AGYPHARMA, LLC — Department of Health and Human Services SBIR Phase I: NCI

Description

DESCRIPTION provided by applicant Because prostate cancer is an androgen dependent malignancy in the early stages androgen depletion therapy ADT has been shown to be effective in improving survival when administered timely in the course of the disease On the other hand the benefits may be offset by severe neurological symptoms primarily hot flushes Since ADT depletes the substrate necessary for estrogen biosynthesis and testosterone replacement is absolutely contraindicated for prostate cancer patients synthetic estrogens have been used primarily to treat ADT associated neurological and psychiatric symptoms However this remedy causes feminization most prominently gynecomastia with high risks for deep vein thrombosis and subsequent pulmonary embolism Because only estrogens can provide adequate relieve from hot flushes based on current clinical practices there is an unmet medical need for an effective and in addition safe intervention to alleviate vasomotor symptoms that affect prostate cancer patients undergoing ADT The overall hypothesis of this Phase I SBIR grant application is that treatment with dihydroxyestra dien one DHED an innovative brain selective bioprecursor prodrug of estradiol will alleviate ADT associated hot flushes without peripheral side effects accompanying the current forms of estrogen therapy In our first specific aim we will produce sufficient quantity of DHED for the proposed assessments In the second specific aim we will perform preclinical pharmacokinetics distribution and bioavailability studies in orchidectomized ORDX male rats to support our hypotheses that DHED treatment confines the formation of estradiol into the brain In the third specific aim our specific hypothesis is that oral treatment with DHED will prevent ORDX induced tail skin temperature elevation in male rats a well established preclinical model of hot flushes In addition we will seek evidence for the brain specific action of DHED derived estradiol by showing that estrogen induced gene expressions are triggered only in the brain but not in the pituitary and prostate Using ORDX athymic nude mice we will also confirm that DHED treatment does not induce proliferation in cancerous prostate cell LNCaP xenographts Our goal with these series of preclinical studies is to support a Phase II SBIR grant application for the continued pursuit of DHEDandapos s therapeutic use to remedy vasomotor symptoms with focus on patients suffering from prostate cancer and undergoing ADT AgyPharma has secured an exclusive license for the development of DHED from bench to bedside its approach has been supported by encouraging preliminary results which provides not only a distinctive andapos nicheandapos but also promises a highly competitive position for business development A supporting environment due to location and unique access to enabling infrastructure further enhance the companyandapos s position to achieve potential breakthrough in developing an innovative drug candidate for the treatment of vasomotor symptom affecting prostate cancer patients receiving ADT PUBLIC HEALTH RELEVANCE Hot flushes are debilitating symptoms frequently experienced by men undergoing prostate cancer management by the so called androgen deprivation therapy Estrogen is the only truly effective remedy for these symptoms However currently available estrogen drugs cause many undesirable side effects in the periphery most prominently the feminization in the breasts This side effect also negatively impacts the patientsandapos compliance to the symptomatic treatment because of the associated physical and psychological discomfort This SBIR Phase I proposal addresses the preclinical development of a liability free remediation of hot flushes in these patients by an innovative approach of brain selective estrogen therapy