FC20 Poster Kirsch CL106 = Brandon Kirsch, MD1, Danielle Armas, MD2, Deepak Chadha, MS, MBA, RAC3 1Kirsch Dermatology, Naples, FL, 2Celerion, Inc., Tempe, AZ, 3Brickell Biotech, Inc., Boulder, CO A Four-Way, Cross-Over Design, Randomized, Double-Blinded, Placebo- and Active-Controlled Study for the Evaluation of the Effect of a Supratherapeutic Dose of Sofpironium Bromide Gel, 15% Applied Topically on the QT/QTc Intervals in Adult Healthy Volunteers (BBI-4000-CL-106) Sofpironium bromide is a retro-metabolically designed analog of glycopyrrolate (anticholinergic) in development for the topical treatment of primary axillary hyperhidrosis. Cardiac safety can be a major factor in clinical development given the potential effect of new drugs in delaying cardiac repolarization. In a study designed to mimic exposure that may occur under extreme circumstances in healthy subjects (BBI-4000-CL-109), a single 6-fold application of sofpironium bromide gel, 15% under occlusion showed a 3-fold increase in maximum sofpironium exposure compared to the intended therapeutic dose. • A topical ~173 mg total dose of sofpironium bromide gel, 15% (intended therapeutic dose) without occlusion to the axillae (T), or • A topical ~1038 mg total dose of sofpironium bromide gel, 15% (supratherapeutic dose) with occlusion that was 6-fold higher than the intended therapeutic dose to the axillae, lateral side of the upper arms, ventral side of the thighs, and central abdomen (ST), or • A topical dose of placebo gel with occlusion applied to the same sites as those used for the supratherapeutic and intended therapeutic doses (P), or • An oral dose of moxifloxacin (400 mg) (M). There was a washout period of at least 7 days between the dosing periods. Administration of ~1038 mg sofpironium bromide gel, 15% (occluded) resulted in a 3.2-fold increase in Cmax compared to the ~173 mg dose of sofpironium bromide gel, 15% (unoccluded). Mean placebo-corrected change-from-baseline QTcF (ΔΔQTcF) ranged from -3.5 ms on the supratherapeutic treatment at 10.5 hr post- dose to +3.3 ms on the therapeutic treatment at 1 hr post-dose. An effect on ΔΔQTcF exceeding 10 ms could be excluded with both sofpironium bromide gel, 15% doses, since the upper bound of the 90% CI was below 10 ms at all post-dose time points. Assay sensitivity was demonstrated by oral dosing with 400 mg of positive control, moxifloxacin. The study constitutes a negative TQT study, as defined in ICH E14 clinical guidance. Systemic exposure increased more than 3-fold following supratherapeutic dosing under occlusion, but no clinically relevant changes in the QTc interval, heart rate, or cardiac conduction were noted. Therapeutic (unoccluded) and supratherapeutic (occluded, 6- fold) doses of sofpironium bromide gel, 15% appeared to be safe and generally well tolerated. Brickell Biotech, Inc. supported the study and preparation of this abstract. Funding Statement Conclusion Background Methods Academic Poster Presented at the 2020 Fall Clinical Dermatology Conference | Las Vegas, NV | October 29 - November 1, 2020 Objective The prospective effect of a drug on cardiac repolarization can be measured as prolongation of the QT interval on electrocardiographic recordings. The primary objective of this thorough QT (TQT) study was to evaluate the effect of a single supratherapeutic dose (6-fold) of sofpironium bromide gel, 15% under occlusion on the Fridericia- corrected QT interval (QTcF). 0 0. 5 1 1. 5 2 2. 5 3 3. 5 Pr ed os e .5 h 1 h 2 h 3 h 4 h 6 h 8 h 9 h 10 .5 h 12 h 16 h 24 h P la sm a S o fp ir o n iu m C o n ce n tr a ti o n ( n g /m L) Sample Collection Hour T re atm e n t ST : 1 0 38 m g sofpi roni u m brom i de ge l , 1 5% (6 x th er ape u ti c dose , occ l ude d) T re atm e n t T: 1 7 3 m g sofpi ron i um brom ide ge l, 1 5 % pl u s pl a ce bo gel (u noc cl u de d) Figure 1: Mean Plasma Concentration of Sofpironium1 Treatment ADVERSE EVENTS T ST P M TOTAL Number of Subjects Dosed 59 (100%) 60 (100%) 60 (100%) 58 (100%) 60 (100%) Number of Subjects With TEAEs 17 (29%) 43 (72%) 54 (90%) 12 (21%) 57 (95%) Number of Subjects Without TEAEs 42 (71%) 17 (28%) 6 (10%) 46 (79%) 3 (5%) Application site erythema 3 (5%) 28 (47%) 41 (68%) 0 (0%) 47 (78%) Application site pain 2 (3%) 18 (30%) 22 (37%) 0 (0%) 33 (55%) Application site pruritis 1 (2%) 18 (30%) 17 (28%) 0 (0%) 28 (47%) Application site exfoliation 7 (12%) 8 (13%) 2 (3%) 0 (0%) 14 (23%) Headache 2 (3%) 3 (5%) 3 (5%) 2 (3%) 9 (15%) Dermatitis contact 2 (3%) 0 (0%) 1 (2%) 1 (2%) 3 (5%) Oropharyngeal pain 0 (0%) 2 (3%) 0 (0%) 1 (2%) 3 (5%) Pruritus 0 (0%) 2 (3%) 1 (2%) 0 (0%) 3 (5%) Upper respiratory tract infection 0 (0%) 2 (3%) 1 (2%) 0 (0%) 3 (5%) Vision blurred 1 (2%) 2 (3%) 0 (0%) 0 (0%) 3 (5%) Table 1: Adverse Event Frequency by Treatment – Number of Subjects Reporting the Event (% of Subjects Dosed) (Safety Population) (≥5%) Results This was a randomized, double-blind (with respect to the supratherapeutic dose (6-fold) of sofpironium bromide gel, 15% and placebo gel only) and active-controlled (with respect to the moxifloxacin and therapeutic dose of sofpironium bromide gel, 15%), single-dose, 4-way crossover TQT study. Sixty healthy adult male and female subjects were enrolled. On Day 1 of each period, subjects aged ≥18 to ≤55 years received one of the following investigational treatments: Figure 2: Placebo-Corrected Change-from-Baseline QTcF Across Time Points -5 0 5 10 15 20 0. 5 1 2 3 4 6 8 9 10 .5 12 16 24 Δ Δ Q T cF ( m s) Hours Post-Dose Tr eat m ent T Tr eat m ent ST M oxif loxac in