Development of a fixed-dose combination therapy for the treatment of chronic musculoskeletal pain

PROJECT SUMMARY Non steroidal anti inflammatory drugsNSAIDsare a first line pharmacologic pain therapy for chronic musculoskeletal painand rheumatoid arthritisRAand moderate to severe osteoarthritisOAspecificallyHoweverinsufficient pain relief by NSAID monotherapy has encouraged the use of combination therapyCombinations of NSAIDs plus weak opioids are widely used although objective evidence for efficacy is limited and they have many adverse eventsWith the opioid crisis in the United States being declared a national public health emergencythe need for neweffectiveand non addictive pain medications has never been greaterNext generation management of chronic musculoskeletal pain must relieve both acute pain componentscaused by structural joint damageand chronic pain componentscaused by disinhibition of central pain regulatory mechanismsThis is substantiated by the many RA patientsthat continue to suffer from chronic pain even though disease modifying antirheumatic drugsDMARDscan effectively reduce inflammatory pain symptomsFurthermoredisinhibition of central pain regulatory mechanisms not only plays a key role in chronic musculoskeletal painbut also leads to increased risk of patients developing chronic widespread pain state comorbidities such as fibromyalgiaFMSwhich affect up toof RA patients andof OA patientsA growing body of evidence suggests thatsubtype selective positive allosteric modulatorsPAMof theaminobutyric acid A receptorGABAARmay effectively restore central pain regulatory mechanisms thus providing effective relief of chronic pain with reduced prevalence and severity of side effectsRecentlyNeuroCycle TherapeuticsNCTcollaboratorProfHanns Ulrich Zeilhofer at University of ZurichSwitzerlanddemonstrated that TPABansubtype selective PAMsignificantly reduced the aversive component of non inflammatory painchronic constriction injury induced neuropathic painusing conditioned place preferenceCPPFurthermoreTPAB robustly reduced Mouse Grimace Scale Scores in a formalin test in micea valid model for acute and tonic painTPAB is a small molecule with exquisite specificity and potency atsubtypesexcellent oral bioavailability and tolerability in humansand has demonstrated target engagement in manBased on these promising preliminary studies and considerable supporting literature datawe propose a SBIR Phase I project to test the hypothesis that combination dosing of TPAB with an NSAID will work synergistically to suppress the acute and chronic pain components of chronic musculoskeletal painOur specific aims areTo investigate the efficacy of TPABNSAID combination in chronic pain relief in complete Freundandapos s adjuvantCFAinduced arthritis in ratsTo investigate the efficacy of combination therapy in chronic pain relief in monosodium iodoacetateMIAinduced arthritis in ratsTo investigate the efficacy of combination therapy in widespread pain relief in acid saline induced pain in ratsThe results will provide strong support for a Phase II projectwhere additional pharmacology studies and IND enabling formulation development will be performed in preparation for initial clinical trials in man PROJECT SUMMARY Chronic musculoskeletal painincluding osteoand rheumatic arthritisis the most common type of chronic painCurrent therapies provide insufficient pain relief and result in many adverse events in patientsSafer and more effective therapies that relieve chronic musculoskeletal pain without risk of addiction are urgently neededNeuroCycle TherapeuticsIncNCTis developing a novel fixed dose combination therapy for chronic musculoskeletal pain with minimal side effects