What is the efficacy and safety of sofpironium (Sofpironium) topical gel for treating primary axillary hyperhidrosis?

Sofpironium Topical Gel for Primary Axillary Hyperhidrosis

Sofpironium bromide 12.45% topical gel (SOFDRA) applied once daily at bedtime is highly effective and well-tolerated for treating primary axillary hyperhidrosis in patients ≥9 years old, with approximately 70-79% of patients achieving clinically meaningful improvement and an excellent safety profile characterized by mild, localized adverse events. 1, 2

Mechanism of Action and Pharmacology

Sofpironium bromide is a retrometabolically-designed topical anticholinergic that competitively inhibits acetylcholine receptors on sweat glands, indirectly reducing sweating by preventing receptor stimulation. 1 The retrometabolic design results in rapid metabolism after systemic absorption, which minimizes systemic anticholinergic side effects while maintaining targeted local efficacy. 2 Plasma protein binding is relatively low (34.8-37.8%), and urinary excretion of sofpironium and its major metabolite (BBI-4010) is less than 0.5% of the applied dose. 1

Efficacy Data

Primary Endpoints from Pivotal Trials

The pooled analysis of two phase 3 randomized controlled trials (Cardigan I and II) involving 701 patients demonstrated robust efficacy:

• ≥2-point improvement on Hyperhidrosis Disease Severity Measure-Axillary (HDSM-Ax): Statistically significant superiority over vehicle (p<0.0001) after 6 weeks of treatment 2
• Gravimetric sweat production reduction: Significantly greater reduction in the treatment group versus control (p=0.0002) 2
• HDSS score improvement: 70-79% of patients achieved ≥1-point improvement in Hyperhidrosis Disease Severity Scale (HDSS) scores across different concentrations (5%, 10%, 15%) in phase 2 trials 3

Clinically Meaningful Outcomes

In the systematic review of 752 patients across five studies, sofpironium demonstrated:

• 53.9% to 86.7% of patients achieved an HDSS score of 1 or 2 (indicating mild or no symptoms) 4
• 48.2% to 69.1% of patients achieved ≥1.5-point improvement in HDSM-Ax score 4
• Greater reduction in Dermatology Life Quality Index (DLQI) scores compared to vehicle, indicating improved quality of life 4

Rapid Onset of Action

A 2-week prospective observational study in 80 Japanese patients revealed early effectiveness:

• 55.0% of patients achieved HDSS score of 1 or 2 by day 7 5
• Statistically significant changes observed as early as day 3 compared to baseline (p<0.05) 5
• Median time to achieve HDSS score of 1 or 2 for continuous 2 days was 6 days (95% CI: 4-8 days) 5

Long-Term Efficacy

A 52-week open-label extension study in 185 Japanese patients demonstrated sustained efficacy:

• 57.4-58.2% of patients maintained HDSS score of 1 or 2 with ≥50% reduction in gravimetric sweat weight at week 52 6
• Efficacy was maintained throughout the entire 52-week treatment period without evidence of tachyphylaxis 6

Safety Profile

Overall Safety Assessment

Sofpironium bromide demonstrates an excellent safety profile with predominantly mild, localized adverse events:

• No serious adverse events were attributed to the study drug across clinical trials 4, 6
• No deaths occurred in any of the clinical trials 6
• Most treatment-related adverse events were mild or moderate in severity 3

Common Adverse Events

In the 52-week safety analysis:

• Application site dermatitis: 25.5-33.0% of patients 6
• Nasopharyngitis: 23.1-31.9% of patients 6
• Overall adverse event incidence: 80.9-83.5% (including non-drug-related events) 6
• Adverse drug reactions: 39.4-45.1% 6

Systemic Anticholinergic Effects

The retrometabolic design minimizes systemic exposure:

• No clinically relevant QTc prolongation at exposures 3 times the maximum approved dose 1
• Low systemic absorption: Mean Cmax of 2.71 ng/mL in adults and 1.30 ng/mL in pediatric patients 1
• No evidence of accumulation after repeated daily dosing 1

Pediatric Safety

In pediatric subjects aged 9-16 years:

• Exposure to the major metabolite (BBI-4010) was similar to sofpironium exposure in adults 1
• After 24 weeks of dosing, trough concentrations remained low with no evidence of accumulation 1

Dosing and Administration

Apply sofpironium bromide 12.45% gel once daily at bedtime to clean, dry axillae. 1, 2 The once-daily bedtime application optimizes efficacy while minimizing potential daytime interference with activities. 2

Drug Interactions

• CYP2D6 inhibitors (e.g., paroxetine 20 mg): Approximately twofold increase in sofpironium Cmax and AUC, but this interaction is not considered clinically significant given the low systemic exposure and localized mechanism of action 1
• No clinically significant interactions with CYP3A4, OCT2, MATE1, or MATE2-K inhibitors 1

Clinical Considerations

Advantages Over Alternative Treatments

Sofpironium offers several advantages as a first-line topical therapy:

• Non-invasive compared to botulinum toxin injections or surgical interventions 2
• Rapid onset with meaningful improvement within 3-7 days 5
• Sustained efficacy maintained for at least 52 weeks 6
• Minimal systemic effects due to retrometabolic design 1, 2
• Once-daily dosing improves adherence compared to twice-daily regimens 2

Common Pitfalls to Avoid

• Do not discontinue prematurely: Patients should be counseled that optimal efficacy may take up to 6 weeks, though many experience improvement within the first week 2, 5
• Application site reactions are expected: Mild dermatitis occurs in approximately 25-33% of patients but is generally well-tolerated and does not require discontinuation 6
• Apply to dry skin: Ensure axillae are completely dry before application to optimize absorption and minimize irritation 1

Patient Selection

Sofpironium is appropriate for:

• Patients ≥9 years old with primary axillary hyperhidrosis 1, 2
• HDSS score of 3 or 4 (moderate to severe symptoms) at baseline 5
• Patients seeking non-invasive treatment before considering botulinum toxin or surgical options 2