Daily Oxymetazoline Cream Demonstrates High and Sustained Efficacy in Patients With Persistent Erythema of Rosacea Through 52 Weeks of Treatment

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1 Accepted Manuscript Daily Oxymetazoline Cream Demonstrates High and Sustained Efficacy in Patients With Persistent Erythema of Rosacea Through 52 Weeks of Treatment Michael H. Gold, MD, FAAD, Mark Lebwohl, MD, Brian S. Biesman, MD, FACS, Deanne Mraz Robinson, MD, Lei Luo, MPH, David R. Berk, MD, Gurpreet Ahluwalia, PhD, Nancy Alvandi, PhD PII: DOI: S (18) Reference: YMJD /j.jaad To appear in: Journal of the American Academy of Dermatology Received Date: 21 May 2018 Accepted Date: 22 May 2018 Please cite this article as: Gold MH, Lebwohl M, Biesman BS, Robinson DM, Luo L, Berk DR, Ahluwalia G, Alvandi N, Daily Oxymetazoline Cream Demonstrates High and Sustained Efficacy in Patients With Persistent Erythema of Rosacea Through 52 Weeks of Treatment, Journal of the American Academy of Dermatology (2018), doi: /j.jaad This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.

2 1 1 Daily Oxymetazoline Cream Demonstrates High and Sustained Efficacy in Patients With Persistent Erythema of Rosacea Through 52 Weeks of Treatment Michael H. Gold, MD, FAAD 1 ; Mark Lebwohl, MD 2 ; Brian S. Biesman, MD, FACS 3 ; Deanne Mraz Robinson, MD 4 ; Lei Luo, MPH 5 ; David R. Berk, MD 5 ; Gurpreet Ahluwalia, PhD 5 ; Nancy Alvandi, PhD 5 1 Tennessee Clinical Research Center, Nashville, TN; 2 Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY; 3 Private practice, Nashville, TN; 4 Connecticut Dermatology Group, Norwalk, CT; 5 Allergan plc, Irvine, CA Address for correspondence: Michael H. Gold, MD, FAAD Tennessee Clinical Research Center 2000 Richard Jones Road, Suite 220 Nashville, TN Phone: drgold@goldskincare.com Running head: Sustained Erythema Response to Long-term Oxymetazoline Keywords: rosacea, persistent facial erythema, oxymetazoline, facial dermatoses, vascular skin diseases, chronic disease, vasoconstrictor agents, topical administration, disease progression, patient compliance

3 2 26 Funding Disclosures This study was sponsored by Allergan plc, Dublin, Ireland. Writing and editorial assistance was provided to the authors by Peloton Advantage, Parsippany, NJ, and was funded by Allergan plc. Neither honoraria nor other form of payments were made for authorship. Author Disclosures MH Gold, BS Biesman, and D Mraz Robinson are investigators for Allergan plc. M Lebwohl is an employee of Icahn School of Medicine at Mount Sinai, which receives research funds from Abbvie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen/Johnson & Johnson, Kadmon, Medimmune/AstraZeneca, Novartis, Pfizer, Valeant, and Vidac. M Lebwohl is a consultant for Allergan plc, Aqua, Leo Pharma, and Promius. L Luo, DR Berk, and N Alvandi are employees of Allergan plc, and G Ahluwalia was an employee of Allergan plc at the time the analysis was conducted; all may own stock/stock options in that company. IRB Statement: The investigators obtained approval of the study from a properly constituted institutional review board prior to study initiation. Clinical trials registration information: Clinicaltrials.gov identifier NCT Text word count: 499; Figures: 2; References: 4

4 3 48 [word count limit: 500; current count: 499] To the Editor: Persistent facial erythema, which may worsen over time, is one of the most common and therapeutically challenging characteristics of rosacea. 1,2 Exacerbations and periods of remission characterize the chronic nature of rosacea 3 ; therefore, treatments that have efficacy and safety with long-term daily use are needed. We describe results of a post hoc analysis of a previously published phase 3, multicenter, 52-week open-label study in 440 patients with persistent facial erythema of rosacea (the REVEAL long-term trial; Clinicaltrials.gov identifier NCT ) 4 that demonstrated the safety and efficacy of long-term, once-daily, topical oxymetazoline hydrochloride cream 1.0% (Rhofade, Allergan plc, Dublin, Ireland). This analysis evaluated the proportion of patients who responded to oxymetazoline from day 1 through week 52 and the probability of response between visits. Adults ages 18 years with moderate to severe persistent facial erythema of rosacea (grade 3 or 4 on the Clinician Erythema Assessment [CEA] scale with photonumeric guide and Subject Self-Assessment for rosacea facial redness [SSA] scale with photoguide) applied oxymetazoline to the face once daily for 52 weeks. Increasing proportions of patients from day 1 (77.5% of patients) through week 52 (88.5% of patients) were responders to oxymetazoline based on achieving composite CEA and SSA 1-grade improvement in erythema at any postdose time point on day 1 (3 or 6 hours), or at any time point during study visits at week 4, week 26, and week 52 (predose or 3 or 6 hours postdose). In general, the proportions of patients with 1-grade

5 4 71 composite improvement in CEA and SSA at separate time points were consistent or increased through week 52 (Figure 1). At the week 52 visit, nearly 50% of patients met the responder criteria before applying oxymetazoline. The probability of responding to treatment with oxymetazoline generally increased with continued use, even for patients who did not respond initially. The probability of a responder continuing to respond from one time point to the next was approximately 90%. Patients who were nonresponders on day 1 had a 44% probability of becoming a responder at week 4. Conversion to responder status later in the study (ie, changing from nonresponder at weeks 4 or 26 to responder at weeks 26 or 52, respectively) had a probability of approximately 60%. When patients were grouped according to response at week 4, the mean level of response tended to be maintained or increased through the end of treatment at week 52 (Figure 2). Among patients with 3-grade improvement at week 4, the mean CEA and SSA scores did not drop below 2-grade improvement. This analysis highlights the effect of oxymetazoline for persistent facial erythema of rosacea with long-term consistent daily use, as the outcomes demonstrate a robust and sustained response to oxymetazoline of 1-grade improvement in persistent erythema in a large proportion of patients over a full year of continuous treatment. Furthermore, the probability of response data may provide clinicians with evidence to encourage

6 5 93 patients to continue once-daily application of oxymetazoline, even in the small subset in whom an initial response may not be noted. ACKNOWLEDGMENTS Writing and editorial assistance was provided to the authors by Peloton Advantage, Parsippany, NJ, and was funded by Allergan plc, Dublin, Ireland. ABBREVIATIONS CEA, Clinician Erythema Assessment SSA, Subject Self-Assessment for rosacea facial redness

7 6 105 REFERENCES Del Rosso JQ, Tanghetti EA, Baldwin HE, Rodriguez DA, Ferrusi IL. The burden of illness of erythematotelangiectatic rosacea and papulopustular rosacea: findings from a web-based survey. J Clin Aesthet Dermatol. 2017;10: Lee WJ, Lee YJ, Lee MH, et al. Prognosis of 234 rosacea patients according to clinical subtype: the significance of central facial erythema in the prognosis of rosacea. J Dermatol. 2016;43: Gallo RL, Granstein RD, Kang S, et al. Standard classification and pathophysiology of rosacea: the 2017 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol. 2018;78: Draelos ZD, Gold MH, Weiss RA, et al. Efficacy and safety of oxymetazoline cream 1.0% for treatment of persistent facial erythema associated with rosacea: findings from the 52-week open label REVEAL trial. J Am Acad Dermatol Jan 31 [Epub ahead of print].

8 7 120 FIGURE LEGENDS Figure 1. Persistent facial erythema associated with rosacea: Patients with at least 1- grade composite improvement in CEA and SSA at each study visit at separate time points. CEA, Clinician Erythema Assessment; SSA, Subject Self-Assessment for rosacea facial redness. Figure 2. Persistent facial erythema associated with rosacea: Maintenance of response from hour 3 at the week 4 visit to hour 3 at the week 26 and week 52 visits in individual CEA or SSA scores. Error bars indicate 95% confidence intervals. CEA, Clinician Erythema Assessment; SSA, Subject Self-Assessment for rosacea facial redness.

9 Patients With Composite 1-Grade Improvement in CEA and SSA, % n/n = 269/ 321/ Predose Postdose Hour 3 Postdose Hour / / / / / / / / 373 Day 1 Week 4 Week 26 Week / 373

10 CEA SSA Improvement From Baseline Improvement From Baseline Week 4 Week 26 Week 52 3-grade CEA improvement at week 4, hour 3 (n=48) 2-grade CEA improvement at week 4, hour 3 (n=186) 1-grade CEA improvement at week 4, hour 3 (n=148) 0-grade CEA improvement at week 4, hour 3 (n=39) Week 4 Week 26 Week 52 Time 3-grade SSA improvement at week 4, hour 3 (n=13) 2-grade SSA improvement at week 4, hour 3 (n=97) 1-grade SSA improvement at week 4, hour 3 (n=207) 0-grade SSA improvement at week 4, hour 3 (n=107)