Sofpironium Targets M3 Receptors In Vitro and Shows Early Clinically Meaningful Improvement in Primary Axillary Hyperhidrosis Symptoms

Abstract

Background: Sofpironium gel 12.45%, a first-in-class, topical anticholinergic (Ach) FDA approved for primary axillary hyperhidrosis (PAH) in persons ≥9 years, was retrometabolically designed to optimize efficacy and minimize Ach side effects. In vitro study results support the mechanism by which sofpironium likely exerts its early and clinically meaningful axilla sweat reduction and M3 receptor selectivity.  

Methods: Sofpironium vs. glycopyrrolate concentrations required to inhibit human muscarinic receptors were examined in vitro. IC50 values for 50% inhibition were determined by non-linear least squares regression analysis; Ki values represented binding affinity.  

Cardigan I (301) and II (302), randomized, double-blinded, vehicle-controlled phase 3 trials, included subjects ≥9 years with PAH ≥6 months. Treatment: 1 pump, sofpironium or vehicle, to each axilla once-daily at bedtime, x42 days (end of treatment, EOT). Co-primary efficacy: proportion achieving ≥2-point improvement in the Hyperhidrosis Disease Severity-Axillary (HDSM-Ax-7) and Gravimetric Sweat Production (GSP) change from baseline-EOT. Secondary: proportion achieving ≥1-point improvement in baseline-EOT HDSM-Ax-7.  Exploratory: proportion achieving either ≥1 or ≥2 point improvement in HDSM-Ax-7 from baseline to each visit; subjects achieving ≥70% reduction in GSP from baseline to each visit. Statistics: multiple imputation, ANCOVA. Safety: Treatment emergent adverse events (TEAEs) and local tolerability. 

Results: In vitro, 10 nM of sofpironium inhibited ≥50% of M3 receptors;100 nM for M1/M2/M4/M5 receptors. Glycopyrrolate targeted multiple muscarinic receptors, achieving >50% inhibition of M1-–M5 receptors with 1 nM. Hence, glycopyrrolate was more potent but 10X less M3 receptor selective than sofpironium.  

Enrollment: 301,302 vehicle:sofpironium,177,171=348: 173,180=353. More sofpironium(s) subjects achieved HDSM-Ax-7 ≥1- and ≥2-point improvements vs. vehicle(v), beginning at day 8 through day 43/EOT.  

≥1-point EOT, 301:v=111/166 (66.9%), s=127/157 (80.9%), P=.0053; 302:v=124/159 (78.0%), s=143/162 (88.3%), P=.0165; and at each visit, (P≤.05). ≥2-point EOT, 301:v=54/166 (32.5%), s=84/157 (53.5%), P=.0004; 302:v=75/159 (47.2%), 108/162 (66.7%). 

 A higher proportion of sofpironium subjects achieved statistically significant GSP changes from baseline-EOT. More sofpironium subjects achieved ≥70% GSP reduction from baseline-EOT, 301:v=51/165 (30.9%), s=76/157 (48.4%), P=.0010; 302:v= 56/157 (35.7%), s=84/160 (52.5%), P=.0065; and at each visit.  

More TEAEs occurred in sofpironium subjects, mostly mild-moderate and transient. TEAEs to EOT, n/N (%), 301:v=20/176 (11.4%), s= 58/173 (33.5%); 302:v=20/171 (11.7%); s=80/180 (44.4%). 

Ach-TEAEs, predominantly mild-moderate and transient, to EOT, n/N (%), 301:v=0/176 (0%), s=30/173 (17.3%); mild: s=18/173 (10.4%). 302:v=3/171 (1.8%), s=42/180 (23.3%); mild: v=3/171 (1.8%),s=21/180 (11.7%).   

The most frequently observed Ach-TEAEs were eye disorders, 301:v=0, 0%; s=22/173, (12.7%), mild, 12, (6.9%). Total mydriasis,13, (7.5%); blurred vision, 9, (5.2%); dry eye,1,(0.6%), all mostly mild. 302:v=1/171, (0.6%) (mild), s=34/180, (18.9%), mild,17, (9.4%).  Total blurred vision, v=1/171, (0.6%), s=21/180, (11.7%) and dry eye, s=6/180, (3.3%), were mostly mild, whereas mydriasis, s=9/180, (5.0%), was mostly moderate. 

Other Ach-TEAES: 301: dry mouth, 20, (11.6%), mostly mild; urinary retention, 2, (1.2%), moderate. 302: dry mouth, v=2/171, (1.2%); s=31/180, (17.2%), mostly mild; urinary retention, s=6/180, (3.3%), 3 mild, 3 moderate.  

Local tolerability baseline-EOT: minimal-mild erythema, burning, itching and stinging occurred more frequently in sofpironium subjects. 

Conclusions:  In vitro, sofpironium exhibits M3 receptor selectivity; early/clinically meaningful improvement and predominantly mild-moderate and transient TEAEs were observed in two phase 3 clinical trials.