Atogepant – an orally-administered CGRP antagonist – attenuates activation of meningeal nociceptors by CSD

Abstract

Background This study investigated the mechanism of action of atogepant, a small-molecule CGRP receptor antagonist recently approved for the preventive treatment of episodic migraine, by assessing its effect on activation of mechanosensitive C- and Aδ-meningeal nociceptors following cortical spreading depression. Methods Single-unit recordings of trigeminal ganglion neurons (32 Aδ and 20 C-fibers) innervating the dura was used to document effects of orally administered atogepant (5 mg/kg) or vehicle on cortical spreading depression-induced activation in anesthetized male rats. Results Bayesian analysis of time effects found that atogepant did not completely prevent the activation of nociceptors at the tested dose, but it significantly reduced response amplitude and probability of response in both the C- and the Aδ-fibers at different time intervals following cortical spreading depression induction. For C-fibers, the reduction in responses was significant in the early phase (first hour), but not delayed phase of activation, whereas in Aδ-fibers, significant reduction in activation was apparent in the delayed phase (second and third hours) but not early phase of activation. Conclusions These findings identify differences between the actions of atogepant, a small molecule CGRP antagonist (partially inhibiting both Aδ and C-fibers) and those found previously for fremanezumab, a CGRP-targeted antibody (inhibiting Aδ fibers only) and onabotulinumtoxinA (inhibiting C-fibers only)- suggesting that these agents differ in their mechanisms for the preventive treatment of migraine.

Efficacy and safety of eptinezumab as preventive treatment for episodic/chronic migraine: A systematic review and meta‐analysis

“…41 Moreover, atogepant is available in the oral formulation, therefore, may be more convenient to take, whereas eptinezumab is only available in the form of intravenous injection. 41 Regardless of that, both of these agents may become a promising therapy and be used for migraine prevention in adults.…”

“…However, there are few differences between atogepant and eptinezumab. Atogepant partially inhibits both mechanosensitive Aδ and C‐meningeal nociceptors, whereas anti‐CGRP antibody including eptinezumab can only inhibit Aδ fibres 41 . Moreover, atogepant is available in the oral formulation, therefore, may be more convenient to take, whereas eptinezumab is only available in the form of intravenous injection 41 .…”

“…Atogepant partially inhibits both mechanosensitive Aδ and C‐meningeal nociceptors, whereas anti‐CGRP antibody including eptinezumab can only inhibit Aδ fibres 41 . Moreover, atogepant is available in the oral formulation, therefore, may be more convenient to take, whereas eptinezumab is only available in the form of intravenous injection 41 . Regardless of that, both of these agents may become a promising therapy and be used for migraine prevention in adults.…”

New migraine prophylactic drugs: Current evidence and practical suggestions for non-responders to prior therapy

“…This difference could be the biological rationale for the combination of anti-CGRP(-R) mAbs and BTA. Gepants seem to act outside the blood–brain barrier (57,58), and atogepant partially inhibits both Aδ and C fibers (59), the pattern of which is different from that of BTA (56). A combination of atogepant and BTA resulted in robust inhibition of neurons in the spinal trigeminal nucleus, probably by blocking both Aδ and C fibers in a preclinical study (60).…”

Gepants for Acute and Preventive Migraine Treatment: A Narrative Review

“…Its affinity at the CGRP receptor in humans is higher than that of ubrogepant. The atogepant also has an affinity for the AMY1 receptors [ 44 ]. The combination with onabotulinumtoxin A effectively reduced sensitization and cortical spreading depression in an animal model [ 45 ].…”