Investigational topical anticholinergics in clinical development for the treatment of hyperhidrosis

KEYWORDS:

• Adverse events
• efficacy
• glycopyrrolate
• oxybutynin
• sofpironium
• therapy
• umeclidinium

1. Introduction

Focal hyperhidrosis has an incidence of up to 4.8%. % [1]. Abnormal sympathetic hyperactivity is the best documented component of its pathogenesis.

Management of focal hyperhidrosis includes aluminum chloride solutions, tap water iontophoresis, botulinum toxin A injections, surgical axillary curettage, and endoscopic sympathectomy or ablation for resistant cases [2].

Because of its chronic and potentially disabling course, there has been a recent boom in research for new therapeutic modalities. Systemic anticholinergic agents, such as oral, oxybutynin and glycopyrrolate have shown benefit in reducing sweat production in patients with hyperhidrosis. Their main limitation is the frequency of adverse effects, that may result in discontinuation of treatment. These include dry mouth, gastrointestinal complaints, headache, dizziness, and blurred vision [3]. Topical anticholinergics could provide comparable efficacy with a better safety profile. Agents that have been recently investigated include glycopyrrolate, umeclidinium (UMEC) sofpironium bromide (SB), and oxybutynin chloride (OC) [4].

2. Topical anticholinergics under investigation

2.1. Glycopyrrolate

Glycopyrronium salts compete with acetylcholine at the muscarinic receptors on the eccrine gland. Glycopyrronium tosylate (GT) 3.75% available as single-use, pre-moistened cloth was FDA approved for the treatment of axillary hyperhidrosis (AH) in adults and children aged 9 years or older in 2018.

Glycopyrronium bromide (GPB) 0.5% in a cream formulation has been evaluated in gustatory sweating, in diabetic patients with encouraging results both in the frequency and severity of episodes [5]. A similar preparation of 1% GBP and subsequently with 2% cream was evaluated for the treatment of axillary hyperhidrosis in patients who had failed aluminum salts applications, with minimal response [6].

A new GPB1% cream has shown significant improvement in sweat production, HDSS and the Hyperhidrosis Quality of Life Index, compared to placebo in both the Phase Ib [7] and Phase IIIa [8] trials after 4 weeks of application in patients with AH. The most frequent adverse event was dry mouth in 16.1% of the patients [7]. Maximum glycopyrronium exposure was well below the Cmax values after oral administration [7].

Assessment of a 2% GBP solution impregnated in cotton pads in the treatment of craniofacial hyperhidrosis showed a statistically significant 25% reduction of sweat, ninety minutes after the application by gravimetry [9]. A spray solution of 2% glycopyrrolate, resulted in a mean reduction in the HDSS score, 1.1 points with the 2% glycopyrrolate spray, and 1.7 points with the Botulinum toxin type A injections. Adverse events were minimal [10].

2.2. Umeclidinium

Umeclidinium blocks muscarinic receptors and has been approved for the treatment of obstructive pulmonary disease. A cutaneous solution of 1.85% UMEC once daily administration to axillae for 14 days, in 23 subjects with AH has been evaluated in a Phase IIa multi-center, double-blind, vehicle-controlled study. Gravimetry showed decrease in hyperhidrosis from day 3 and onwards. Efficacy was not compared between the UMEC and the vehicle groups, Local tolerability assessment scores were excellent [11].

2.3. Sofpironium bromide

SB is an ester analog of glycopyrrolate. SB follows the principles of retrometabolic drug design. A recent multicentric, double blind, placebo-controlled phase II trial compared three concentrations of 5%, 10%, 15% of SB gel applied once daily for 42 days in 227 patients with AH. A significantly higher percentage of participants in each SB group exhibited ≥1 and ≥2 points improvement in the Hyperhidrosis Disease Severity Measure-Axillary score (HDSM-Ax) vs the vehicle group. Gravimetry and HDSS also showed statistically significant improvement. Adverse events resulted in 12 participants discontinuing, the study and included dry eyes, dry mouth, blurred vision, mydriasis, urinary retention, constipation, as well as topical erythema, burning or itching sensation and dryness at the application site [12]. A Phase III with the 5% gel in 281 Japanese patients resulted in approval in Japan. Patients who achieved both HDSS of 1 or 2 and a 50% reduction in gravimetric weight of sweat at the end of 6 weeks were 44.0% in the SB group and 30.7% in the vehicle group. SB is contraindicated in patients with angle-closure glaucoma and in those with dysuria due to benign prostatic hyperplasia [13].

2.4. Topical oxybutynin

A topical formulation of OC as gel and transdermal patch is approved for the treatment of urinary incontinence.

A case series reported improvement of HDSS with OC 3% gel in 10 patients with AH. Adverse events were mild or moderate in severity, except one patient who developed pyelonephritis and was hospitalized [14].

A higher concentration of topical OC 10% gel twice daily for 4 weeks was evaluated in the treatment of axillary, palmar or plantar hyperhidrosis. The dosage of OC was 50 mg per application. There was statistically significant improvement in the HDSS of all treated sites, both compared to baseline and placebo treated sites. Adverse events were minimal [15].

The transdermal patches of OC release 3.9 mg of OC within 24 hours and the frequency of application is twice per week. In the first study 15 out of 25 patients with multiple site focal hyperhidrosis reported an improvement in HDSS [16]. In the second trial, most of the patients discontinued application of the patches within 3 months because of adverse events or ineffectiveness [17].

2.5. Discussion

There is a plethora of new topical anticholinergics under investigation (Table 1).

Table 1. Studies of topical anticholinergics in patients with focal hyperhidrosis

Active agent	Preparation	Disorder	Efficacy	Tolerability
Glycopyrronium bromide
Shaw et al. 1997 [4]	Cream 0.5%	GS	+	+
Hale et al. 2000 [5]	Cream 2%	AH	–	±
Masur et al. 2020 [6]	Cream 0.5%, 1%, 2%	AH	2%: ++ 1%: + 0.5%: ±	2%: ± 1%: ± 0.5%: ±
Abels et al. 2021 [7]	Cream 1%	AH	++	±
Hyun et al. 2015 [8]	Solution 2% in cotton pads	CF	+	+
Baker et al. 2016 [9]	Spray 1%,2%	AH	1%: ± 2%: +	1%: + 2%: +
Umeclimidium
Nasir et al. 2018 [10]	Solution 1.85%	AH	±	+
Oxybutinin Chloride
Nguyen et al. 2018 [13]	Gel 3%	AH	+	±
Artzi et al. 2017 [14]	Gel 10%	AH, PPH	+	+
Millán-Cayetano et al. 2017 [15]	Patch	AH, PPH	±	–
Bergón-Sendín et al. 2016 [16]	Patch	AH, CF, PPH	±	-
Sofpironium bromide
Kirch et al. 2020 [11]	Gel 5%, 10%, 15%	AH	++ (all)	+ (all)
Yokozeki et al. 2021 [12]	Gel 5%	AH	++	±

GS: Gustatory sweating, AH: Axillary hyperhidrosis, CF: Craniofacial hyperhidrosis, PPH: Palmoplantar Hyperhidrosis.

Efficacy

++ Significant sample of participants, double blind design, statistically

significant efficacy compared to placebo.

+ One of the above is not fulfilled.

± Two of the above are not fulfilled.

Tolerability

+Low incidence of significant adverse events that could lead to

discontinuation of treatment.

± Significant incidence of adverse events that could lead to discontinuation

of treatment.

- Verified discontinuation of treatment for a significant number of participants.

Glycopyrronium is highly polarized resulting in reduced crossing of the blood-brain barrier. Both the aqueous and cream GPB formulations of 0.5% or 1% concentration are associated with minimal adverse events. Penetration enhancing agents should probably be part of the final formulation to improve GPB efficacy. UMEC has good tolerability but the efficacy at the 1.85% concentration was not evaluated comparatively to placebo in the Phase II study. OC i is a small molecule and compatible with skin PH ranges. The half-life of the topical application is 62–84 hours. However, due to its lipophilicity, OC can pass the blood-brain barrier. The 10% concentration in a hydroalcoholic gel formulation seems to be the preparation of choice. More studies are needed to conclude if the gel formulation can achieve a better safety profile. Sofpironium bromide is a new agent, part of the emerging group of soft drugs with a retrometabolic drug design. Although the hope for lack of anticholinergic adverse events was not confirmed in the clinical trials, tolerability is high. The gel formulation is a choice that can be expected to enhance compliance.

Comparison between the new topical anticholinergics, is impossible since no head-to-head studies have been undertaken. However, GPB has been tried in more patients than the other anticholinergics and exhibits a favorable efficacy and safety profile when compared to placebo, based on available evidence (Table 2). GPB shares the same active anticholinergic moiety; the glycopyrroinium cation, with the GT wipes that are commercially available and longer duration pharmacokinetic data have been published at this time [18]. Based on the evidence available, GBP 1% cream is the most promising of the topical anticholinergics for the treatment of AH.

Table 2. Comparison and evaluation of available data for the topical anticholinergics under investigation

	Most promising preparation under investigation	Most promising concentration under investigation	Evidence from studies	Pharmacology considerations
Glycopyrronium bromide	Cream and solution	1% Penetration enhancers should probably need to be added to the final formulation	Strong: multiple studies. multicenter, randomized, compared to vehicle design	Minimal blood-brain barrier penetration expected, due to glycopyrronium being highly polarized
Umeclidinium	Solution	1.85%	Poor: One phase II study, few patients, no statistical comparison with vehicle undertaken	Poor penetration of blood-brain barrier has been reported
Sofpiromiuum bromide	Gel	5%	Moderate: Phase II, and Phase III studies, already approved in Japan	Analogue of glycopyrrolate, retrometabolic design, minimal penetration of blood-brain barrier expected
Oxybutinin chloride	Gel	5%	Poor: case series and small studies open label design	Considerable penetration of blood-brain barrier expected due to lipophilicity

The placement of the new topical anticholinergics within the treatment algorithm is easier to discern. The International Hyperhidrosis Society has included the GT cloth among first-line treatments for axillary hyperhidrosis. We consider that any of the other topical anticholinergic agents that get approval could also be employed as first-line treatment for moderate hyperhidrosis. In addition, all topical formulations can be used on multiple localizations of focal hyperhidrosis an advantage not shared by iontophoresis or surgical options. On the other hand, all topicals provide a temporary control of the disorder; device-based treatments such as microwave thermolysis for severe axillary hyperidrosis or endoscopic interventions such as sympathetic ablation for severe palmar hyperhidrosis have more permanent results.

2.6. Conclusion

SB gel 5% has already been approved in Japan and studies have been undertaken to be evaluated by the FDA. GPB 1% cream has also Phase III published studies and efficacy and safety data indicate that it could also be approved by the FDA. For UMEC and OC more data and studies are needed. Assuming that some of the new topical anticholinergics will be included as first-line treatment for mild/moderate axillary hyperhidrosis, trials comparative to topical aluminum chloride salts are needed to establish the comparative benefit to the patients

3. Expert opinion

The main challenge for the new topical anticholinergics under investigation is to provide sufficient cutaneous concentrations to facilitate anhidrosis, with minimal systemic absorption, that results in anticholinergic adverse events. Since both eccrine glands and cutaneous microcirculation are in the dermis, targeting the former and sparing the latter is difficult to achieve. Utilization of retrometabolic design has resulted in significant achievements in soft drug development and could hopefully provide a selective agent in the near future. Soft drugs consist of therapeutically useful chemical compounds that present a predictable and controllable in vivo metabolism to nontoxic moieties after they achieve their therapeutic role. Alternatively, agents utilizing delivery systems on specific receptors could be a potential breakthrough. However, our current knowledge on the exact function of potential receptors such as the G-protein coupled receptor pathway of the sweat glandular cells is still limited. Development of anticholinergics that could block the post-synaptic muscarinic receptors enervating the sweat glands, but could not pass the blood-brain barrier to exert systemic adverse events could also be a viable approach to the problem. Finally, a novel approach of combining oxybutynin, a muscarinic antagonist, and pilocarpine, a muscarinic agonist in an oral formulation, has been employed to control hyperhidrosis while reducing dry mouth incidence. However, combining an agent with just peripheral action with one with central action capability, in a topical formulation seems to be beyond our current innovation capabilities.

Focal hyperhidrosis involves several localizations with different characteristics and this poses a significant challenge when striving to develop a formulation suitable for the treatment of all regions. Skin thickness necessitates higher concentrations or the addition of penetration enhancers for palmoplantar hyperhidrosis. Axillary fossae create an occlusion effect that enhances penetration of even low concentrations of the active agent. On the other hand, higher concentrations suitable for palmoplantar hyperhidrosis could result in more significant systemic absorption when applied to the axillae. Low viscosity gels or sprays could be more suitable for craniofacial or axillary hyperhidrosis from a cosmetic point of view and consequently more popular with the patients. This means that a single formulation/concentration might not be ideal for all patients; novel agents should include versatility in their design.

Focal hyperhidrosis follows a chronic course; developing a formulation that combines good compliance and affordable cost, presents another challenge for the topical anticholinergics. Formulations that could be applied once daily are more likely to result in better compliance. This means that a prolonged half-life of the agent under investigation provides a comparative advantage. Since most guidelines suggest topicals as first-line treatment for mild/moderate focal hyperhidrosis, comparative studies of topical anticholinergics versus aluminum chloride salts should be designed to provide a more-clear understanding of their place within the treatment algorithm. The fact that these new agents will probably not be reimbursed by the payers in most countries acts as a counterincentive for such studies to be undertaken by the developers

Overcoming the adverse events of systemic absorption is a major challenge. Besides the well-documented adverse events, there is a concern for the possible association of anticholinergic uptake and the risk for cognitive impairment, dementia and Alzheimer’s disease. Counseling on the risks evident in the literature, prescribing the lowest effective dose, and considering alternative agents in patients with cognitive impairment has been proposed for the systemic anticholinergics. Measuring plasma levels after anticholinergic topical application should be included in the clinical trials design. However, a recent study on the systemic absorption after application of GT 0.8–3.2% reported limited absorption of GT compared to oral glycopyrrolate [18]. Counseling for extreme care during application in patients with craniofacial hyperhidrosis should be emphasized in order to avoid eye contamination

Real-world data are needed to confirm whether these new topical anticholinergics will fulfill the unmet needs in the treatment of focal hyperhidrosis. The data available from the trials suggest that both efficacy and safety should be further improved before we have an ideal topical anticholinergic compound. Agents that achieve an anticholinergic effect and subsequently metabolize to nontoxic compounds with minimal systemic effect could be available within the next 5 years. Identifying the sweat gland receptors, understanding their functions and designing selectively binding agents is probably a longer-term goal

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.