Company and Tech History
Repurposed Therapeutics, Inc., DBA Defender Pharmaceuticals, Inc., was formed early in 2014 and acquired Epiomed Therapeutics, Inc., in September of 2014. Epiomed had been created in late 2010 based upon technology discovered at Cenomed BioSciences, LLC, and assigned to Epiomed by Cenomed, Inc. The vision of co-founders David Helton, Ernest
Pfadenhauer, and Richard Burgoon was to establish a drug-discovery and -development organization with its therapeutic focus on—[dnd1] and the intellectual, scientific, human, and financial resources of the company geared toward—[dnd2] emesis. This vision further included the objective of going back to the early days of the biopharmaceutical industry, targeting the vast majority of the company’s financial resources on drug discovery and development, and working virtually, with limited infrastructure.
Technology Development History
The possibility of a universal-spectrum antiemetic that would not interfere with critical life processes was first elucidated in a study of the broad-spectrum antiemetic serotonin receptor 5-HT1a agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In preclinical models, 8-OH-DPAT inhibited emesis elicited by three different stimuli (motion, chemical/drug, and chemotherapy), which activated the final common emesis pathway via different stimulatory pathways (Lucot and Crampton, 1989). Specifically, motion involves the vestibular nuclei, and the pathway courses through area subpostrema to the nucleus tractus solitarius; drugs such as nicotine or xylazine act on the area postrema; and cisplatin
activates vagal afferents that ascend to the point of convergence in the nucleus tractus solitarius. Summation most likely occurs in the region of the nucleus tractus solitarius to trigger the sequence of nausea and autonomic and skeletal muscle effects (Davis, 1995). Subsequent preclinical studies in three species established the efficacy of this mechanism against all known emetic stimuli effective in these species (Okada et al., 1994; Wolff and Leander, 1994). Further, several putative 5-HT1a agonists all demonstrated efficacy in these preclinical models (Okada et al, 1994; Lucot, 1994; Forman et al., 1993).
Subsequently there was considerable interest in the development of effective antiemetics with agonism at the serotonin 5-HT1a receptors. These agonists, however, produced unanticipated side effects in animals and humans. 5-HT1a receptor agonists produced defensive-anxiety behavior in animals at antiemetic doses (Lucot and Crampton, 1989; Lucot, 1994). In a large series of dose-response studies of 5-HT1a receptor agonists, the antiemetic ED50 against any one stimulus and the threshold dose for the observation of defensive-anxiety behavior did not remain constant. Indeed, one compound ostensibly identical to the others produced anxiety behavior and nearly no antiemetic effects, demonstrating separability of the therapeutic and toxic effects, but in the wrong direction (Lucot and Helton, unpublished observation). The important observations that full 5-HT1a receptor agonists administered to humans produced anxiety and/or[dnd1] panic attacks almost completely terminated the further evaluation of these compounds as antiemetics (van Vliet et al., 1996). At the time, pharmacologic tools and appreciation of 5-HT-receptor pharmacology were inadequate to dissect and solve this side-effect problem.
More recently, David Helton, Defender’s Chief Scientific Officer and one of the original investigators in the seminal studies, returned to the problem of the anxiogenic properties of the originally tested 5-HT1a receptor agonists and used more current receptor-binding and functional data to deduce the receptor profile necessary to separate the antiemetic effects from the anxiogenic effects. In preclinical models, Epiomed's lead compound, ETI-0001, was effective against motion, xylazine, nicotine and cisplatin in two species.