Development of Pirenzepine for CIPN

PROJECT SUMMARY Chemotherapy induced peripheral neuropathyCIPNis a debilitating condition that afflictsof cancer patients undergoing chemotherapy and limits the dose and duration of treatmentSymptoms range from sensory loss to painful neuropathy and are accompanied by electrophysiological and structural indices of nerve damageThe American Society of Clinical Oncology currently makes no recommendations for the prevention or reversal of CIPN and provides only a moderate recommendation for symptomatic pain reliefCIPN is therefore a major unmet clinical concernWinSanTorandapos s founders have discovered a novel homeostatic mechanism in peripheral neurons that restrains axonal growth via regulation of mitochondrial energy supplyManipulation of this endogenous mechanism can be exploited to improve energy supply to neurons undergoing toxic or metabolic stressthereby supporting both neuroprotection and recovery from established injuryWe have recently reported that the key neuronal receptor regulating this mechanism is the muscarinic acetylcholine typereceptorM Rand that M R antagonists increase neuronal respiratory capacity and drive neurite outgrowthAdditionallyin vivo studies demonstrated that the selective M R antagonist pirenzepinewhich has been used worldwide foryears to treat gastric ulcersprevented and or reversed multiple indices of neuropathy in rodent models of toxic and metabolic injuryEncouraging preliminary studies supported by a Phase I STTR award demonstrate that pirenzpine both prevents and reverses indices of neuropathic pain and degenerative neuropathy in models of paclitaxel induced CIPN without impeding the tumoricidal properties of paclitaxelThe goals of this Phase II STTR project are to define the optimal therapeutic regimen for pirenzepine against paclitaxel induced CIPNAimto establish the broadest market for this approach by extending studies to CIPN induced by three distinct chemotherapeuticsAimand to complete necessary IND enabling studies in preparation for clinical trialsAimen route to advancing pirenzepine as a first in class therapy against CIPN NARRATIVE Chemotherapy induced peripheral neuropathyCIPNafflicts aroundof patients being treated with paclitaxel for breast or ovarian cancer and can impede the optimal treatment regimenWe will build on preliminary data obtained via PhaseSTTR funding that demonstrates that the muscarinic receptor antagonist pirenzepine can prevent and or reverse multiple indices of CIPN in paclitaxel treated rodentsStudies will define the optimal therapeutic regimen for pirenzepine against paclitaxel induced CIPN in rodentsexpand potential efficacy to three other chemotherapeutics that cause CIPN and perform IND enabling studies to prepare pirenzepine for future clinical trials