Peripherally-restricted and long-acting MAS1(LA-MAS1) agonists for pain

PROJECT SUMMARYThe current USopioid crisisfueled by overmillion annual prescriptions of mu opioid receptorMORagonist analgesics and characterized by unprecedented levels of addictionabuse and death by overdosehas emphasized the need for novelefficaciousnon addictive and safe analgesicsThe proposed program seeks to develop a first in classFICperipherally restricted and long acting MASLA MASagonist with potential to reduce or replace MOR agonists for moderate to severe painand that will be non addictivesafe and convenient to useThe program is based on strong scientific evidence showing that activation of MASa peptidic G proteincoupled receptorGPCRproduces opioid independent and peripheral antinociceptive activity in a wide range of animal models of chronic painincluding inflammatoryneuropathic and bone cancer painWe propose to conjugate existing short acting peptidic MASagonists to CVXaplug and playand re usable antibody carrierpreviously clinically validated for extending the half life of peptidesand successfully used by us to create other long acting peripheral analgesicsLPAsincluding long acting kappa opioid receptorLA KORagonists and long acting somatostatin receptor typeLA SSTRagonistsThe resulting LA MASpeptide antibody conjugatesPACswill retain potent agonistic activity and selectivity at MASwhile acquiring the pharmacokineticPKproperties of the antibody carrierthereby achieving bothilong elimination half life andiihigh peripheral selectivityThese two key features will provide LA MASagonists with a highly differentiated and superior target product profileTPPin terms of efficacysafety and convenience compared to short acting and brain penetrating small molecule analgesics currently in developmentThe extended half life will enable less frequentsimpler and more convenient administrationi eonce weekly or twice monthly subcutaneous dosing that in turn will improve compliance while ensuring continuous drug exposure at effective plasma concentrationwhich combinedwill maximize efficacyThe lack of penetration in the central nervous systemCNSwill prevent unnecessary and undesired interaction with the widely distributed MASin the CNSthereby eliminating any risk of CNS mediated MASadverse effectsFinallyunlike MOR agonistsLA MASagonists will not induce respiratory depressionnauseavomitingitchingconstipationdrowsinessmental cloudinessdependenceaddiction or abuseThe current SBIR Phase I program aims to assess the chemical feasibility of creating potentselective and stable LA MASagonistsThe subsequent Phase II program will include further lead optimizationevaluation of efficacypotency and duration of action in animal pain modelspreclinical PK studies and selection of a clinical candidate new biological entityNBEfor nonclinical developmentIMPACT andampRelevance to Public HealthThis program has potential to bring forward novelefficaciousnon addictivesafe and 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 life and helping society to curb theopioid crisisPROJECT NARRATIVEThis program seeks to develop novelefficaciousnon addictivesafe and 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 life and helping society to curb theopioid crisis