.9) 26 (12.8) 5-Very severe 1 (1.0) 0 1 (0.5) BSA, body surface area; PGA, physician global assessment; SD, standard deviation; sPGA, static patient global assessment; WI-NRS, worst itch numeric rating scale.
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385 386
387 388 389 390 391 392
Table II. Overall Summary of Treatment-Emergent Adverse Events (TEAEs), Safety Population Serlopitant 5 mg Placebo n (%) (N=102) (N=100) Patients with any TEAE 38 (37.3) 35 (35.0) Number of TEAEs 47 65 Patients with any related TEAE 5 (4.9) 4 (4.0) Number of related TEAEs 5 5 Patients with any serious TEAE 0 2 (2.0) Number of serious TEAEs 0 2 Patients with any related serious TEAE 0 0 Number of related serious TEAEs 0 0 Patients who died 0 1 (1.0) Patients who discontinued study drug due to TEAE 5 (4.9) 1 (1.0) Patients who discontinued study due to TEAE 1 (1.0) 1 (1.0)
Table III. Summary of Patients Reporting Treatment-Emergent Adverse Events (TEAEs) by Preferred Term (≥3 Patients in Any Group) Serlopitant 5 mg Placebo TEAE, n (%) (N=102) (N=100) Total 38 (37.3) 35 (35.0) Headache 3 (2.9) 5 (5.0) Diarrhea
3 (2.9)
3 (3.0)
Nasopharyngitis
2 (2.0)
6 (6.0)
Upper respiratory tract infection
1 (1.0)
4 (4.0)
393 394
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395
Figure 1. 4-Point Reduction from Baseline Responder Rate for Worst Itch Numeric Rating Scale (WI-NRS),
396
Full Analysis Set at Week 8 (Primary Endpoint) and Week 4 (Secondary Endpoint)
397
398 399
a
400
randomization stratification. Value has been adjusted for multiple imputation.
One-sided P value from a Cochran-Mantel-Haenszel test stratified by baseline WI-NRS used for
401 402
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