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.