Hyperhydrosis – Maui Derm

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

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.