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A phase 2a randomized, placebo-controlled study to evaluate the efficacy and safety of the oral Janus kinase inhibitors ritlecitinib and brepocitinib in alopecia areata: 24-week results

Open AccessPublished:March 20, 2021DOI:https://doi.org/10.1016/j.jaad.2021.03.050

      Background

      Alopecia areata (AA) is an autoimmune form of hair loss with limited treatments.

      Objective

      To evaluate the efficacy and safety of the Janus kinase inhibitors ritlecitinib and brepocitinib in patients who have AA with ≥ 50% scalp hair loss.

      Methods

      Patients were randomized to once-daily ritlecitinib, brepocitinib, or placebo. The primary efficacy endpoint was a 24-week change from baseline in the Severity of Alopecia Tool (SALT) score. The key secondary efficacy endpoint was the proportion of patients achieving 30% improvement in SALT score (SALT30).

      Results

      The ritlecitinib, brepocitinib, and placebo groups included 48, 47, and 47 patients, respectively. At week 24, least-squares mean difference from placebo in SALT score change from baseline was 31.1 (95% confidence interval [CI], 18.8-43.5) for ritlecitinib and 49.2 (95% CI, 36.6-61.7) for brepocitinib (P < .0001 for both comparisons with placebo). SALT30 was achieved by 50% (90% CI, 38%-62%) of patients receiving ritlecitinib, 64% (90% CI, 51%-75%) receiving brepocitinib, and 2% (90% CI, 0%-9%) receiving placebo. Two patients experienced a serious adverse event (rhabdomyolysis) in the brepocitinib group only.

      Limitations

      Only a single-dosage regimen of each study drug was included.

      Conclusion

      Treatment with ritlecitinib or brepocitinib for 24 weeks was efficacious and generally well tolerated.

      Key words

      Abbreviations used:

      AA (alopecia areata), AASIS (Alopecia Areata Symptom Impact Scale), AE (adverse event), AT (alopecia totalis), AU (alopecia universalis), CI (confidence interval), IC50 (50% inhibitory concentration), IL (interleukin), IFN (interferon), IGA (Investigator Global Assessment), IP-10 (induced protein 10), JAK (Janus kinase), QD (once daily), SALT (Severity of Alopecia Tool), TEC (tyrosine kinase expressed in hepatocellular carcinoma), TYK2 (tyrosine kinase 2), ULN (upper limit of normal)
      • Results from published open-label clinical trials of Janus kinase inhibitors in patients with alopecia areata suggest that they can reverse hair loss.
      • Treatment with ritlecitinib and brepocitinib for 24 weeks was well tolerated and resulted in clinically significant hair regrowth in patients who had alopecia areata with ≥ 50% scalp hair loss.

      Introduction

      Alopecia areata (AA) is an autoimmune disease characterized by hair loss, with an estimated global incidence of 0.6%-3.8% and a prevalence of 0.1%-0.2%.
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      The objective of the randomized, placebo-controlled portion of this study was to evaluate the efficacy and safety of ritlecitinib and brepocitinib in patients who have AA with ≥ 50% scalp hair loss.

      Methods

       Study design

      ALLEGRO was a phase 2a, randomized, double-blind, multicenter study with an initial 24-week primary efficacy endpoint evaluation period, followed by 2 extension periods. The data presented are from the first 24 weeks. The study was conducted in 31 centers in Australia, Canada, and the United States according to the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonization, and local country regulations, where applicable. The ethics committee or institutional review board at each participating center approved the study protocol and all patients provided written informed consent.

       Patients

      Adults at least 18 years of age qualified for inclusion if they had AA with ≥ 50% scalp hair loss, no hair regrowth within 6 months of the screening and baseline visits, and a current episode of fixed hair loss of 7 years or less in duration.
      Patients were excluded if they had another type of alopecia or active inflammatory disease involving the scalp, or if they used an oral or topical JAK inhibitor within 12 weeks of the first dose of the study drug, a biologic within 12 weeks or 5 half-lives (whichever is longer), systemic or intralesional treatment that could affect AA within 8 weeks or 5 half-lives, phototherapy within 4 weeks, or a topical treatment that could affect AA within 2 weeks.

       Randomization and masking

      Interactive response technology randomly allocated patients (2:1:2:1) to receive ritlecitinib (200 mg once daily [QD] for 4 weeks, then 50 mg QD for 20 weeks) or matching placebo, or brepocitinib (60 mg QD for 4 weeks, then 30 mg QD for 20 weeks) or matching placebo. Patients were stratified according to their agreement to participate in an optional biopsy substudy and then further stratified according to the presence or absence of AT/AU. The interactive response technology provided study coordinators with the randomization number and treatment assignment; investigators, patients, and the sponsor were blinded to treatment group.

       Procedures

      Complete physical examinations, including a 12-lead electrocardiogram, were conducted during screening, on day 1, and at week 24. Targeted physical examinations were conducted at weeks 2, 4, 6, 8, 12, 16, and 20. Vital signs, hematology, blood chemistry, and urinalysis were evaluated at every visit. Adverse events (AEs) were monitored throughout the study.

       Outcomes

      The primary efficacy endpoint was change from baseline in Severity of Alopecia Tool (SALT) score at week 24. SALT is an instrument for measuring the amount of scalp hair loss and scores range from 0 (no scalp hair loss) to 100 (complete scalp hair loss).
      • Olsen E.A.
      • Hordinsky M.K.
      • Price V.H.
      • et al.
      Alopecia areata investigational assessment guidelines: part II.
      The key secondary efficacy endpoint was the proportion of patients achieving 30% improvement in SALT score (SALT30) at week 24. Other secondary efficacy endpoints were proportion of patients achieving SALT50/75/90/100, percentage change from baseline in SALT score, and change in the Investigator Global Assessment (IGA; Supplemental Table 1, available via Mendeley at https://data.mendeley.com/datasets/b6sct48jmb/1). IGA and SALT scores were assessed at baseline and weeks 2, 4, 6, 8, 12, 16, 20, and 24.
      Prespecified exploratory endpoints included the proportion of eyelash and eyebrow responders; change in the pharmacodynamic and disease-related biomarkers IFN-γ-induced protein 10 (IP-10/CXCL10) and high-sensitivity C-reactive protein; and change in the Alopecia Areata Symptom Impact Scale (AASIS) total and subscores.
      • Mendoza T.R.
      • Osei J.S.
      • Shi Q.
      • Duvic M.
      Development of the alopecia areata symptom impact scale.

       Statistical analysis

      The sample size was based on the primary efficacy endpoint. Placebo groups were combined for data analysis and all comparisons were between each active treatment and pooled placebo. Using a between-group comparison at week 24 for ritlecitinib versus placebo and brepocitinib versus placebo, 30 completers in each arm (with a combined placebo arm) would provide approximately 90% power to detect a true mean change from baseline in SALT score of 15, at a 1-sided significance level of 2.5% (adjusted for 2 comparisons of active treatment vs placebo using Bonferroni correction). Assuming a 30% dropout rate, the planned sample size was 132.
      The primary endpoint analysis was conducted in all patients assigned to randomized treatment, regardless of whether treatment was received (full analysis set). The 97.5% upper confidence bounds [ie, 95% 2-sided confidence interval (CI)] comparing mean change from baseline for ritlecitinib versus placebo and brepocitinib versus placebo were calculated using an unstructured variance-covariance model. Sensitivity analyses for the primary endpoint used imputation of missing values and a linear mixed-effect model for longitudinal data.
      For continuous efficacy endpoints, data were analyzed using linear mixed-effect models with repeated measures. Binary endpoints were evaluated as 2-sample proportions using Chan and Zhang's exact unconditional method for CI with small sample size. Patients with missing values were considered nonresponders. Adjustments for multiple comparisons were made for the primary endpoint only, using the Benjamini-Hochberg procedure. For secondary endpoints, point estimates were reported with unadjusted CI; P values were not reported. Baseline demographics and disease characteristics were compared across the groups in a post hoc analysis using analysis of variance and the chi-square test.

      Results

       Patient population

      Between December 15, 2016 and July 14, 2017, there were 261 patients screened and 142 randomized to receive placebo (n = 47), ritlecitinib (n = 48), or brepocitinib (n = 47; Supplemental Fig 1). From baseline to week 24, there were 13 (28%), 3 (6%), and 12 (26%) patients, respectively, who discontinued treatment. Mean patient age was 36 years, 69% were women, 84% were White, median duration of the current episode of fixed hair loss was 2.4 years, and 44% had AT/AU (Table I). There were no statistically significant differences among groups at baseline.
      Table IBaseline demographics and disease characteristics of the full analysis set
      CharacteristicsPlacebo (n = 47)Ritlecitinib (n = 48)Brepocitinib (n = 47)
      Sex, n (%)
       Female29 (62)37 (77)32 (68)
       Male18 (38)11 (23)15 (32)
      Age, y, mean (SD)38 (14)37 (13)34 (11)
      Race, n (%)
       White45 (96)38 (79)36 (77)
       Black04 (8)3 (6)
       Asian2 (4)3 (6)3 (6)
       Other03 (6)5 (11)
      Duration since onset of disease, y, median (range)4.8 (0.2-53.4)6.7 (0.6-52.3)8.4 (0.3-48.5)
      Duration of current episode of fixed hair loss, y, median (range)
      One patient in each treatment group had a current episode of fixed hair loss < 6 months.
      ,
      Three patients in the placebo group and 1 patient in the ritlecitinib group had a current episode of fixed hair loss > 7 years; these were protocol deviations.
      2.4 (0.2-29.5)2.6 (0.3-7.5)1.9 (0.2-7.0)
      SALT score, mean (SD)88.4 (18.1)89.4 (15.8)86.4 (18.1)
      AASIS total score, mean (SD)30.1 (21.9)36.6 (24.0)33.9 (24.3)
      Alopecia totalis, n (%)
      Defined in this study as a SALT score of 100 (ie, no hair on the scalp).
      5 (11)7 (15)8 (17)
      Alopecia universalis, n (%)
      Defined in this study as a SALT score of 100 and no eyelashes (“none” on the eyelash assessment scale) and no eyebrows (“none” on the eyebrow assessment scale).
      15 (32)13 (27)14 (30)
      Eyelash assessment, n (%)
       Normal12 (26)11 (23)11 (23)
       Moderate5 (11)5 (10)6 (13)
       Minimal9 (19)8 (17)8 (17)
       None21 (45)24 (50)22 (47)
      Eyebrow assessment, n (%)
       Normal7 (15)7 (15)8 (17)
       Moderate11 (23)11 (23)4 (9)
       Minimal6 (13)8 (17)13 (28)
       None23 (49)22 (46)22 (47)
      There were no statistically significant differences among the groups at baseline. Percentages have been rounded to the nearest integer and for this reason may not total 100.
      AASIS disease severity subscore ranges from 0 to 70 and the disease impact subscore ranges from 0 to 60; the AASIS total score ranges from 0 to 130. Higher score indicates greater severity/impact.
      AASIS, Alopecia Areata Symptom Impact Scale; n, number of patients in the group; SALT, Severity of Alopecia Tool; SD, standard deviation; y, years.
      One patient in each treatment group had a current episode of fixed hair loss < 6 months.
      Three patients in the placebo group and 1 patient in the ritlecitinib group had a current episode of fixed hair loss > 7 years; these were protocol deviations.
      Defined in this study as a SALT score of 100 (ie, no hair on the scalp).
      § Defined in this study as a SALT score of 100 and no eyelashes (“none” on the eyelash assessment scale) and no eyebrows (“none” on the eyebrow assessment scale).

       Efficacy

      For the placebo group at week 24, the least-squares mean value for SALT score change from baseline was 1.4. The least-squares mean difference from placebo in the SALT score change from baseline was 31.1 (95% CI, 18.8-43.5) for the ritlecitinib group and 49.2 (95% CI, 36.6-61.7) for the brepocitinib group (P < .001 for both). In a sensitivity analysis of the primary endpoint, which excluded the 4 patients with a current episode of fixed hair loss of more than 7 years, the overall results and interpretation did not change meaningfully; the least-squares mean difference from placebo in the SALT score change from baseline was 31.7 (95% CI, 18.9-44.4) for the ritlecitinib group and 49.0 (95% CI, 36.1-61.9) for the brepocitinib group (P < .001 for both; Supplemental Table 2). Fig 1, A presents placebo-adjusted change from baseline in SALT score over time. Supplemental Fig 2 presents percentage change from baseline in SALT score over time.
      Figure thumbnail gr1
      Fig 1Response in patients with AA from baseline to week 24 according to SALT score for the full analysis set. A, LS mean difference from placebo in the SALT score change from baseline (MMRM [OC]). The absolute SALT score ranges from 0 to 100. A positive change from baseline in the SALT score indicates improvement. B, Proportion of patients in the full analysis set with SALT30 response and SALT90 response, baseline to week 24, Chan and Zhang's exact statistical method (NRI). SALT30,90 response corresponds to 30% and 90% improvement in SALT score from baseline. ∗P < .0001 versus placebo. AA, Alopecia areata; LS, least-squares; MMRM, Mixed Model Repeated Measure; NRI, nonresponder imputation; OC, observed case; SALT, Severity of Alopecia Tool.
      At week 24, 50% (90% CI, 38%-62%) and 64% (90% CI, 51%-75%) of patients in the ritlecitinib and brepocitinib groups, respectively, achieved SALT30 compared with 2% (90% CI, 0%-9%) in the placebo group (Fig 1, B). SALT90 was achieved by 25% (90% CI, 15%-37%) and 34% (90% CI, 23%-47%) of patients in the ritlecitinib and brepocitinib groups, respectively, compared with 0% (90% CI, 0%-6%) in the placebo group (Fig 1, B). Supplemental Fig 3, A-C presents the proportions of patients achieving SALT50/75/100. Supplemental Fig 4 presents photos over time of representative patients who responded to ritlecitinib and brepocitinib.
      At baseline, all patients received an IGA score of 0 (no change or further loss). At week 24, the proportion of patients with an IGA score of 0 (no change or further hair loss) was 13 of 44 (30%), 4 of 40 (10%), and 27 of 35 (77%) in the ritlecitinib, brepocitinib, and placebo groups, respectively (Supplemental Fig 5 and Supplemental Table 3). The proportions of patients with eyelash involvement at baseline who achieved ≥ 1 grade improvement in the eyelash assessment at week 24 were 22 of 37 (60%), 29 of 36 (81%), and 5 of 35 (14%), respectively (Supplemental Fig 6, A). The proportions achieving ≥ 1 grade improvement in the eyebrow assessment were 21 of 41 (51%), 28 of 39 (72%), and 6 of 40 (15%), respectively (Supplemental Fig 6, B). At 24 weeks, the least-squares mean improvement in the AASIS total score was greater for the ritlecitinib (−10.8 [90% CI, −15.6, −5.9]) and the brepocitinib groups (−17.4 [90% CI, −22.4, −12.3]) than the placebo group (3.0 [90% CI, −2.1, 8.1]) (Supplemental Fig 7, A). Similar results were observed in the disease severity and disease impact subscores (Supplemental Fig 7, B, C).
      There were no changes in high-sensitivity C-reactive protein, but median values for change from baseline in IP-10 decreased in both active groups (Supplemental Table 4). The median change from baseline for IP-10 was greater in the brepocitinib group than in the ritlecitinib group, respectively (−25.4 and −23.0 pg/mL at week 4; −25.5 and −10.0 pg/mL at week 24). IP-10 did not change in the placebo group; however, in comparing the range of IP-10 values at baseline (42.1-506.0), there were no substantial differences between the active and placebo groups.

       Safety

      AEs were reported in 35 of 47 (74%), 32 of 48 (67%), and 36 of 47 (77%) of patients in the placebo, ritlecitinib, and brepocitinib groups, respectively (Table II). The most common AEs were upper respiratory tract infection, nasopharyngitis, headache, acne, and nausea. There were no cases of opportunistic infections. Two patients receiving brepocitinib experienced the serious AE of rhabdomyolysis not accompanied by acute kidney injury; both were preceded by strenuous physical activity and resolved without sequelae. AEs that led to study drug discontinuation occurred in 3 (6%), 2 (4%), and 4 (9%) patients in the placebo, ritlecitinib, and brepocitinib groups, respectively (Supplemental Table 5).
      Table IISummary of adverse events, serious adverse events, and discontinuations in the safety analysis set
      Adverse eventsPlacebo (n = 47)Ritlecitinib (n = 48)Brepocitinib (n = 47)
      Total number of AEs10582124
      Patients with AEs, n (%)35 (74)32 (67)36 (77)
      Patients with serious AEs, n (%)002 (4)
      Deaths, n (%)000
      Patients discontinuing study drug due to AEs and continuing study, n (%)1 (2)2 (4)2 (4)
      Patients discontinuing study due to AEs, n (%)2 (4)02 (4)
      AEs occurring in > 5% of patients in a study group, n (%)
       Upper respiratory tract infection5 (11)4 (8)11 (23)
       Nasopharyngitis6 (13)6 (13)4 (9)
       Headache5 (11)6 (13)4 (9)
       Acne2 (4)5 (10)5 (11)
       Nausea5 (11)3 (6)3 (6)
       Diarrhea3 (6)4 (8)1 (2)
       Abdominal discomfort4 (9)01 (2)
       Sinusitis2 (4)03 (6)
       Viral upper respiratory tract infection02 (4)3 (6)
       Folliculitis1 (2)3 (6)1 (2)
       Atopic dermatitis03 (6)1 (2)
       Neutrophil count decreased1 (2)03 (6)
       Abdominal pain003 (6)
       Fatigue3 (6)00
       Oropharyngeal pain003 (6)
      Data have been rounded to the nearest integer. Adverse events are all causality. The safety analysis set includes all patients who received at least 1 dose of study drug.
      AE, adverse event; n, number of patients.
      In all 3 treatment groups, there were no clinically relevant changes from baseline in hematology tests, electrocardiogram findings, or vital signs. Three patients had laboratory abnormalities of grade 3 at a single time point according to the Common Terminology Criteria for AEs: 1 patient receiving ritlecitinib had a decreased lymphocyte count and 2 patients receiving brepocitinib had decreased neutrophil counts. Three patients (6%) receiving brepocitinib had laboratory test values, confirmed through retesting, that met discontinuation criteria: 2 patients with aspartate aminotransferase > 2.5× upper limit of normal (ULN), alanine aminotransferase > 2.5× ULN, and creatine kinase > 10× ULN; and 1 patient with creatine kinase > 10× ULN. None of the patients in the placebo and ritlecitinib groups had laboratory test values meeting these criteria.
      Fasting total and low-density lipoprotein-cholesterol levels, and the low-density lipoprotein-/high-density lipoprotein-cholesterol ratio remained comparable to baseline values in all treatment groups. One patient receiving brepocitinib had an elevated fasting cholesterol level > 1.3× ULN. In the placebo and ritlecitinib groups, the high-density lipoprotein-cholesterol level remained comparable to baseline values, whereas a slight increase was observed in the brepocitinib group.
      The serum creatinine level in the placebo and ritlecitinib groups remained comparable to baseline (mean percent change from baseline ≤ 5% at each visit), whereas in the brepocitinib group it increased slightly (mean percent change from baseline 21% and 20% at weeks 2 and 24, respectively). Overall, 2, 0, and 13 patients in the placebo, ritlecitinib, and brepocitinib groups, respectively, experienced a decline ≥ 30% from baseline in serum creatinine-based estimated glomerular filtration rate; these were not accompanied by a concomitant decline of ≥ 30% in serum cystatin C-based estimated glomerular filtration rate.

      Discussion

      These are the first results from a randomized controlled study of ritlecitinib and brepocitinib in patients who had AA and ≥ 50% scalp hair loss. At 24 weeks, there was a significant difference between both JAK inhibitors and placebo in the primary endpoint, and 25%, 34%, and 0% of patients in the ritlecitinib, brepocitinib, and placebo groups, respectively, achieved near-complete regrowth of hair, as measured by SALT90.
      In this study, both JAK inhibitors were generally well tolerated. Data from in vitro evaluation of brepocitinib indicated that the slight increase in serum creatinine was due to inhibition of renal transporters rather than nephrotoxicity, as supported by the lack of changes from baseline in serum cystatin C-based estimated glomerular filtration rate.
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      • et al.
      The safety, tolerability, pharmacokinetics, and pharmacodynamics of a TYK2/JAK1 inhibitor (PF-06700841) in healthy subjects and patients with plaque psoriasis.
      Further clinical assessment is required to understand the risk for OCT2 (organic cation transporter 2)-mediated drug-drug interactions.
      Considering the known negative impact of AA on patients' lives in social, psychological, quality of life, and other aspects,
      • Okhovat J.-P.
      • Marks D.H.
      • Manatis-Lornell A.
      • Hagigeorges D.
      • Locascio J.J.
      • Senna M.M.
      Association between alopecia areata, anxiety, and depression: a systematic review and meta-analysis.
      ,
      • Liu L.Y.
      • King B.A.
      • Craiglow B.G.
      Alopecia areata is associated with impaired health-related quality of life: a survey of affected adults and children and their families.
      we included the AASIS, an internally consistent patient-reported outcome measurement tool, to assess AA-related symptoms and the impact on daily functioning.
      • Mendoza T.R.
      • Osei J.
      • Duvic M.
      The utility and validity of the alopecia areata symptom impact scale in measuring disease-related symptoms and their effect on functioning.
      The improvements in AASIS scores after 24 weeks in the active treatment groups, but not in the placebo group, suggest that successful treatment of AA positively impacts patients' daily lives.
      This study is limited by the inclusion of a single-dosage regimen of each study drug. Additionally, 84% of the patients were White and 69% were women, and it is not known whether efficacy and safety would be the same with greater demographic representation. Longer-term studies are needed to evaluate efficacy and safety of continued JAK inhibition beyond 24 weeks. This trial has 2 extension periods that will evaluate (1) safety and efficacy of an additional 24 weeks of active treatment with ritlecitinib or brepocitinib, (2) withdrawal of therapy and re-treatment, and (3) crossover of therapy in nonresponders.

      Conclusions

      Treatment with the JAK3/TEC inhibitor ritlecitinib and TYK2/JAK1 inhibitor brepocitinib for 24 weeks resulted in clinically significant hair regrowth in patients who have AA with ≥ 50% scalp hair loss. This confirms that JAK inhibitors induce hair regrowth in patients with AA. Additional studies are warranted.

       Data availability

      Upon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer -sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.

      Conflicts of interest

      Dr King is a clinical trial investigator for Pfizer, Concert Pharmaceuticals, and Eli Lilly and Company and has received honoraria and/or consulting fees from Aclaris Therapeutics, Arena Pharmaceuticals, Bristol-Meyers Squibb, Celgene, Concert Pharmaceuticals, Dermavant Sciences, Eli Lilly and Company, Pfizer, Regeneron, and Sanofi Genzyme. Dr Guttman-Yassky has received institutional grants from AbbVie , Celgene , Eli Lilly , Janssen , Dermavant , DS Biopharma , Novartis , Pfizer , Regeneron , Glenmark , Galderma , Asana Biosciences , Innovaderm , Dermira , LEO Pharma , Novan , Kyowa Kirin , Concert , Union Therapeutics , and Ralexar and is a consultant for Sanofi, Regeneron, Celgene, Dermira, Galderma, Glenmark, Novartis, Pfizer, LEO Pharma, AbbVie, Eli Lilly, Kyowa Kirin, Mitsubishi Tanabe, Asana Biosciences, Union Therapeutics, Allergan, Amgen, Concert, DS Biopharma, EMD Serono, Escalier, and Flx Bio. Drs Peeva and Banerjee are employees and stockholders of Pfizer. Dr Sinclair has provided professional services for Novartis, Merck & Co, Janssen, Samson Clinical, Pfizer, Eli Lilly and Company, Arena, Demira, AstraZeneca, Sanofi, AbbVie, Galderma, Principia, Reistone Pharma, Aclaris, and Sun Pharma. Dr Zhu is an employee and stockholder of Pfizer. Dr Cox is a paid consultant to Pfizer. Dr Craiglow has participated on advisory boards, received honoraria and consulting fees from Aclaris, Arena Pharmaceuticals, and Pfizer, and participated on the speaker's bureau for Regeneron and Sanofi-Genzyme. Drs Chen and Zhang were employees of Pfizer at the time the study was conducted. Drs Banfield, Page, and Vincent are employees and stockholders of Pfizer. Dr Pavel has no conflicts of interest to declare.
      The authors thank the patients involved in this study. Editorial and medical writing support was provided by Jennica Lewis , PharmD, of Engage Scientific Solutions and was funded by Pfizer .

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