FC21 SB Retro Poster Kirsch Sofpironium Bromide Comparison to Glycopyrrolate Once in circulation, sofpironium bromide rapidly hydrolyzes into its metabolite (BBI-4010), a less active anticholinergic agent, therefore reducing its potential for side effects Anticholinergic medications are useful for the management of primary axillary hyperhidrosis (AHH). However, due to inhibition of cholinergic receptors in tissues other than the targeted sweat glands, the use of both oral and topical anticholinergics for the treatment of AHH often results in systemic side effects, such as dry mouth, blurred vision, mydriasis, and urinary hesitation. Sofpironium bromide (SB) is a novel, quaternary ammonium, anticholinergic drug that is a retrometabolically designed structural analogue of glycopyrrolate. Unlike glycopyrrolate, SB includes a readily hydrolyzable ester moiety. To obtain this metabolically sensitive site, the “inactive metabolite” approach to retrometabolic drug design was used.1 A hydrolytically sensitive function was introduced in a remote site of the molecule, away from the pharmacophore.2 The molecular structure was further refined based on binding to the relevant muscarinic receptors, and the most potent optical isomer was selected.3 The specific enzyme responsible for hydrolytic metabolism of SB was identified.4 Here we review existing pharmacokinetic and pharmacodynamic data for the retrometabolically designed investigational drug SB. Binding studies at human muscarinic receptors (M1–M4) and guinea-pig ileum assays have found SB to have potency close to glycopyrrolate with a shorter duration of action.2 The mydriatic effects of SB were compared to those of glycopyrrolate in rabbits,2 where the activity of SB and glycopyrrolate lasted for approximately 48 hours and 144 hours, respectively. In vitro SB half-life in human plasma was short (3.86 hours). In a separate maximum-use pharmacokinetic (PK) study of SB in human subjects with AHH, 3- fold supratherapeutic application to the axillae, thighs, and palms had no meaningful impact on systemic exposure compared with the intended therapeutic dose.5 Systemic exposure to SB and its major metabolite BBI-4010 was minimal with most samples <1 ng/mL and many results below the limit of quantitation.5 To date, more than 1300 subjects have been exposed to SB across various clinical studies, and <5% subjects have been discontinued due to adverse events. Results Methods A need exists to find new anticholinergics with maximal therapeutic benefits and minimal systemic side effects for the treatment of AHH. Retrometabolic drug design is intended to create drugs with an increased therapeutic index by integrating metabolism considerations into the drug design process.1 SB is an anticholinergic agent synthesized according to the principles of retrometabolic drug design. Both nonclinical and clinical studies support the concept that the retrometabolic design of SB may confer certain safety and PK benefits without compromising desired anticholinergic effect. Conclusion Funding Statement References 1 Bodor N, Buchwald P. Retrometabolic Drug Design and Targeting. Wiley; 2013. 2 Ji F, Wu W, Dai X, et al. Synthesis and pharmacological effects of new, N-substituted soft anticholinergics based on glycopyrrolate. J Pharm Pharmacol. 2005;57(11):1427-1435. doi:10.1211/jpp.57.11.0008 3 Tóth-Sarudy E, Tóth G, Pallagi I, et al. Preparation and biological effects of pure stereoisomeric novel soft anticholinergics. Pharm. 2006;61(2):90-96. 4 Samir A, Ohura K, Bodor N, Imai T. Identification of Major Esterase Involved in Hydrolysis of Soft Anticholinergic (2R3’R-SGM) Designed From Glycopyrrolate in Human and Rat Tissues. J Pharm Sci. 2019;108(8):2791-2797. doi:10.1016/j.xphs.2019.03.030 5 Kirsch B. An Open-Label, Repeat-Dose, Maximum-Use Study to Evaluate the Pharmacokinetics of Sofpironium Bromide Gel, 15% Topically Applied in Subjects with Primary Axillary Hyperhidrosis (Study BBI-4000-CL-102). Presented at the: Fall Clinical; November 29, 2020; Las Vegas, Nevada. Brickell Biotech, Inc. supported the study and preparation of this abstract. Academic Poster Presented at the 2021 Fall Clinical Dermatology Conference | Las Vegas, NV | October 21 – October 24, 2021 H2O PHYSIOLOGIC CONDITIONS NO REACTION Glycopyrrolate Sofpironium Bromide BBI-4010 H2O PHYSIOLOGIC CONDITIONS MAKING FRESH TRACKS IN DERMATOLOGY® Objective Investigating Treatment of Primary Axillary Hyperhidrosis With a Topical Retrometabolic Anticholinergic Drug Nicholas Bodor, PhD1, Adam Friedman, MD2, Stacy Smith, MD3, James Del Rosso, MD4, Janet Dubois, MD5, Adelaide Hebert, MD6, Tory Sullivan, MD7, Zakiya Rice, MD8, Joe Gorelick, NP9, Leon Kircik, MD10, Lawrence Green, MD2, Brandon Kirsch, MD11, Deepak Chadha12, MS, MBA Background 1Bodor Laboratories, Miami, FL, 2George Washington University School of Medicine, Washington, DC, 3California Dermatology and Clinical Research Institute, Encinitas, CA, 4JDR Dermatology Research/Thomas Dermatology, Las Vegas, NV, 5DermResearch, Inc., Austin, TX, 6Department of Dermatology, The University of Texas Health Science Center, Houston, TX, 7Sullivan Dermatology, North Miami Beach, FL, 8Department of Dermatology, Emory University School of Medicine, Atlanta, GA, 9California Skin Institute, San Jose, CA, USA, 10Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, 11Kirsch Dermatology, Naples, FL, 12Brickell Biotech, Inc., Boulder, CO