Peripherally-restricted and long-acting kappa-opioid receptor (LA-KOR) agonists for pain

PROJECT SUMMARYPain management poses significant clinical challenges due to its very high prevalencethe diversity of patients and underlying mechanismsand the lack of safe and effective treatment optionsApproximatelymillion Americans experience acute post operative painwhereas aboutmillion US adults suffer from chronic painOpioids remain the most effective class of analgesics for moderate to severe painand are thus broadly usedTheir analgesic activity is mediated through activation of mu opioid receptorsMORUnfortunatelyMOR activation also results in serious adverse effectsespecially respiratory depressiona primary cause of death in addict overdoses as well as in patients with compromised respiratory and kidney function or who self medicate with other drugse gtranquilizersalcoholOther serious generally non lethal adverse effects include mental clouding and somnolenceaddictionphysical dependenceand constipationDespite these concerns and for the lack of better optionsthe number of opioid prescriptionsdose per prescriptionand number of days of treatment have increased in recent yearsThis has led to aprescription opioid epidemicresulting in unprecedented levels of addiction and overdose related deathsPeripherally restricted peptidic kappa opioid receptorKORagonists are emerging as a new class of non addictive and safe analgesicsCRa first inclass all D amino acid tetrapeptide KOR agonist with high potency and selectivity for the KOR and lack of brain penetrationhas established in clinical trials that peptidic KOR agonistsiproduce analgesiaiilack central adverse effectsiiido not produce constipation or respiratory depressionandivreduce the need for MOR agonist supplemental therapy in post operative painCRis however short actingrequiring multiple daily intravenous dosingthus limiting its clinical utility and commercial interestUnder a previous SBIR Phase I awardwe have established the feasibility to conjugate the above tetrapeptide KOR agonists to CVXa proprietary monoclonal antibody carrier previously used and clinically validated to create long acting peptide antibody conjugatesPACsenabling once weekly subcutaneous dosingOur current long acting KORLA KORagonist lead series has achieved potent KOR agonist activity and selectivityand demonstrated preclinical analgesic activityThe proposed follow up SBIR Phase II program seeks toAimfurther optimize the existing lead LAKOR agonist series allowing selection of a LA KOR agonist clinical candidate for developmentAimcharacterize the antinociceptive profile of LA KOR agonists in a broad range of disease relevant pain modelsin both male and female animalsto validate clinical indicationsAimcomplete key preliminary preclinical studies to help design investigational new drugINDenabling studiesIMPACT andampRelevance to Public HealthIf successfulthis program will bring forward novelefficaciousnon addictivesafeand convenient analgesics able to reduce or replace opioids for the treatment of moderate to severe painthus improving pain control while maintaining patient safety and quality of lifeand helping society to address the opioid crisis PROJECT NARRATIVE This program seeks to develop novelefficaciousnon addictivesafeand convenient analgesics able to reduce or replace opioids for the treatment of moderate to severe painThe program goal is to ultimately improve pain control while maintaining patient safety and quality of lifeand helping society to address the opioid crisis