2nd-Generation Spinal Analgesic Resiniferatoxin

RTX is the most potent known agonist of the transient receptor potential cation channel subfamily V memberTRPVIt is a selective neurotoxin that can ablate TRPVbearing neural structuresmost importantlynociceptivepain sensingspinal nerve fibersand has been unequivocally demonstrated by several laboratories to induce long lasting analgesiachronic pain reliefWhy has RTX not be turned into a commercially available drug to dateWe identified a trifecta of barriers to progress that guided our unpublished studies and led to the enclosed SBIR Phase I applicationThe first is the formulation as a drugspecifically toxic diluents relied upon such as Tween polysorbatea cause of life threatening anaphylaxisto solubilize RTXThe second is a lack of patent protection for any financial investment into the preclinical and clinical development processThe third is a lack of effective contenders in the commercial spacePreliminary data demonstrates that we have overcome the first barrier by developing and generation formulation of RTX using the FDA approved cyclodextrin Captisolas solubilizerCap RTXthat we have overcome the second barrier by securing patent protection via licensing of Captisolfrom Ligand Pharmaceuticalsand that we have validated the mechanism and analgesic efficacy of the new formulation in a large animal model of painMarket research has identified interventional pain physicians and health insurance managers as primary customers and determined a first yearafter FDA approvalsales revenue potential of $Matmarket penetrationThe proposed commercial product Cap RTX translates the broad existing knowledge base on TRPVmediated neural ablation into a minimally toxic commercial product with the potential to engender a paradigmshift in the treatment of hitherto intractable chronic locoregional painHypothesisLyophilization preserves Cap RTX permitting the production of single dose vialsstorage at room temperatureease of reconstitutionand subsequent undiminished pharmacological activity in vivoAimTo test lyophilization of Cap RTX by critical process parameter optimizationProlonged shelf life and bedside preparability would facilitate clinical testing of Cap RTX and future marketing as a drugThis will be accomplished through the systematic development and testing of a lyophilized formulationAimTo test the minimal effective dose of Cap RTXSafety of RTX depends not only on its formulation but equally importantly on the selectivity of its delivery that will be optimized by determining minimum effective dose and volume delivered by the periganglionic epidural route ung real time image guidanceAimTo produce a small scale run of individual dose vialsdose vials will be produced and tested for shelf life atdwandmo using a validated HPLC assay with detection by Mass SpectrometryImpact and Future DirectionsIf successfulthe proposed studies lead to the commercial developmenta pre IND meeting with the FDAand formal toxicology studies to test Cap RTX as a drug for intractable pain Project Narrative Chronic pain affectsmillion AmericansThe total financial costs of this epidemic are andgt $billionas stated in PAConventional treatments use a variety of drug regimens but frequently fail to control painThe development of the proposed new pain controlling drug is an important goalbecause it addresses a public health crisis caused by the effects of opioid medications such as oxycontinAmericans died from prescription opioids inandmillion were addicted to themdied from heroin andwere usersmost of whom were first addicted to prescription opioidsRecent studies have demonstrated that chronic pain can be controlled by resiniferatoxinRTXbut preparation of RTX as a drug has been compromised by the need for toxic additivesThe proposed research will develop and generation RTX that is less toxic and will allow us to determine the most viable treatment approach for use in patients with severehitherto intractable locoregional pain