Author: Kuan-Po Peng

The efficacy of anti-CGRP therapies (CGRP mAbs and gepants) in migraine is well established.¹ However, the precise mechanisms of action are unclear and the question of whether a central or peripheral mechanism is responsible for their efficacy remains unresolved. Dr Kuan-Po Peng, from the Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Germany, reviews the latest evidence.

Both CGRP and CGRP receptors are extensively expressed within the trigeminal vascular system (peripheral) and various brain regions, including the brainstem and the trigeminal nucleus caudalis (central).² The estimated permeability of CGRP mAbs across the blood-brain barrier (BBB), is as low as 0.01% to 0.1% due to their large molecular size,² though the results of animal models suggest that the actual concentration of CGRP mAbs in the central nervous system may be slightly higher than expected. For example, concentrations of 0.34% have been observed in the hypothalamus and 0.12% in the cerebrospinal fluid (CSF), compared to 5.2% in the trigeminal ganglia, which are located outside the BBB.³

Consequently, it is reasonable to assume that CGRP mAbs primarily operate in the periphery. This assumption is supported by the clinical observation that CGRP mAbs can significantly reduce migraine prodromes followed by migrainous headaches.⁴ Nevertheless, evidence suggests that CGRP mAbs may also exert a central modulating effect. For instance, functional MRI studies have demonstrated that patients treated with either galcanezumab (an anti-CGRP ligand antibody) or erenumab (an anti-CGRP receptor antibody) exhibited a significant reduction in hypothalamic activation to trigeminal nociception within 2-3 weeks post-treatment, particularly in clinical responders.^5,6 Moreover, erenumab demonstrated a distinct reduction in thalamic, opercular, and putaminal activities when compared to placebo.⁷ These findings suggest that central effects of CGRP mAbs may be relevant to clinical response. However, they do not clarify whether the central effects result from direct binding of CGRP mAbs to central regions or are secondary to reduced nociceptive inputs from the periphery.

It is not possible to account for the discrepancy between peripheral CGRP ligand/receptor binding and clinical efficacy on the grounds of a pure peripheral mechanism of action. Erenumab at a dose of 21mg is sufficient to induce over 75% inhibition of capsaicin-induced dermal blood flow (CIDBF),⁸ a method that has been employed to assess the effectiveness of peripheral CGRP blockade. However, this dosage offered no clinical benefit over placebo in migraine reduction.⁹ As the clinical efficacy is only observable with a clinical dosage of 70mg, or even 140mg,¹⁰ the clinically effective dosage is much higher than that required for effective peripheral blockade. A recent study also demonstrated a dissociation between the reduction of CIDBF and the clinical efficacy of galcanezumab.¹¹ This indicates that binding to central ligands/receptors, despite their low proportion, may be critical in achieving clinical efficacy, and sufficient central binding can only be attained with higher dosages. Moreover, a recent study reported that over 60% of patients with chronic migraine experienced a notable improvement in brain fog following eptinezumab treatment, another anti-CGRP ligand antibody.¹² This phenomenon (improvement in brain fog) cannot be explained by a peripheral mechanism such as blockade of trigeminovascular activation.

In comparison to CGRP mAbs, gepants exhibit better CNS penetration – approximately 2% – due to their smaller molecular sizes.¹³ In the case of ubrogepant, in vivo human studies have demonstrated that stable blockade of the CIDBF is achieved with a dosage of 20mg.¹⁴ Nevertheless, a Phase 3 trial of ubrogepant evaluating the efficacy of 25mg and 50mg doses of ubrogepant against placebo demonstrated that both doses were comparable in achieving 2-hour pain freedom. However, only the 50 mg dose was effective in achieving a 2-hour absence of the most bothersome symptoms.¹⁵ Given that peripheral inhibition of CIDBF is similar for both 25 mg and 50 mg doses,¹⁴ it can be inferred that the efficacy observed in the 2-hour absence of the most bothersome symptoms must be attributed to a non-peripheral (central) mechanism of action. A recent study examining plasma and CSF concentrations of ubrogepant indicated that the CSF/plasma concentration ratio increased from 0.36% to 1% from 2-hour post-dose to 4-hour post-dose.¹⁶ This peak in CSF concentration coincides with the clinical observation that the magnitude of efficacy increases between 1-2 hours, peaking at 4 hours post-dose.¹⁷

The available clinical evidence from both gepants and CGRP mAbs indicates that the peripheral mechanism of action is indispensable for the treatment of migraine using anti-CGRP medications. However, additional evidence suggests the existence of a central mechanism of action, which correlates more closely with clinical responses. Notwithstanding the efficacy of anti-CGRP treatments, the issue of non-responders remains a topic warranting further investigation. Possible mechanisms for insufficient treatment response include alternative mechanisms of headache generation (such as neuropeptides other than CGRP) or insufficient action at central structure (individual difference to CNS penetration, superimposed central hypersensitisation, etc.). In either case, studies aimed at elucidating the mechanism (and site) of action of these medications may provide crucial insights into the identification of those patients who would derive the greatest benefit from them.

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