Glycopyrronium Tosylate (Qbrexza) for Hyperhidrosis

Crystal E. Nwannunu, BS¹; Allison L. Limmer, BA, BS¹; Kendall Coleman, BSA¹; Radhika Shah, BA, BS²; Ravi R. Patel, MD³; Uyen Ngoc Mui, MD³; Stephen K. Tyring, MD, PhD^1,3

¹Department of Dermatology, McGovern Medical School, The University of Texas Health Sciences Center, Houston, TX, USA
²Texas A&M University College of Medicine, Dallas, TX, USA
³Center for Clinical Studies, Houston, TX, USA

Conflict of interest:
All of the authors have no conflicts to declare for this work.

Abstract
Hyperhidrosis is a condition characterized by excessive sweat production beyond which is physiologically necessary for thermal regulation. Affecting over 4.8% of the United States population, studies have shown that severe primary hyperhidrosis interferes with daily activities and can be considered intolerable, negatively impacting a patient’s quality of life. Glycopyrronium tosylate is a topical anticholinergic agent that reduces sweat production by blocking the activation of acetylcholine receptors in peripheral sweat glands. In clinical trials, topical glycopyrronium tosylate, a pre-moistened cloth containing 2.4% glycopyrronium solution, was shown to be an effective, safe and non-invasive treatment for patients suffering from primary hyperhidrosis. This review examines the clinical trials of topical glycopyrronium tosylate and its role in primary hyperhidrosis. Glycopyrronium tosylate was recently US FDA-approved (as of June 2018) to manage patients with primary axillary hyperhidrosis.

Key Words:
anticholinergic, axillary hyperhidrosis, glycopyrronium tosylate, Qbrexza, sweat, treatment

Introduction

Hyperhidrosis is a condition characterized by sweat production beyond which is physiologically necessary for thermal regulation. A recent study estimates the prevalence of hyperhidrosis in the United States to be 4.8%, with over 70% of sufferers experiencing severe sweating that is considered intolerable or interfering with daily activities.¹ Hyperhidrosis has been shown to correlate with anxiety, depression and diminished quality of life.^2-5 Patients often report frustration with the length of time until diagnosis, as well as the cost and efficacy of treatments once a diagnosis is established.^4,5

Pathogenesis of Hyperhidrosis

The pathogenesis of primary hyperhidrosis is not well-delineated. The condition is thought to be the result of a dysregulated autonomic nervous system and has a clear genetic component.^6,7 Hyperhidrotic skin regions do not exhibit increased number or size of sweat glands; rather, the grossly normal sweat glands hyperfunction.⁸ Whether or not this hyperfunctioning is secondary to an increased sensitivity to specific stimuli, emotional, sensory, or otherwise, remains a topic of debate.

Current Treatments

Several treatment options exist for patients with primary hyperhidrosis. First-line agents include topical antiperspirants containing aluminum chloride hexahydrate that obstruct eccrine glands, and glycopyrrolate, which works by competitively binding muscarinic acetylcholine receptors. Oral anticholinergics, such as glycopyrrolate, oxybutynin, and bornaprine, are also effective in treating hyperhidrosis. Other oral medications have shown some benefit in treatment as well. Beta-blockers and benzodiazepines are particularly effective if the patients have anxiety triggers, and methanthelinium bromide and clonidine work well for axillary hyperhidrosis and cranial hyperhidrosis, respectively. In addition to topical and oral treatments, an injectable method utilizing botulinum toxin is available. This toxin works as an acetylcholine release inhibitor causing a neuromuscular blockade. Different types of the toxin are effective for different forms of primary hyperhidrosis, including axillary, palmar, and plantar. The use of medical devices through iontophoresis and microwave thermolysis have also shown benefit in reducing sweat production through unclear mechanisms.⁹

When pharmacological measures are exhausted, surgery may be performed. Surgeons have utilized endoscopic thoracic sympathectomy (ETS) in treating primary hyperhidrosis of the face, extremities, and axillae.10 Pharmacological and surgical treatments have demonstrated substantial success in patients with hyperhidrosis, but adjunctive therapies tailored for individualized treatment plans are recommended. Specialized clothing and bedding to prevent moisture can provide relief as well.⁹

Phase Studies

Glycopyrronium tosylate (GT, Qbrexza™), formerly DRMO4, is a topical competitive inhibitor of acetylcholine receptors that targets cholinergic peripheral tissues including sweat glands.¹¹ Blockade of acetylcholine receptors that activate sweat glands leads to the reduction in sweat production, an essential component in the treatment of primary axillary hyperhidrosis. Glycopyrronium tosylate is administered topically as a single-use, pre-moistened cloth containing 2.4% glycopyrronium solution.¹¹

The first Phase 2b clinical trial, DRM04-HH01, enrolled 198 patients with severe hyperhidrosis. The study was conducted as a randomized, double-blind, vehicle-controlled trial evaluating dose dependence and statistical significance in the reduction of signs and symptoms of primary axillary hyperhidrosis. Patients were randomized to receive either the topical agent at one of the four concentrations (1%, 2%, 3% and 4%) or the vehicle wipes for 4 weeks.¹² Results in the DRM04-HH01 study demonstrated dose dependence and statistically significant improvement in the topical GT group compared to the vehicle group.¹²

Due to the significant clinical results in DRM04-HH01, the second Phase 2b study, DRM04-HH02, was designed to gain clinical experience with DRM04 prior to Phase 3 investigations.¹³ Accordingly, the DRM04-HH02 study was not powered to demonstrate statistical significance but did support advancement into Phase 3 clinical development.¹³ DRM04-HH02 was conducted in a similar fashion as the first Phase 2b trial (randomized, double-blind, vehicle-controlled), but differed in that this second trial would aid in assessing the efficacy, safety, and pharmacokinetics of topical glycopyrronium wipes. In this study, 105 patients were recruited and instructed to apply either the topical agent or vehicle product to each axilla once a day for 4 weeks. Sweat production measurement tools used to establish baseline sweat production and analyze post-treatment changes included gravimetrically measured sweat production and the Hyperhidrosis Disease Severity Scale (HDSS). DRM04-HH02 also explored a new patient-reported outcome instrument, the Axillary Sweating Daily Diary (ASDD) [see “Patient-Reported Outcomes” below]. Results of the study showed an average reduction in sweat production from baseline to week 4 ranging from 67.7% to 79.8% in patients receiving topical GT cloth compared to 48.7% reduction in patients who received the vehicle only.¹³ Patients who achieved at least a 2-grade improvement in HDSS score after week 4 ranged from 40.9% to 50% with DRM04 use compared to 27.3% in patients who received vehicle only.¹³ ASDD data demonstrated that patients who received DRM04 experienced greater improvements in disease severity compared with vehicle treatment. At the end of the trial, ASDD data was still being validated during the publication of this review.

In both DRM04-HH01 and DRM04-HH02 clinical trials, the GT treatment was well-tolerated and displayed a low incidence of manageable side effects, with the most common being dry mouth, application site pain, and headache.¹³

Glaser et al. published the only Phase 3 trial data to date. The clinical trials ATMOS-1 and ATMOS-2 were replicated, randomized, double-blinded, vehicle-controlled, parallel-group 4 week trials conducted to further assess the efficacy and clinical significance of GT in hyperhidrosis. Each trial had an overall sample size of 330 to provide at least a 95% power at a significance level of 0.05 in efficacy assessment.¹⁴ Patients were randomized within two treatment groups, glycopyrronium tosylate 3.75% (equivalent to 2.4% glycopyrronium) or a matched vehicle group. Participants were instructed to apply their assigned product once daily to a clean and dry axilla, and were assessed at weekly clinical visits for 4 weeks. The participant population included male and non-pregnant females aged 9 years and older who presented with primary axillary hyperhidrosis for more than 6 months, sweat production of >50 mg/5 min in each axilla on at least 1 of 3 gravimetrically performed measurements, ASDD sweating severity score >4, and HDSS grade 3 or 4 (based on a 4-point scale).¹¹ At week 4, a statistically significant change from baseline sweat production was observed in ATMOS-2 (p<0.001) but not in ATMOS-1 (p=0.065).⁹ In these trials, GT application was generally well tolerated with the most common side effects being dry mouth, headache, sore throat, and mydriasis, occurring in only 2% of patients.¹⁵

Patient-Reported Outcomes

Patients treated with GT or vehicle in the ATMOS-1 and ATMOS-2 Phase 3 trials were asked to complete Axillary Hyperhidrosis Patient Measures (AHPM) on a nightly basis, including the ASDD if aged 16 or over, or the Axillary Sweating Daily Diary-Children (ASDD-C) if under 16. Patients aged 16 and over were also asked Weekly Impact Items, to determine the effect and bother of hyperhidrosis on daily activities, as well as one Patient Global Impression of Change (PGIC) item at the end of the study.¹⁴ These measures gave patients the opportunity to express the impact of treatment on their perceived sweat burden.

Item 2 of the ASDD/ASDD-C asked participants to rate their worst sweating over the past 24 hours on a scale from 0 to 10. At the 4-week point, the proportion of patients who reported improvements of greater than or equal to 4 points from baseline was statistically significant between GT- and vehicle-treated patients in ATMOS-1 (53% versus 28%) and in ATMOS-2 (66% versus 27%), with p<0.001 in both.¹⁴

ATMOS-1 and ATMOS-2 also utilized the 4-point Hyperhidrosis Disease Severity Scale (HDSS) to screen patients. Patients were determined to be grade 3 or 4 at baseline. A greater than or equal to 2-grade improvement was noted in GT versus vehicletreated patients as early as week 1. By week 4, ATMOS-1 showed an improvement in 57% versus 24% of patients and ATMOS-2 an improvement in 62% versus 28% (both with p<0.001).¹⁴

Efficacy and Safety

In addition to the subjective efficacy endpoints evaluated in the previous section on patient-reported outcomes, sweat production was measured gravimetrically weekly throughout both ATMOS-1 and ATMOS-2. In ATMOS-2, a statistically significant difference favoring GT in mean absolute change from baseline in sweat production was noted compared to vehicle (p<0.001).¹⁴ Mean absolute change seen in ATMOS-1 at week 4 was not statistically significant (p=0.065). However, when ATMOS-1 data was adjusted via pre-specified sensitivity analysis and an identified outlier focus was eliminated, ATMOS-1 also showed a significant change from baseline in GT- versus vehicle-treated patients.¹⁴ Ultimately, ATMOS-1 and ATMOS-2 were able to demonstrate a significant reduction in axillary sweat production in participants, meeting both co-primary efficacy endpoints of ASDD-Item 2 response rate and mean absolute change from baseline in axillary sweat production.¹⁴

Treatment-emergent adverse events (TEAEs) and local skin reactions (LSRs), along with laboratory testing results, vital signs, ECG results, and physical exam findings were used to assess safety. Adverse events were mostly mild to moderate, and the incidence remained consistent across trials.¹⁴ Approximately one-third (33.9%) of TEAEs were treatment-related in the GT group in ATMOS-1, similar to the 44% observed in ATMOS-2.¹⁴ Dry mouth and mydriasis were the most commonly reported anticholinergic-related TEAEs, and led to discontinuation in less than 4% of patients. A decreased percentage of TEAEs was noted in vehicle-treated groups in both trials. TEAEs of special interest, such as blurry vision, mydriasis, and urinary hesitancy and/or retention, were seen in 11% and 15.5% of GT-treated patients in ATMOS-1 and ATMOS-2 trials, respectively.¹⁴ The onset of all TEAEs occurred in week 1 but decreased throughout the trials. One serious TEAE of treatment-related unilateral mydriasis was noted in ATMOS-1, and another serious TEAE of treatmentunrelated moderate dehydration was noted in ATMOS-2.¹⁴ TEAE differences between GT and vehicle treatment groups were unremarkable in regards to laboratory and physical exam findings, ECG results, and vital signs. LSRs were mostly absent and, if observed, were mild and comparable in incidence in both GT- and vehicle-treated groups for both trials.¹⁴

Future Trials

Future trials for glycopyrronium tosylate include a long-term, open-label extension of the Phase 3 randomized controlled trials (ATMOS-1 and ATMOS-2) to assess the long-term safety and efficacy of GT for primary hyperhidrosis management. Notably, in the studies published by Glaser et al., patients with a history of prior surgical intervention for hyperhidrosis or treatment with botulinum toxin within 1 year of baseline were excluded from the Phase 3 trials.¹⁴ Including these patient cohorts in future trials may provide additional comparative data to augment the current safety and efficacy profiles of GT. Furthermore, hyperhidrosis can be generalized or focal, most often affecting the face, axillae, palms, and soles. Future trials could include an analysis of efficacy in the treatment of non-axillary hyperhidrosis.

Conclusion

Glycopyrronium tosylate, a topical anticholinergic therapy, has been shown to be effective in the treatment of primary axillary hyperhidrosis. Primary hyperhidrosis is a condition with the potential to significantly affect patients’ quality of life. Thus, optimal management is a priority. The clinical trials described here have shown GT to be clinically effective in reducing excess sweat production in the axillae as well as presenting a low side effect risk, garnering the drug recent US FDA approval as the first and only topical agent indicated to treat primary hyperhidrosis. Though further investigation is needed to confirm the longterm safety and efficacy of glycopyrronium tosylate, it should be considered in the treatment algorithm for hyperhidrosis.

Purchase Article PDF for $1.99