There are many drugs available for the prevention of frequent migraines. For the most part, they are medications that have been developed for other conditions such as depression or epilepsy. However, a number of injectable compounds have recently been developed specifically for migraine prophylaxis. These include erenumab and the newly registered fremanezumab and galcanezumab. These monoclonal antibodies all block the activity of calcitonin gene-related peptide (CGRP).
The precise pathogenesis of migraines is not entirely understood. However, current thinking describes migraine as a predominantly neural disorder with any vascular changes considered likely to be secondary. The trigeminal system is particularly important for the progression of migraine signals and CGRP is the most abundant peptide in this system. Release of CGRP initiates a cascade that includes the increased production of nitric oxide, sensitisation of nociceptive neurons, and vasodilation.
Studies demonstrate that people who suffer from migraines are unusually sensitive to CGRP. Intravenous injection of CGRP was shown to induce migraine-like headaches in migraine sufferers, while only producing mild headache or discomfort in non-migraine sufferers. Additional evidence to implicate the importance of CGRP in migraines includes the findings that triptan medications reduce CGRP levels as pain relief occurs. Studies demonstrate that around two-thirds of migraine sufferers respond to CGRP antagonists, suggesting that different aetiologies are involved in migraine headaches.
While these three monoclonal antibodies all reduce the activity of CGRP, they achieve this end in a slightly different way. Fremanezumab and galcanezumab potently and selectively bind to the CGRP ligand to prevent it from interacting with the CGRP receptor. The association with CGRP occurs rapidly for each medication. However, while fremanezumab dissociates from its target very slowly, galcanezumab does so rapidly. This rapid dissociation may allow significant levels of CGRP to remain free to interact with the receptor. In contrast, erenumab is an antagonist at the CGRP receptor that potently and specifically competes with CGRP. The end result of all three medications is reduced activation of the trigeminal system.
Like all monoclonal antibodies, these agents are large molecules. It is, therefore, unlikely that these agents could cross the blood-brain barrier to any great extent. Instead, it is thought that the peripheral vasculature is the likely site of action. Studies demonstrate that these agents are effective in inhibiting CGRP-induced neurogenic vasodilation in the middle meningeal artery, but not of the pial artery. The middle meningeal artery, the main supplier of the dura mater, is located outside of the blood-brain barrier. Studies demonstrate that at the onset of migraine, it is this artery that increases in circumference more on the pain side than the non-pain side.
Erenumab, fremanezumab, and galcanezumab are all intended for subcutaneous injection. They have long half-lives (27 days, 31 days, and 28 days respectively) which allows for monthly dosing. Fremanezumab is also approved in a higher strength product for administration every three months. This may offer compliance advantages for patients when compared to other prophylactic agents that must be taken daily. Adherence to daily prophylactic medications is thought to be low in this population. Studies suggest that adherence at six-months may be as low as 26% and reduce further to 17% at 12 months.
All three monoclonal antibodies are presented in prefilled devices suitable for self-administration. Local reactions at the injection site were the most commonly reported adverse reactions for all three agents. There is limited data on safety and efficacy of use beyond 12 months, although no signals or trends have currently been identified that suggest a potential problem. Some concerns have been raised regarding the long-term blockade of CGRP due to its variety of biological functions. CGRP is known to have a protective role in the cardiovascular system and possibly also the gastrointestinal system. There is particular concern that CGRP blockade could inhibit protective vasodilatory responses to cerebral and cardiac ischaemia. One placebo-controlled study of erenumab in a high-risk cardiovascular population may allay some of these fears. In this study, erenumab did not adversely affect exercise time which suggests that CGRP blockade may not worsen myocardial ischaemia. It has also been theorised that targeting the CGRP ligand, as occurs with fremanezumab and galcanezumab, may be safer as it allows the receptor to still interact with other ligands important in biological functions.
These medicines are not currently listed on the Pharmaceutical Benefits Scheme (PBS). However, galcanezumab recently received a positive recommendation from the Pharmaceutical Benefits Advisory Committee while a decision for fremanezumab was deferred. The newly launched Medicine Status Website can be used to track the status of these medicines as they move through the PBS listing process.
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- Khan S, Amin FM, Christensen CE, Ghanizada H, Younis S, Olinger AC, et al. Meningeal contribution to migraine pain: a magnetic resonance angiography study. Brain 2019; 142(1): 93-102.
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