Open-label study (ARIDO) evaluating long-term safety of topical glycopyrronium tosylate (GT) in patients with primary axillary hyperhidrosis

Open-label study (ARIDO) evaluating long-term safety of topical glycopyrronium tosylate (GT) in patients with primary axillary hyperhidrosis

Presenters: Glaser DA1, Hebert AA2, Nast A3, Werschler WP4, Shideler S5, Green L6, Mamelok RD7, Drew J8, Quiring J9, Pariser DM10

Affiliations: 1Saint Louis University, St. Louis, MO; 2UTHealth McGovern Medical School, Houston, TX; 3Charité–Universitätsmedizin Berlin, Berlin, Germany; 4Premier Clinical Research, Spokane, WA; 5Shideler Dermatology and Skin Care Center, Carmel, IN; 6George Washington University School of Medicine, Washington, DC; 7Mamelok Consulting, Palo Alto, CA; 8Dermira, Inc., Menlo Park, CA;

9QST Consultations, Allendale, MI; 10Eastern Virginia Medical School and Virginia Clinical Research, Inc., Norfolk, VA

Background/Objective: Hyperhidrosis affects an estimated 4.8 percent of the United States population, or approximately 15.3 million people, and the impact of hyperhidrosis on quality of life is reported as comparable to or greater than psoriasis or eczema. Glycopyrronium tosylate (GT; formerly DRM04) is a topical cholinergic receptor antagonist being developed for the treatment of primary axillary hyperhidrosis in patients nine years of age or older. GT has been assessed in two replicate, randomized, double-blind, vehicle?controlled, pivotal Phase III lead-in trials (ATMOS-1 and ATMOS?2). GT was generally well tolerated and demonstrated clinically meaningful improvements in disease severity and reductions in sweat production through four weeks in these trials. ARIDO (NCT02553798) assessed the long-term safety of GT in a minimum of 100 patients with primary axillary hyperhidrosis treated for at least 12 months.

Methods: ARIDO was a 44-week, open-label extension of ATMOS-1 (NCT02530281) and ATMOS-2 (NCT02530294). In ATMOS-1/ATMOS-2, patients with primary axillary hyperhidrosis were randomized 2:1 to GT (3.75% topical solution) or vehicle applied once daily to each axilla for 28 days (Figure 1). Patients who completed ATMOS-1/ATMOS-2 with at least 80-percent treatment adherence were eligible to continue onto ARIDO and receive open-label GT for up to 44 weeks or until early termination, including patients terminated once the study objective of 100 patients receiving treatment for at least 12 months was achieved. Subjects included in ATMOS-1/ATMOS-2 were at least nine years of age (patients older than 16 were recruited only at US sites), had primary axillary hyperhidrosis for at least six months, showed gravimetrically measured sweat production of at least 50mg per five minutes in each axilla. Included subjects scored a 4 or above on Item 2 (0–10 numeric rating scale) of the Axillary Sweating Daily Diary (ASDD; for patients 16 years of age or older) or ASDD?Children (ASDD-C; for patients under 16 years of age) and 3 or above on the Hyperhidrosis Disease Severity Scale (HDSS). Exclusion criteria included history of a condition that could cause secondary hyperhidrosis; prior surgical procedure or treatment with a medical device for axillary hyperhidrosis, treatment with iontophoresis within four weeks or treatment with botulinum toxin within one year for axillary hyperhidrosis; axillary use of nonprescription antiperspirants within one week or prescription antiperspirants within two weeks; new or modified psychotherapeutic medication regimen within two weeks; treatment with medications having systemic anticholinergic activity, centrally acting alpha-2 adrenergic agonists, or beta-blockers within four weeks (unless dose had been stable for at least four months with no anticipated change); and conditions that could be exacerbated by study medication.

Results: The majority of patients (86.6%; N=564) completing ATMOS-1/ATMOS-2 (369 patients [65.4%] had received GT, and 195 [34.6%] had received vehicle) continued into ARIDO. Of the patients enrolled in ARIDO, most patients were female (55.3%) and Caucasian (83.3%) with a mean age of 33.0 years and mean body mass index (BMI) of 27.3kg/m2. The trial was terminated, per protocol, once study objectives were reached. A total of 226 patients completed 44 weeks of treatment. Through Week 44/ET in ARIDO (up to 48 weeks of GT), GT?treated patients continued to demonstrate improvements in efficacy measures, including sweat production and HDSS responder rate. From baseline in ATMOS-1/ATMOS-2 to Week 44/ET in ARIDO, mean sweat production decreased by 95.7±140.8mg per five minutes, which was maintained from a decrease of 107.6±207.2mg per five minutes in GT?treated patients after four weeks in ATMOS-1/ATMOS-2. At Week 44/ET in ARIDO, HDSS responder rate (?2-grade improvement) was 63.2 percent, a further improvement from 59.1 percent in GT-treated patients at Week 4 in ATMOS-1/ATMOS-2. HDSS grade improved by 1, 2, and 3 grades in 30.9 percent, 46.7 percent, and 16.5 percent of patients, respectively. After 44 weeks, 329 (59.8%) patients reported at least one treatment-emergent adverse event (TEAE), though most were mild or moderate in severity. Most common TEAEs were dry mouth, blurred vision, application site pain, nasopharyngitis, and mydriasis. A total of 44 (8.0%) patients discontinued due to a TEAE and 7 (1.3%) reported at least one serious TEAE. Prespecified anticholinergic TEAEs of interest were reported in 78 (14.2%) patients; most were mild or moderate in severity and were able to be managed by dose interruption. Thirty-seven patients reported 45 vision blurred events; 40 (88.9%) were bilateral. Twenty-nine patients reported 37 mydriasis events; 31 (83.8%) were unilateral.

Conclusion: Safety results were consistent with anticholinergic treatment and with the safety profile observed in prior GT studies, with no new or unexpected findings. Most TEAEs were mild or moderate in severity and considered by the

Investigator to be related to study drug. A low number of subjects discontinued due to a TEAE. While approximately one-third of patients reported local skin reactions, most were mild or moderate in severity. Incidence of TEAEs, including prespecified anticholinergic TEAEs of interest, did not increase with long-term treatment. Efficacy measures obtained at the end of treatment in ARIDO indicated that subjects had maintained sweat production reduction and less bothersome sweating compared with baseline in ATMOS-1/ ATMOS-2. GT was generally well tolerated, and improvements in efficacy measures were maintained in patients with primary axillary hyperhidrosis when applied once-daily to both axillae over a maximum of 48 weeks.

Funding/Disclosures: This study was funded by Dermira, Inc. Medical writing support was provided by Prescott Medical Communications Group (Chicago, IL). Dee Anna Glaser is a consultant and investigator for Dermira, Inc. Adelaide A. Herbert is a consultant for Dermira, Inc. and employee of the University of Texas Medical School, Houston, which received compensation from Dermira, Inc. for study participation. Alexander Nast is an employee of Charité – Universitätsmedizin Berlin, which received compensation from Dermira, Inc. for study participation. William P. Werschler is a consultant and investigator for Dermira, Inc. Stephen Shideler is an investigator for Dermira, Inc. Lawrence Green is a consultant and investigator for Dermira, Inc. and an investigator for Brickell. Richard D. Mamelok is a consultant for Dermira, Inc. Janice Drew is an employee of Dermira, Inc. John Quiring is an employee of QST Consultations. David M. Pariser is a consultant and investigator for Dermira, Inc.

Confirmatory psychometric evaluation of the axillary sweating daily diary: a validated patient-reported outcome measure to assess axillary hyperhidrosis sweating severity

Confirmatory psychometric evaluation of the axillary sweating daily diary: a validated patient-reported outcome measure to assess axillary hyperhidrosis sweating severity

Presenters: Glaser DA1,1 Hebert AA2, Fehnel S3, DiBenedetti D3, Nelson L3, Drew J4, Pariser DM5

Affiliations: 1Saint Louis University, St. Louis, MO; 2UTHealth McGovern Medical School at Houston, Houston, TX; 3RTI Health Solutions, Research Triangle Park, NC; 4Dermira, Inc., Menlo Park, CA; 5Eastern Virginia Medical School and Virginia Clinical Research, Inc., Norfolk, VA

Background/Objective: Hyperhidrosis affects an estimated 4.8 percent of the United States population; approximately three-quarters of patients experience negative psychological effects, with anxiety and depression occurring over

3.5?times more frequently in people with hyperhidrosis than in people without it. Despite high prevalence and burden of disease, few disease-specific outcome measures are available. The Hyperhidrosis Disease Severity Scale (HDSS) is widely used in clinical studies and well understood in clinical practice; however, it does not conform to current regulatory standards for patient-reported outcome (PRO) measures used to support product approvals and labeling. The four-item Axillary Sweating Daily Diary (ASDD) and a child-specific two?item version (ASDD-C) for use in patients between 9 and 16 years of age were developed according to current regulatory standards. The ASDD/ASDD-C axillary sweating severity item (Item 2) was specifically developed for use as an endpoint in clinical trials in support of approval and labeling (and also as a useful clinical parameter). In addition to the ASDD, patients 16 years of age or younger were asked to complete six Weekly Impact Items designed to assess the impact and bother of hyperhidrosis on daily activities and a single?item Patient Global Impression of Change (PGIC) to assess overall change in sweating severity. Initial psychometric evaluation of the ASDD was conducted using data from a Phase II study of topical glycopyrronium tosylate (GT; formerly DRM04), an investigational treatment for primary axillary hyperhidrosis in patients nine years of age or older; results have been previously reported and provide preliminary support for the use of this measure to evaluate the efficacy of axillary hyperhidrosis treatment in clinical trials. In this study, we aimed to confirm and extend the psychometric evidence supporting ASDD/ASDD-C axillary sweating severity item (Item 2) based on pooled data from two Phase III clinical trials of GT: ATMOS-1

(DRM04-HH04; NCT02530281) and ATMOS-2 (DRM04-HH05; NCT02530294)

Methods: ATMOS-1 and ATMOS-2 were Phase III, multicenter (ATMOS-1: sites in the United States and Germany; ATMOS-2: sites in United States), parallel-group, four-week, double-blind clinical trials in which patients with primary axillary hyperhidrosis were randomized (2:1) to GT or vehicle. Eligible patients were at least nine years of age (patients <16 years were only recruited at United States sites) and had primary axillary hyperhidrosis for at least six months, with gravimetrically measured sweat production of at least 50mg per five minutes in each axilla, ASDD/ASDD-C axillary sweating severity item (Item 2) score 4 or above, and Hyperhidrosis Disease Severity Scale (HDSS) Grade 3 or 4. ASDD/ASDD-C Item 2 responses and sweat production were assessed in two age groups (?9 years and ?16 years). ASDD/ASDD-C items were scored as a weekly average of daily responses; at least four days of daily data were required for analysis. Weekly Impact Items and PGIC were included to evaluate construct validity. Potential floor and ceiling effects and nonresponse bias were evaluated based on both summary statistics and graphical techniques. Test-retest reliability was evaluated through the computation of intraclass correlation coefficients (ICCs) between Week 3 and Week 4; a value of at least 0.70 was considered acceptable. Construct validity was evaluated at Week 4 based on correlations between ASDD/ASDD-C Item 2 and ASDD items related to the impact and bother of sweating (Items 3 and 4, respectively), HDSS, sweat production, and other PRO measures, as available. All statistical tests were two-tailed using a type I error rate of one percent (?=0.01).

Results. The pooled Phase III study population (n=697) included 665 patients who were at least 16 years of age and 32 patients aged 9 to 15 years of age. The response distribution for the ASDD/ASDD-C axillary sweating severity item (Item 2) demonstrated no floor or ceiling effect and no nonresponse bias. Construct validity was supported by strong correlations between ASDD Item 2 and the ASDD items addressing the impact and bother of axillary sweating (Items 3 and 4, respectively).

Test-retest reliability was supported by ICCs of 0.93 for both age subgroups, which is well above the 0.70 criterion and within the confidence interval (CI) of the Phase II estimate of 0.91 (95% CI: 0.87, 0.94. The ASDD/ASDD-C Item 2 responsiveness, or ability to detect change in sweating severity, was demonstrated by large effect sizes and correlations that were within the expected range for the change in ASDD/ASDD-C Item 2 and the change in the gravimetric measures of sweat production.

Conclusion: The current study confirms and extends the psychometric evidence supporting the

ASDD/ASDD?C as a new PRO measure developed according to current regulatory standards. The psychometric findings presented here continue to support use of the ASDD/ASDD-C axillary sweating severity item (Item 2) as an endpoint in assessing the efficacy of treatments for patients with axillary hyperhidrosis.

Funding/Disclosures: This study was funded by Dermira, Inc. Dee Anna Glaser is a consultant and investigator for Dermira, Inc. Adelaide A. Herbert is a consultant for Dermira, Inc. and employee of the University of Texas Medical School, Houston, which received compensation from Dermira, Inc. for study participation. Dana DiBenedetti, Lauren Nelson, and Sheri Fehnel are employees of RTI Health Solutions. Janice Drew is an employee of Dermira, Inc. David M. Pariser is a consultant and investigator for Dermira, Inc.

Perceptions regarding use of anti-tumor necrosis factor treatments for women of childbearing age among healthcare professionals

Perceptions regarding use of anti-tumor necrosis factor treatments for women of childbearing age among healthcare professionals

Presenters: Voorhees AV1, Afzali A2, Schwartzman S3, Ecoffet C4, Pisenti L5, Stark J5, Yassine M5, Abraham B6

Affiliations: 1Eastern Virginia Medical School, Norfolk, VA; 2The Ohio State University Wexner Medical Center, Columbus, OH; 3Hospital for Special Surgery, New York, NY; 4UCB Pharma, Brussels, Belgium; 5UCB Pharma, Smyrna, GA; 6Houston Methodist Hospital, Houston, TX

Background/Objective: For women with chronic inflammatory diseases (e.g., psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, inflammatory bowel disease), disease onset, diagnosis, and treatment initiation often overlap with peak reproductive years. High disease activity is associated with increased risk of pregnancy complications and adverse outcomes, and achieving disease control is therefore an important goal for the success of these pregnancies. Tumor necrosis factor antagonists (anti-TNFs) are effective treatments, but use among women of childbearing age (WoCBA) varies due to differing attitudes regarding their safety profiles versus benefits. This survey aimed to better understand perceptions and attitudes of healthcare professionals (HCPs) across different specialties regarding treatment of WoCBA patients with anti-TNFs during pregnancy and lactation.

Methods: An online survey was conducted in the United States on July 6, 2017, by SERMO RealTime. WoCBA was defined as women between the ages of 18 and 45 years. Survey participants included dermatologists (DM), gastroenterologists (GI), rheumatologists (RA) and obstetricians/gynecologists (OB).

Results: Two-hundred and fifty-six HCPs participated in the survey, including 53 DMs, 50 GIs, 50 RAs, 50 OBs. Half of the female patient population across specialties were WoCBA. DMs had the lowest proportion (27%) of female patients prescribed anti-TNFs (GI: 31%; RA: 43%). While physicians indicated being comfortable prescribing anti-TNFs for WoCBA patients, concerns were more prevalent once patients actively started family planning. DMs (57%) and OBs (62%) were more likely to recommend discontinuation of anti-TNFs before conception than GIs (36%) and RAs (46%); 45 percent of DMs and 54 percent of OBs agreed that WoCBA patients should stop anti-TNFs once they are pregnant (compared to <35% GIs and RAs). GIs (46%) and RAs (42%) agreed more strongly than DMs (15%) and OB (20%)on making disease control during pregnancy their priority . Only 17 percent of DMs felt that disease control reduces the risk of pregnancy complications and adverse outcomes, compared to GIs (52%), RAs (42%) and OBs (28%). More DMs and OBs than GIs and RAs believed patients who are breastfeeding should not take anti-TNFs, although a high degree of uncertainty was indicated. Overall, HCPs believed that more safety data during and after pregnancy are needed to feel more comfortable with prescribing anti-TNFs to WoCBA patients who are or might become pregnant in the future.

Conclusion: Our survey demonstrates the variability in clinical management of women with inflammatory or autoimmune diseases. Uncertainty about risks of anti-TNF use during pregnancy and lactation is common. Further research and multidisciplinary engagement among HCPs are needed to discuss and safely treat WoCBA.

Fundings/Disclosures: AVV: Consultant for: Dermira, Novartis, Celgene, AbbVie; board member: Dermira, Novartis, Celgene, AbbVie, Allergan, Derm Tech, Valeant, WebMD; ex-spouse pension: Merck; AA: Consultant for AbbVie, Takeda, UCB Pharma, research grant support from AbbVie, non-profit consultant and board member for IBD Horizons; SS: Consultant for Abbvie, Antares, Genentech, Janssen, Lilly, Novartis, Pfizer, Regeneron, Sanofi, UCB Pharma; speaker fees: Abbvie, Janssen, Genentech, Pfizer, UCB Pharma, Crescendo, Novartis; board member: Crescendo Biosciences, Discus Analytics, National Psoriasis Foundation; CE, LP, JS, MY: Employee of UCB Pharma; MC: Employee of Dermira Inc; BA: Grant/research support: Janssen, UCB Pharma; speaker’s fees: AbbVie, American Reagent, Janssen, UCB Pharma

Long-term results of investigator-assessed efficacy and safety of 200mg dose of sonidegib for locally advanced basal cell carcinoma: 30-month BOLT analysis

Long-term results of investigator-assessed efficacy and safety of 200mg dose of sonidegib for locally advanced basal cell carcinoma: 30-month BOLT analysis

Presenters: Migden M1, Lewis KD2

Affiliations: 1University of Texas MD Anderson Cancer Center, Departments of Dermatology, Division of Internal Medicine, and Head and Neck Surgery, Division of Surgery, Houston, TX; 2University of Colorado Denver, School of Medicine, Division of Medical Oncology, Denver, CO

Background/Objective: The 200mg dose of sonidegib was approved in 2015 in the European Union, Switzerland, Australia, and the United States for the treatment of patients with locally advanced basal cell carcinoma (laBCC) who are not amenable to curative surgery or radiation therapy. In both Switzerland and Australia, sonidegib is also approved for the treatment of metastatic BCC (mBCC). Sonidegib is a selective smoothened (SMO) inhibitor that blocks hedgehog pathway signaling. Approvals were based on results from the pivotal BOLT Phase II clinical trial (NCT01327053). Efficacy and safety data from BOLT were assessed by both investigator and central review. Here, we report the investigator-assessed efficacy and safety data of sonidegib 200mg QD from the 30-month analysis.

Methods: BOLT is a randomized, double-blind clinical trial that was conducted in 58 centers across 12 countries. Patients received either 200mg or 800mg of sonidegib once daily. Only the 200mg dose data will be presented here, as this dose was found in earlier studies to be more tolerable and equally as effective as the higher dose. As a primary endpoint, investigators evaluated objective response rate (ORR), which is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Tumor evaluations were done using BCC-modified Response Evaluation Criteria In Solid Tumors (mRECIST) for laBCC. Sonidegib safety was monitored, including the monitoring of adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.

Results: In patients with laBCC who received sonidegib 200mg (n=66), the investigator-assessed ORR was 71 percent. Median overall survival was not reached at this time point, but the two-year overall survival rate was 93 percent. Tumor responses were durable with a median duration of response of 15.7 months. At the 30-month data cutoff, the median duration of PFS was 19.4 months. One death was reported in the 200mg dose arm of patients with laBCC, but it was not considered to be related to study treatment. The safety profile of sonidegib 200mg was manageable, and no new safety concerns were found compared to the earlier BOLT data analyses. In summary, 43 percent of patients experienced grade 3/4 adverse events and AEs requiring dose interruptions/reductions. AEs that led to discontinuation occurred in 30 percent of patients, and the most commonly reported AEs included muscle spasms (56%), alopecia (52%), and dysgeusia (47%).

Conclusion: In the BOLT 30-month analysis, sonidegib 200mg QD provided sustained efficacy and a continued long-term acceptable safety profile in patients with laBCC. Interestingly, both the median DOR and median PFS data were higher when assessed by central review compared to investigator review. Given the stringent criteria used to assess tumor responses in the BOLT trial, these data support the use of sonidegib 200mg QD in patients with laBCC when used according to local treatment guidelines.

Safety and efficacy of A-101 hydrogen peroxide topical solution 40% in adults with seborrheic keratosis: results from the Phase III, randomized, double-blind, vehicle-controlled, parallel-group study

Safety and efficacy of A-101 hydrogen peroxide topical solution 40% in adults with seborrheic keratosis: results from the Phase III, randomized, double-blind, vehicle-controlled, parallel-group study

Presenters: Draelos ZD1, Kempers SE2, Smith SR3, Wilson DC4; Powala C5, Bradshaw M6; Estes E5; Shanler S5

Affiliations: 1Dermatology Consulting Services, High Point, NC; 2Minnesota Clinical Study Center, Fridley, MN; 3California Dermatology & Clinical Research Institute, Encinitas, CA; 4The Education and Research Foundation, Inc., Lynchburg, VA; 5Aclaris Therapeutics, Malvern, PA

Objective: Seborrheic keratosis (SK) is one of the most common benign skin lesions, affecting over 80 million Americans, yet there is no United States Food and Drug Administration (FDA)-approved treatment available. The purpose of this study was to evaluate the safety and efficacy of a proprietary 40% hydrogen peroxide topical solution (A-101) versus its matching vehicle for the treatment of seborrheic keratosis.

Design: Adults with four eligible SK lesions identified by the study investigator were randomized 1:1 to A-101 or a matching A-101 vehicle. Eligible lesions were stable, typical SKs, measuring 5 to 15mm in both width and length and less than 2mm in thickness. Subjects were required to present with at least one lesion on the trunk or extremities and at least one lesion on the face. All treatments were performed by a non- physician sub-investigator to maintain blinding. All lesions were treated on Day 1. Previously treated SK lesions with a Physician’s Lesion Assessment score over 0 were re-treated on Day 22 (PLA scale: 0=clear, 1=near clear, 2=thickness ?1mm, and 3=thickness>1mm). At Day 106, the investigator assessed the lesions using the validated PLA scale.

Results: Total of 450 subjects were enrolled. At Day 106, significantly more subjects receiving A-101 (intent-to-treat ITT population) completely cleared (PLA=0) all four lesions (4% vs. 0%, P<0 .002) and 3 of 4 lesions (13.5% vs. 0%, P<0.0001) versus vehicle in the primary and secondary endpoints, respectively. In the a priori exploratory analyses (per protocol population [PPP], n=439), significantly higher mean per-subject percentage of lesions achieving clear or near clear (PLA?1) was observed in the A-101 arm (47.5% vs. 10.2%; P<0.0001). Significantly higher mean per-subject percentage of facial lesions achieving clear or near clear (PLA?1) was also observed (64.4% vs.15.0% at Day 106; P<.0001). Adverse events were comparable between groups.

Local skin reactions were predominantly mild and generally resolved by Day 106. At all visits, atrophy, erosion, hypopigmentation, scarring, or ulceration were reported for at least four percent of lesions.

Conclusion: A-101, a 40% hydrogen peroxide topical solution, is a safe, effective, and well-tolerated treatment for SK. If approved, it would offer the first FDA-approved topical treatment for SK.

Cemiplimab (REGN2810), a fully human anti-PD-1 monoclonal antibody, for patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC): Initial safety and efficacy from expansion cohorts of Phase I study

Cemiplimab (REGN2810), a fully human anti-PD-1 monoclonal antibody, for patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC): Initial safety and efficacy from expansion cohorts of Phase I study

Presenters: Papadopoulos KP1,Owonikoko TK2, Johnson ML3, Bra?a I4, Gil-Martin M5, Perez RP6, Moreno V7, Salama AK8, Calvo E9,Yee NS10, Safran H11, González-Martín A12, Aljumaily R13, Mahadevan D14, Mohan KK15, Li J16, Stankevich E15, Israel Lowy I15, Fury MG15, Homsi J17

Affiliations: 1South Texas Accelerated Research Therapeutics, San Antonio, TX; 2Emory Winship Cancer Institute, Atlanta, GA; 3Sarah Cannon Research Institute, Nashville, TN; 4Vall D’HebronInstitute of Oncology, Barcelona, Spain; 5InstitutCatalàd’Oncologia, Barcelona, Spain; 6Unversity of Kansas, Fairway, KS; 7START Madrid Fundacion Jimenez Diaz, Madrid, Spain; 8Duke University Medical Center, Durham, NC; 9START Madrid, Hospital Madrid Norte Sanchinarro, Madrid, Spain; 10Penn State Cancer Institute, Hershey, PA; 11Miriam Hospital, Providence, RI; 12Formerly of MD Anderson International España, Madrid, Spain; 13University of Oklahoma Health Sciences Center, Oklahoma City, OK; 14Formerly of University of Arizona Cancer Center, Tucson, AZ; 15Regeneron Pharmaceuticals Inc., Tarrytown, NY; 16Regeneron Pharmaceuticals Inc., Basking Ridge, NJ; 17Formerly of Banner MD Anderson Cancer, Gilbert, AZ.

Background/Objective: Cemiplimab (REGN2810) is a human immunoglobulin G4 monoclonal antibody directed against PD-1.1. Phase I results from the first 60 patients with advanced solid tumors showed no dose-limiting toxicities. The most common treatment-related adverse events (AEs) in these patients were fatigue (28%), arthralgia (12%), and nausea(12%); the overall response rate was 18 percent. Cemiplimab 3mg/kg every two weeks (Q2W) was selected for further study in Expansion Cohorts. As of April 27, 2017, 392 patients have been enrolled in the Phase I study. The coprimary objectives of the CSCC Expansion Cohorts of this Phase I open-label study were to characterize the safety and tolerability of intravenous cemiplimab 3mg/kg and to evaluate the efficacy of cemiplimab by measuring overall response rate (ORR).

Methods: CSCC Expansion Cohorts (NCT02383212): Cohort 7 enrolled 10 patients with mCSCC, and Cohort 8 enrolled 16 patients with unresectable locally and/or regionally advanced CSCC. All patients received cemiplimab 3mg/kg Q2W for up to 48 weeks (if no progression or intolerance), followed by post-treatment follow-up. There was an option for re-treatment for patients who experienced disease progression during post-treatment follow-up, but no CSCC patients required this re-treatment option at the time of this study. All patients underwent tumor imaging every eight weeks, and response assessments were per RECIST 1.1. Research biopsies were performed at baseline and at Day 29. Subjects included scored a 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status, had a measurable disease by RECIST 1.1, had adequate organ function (bone marrow, kidney, liver), were in the mCSCC(M1): Expansion Cohort 7 and/or the unresectablelocally and/or regionally advanced CSCC (M0): Expansion Cohort 8. Exclusion criteria included presence of an autoimmune disease within five years, active brain metastases, or other invasive malignancy within five years (no exclusion for tumors considered cured by localized treatment), immunosuppressive doses of steroids (>10mg prednisone daily or equivalent), systemic antitumor treatment within four weeks of initial dose of cemiplimab, history of solid organ transplant, and tumors of lip or eyelid not eligible for CSCC cohorts.

Results: Investigator-assessed preliminary ORR (complete response [CR] + partial response [PR] + one unconfirmed PR) by RECIST 1.1 was 46.2 percent (12/26 patients; 95% confidence interval [CI]: 26.6–66.6; intent-to-treat [ITT] population). Disease control rate (DCR = ORR + stable disease [SD]) was 69.2 percent (18/26 patients; 95% CI: 48.2–85.7). Cemiplimab also produced rapid, deep, and durable tumor reductions in target lesions in both cohorts. As of April 27, 2017 (data cut-off date), 26 patients (median age, 73 years) from the CSCC expansions cohorts have been treated with cemiplimab. A total of 17 of 21 evaluated tumors (81%) were positive (?1%) for tumor expression of PD-L1 by immunohistochemistry. There was no apparent association between PD-L1 immunohistochemistry results and objective responses. The most common treatment-emergent adverse event (AEs) were fatigue, occurring among six patients. Two patients discontinued study treatment after treatment-related AEs: an 86-year-old woman developed a Grade 3 rash after three doses (she continued post-treatment follow-up) and an 88-year old male withdrew consent following Grade 3 transaminase elevation and Grade 2 fatigue after six doses. There were two deaths within 30 days of last dose of study drug, both considered unrelated to study drug.

Conclusion: This is the first prospective study of a PD-1 inhibitor in patients with advanced CSCC. Cemiplimab was generally well tolerated in CSCC in this predominantly older population. Both locally advanced and mCSCC are highly responsive to cemiplimab (combined ORR 46.2%), and durability is emerging. Eighty-one percent of pre-treatment tumor samples were PD-L1 positive. A unifying characteristic of cutaneous malignancies appears to be responsiveness to immune checkpoint inhibition. A Phase II study is ongoing in patients with unresectablelocally advanced and mCSCC(NCT02760498).

Funding/Disclosures: This study was funded by Regeneron Pharmaceuticals Inc, and Sanofi. Dr. Papadopoulos has received institutional research funding from Regeneron and Sanofi. Taofeek Owonikoko holds a consulting/advisory role for Regeneron. Melissa Johnson receives research funding from Regeneron. Raymond Perez receives institutional research funding from Regeneron. Emiliano Calvo receives institutional research funding from Sanofi. Nelson Yee receives institutional research funding from Regeneron. Kosalai Mohan, Jingjin Li, Elizabeth Stankevich, Israel Lowy, Matthew Fury, are stockholders and employees of Regeneron Pharmaceuticals, Inc. Matthew Fury also receives research funding, institutional patents, royalties, and other intellectual property from Regeneron. Jade Homsi receives research funding from Regeneron.

A real-world study evaluating adequacy of existing systemic treatments for patients with moderate-to-severe atopic dermatitis (AD-QUEST): baseline treatment patterns and unmet needs assessment

A real-world study evaluating adequacy of existing systemic treatments for patients with moderate-to-severe atopic dermatitis (AD-QUEST): baseline treatment patterns and unmet needs assessment

Presenters: Wei W1, Ghorayeb W2, Andria ML3, Walker V4, Chao J3, Schnitzer J2, Kennedy M3, Chen Z3; Belland A4, White J4, Silverberg JI5

Affiliations: 1Formerly of Sanofi, Bridgewater, NJ; 2Sanofi, Bridgewater, NJ; 3Regeneron Pharmaceuticals, Inc., Tarrytown, NY; 4Optum, Eden Prairie, MN; 5Northwestern University Feinberg School of Medicine, Chicago, IL

Objective: To evaluate potential unmet needs in the treatment of moderate-to-severe atopic dermatitis (AD) from a patient perspective.

Methods: Adults with an AD diagnosis in the last five years and a prescription for systemic treatment in the last six months were identified using claims data from Optum Research Database. Patients with self-assessed moderate-to-severe AD were invited to participate in monthly surveys over 12 months about disease signs and symptoms, quality of life (QoL) and AD treatment. We report baseline survey data.

Results: Of 6,000 patients invited to participate, 1,485 responded and 801 were eligible for inclusion (mean age: 45 years; female: 72%; Caucasian: 84%; employed: 79%; AD severity [Rajka & Langeland criteria]: moderate 74%, severe 26%). In the 12 months before baseline, 38 percent and 36 percent reported no remission or less than three months remission from AD. In the month before baseline, most reported using topical corticosteroids (64%) or calcineurin inhibitors (8%), some reported using antihistamines (38%), and a few reported using systemic steroids (11%) or immunosuppressants (5%). In the same period over 81 percent reported AD flares (1: 23%; 2: 20%; ?3: 38%), of which, 65 percent and 22 percent had partial or no recovery. Patients experiencing a flare versus those with no flare at baseline reported significantly worse POEM (13.5 vs. 6.2), peak pruritus NRS (worst itch in previous 24 hours: 6.3 vs. 3.5) and DLQI scores (8.6 vs. 3.7), and greater work productivity loss in previous seven days (8.2 vs. 3.4) (all P<0.001).

Conclusion: This suggests that despite standard-of-care treatments, adults with moderate-to-severe AD report disease symptoms, recurrent flares, and impaired QoL, suggesting unmet therapeutic needs.

Funding/Disclosures: Wenhui Wei is a former employee and current stockholder of Sanofi and an employee of Regeneron Pharmaceuticals, Inc. Eric Ghorayeb and James Schnitzer are employees of and stockholders in Sanofi. Michael Andria, Jingdong Chao, Martha Kennedy and Zhen Chen are employees of and stockholders in Regeneron Pharmaceuticals, Inc. Valery Walker, Angela Belland, and John White are employees of Optum, a company that received research funding for the current study. Jonathan Silverberg is a member of an institution that received research funding for the current study. This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.

An investigator blinded randomized study evaluating hypochlorous acid (HOCl) in the treatment of atopic dermatitis-associated pruritus

An investigator blinded randomized study evaluating hypochlorous acid (HOCl) in the treatment of atopic dermatitis-associated pruritus

Presenters: Berman B, Nestor M

Affiliation: Center for Clinical and Cosmetic Research and University of Miami Miller School of Medicine, Miami, FL

Background/Objective: Hypochlorous acid (HOCl) might potentially reduce pruritus in atopic dermatitis (AD) by its microbicidal qualities, particularly in reducing Staphylococcus aureus, and by its anti-inflammatory qualities that reduce the activities of histamine, leukotriene B4, and interleukin-2, all of which contribute to the pathophysiology of itch. Here, we present the results of a three-day study designed to evaluate the effect of HOCl on pruritus in patients with AD.

Methods: The study was conducted according to the protocol and in compliance with Good Clinical Practice (GCP) and other applicable regulatory requirements. This investigator-blinded, randomized Phase II, 72-hour study investigated the antipruritic effect of HOCl with patients diagnosed with AD. Subjects enrolled had AD as defined by the Hanifin criteria and had scored higher than 2 on an itch severity scale (0–4). Thirty subjects were enrolled, 20 randomized to the treatment group (HOCl), and 10 randomized to the untreated control group. Subjects used a HOCl containing solution BID or PRN for 72 hours and recorded applications in a diary. Subjects randomized to the untreated group received no treatment and were only instructed to come to follow-up visits for study-specific assessments.

The three primary measures used were Participant Global Assessment (PGA), Investigator Global Assessment (IGA), and Visual Analog Scale (VAS) itch score. Adverse events (AEs) and serious adverse events (SAEs) and incidence of local skin reactions leading to discontinuation were recorded as well. Measurements were taken at baseline, 24 hours, and 72 hours post-treatment. Photographs of representative areas of affected skin were taken.

Results: The mean VAS itch score between the two groups was similar at baseline. Mean change in PGA and IGA scores between baseline and 72 hours both significantly decreased in favor of the HOCl treatment group (PGA: p value=0.128; IGA: p=0.012). The mean itch VAS scores between the treated and untreated groups were significantly different between baseline and 72 hours post-application, with the percent mean change shown to be significantly lower (improved) in the HOCl treated group.

The analysis showed 73.7 percent of the subjects in the HOCl treated and 30.0 percent of the subjects in the untreated group experienced a reduction in itching between baseline and 72 hours after initial application. There were no treatment related discontinuations or SAEs.

Conclusion: This study demonstrated that application of HOCl-containing solution leads to a reduction in itching associated with AD at 24 hours with significantly better results when compared to the untreated cohort at 72 hours.

A Phase IIb dose-ranging efficacy and safety study of tralokinumab in adult patients with moderate-to-severe atopic dermatitis (AD)

A Phase IIb dose-ranging efficacy and safety study of tralokinumab in adult patients with moderate-to-severe atopic dermatitis (AD)

Presenters: Wollenberg A1, Howell MD2, Guttman-Yassky E3, Silverberg JI4, Birrell C5, Kell C5, Ranade K2, Dawson M5, van der Merwe R5

Affiliations: 1Ludwig Maximillian University, Munich, Germany; 2MedImmune, LLC, MD; 3Mount Sinai School of Medicine, NY; 4Northwestern University Feinberg School of Medicine, IL; 5MedImmune, Ltd., Cambridge, UK

Background/Objective: AD is a chronic inflammatory skin disease characterized by increased interleukin (IL)-13 levels. Tralokinumab, an anti-IL-13 monoclonal antibody, has shown efficacy and an acceptable safety profile in patients with severe, uncontrolled asthma driven by the T-helper 2 pathway. Serum dipeptidyl peptidase 4 (DPP-4) has been reported as a predictive marker for tralokinumab in patients with severe asthma. Here, we evaluated whether tralokinumab offers therapeutic benefit to adults with moderate-to-severe AD.

Methods: In this Phase IIb, randomized, placebo-controlled, double-blind study (NCT02347176), patients were randomized 1:1:1:1 to receive tralokinumab 45mg, 150mg, or 300mg, or placebo every two weeks with mid-strength topical corticosteroids (TCS) for 12 weeks. Coprimary endpoints were change from baseline in Eczema Area Severity Index (EASI) and percentage of patients with clear or almost clear Investigator’s Global Assessment (IGA 0/1) at Week 12. Further efficacy, patient-reported outcomes, serum biomarkers, and safety endpoints were assessed.

Results: Overall, 204 patients were randomized. Tralokinumab 300mg treatment significantly reduced EASI scores (adjusted mean [standard error] change from baseline: 15.7 [1.3]; p=0.011) vs. placebo (-10.8 [1.4]) and more patients had IGA 0/1 (26% vs. 12%). Significant improvements were observed in patients who received tralokinumab 300mg versus placebo for Scoring of Atopic Dermatitis (p=0.002), Dermatology Life Quality Index (p=0.006), Pruritus Numeric Rating Scale (p=0.002), EASI75 (p=0.003), and EASI50 (p=0.025). Tralokinumab 300mg significantly reduced the number of Staphylococcus aureus-colonized patients (p=0.015), the concentration of serum immunoglobulin E, periostin, and TARC/CCL17, dose-dependently versus placebo (p<0.001). Patients with increased IL-13 activity (n=102), identified by baseline serum DPP-4 concentrations above median, showed an increased response to tralokinumab 300mg; more patients achieved IGA 0/1 (35% vs. 8%) and EASI75 (52% vs. 13%) than patients receiving placebo. The most frequent adverse events in all groups were nasopharyngitis (17%), upper respiratory tract infection (9%), headache (6%) and AD (6%).

Conclusion: Tralokinumab with TCS was more efficacious than TCS alone and demonstrated clinically relevant efficacy and an acceptable safety profile in patients with moderate-to-severe AD. DPP-4 might become a predictive marker for patients with AD who respond to tralokinumab 300mg, allowing a personalized medicinal approach.

Funding: This study was funded by MedImmune.

Clinical efficacy and tolerability of a hydroquinone-free and retinol-free topical brightening serum on females with facial melasma

Clinical efficacy and tolerability of a hydroquinone-free and retinol-free topical brightening serum on females with facial melasma

Presenters: Makino ET, Tan P; Mehta RC

Affiliation: Research & Development SkinMedica, an Allergan Company, Irvine, CA

Background/Objective: Melasma, a progressive form of hyperpigmentation, occurs more often in healthy women than men. The actual etiology is indefinite; however, pregnancy, hormonal changes, ultraviolet (UV) light exposure, photosensitizing medications, and genetic predisposition have all been considered as contributing factors. This dysfunction of the pigmentary system results in symmetric brown or gray-brown patches on sun exposed areas of the face, particularly on the forehead, cheeks, upper lip, and chin. Often, the psychosocial impact of melasma leads to a negative effect on quality of life and emotional well-being. The purpose of this study was to assess the cosmetic efficacy and tolerability of a HQ-free and retinol-free serum (LYT2) in nonpregnant women with mild-to-severe melasma that was self-perceived as being induced by a previous pregnancy.

Methods: This was a 12-week, single-center, clinical usage study with visits at baseline and Weeks 4, 8 and 12. Thirty female subjects aged 30 to 50 years with Fitzpatrick Skin Types (FST) II to IV presenting with mild-to-severe overall hyperpigmentation on the face due to melasma, which was self-perceived to be induced by a previous pregnancy, completed the study. Seventy-three percent of the subjects were Caucasian, 20 percent were Asian, and seven percent were African American. All subjects received LYT2, cleanser, moisturizer, and sunscreen. Subjects applied LYT2 twice-daily after cleansing. All subjects used cleanser and moisturizer twice-daily and a physical sunscreen once in the morning (and as needed throughout the day). At all visits, the investigator assessed for overall hyperpigmentation (0–9 scale; 0=none, 1–3=mild, 4–6=moderate, 7–9=severe), global Improvement in Overall Hyperpigmentation (0–5 scale), and Melasma Area and Severity Index (MASI). Each subject’s face was divided into four areas that were evaluated separately (forehead [F], right malar region [MR], left malar region [ML], and chin [C]). For each area, the pigment intensity (PI), lesion size (A), and homogeneity (H) were assessed. MASI score for the whole face was calculated using the following equation: MASI=0.3 (PIF + HF) AF + 0.3 (PIMR + HMR) AMR + 0.3 (PIML+ HML) AML + 0.1 (PIC + HC) AC. The values 0.3, 0.3, 0.3, and 0.1 represent the respective percentages of total facial area. The maximum score for MASI is 48 and the minimum score is 0. Tolerability assessments for erythema, scaling, edema, burning, stinging, and itching were graded on a 4-point scale at all visits. At all follow-up visits, subjects completed a self-assessment questionnaire on self- perceived efficacy, product texture, and product attributes. At baseline and Week 12, subjects completed a Melasma Quality of Life (MelasQol) Questionnaire (Likert Scale: 1=not bothered at all to 7=bothered all the time).Standardized digital photographs were taken using the VISIA-CR Imaging System (Canfield Imaging Systems) at all visits. Image analysis on a target dark spot for skin brightness (L*) was conducted for each time point. Corneometer and tewameter measurements were conducted for all visits.

Results: The HQ-free and retinol-free serum demonstrated a statistically significant decrease in clinical grading scores at Weeks 4, 8, and 12 when compared with baseline for overall hyperpigmentation, global improvement in overall hyperpigmentation, and MASI (all p<0.001; Wilcoxon Signed-Rank Test). Statistically significant increase in mean scores for global improvement in overall hyperpigmentation at all visits (all p<0.001; Wilcoxon Signed-Rank Test). MelasQol Combined Score showed a statistically significant improvement at Week 12 compared to baseline, indicating an increased perception of quality of life (p<0.03; Wilcoxon signed-rank test). Corneometer and tewameter measurements continuously improved from baseline at all follow-up visits, indicating an improvement in skin hydration and skin barrier function, respectively. Image analysis for brightness (L*) showed statistically significant improvements from baseline at all follow up visits (all p?0.025; paired t-test). LYT2 was well tolerated with tolerability scores remaining similar to baseline scores, and highly rated by subjects for self-perceived efficacy and product attributes with a significant proportion of subjects agreeing to favorable responses by Week 12. Ninety-seven percent of subjects were satisfied with LYT2 by Week 12. Seventy-seven percent of subjects saw moderate or marked improvement by Week 12. Eighty-three percent of subjects agreed it performed better than past facial treatments.

Conclusion: Results from this study support the efficacy and tolerability of this HQ-free and retinol-free serum in improving the appearance of mild-to-severe facial melasma in subjects with self-perceived pregnancy-induced melasma.

Funding/Disclosures: This study was sponsored by Allergan. All authors met the ICMJE authorship criteria. All authors are employees of Allergan.