Calcitonin Gene‐Related Peptide Modulators – The History and Renaissance of a New Migraine Drug Class

Abstract

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 [11C]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.

Characterization of Ubrogepant: A Potent and Selective Antagonist of the Human Calcitonin Gene‒Related Peptide Receptor*

“…Inhibition of the CGRP receptor has emerged as a promising target for the acute and preventive treatment of migraine (Edvinsson, 2018). Previously investigated small-molecule CGRP antagonists have demonstrated efficacy in the treatment of migraine; however, clinical studies involving telcagepant and MK-3207 revealed potential concerns regarding drug-induced elevation of liver enzymes, and clinical development of these compounds was discontinued (Hewitt et al, 2011;Ho et al, 2014;Hargreaves and Olesen, 2019). Although the exact mechanism of this hepatotoxicity is unknown, it was hypothesized to be partly attributable to the formation of reactive metabolites and not specific to CGRP receptor antagonism (Hargreaves and Olesen, 2019).…”

“…Previously investigated small-molecule CGRP antagonists have demonstrated efficacy in the treatment of migraine; however, clinical studies involving telcagepant and MK-3207 revealed potential concerns regarding drug-induced elevation of liver enzymes, and clinical development of these compounds was discontinued (Hewitt et al, 2011;Ho et al, 2014;Hargreaves and Olesen, 2019). Although the exact mechanism of this hepatotoxicity is unknown, it was hypothesized to be partly attributable to the formation of reactive metabolites and not specific to CGRP receptor antagonism (Hargreaves and Olesen, 2019). The absence of any ubrogepant-associated hepatotoxicity has been supported by safety data from recent clinical studies (Goadsby et al, 2019;Hutchinson et al, 2019).…”

“…A substantial amount of scientific data implicates the CGRP pathway in the underlying physiologic mechanisms associated with migraine (Goadsby et al, 1990;Lassen et al, 2002;Edvinsson, 2015). Furthermore, previously investigated small-molecule CGRP receptor antagonists have demonstrated efficacy in the treatment of migraine, although development was eventually halted because of safety concerns (Hewitt et al, 2011;Ho et al, 2014;Hargreaves and Olesen, 2019). The clinical success of monoclonal antibodies targeting CGRP also provides support for the CGRP receptors as a promising therapeutic target for migraine (Dodick, 2019).…”

Trigeminal‐Targeted Treatments in Migraine: Is 60% the Magic Number?

“…When considering acute treatments, the various TTTs are characterized by a striking comparable proportion of responders in terms of pain response at 2 hours, the most common efficacy indicator for abortive migraine treatments: 59% with triptans at standard doses (range 42.4% with oral frovatriptan-75.7% with subcutaneous sumatriptan), 59% with lasmiditan (100 and 200 mg), 61.4% with telcagepant (280/300 mg), 56.2% with BI 44370 TA (400 mg), and 60.8% with MK-3207 (100-200 mg). 17 As acutely observed by Olesen, "classification of migraine into different endophenotypes could aid diagnosis and treatment, but requires detailed characterization of different phenotypes." 11 By pooling together all the aforementioned findings it emerges that TTTs are effective in approximately 60% of migraineurs regardless of the type treatment (acute o preventative) or the drug mechanism (block of the trigeminal sensory system or antagonism of its principal neuropeptide).…”

“…[14][15][16] This hypothesis has been recently taken into account also by Hargreaves and Olesen who raised the possibility that super-responders to CGRP mAbs might be those patients with autonomic signs in cranial tissues supplied by trigeminal innervation. 17 As acutely observed by Olesen, "classification of migraine into different endophenotypes could aid diagnosis and treatment, but requires detailed characterization of different phenotypes." 18 A very simple stepping stone in identifying TTTs responders could be the identification of migraineurs with unilateral pain.…”