ABSTRACT The rare genetic disorder pachyonychia congenita (PC) results from dominant mutations in the inducible keratins (K) including K6a, K6b, K16 and K17. While disabling painful plantar keratoderma is commonly accepted as the primary symptom affecting patient quality of life, hyperhidrosis appears to contribute to blister formation and pain. Supporting the involvement of hyperhidrosis to PC pain, several teams worldwide have shown that multiple intradermal injections of botulinum toxin (BTX), known to effectively treat hyperhidrosis, substantially reduce pain and blistering in PC patients (similar results were observed with the related genodermatosis, epidermolysis bullosa simplex). Unfortunately, the number of dermal injections associated with the current treatment protocol makes this procedure costly and difficult on the patient (regional nerve blocks or general anesthesia are used). We propose to use TransDerm's proprietary Flex-PAD delivery system to administer BTX to the skin in a patient-friendly manner with little or no pain and with no requirement for anesthetic. In Phase 1, we aim to demonstrate that BTX can be effectively and efficiently loaded on Flex-PADs and that the resulting drug product has sufficient stability to be evaluated in mouse models and for future clinical trial use. The ability of the Flex-PADs to delivery BTX will be evaluated in head-to-head studies with intradermal injection of BTX and scored for its ability to block pilocarpine- induced sweating in mouse paws. In Phase 2, we refine and streamline manufacture and loading of the Flex-PADs with BTX and perform IND-enabling stability and toxicity studies in mice and minipig models in preparation for human studies. !