Development of a novel anti-migraine therapeutics

AbstractMigraine affectsof the adult population worldwideand the standard treatment for acute and chronic migraine include the use of triptansergotaminesand analgesicsHoweverthese medications are inadequate for the control of severe migraineand many migraine patients suffer continuous struggle with painClearlynew approaches that can effectively ameliorate acute and chronic migraine pain are urgently neededImportantlystudies in the last decade have established that migraine pain is associated with CGRP mediated nociception sensitivityCGRP levels increase during a migraine attackwhereas the treatment of CGRP triggers migraine attack in sensitive patientsDue to its critical roles in inducing migraine painCGRP and its receptor complexthe calcitonin receptor like receptorCLRand receptor activity modifying proteinRAMPhave been targeted for migraine treatmentThus farthree distinct approaches have been used to block the CGRP signalingsmall molecule CGRP antagonistssynthetic peptide antagonistsandanti CGRP or anti RAMPantibodyAll of these approaches were effective in reducing migraine phenotypes in animals and or humansHowevereach of these approaches suffers efficacy or safety concernsWhile existing small molecule antagonists can cause liver toxicitythe anti CGRP and anti RAMPantibodies have limited efficacy in reducing migraine attacksperhaps due to limited access to target cellsOn the other handthere is a lack of potent peptide antagonistsObviouslya new strategy for targeting the CGRP mediated signaling pathway is needed to meet the medical need of migraine patientsTo overcome these obstacleswe have developed a group of long acting CGRP RAMPspecific peptide super antagonists that form gels in situ in aqueous solutionBased on this exciting findingwe propose to develop and identify the most potent antagonistic analog candidatesAimand characterize the pharmacokinetics of gel depots made of the selected candidates in vivoAimThis feasibility study is needed to explore the translational potential of these newly invented super antagonists for the treatment of chronic migraine in combination with conventional migraine agentsAt the end of this studywe expect to identify a potent antagonistic analog that is ready for preclinical development and a gel depot formulation that slowly releases the analog in vivo for at least two to four weeks Based on human hormones that are essential for the regulation of nociceptionwe have developed novel therapeutic candidates for the inhibition of migraine headacheWe will identify a lead candidate and characterize the pharmacokinetics of the selected anti migraine drug candidate in vivoSuccessful development of these novel drug candidates has the potential to greatly improve the care of patients with migraine headache or other pain