Migraine/Headache

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 [ 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.

Migraine is a disabling primary headache disorder that requires effective treatments. Inhalation is currently being explored for the delivery of drugs for migraine. Pulmonary-route delivery of drugs shows potential advantages for its use as a treatment, particularly compared the oral route. Areas covered: The authors highlight the current state of the literature and review multiple therapies for migraine-utilizing inhalation as the route of administration. The following therapeutics are discussed: inhaled ergotamine, inhaled dihydroergotamine mesylate (MAP0004), inhaled prochlorperazine, and inhaled loxapine. Coverage is also given to normobaric oxygen, hyperbaric oxygen, and nitrous oxide therapies. Expert opinion: Inhalation of MAP0004 showed promising results in terms of efficacy for acute migraine treatment in phase 3 studies, together with a more favorable tolerability profile compared to parenteral dosing and a better pharmacokinetic profile versus oral or intranasal delivery. In phase 2 trials, inhaled prochlorperazine shows good pharmacokinetics and efficacy, in contrast to inhaled loxapine that did not provide encouraging results in terms of efficacy. The authors see the potential for the use of dihydroergotamine mesylate in clinical practice pending regulatory approval.

Calcitonin gene-related peptide (CGRP), is a peptide neurotransmitter with potent vasodilating properties. CGRP is believed to play a primary role in the pathogenesis of migraine. As such, CGRP and its receptors are obvious druggable targets for novel anti-migraine agents. While the development of small-molecule CGRP receptor antagonists started first, none of these agents is yet available in clinical practice. Conversely, both anti-CGRP and anti-CGRP receptor monoclonal antibodies (mABs) completed clinical development, and the first representatives of these 2 classes are available on the market. MABs are approved for prevention of migraine attacks in chronic or episodic migraine, involving long-term treatments. In light of the physiological role exerted by CGRP in the regulation of vascular tone, the potential risks of a long-term inhibition of CGRP functions raised diffuse concerns. These concerns were correctly addressed by the anti-CGRP receptor mABs erenumab with a 5-year open-label clinical trial; however, this study is currently ongoing and results are not yet available, leaving some uncertainty on the profile of erenumab long-term safety. Similar concerns can be raised with direct anti-CGRP mABs, which entrap the peptide preventing receptor activation. However, evidence exists that plasma CGRP is detectable in patients chronically treated with anti-CGRP mABs. Assuming that plasma CGRP is an indirect marker of peptide levels at the vascular receptor sites, such residual CGRP would maintain a physiological level of receptor stimulation, in spite of a well-established anti-migraine activity of the mABs. This might represent a potential advantage in the safety profile of anti-CGRP mABs, but it needs to be confirmed and expanded with data on free plasma CGRP.