SERINA THERAPEUTICS INC SBIR Phase I Award, September 2019

PAProject Summary Abstract SERis a long acting polymer pro drug of buprenorphine that is being developed to treat postoperative pain following major surgeries such as bunionectomyabdominoplastythoracotomy and knee and hip surgerySERhas no biological activity by itselfbut when administered in vivo by subcutaneous injection it enters the vascular compartment where a plasma esterasebutyrylcholinesteraseBChEenzymatically releases the active pharmaceutical ingredientbuprenorphineThe polymer confers prolonged circulatory half lifeallowing buprenorphine to be released continuously overdaysBuprenorphine is a mixed mu agonist antagonist at the mu opioid receptorMORand an antagonist at the kappa opioid receptorA single administration of SERhas been shown to provide both immediate and prolonged analgesia in the Brennan modelPrompt analgesiawhich subsequently lastsdaysshould obviate the need to initiate therapy by a potentially addictive opioid in the hospital and allow patients to be discharged on non additive drugs such as acetaminophen or NSAIDsSERis to be administered as a subcutaneous injection in the immediate post operative periode grecovery roomThis product is intended to be a one time injectionby a surgeon anesthesiologistthat will provide both immediate and andgtdays of analgesiaSERis predicted to demonstrate very low abuse liabilityindeedlong acting implants of buprenorphine are used to treat opioid use disorderand is likely to be used largely in surgical centersit is not intended for self administrationA Research Strategy is presented that will focus on the early development and preclinical objectives of this programwhere the ultimate goal is to demonstrate that SERcan be manufactured and tested preclinically to show that it is safe for use in a Phase I clinical studySERchemistry and process optimization to generate a technical packageandSERmanufactured under current Good Manufacturing PracticesandEvaluated in formal toxicology studies in rodent and non rodent animals so that justificationscan be made to support afirst in manstudySubmission of an Investigational New Drug applicationINDalong with a Phase I clinicalprotocol in normal volunteers to measure the safetytolerability and pharmacokinetics ofbuprenorphine that is released from SERThisDirect to Phase IIsubmission is made under theHEAL InitiativeNotice of Interest in Small Business Innovation ResearchSBIRand Small Business Technology TransferSTTRApplications Directed at Enhanced Pain Management and Improved Treatments for Opioid Misuse and AddictionBased upon prior experience in studies of similar designwe anticipate this Phase of the program would taketomonths to complete PAProject Narrative The current standard of treatment for post operative painin particular in hospital proceduresthose that require a hospital stayis the administration of opioid drugsThis is frequently accomplished by an intravenous administration of morphineor similar opioidthat can be controlled by the patientpatientcontrolled analgesiaor PCA pumpIn generalpatients are transitioned to an oral opioid on dayat which time they undergo progressive ambulation in preparation for dischargePatients are frequently discharged with a prescription for a potentially addictive opioidIn the event patients fill a prescription for an opioid following dischargeindependent of whether they have had minor or major surgerythey aretimes more likely to transition to chronic use of an opioid within the nextdaysFor patientsfamilies and the medical communitythe emergence of dependence and addiction following the use of opioids has become a serious concern and has driven the development of new approaches to pain managementThe prevention and treatment of opioid use disorderOUDis a pressing socialethical and medical challengeInit was estimated that approximatelypeople died every day from an opioid overdosemaking it the single highest cause of accidental death in the USThe amount of prescription opioids sold to pharmacieshospitals and physician s offices quadrupled fromyet there was not a coincident increase in the amount of pain reported in the US populationIn one of the largest cohort studies reported approximatelyinindividuals prescribed an opioid for control of post operative pain transitioned to chronic use within one yearThe current crisis posed by OUD has been decades in the making and combatting it will take time and a coherent plan involving a number of different strategies aimed at preventionintervention and treatmentThe reduction or elimination of the need to administer addictive opioid drugs in the immediate post operative period would target the initial gateway where patients are first exposed to addictive drugsSERis a long acting formulation of buprenorphine that is being developed to treat patients with postoperative pain that may be administered as a subcutaneous injection in the immediate post operative periodThis product is intended to be a one time injectionby a surgeon anesthesiologistthat will provide andgtdays of analgesiaafter which patients would transition to non addictive medicationssuch as ibuprofen or acetaminophenSERwill have limited abuse liability and is not intended for selfadministrationWhile some consider buprenorphine a relatively weak mu agonista very recentmeta analysis of randomizedcontrolled clinical trials comparing buprenorphine in its existing formulationBuprenexto IV morphine via a PCA pumpshowed that buprenorphinewas equal to morphine in analgesic efficacybuprenorphine had a ceiling effect on respiratory depression but not analgesia whereas morphine risk increases with dosethere was no difference for major side effects such as nausea and sedationno difference in need for rescue analgesia or time to rescue analgesiaandbuprenorphine was superior to morphine in some adverse eventsprimarily pruritisa troublesome side effect in the post operative management of patientsSERmay be a very important advance in the treatment of post operative painwhile simultaneously addressing the initial gateway in the hospital to a potentially addictive opioid