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      Efficacy and Safety of Oral Janus Kinase 1 Inhibitor Abrocitinib for Patients With Atopic Dermatitis : A Phase 2 Randomized Clinical Trial

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          Key Points

          Question

          Does the oral Janus kinase 1 selective inhibitor abrocitinib improve atopic dermatitis signs and symptoms in adults with moderate to severe atopic dermatitis at doses that are well tolerated?

          Findings

          In this randomized, double-blinded, phase 2b clinical trial including 267 participants, the proportion of patients achieving substantial improvement from baseline was significantly greater for those receiving 200 mg and 100 mg of abrocitinib compared with placebo. Dose-related decreases in platelet count were observed for all doses greater than 10 mg, but platelet values trended upward toward baseline after the maximum decrease at week 4 and despite ongoing treatment with abrocitinib; most adverse events were mild and considered unrelated to treatment.

          Meaning

          The findings of this study show that 12 weeks of once-daily treatment with 200 mg or 100 mg of oral abrocitinib resulted in significant improvement in the signs and symptoms of atopic dermatitis.

          Abstract

          Importance

          Atopic dermatitis is associated with substantial patient and caregiver burden. Currently available treatments for atopic dermatitis are inadequate or contraindicated for some patients. Abrocitinib (PF-04965842) is an oral Janus kinase 1 selective inhibitor under investigation for the treatment of atopic dermatitis.

          Objective

          To investigate the efficacy and safety of abrocitinib for patients with moderate to severe atopic dermatitis.

          Design, Setting, and Participants

          A phase 2b, randomized, double-blinded, placebo-controlled, parallel-group trial was conducted from April 15, 2016, to April 4, 2017, at 58 centers in Australia, Canada, Germany, Hungary, and the United States among 267 patients 18 to 75 years of age with a clinical diagnosis of moderate to severe atopic dermatitis for 1 year or more and inadequate response or contraindication to topical medications for 4 weeks or more within 12 months. Efficacy was assessed in the full analysis set, which was a modified intention-to-treat population that included all patients who received 1 dose or more of the study drug except for 4 patients from 1 site.

          Interventions

          Participants were randomly assigned 1:1:1:1:1 to receive abrocitinib (200 mg, 100 mg, 30 mg, or 10 mg) or placebo once daily for 12 weeks.

          Main Outcomes and Measures

          The primary outcome was the proportion of patients achieving an Investigator’s Global Assessment of clear (0) or almost clear (1) with an improvement from baseline of 2 grades or more at week 12. The secondary outcome was the percentage change from baseline in the Eczema Area and Severity Index at week 12.

          Results

          Of the 267 participants, 144 were women (mean [SD] age, 40.8 [16.1] years). At week 12, 21 of 48 patients receiving 200 mg of abrocitinib (43.8%; P < .001, 2-sided), 16 of 54 patients receiving 100 mg of abrocitinib (29.6%; P < .001), and 3 of 52 patients receiving placebo (5.8%) achieved grades of clear or almost clear on the Investigator’s Global Assessment scale with improvement of 2 grades or more; these rates correspond to maximum effect model-based estimates of 44.5% (95% CI, 26.7%-62.3%) for those receiving 200 mg of abrocitinib, 27.8% (95% CI, 14.8%-40.9%) for those receiving 100 mg of abrocitinib, and 6.3% (95% CI, −0.2% to 12.9%) for those receiving placebo. Reductions in the Eczema Area and Severity Index were 82.6% (90% CI, 72.4%-92.8%; P < .001) for those receiving 200 mg of abrocitinib, 59.0% (90% CI, 48.8%-69.3%; P = .009) for those receiving 100 mg of abrocitinib, and 35.2% (90% CI, 24.4%-46.1%) for those receiving placebo. Adverse events were observed in 184 of 267 patients (68.9%); the most frequently reported adverse events (in ≥3 patients in any group) were dermatitis atopic, upper respiratory tract infection, headache, nausea, and diarrhea. Dose-dependent decreases in platelet count were observed but trended upward toward baseline levels after week 4.

          Conclusions and Relevance

          Once-daily oral abrocitinib was effective and well tolerated for short-term use in adults with moderate to severe atopic dermatitis. Additional trials are necessary to evaluate long-term efficacy and safety.

          Trial Registration

          ClinicalTrials.gov identifier: NCT02780167

          Abstract

          This randomized clinical trial investigates the efficacy and safety of once-daily oral abrocitinib, a Janus kinase 1 selective inhibitor, for patients with moderate to severe atopic dermatitis.

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          Most cited references17

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          World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.

          (2013)
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            Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis.

            Background Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis. Methods In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator's Global Assessment and a reduction of 2 points or more in that score from baseline at week 16. Results We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo (P<0.001 for both comparisons with placebo). The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo (P<0.001 for both comparisons). In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo (P<0.001 for all comparisons). Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups. Conclusions In two phase 3 trials of identical design involving patients with atopic dermatitis, dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo. Trials of longer duration are needed to assess the long-term effectiveness and safety of dupilumab. (Funded by Sanofi and Regeneron Pharmaceuticals; SOLO 1 ClinicalTrials.gov number, NCT02277743 ; SOLO 2 ClinicalTrials.gov number, NCT02277769 .).
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              Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis.

              Atopic dermatitis (AD) is a chronic, pruritic, inflammatory dermatosis that affects up to 25% of children and 2% to 3% of adults. This guideline addresses important clinical questions that arise in the management and care of AD, providing updated and expanded recommendations based on the available evidence. In this first of 4 sections, methods for the diagnosis and monitoring of disease, outcomes measures for assessment, and common clinical associations that affect patients with AD are discussed. Known risk factors for the development of disease are also reviewed. Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.
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                Author and article information

                Journal
                JAMA Dermatol
                JAMA Dermatol
                JAMA Dermatology
                American Medical Association
                2168-6068
                2168-6084
                2 October 2019
                December 2019
                26 December 2019
                2 October 2019
                : 155
                : 12
                : 1371-1379
                Affiliations
                [1 ]SKiN Centre for Dermatology, Peterborough, Ontario, Canada
                [2 ]Forward Clinical Trials, Tampa, Florida
                [3 ]Department of Dermatology, Innovaderm Research, Montreal, Quebec, Canada
                [4 ]Inflammation and Immunology Research Unit, Pfizer Inc, New York, New York
                [5 ]Pfizer Innovative Health Statistics, Pfizer Inc, New York, New York
                [6 ]Early Clinical Development Unit, Pfizer Inc, New York, New York
                Author notes
                Article Information
                Accepted for Publication: July 31, 2019.
                Published Online: October 2, 2019. doi:10.1001/jamadermatol.2019.2855
                Correction: This article was corrected on December 20, 2019, to fix an error in the x-axis label of Figure 2C.
                Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2019 Gooderham MJ et al. JAMA Dermatology.
                Corresponding Author: Melinda J. Gooderham, MD, SKiN Centre for Dermatology, 775 Monaghan Rd, Peterborough, ON K9J 5K2, Canada ( mgooderham@ 123456centrefordermatology.com ).
                Author Contributions: Dr Gooderham had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
                Concept and design: Beebe, Zhang, Banfield, Zhu, Vincent, Peeva.
                Acquisition, analysis, or interpretation of data: All authors.
                Drafting of the manuscript: Forman, Beebe, Zhang, Banfield, Papacharalambous, Vincent, Peeva.
                Critical revision of the manuscript for important intellectual content: Gooderham, Forman, Bissonnette, Beebe, Banfield, Zhu, Papacharalambous, Vincent, Peeva.
                Statistical analysis: Beebe, Zhang.
                Obtained funding: Beebe, Peeva.
                Administrative, technical, or material support: Forman, Beebe, Banfield, Zhu.
                Supervision: Bissonnette, Zhu, Vincent, Peeva.
                Conflict of Interest Disclosures: Dr Gooderham reported receiving grants, personal fees, and/or nonfinancial support from AbbVie, Amgen, Akros, Arcutis, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Coherus, Dermira, Eli Lilly, Galderma, Glenmark, Janssen Pharmaceuticals, Kyowa Kirin, LEO Pharma, MedImmune, Merck, Novartis, Pfizer, Roche, Sanofi Genzyme, Regeneron, UCB, and Valeant. Dr Bissonnette reported receiving grants, personal fees, and/or nonfinancial support from Aquinox Pharma, Antiobix, Asana, Astellas, Brickell Biotech, Dermavant, Dermira, Dignity Sciences, Galderma, Glenmark, GSK-Stiefel, F. Hoffman-La Roche Ltd, LEO Pharma, Neokera, Pfizer, Regeneron, and Vitae; and being a shareholder of lnnovaderm Research. Drs Beebe, Zhang, Banfield, Zhu, Papacharalambous, Vincent, and Peeva reported being employees of Pfizer Inc. No other disclosures were reported.
                Funding/Support: The study was funded and managed by Pfizer Inc.
                Role of the Funder/Sponsor: The study was designed, funded, and managed by Pfizer Inc and conducted by investigators contracted by and under the direction of the sponsor. Data collection, management, and analysis were conducted by Pfizer Inc. Confidentiality agreements were established between the authors and the sponsor. All authors participated in interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication with no participation by or financial compensation from the sponsor. Medical writing and editorial support were provided and funded by Pfizer Inc.
                Data Sharing Statement: See Supplement 3.
                Additional Contributions: Editorial and medical writing support under the guidance of authors was provided by Jemimah Walker, PhD; Corey Mandel, PhD; and Jennifer C. Jaworski, MS, ApotheCom, and was funded by Pfizer Inc, in accordance with Good Publication Practice (GPP3) guidelines ( Ann Intern Med. 2015;163:461-464).
                Additional Information: 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 deidentified 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 United States and/or European Union or (2) in programs that have been terminated (ie, 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 deidentified 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.
                Article
                doi190050
                10.1001/jamadermatol.2019.2855
                6777226
                31577341
                fea353ec-a988-4a31-bd5d-abcbb0c45629
                Copyright 2019 Gooderham MJ et al. JAMA Dermatology.

                This is an open access article distributed under the terms of the CC-BY-NC-ND License.

                History
                : 18 February 2019
                : 31 July 2019
                Categories
                Research
                Research
                Original Investigation
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