Several lines of evidence pointed to an important role for CGRP in migraine. 
These included the anatomic colocalization of CGRP and its receptor in sensory 
fibers innervating pain-producing meningeal blood vessels, its release by 
trigeminal stimulation, the observation of elevated CGRP in the cranial 
circulation during migraine with normalization concomitant with headache relief 
by sumatriptan, and translational studies with intravenous (IV) CGRP that evoked 
migraine only in migraineurs. The development of small molecule CGRP receptor 
antagonists (CGRP-RAs) that showed clinical antimigraine efficacy acutely and 
prophylactically in randomized placebo-controlled clinical trials subsequently 
gave definitive pharmacological proof of the importance of CGRP in migraine. 
More recently, CGRP target engagement imaging studies using a CGRP receptor PET 
ligand [11 C]MK-4232 demonstrated that there was no brain CGRP receptor 
occupancy at clinically effective antimigraine doses of telcagepant, a 
prototypic CGRP-RA. Taken together, these data indicated that (1) the 
therapeutic site of action of the CGRP-RAs was peripheral not central; (2) that 
IV CGRP had most likely evoked migraine through an action at sites outside the 
blood-brain barrier; and (3) that migraine pain was therefore, at least in part, 
peripheral in origin. The evolution of CGRP migraine science gave impetus to the 
development of peripherally acting drugs that could modulate CGRP chronically to 
prevent frequent episodic and chronic migraine. Large molecule biologic antibody 
(mAb) approaches that are given subcutaneously to neutralize circulating CGRP 
peptide (fremanezumab, galcanezumab) or block CGRP receptors (erenumab) have 
shown consistent efficacy and tolerability in multicenter migraine prevention 
trials and are now approved for clinical use. Eptinezumab, a CGRP neutralizing 
antibody given IV, shows promise in late stage clinical development. Recently, 
orally administered next-generation small molecule CGRP-RAs have been shown to 
have safety and efficacy in acute treatment (ubrogepant and rimegepant) and 
prevention (atogepant) of migraine, giving additional CGRP-based therapeutic 
options for migraine patients.