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Abstract Details

Atogepant – an orally-administered CGRP antagonist – attenuates activation of meningeal nociceptors by Cortical Spreading Depression (CSD)
Headache
S31 - Advances in Migraine Therapeutics (3:54 PM-4:06 PM)
003
Atogepant is a small-molecule CGRP receptor antagonist recently approved for episodic migraine prevention.

This study investigated the mechanism of action of atogepant by assessing its effect on the immediate and delayed activation of mechanosensitive unmyelinated C- and thinly-myelinated Aδ -meningeal nociceptors following cortical spreading depression (CSD). 

Single-unit recordings of activity in trigeminal ganglion neurons (32 Aδ and 20 C-fibers) innervating the dura was used to document change in response to CSD following oral administration of atogepant (5mg/kg) or its vehicle in anesthetized male rats.

While atogepant did not fully prevent activation of nociceptors [incidence of response to CSD in Aδ -fibers (vehicle 73%, atogepant 57%, p=0.42); C-fibers (vehicle 83%, atogepant 56%, p=0.26)], Bayesian analysis of time effects found that it significantly reduced response amplitude and probability of response in both the C- and the Aδ -fibers at different time intervals following CSD induction. For C-fibers, the reduction in responses was significant in the immediate [first hour; -0.29 (90% credible interval (CrI): -0.60 to -0.04)], but not delayed phase of activation, whereas in Aδ -fibers, significant reduction in activation was apparent in the delayed [second hour; -0.53 (90%CrI: -1.0 to -0.05), and third hour -0.57 (90%CrI: -1.0 to -0.1,)] but not early phase of activation.

These findings suggest that atogepant can partially prevent activation of both the Aδ -fiber and C-fiber meningeal nociceptors (by CSD), which differs from results found in similar models for fremanezumab, a CGRP-targeted mAb, and onabotulinumtoxinA.

Authors/Disclosures
Rami Burstein (Beth Isreal Deacones Medical Center)
PRESENTER
Dr. Burstein has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Allergan. Dr. Burstein has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eli Lilly. Dr. Burstein has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. Dr. Burstein has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. Dr. Burstein has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biohaven. Dr. Burstein has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Dr. Reddy. Dr. Burstein has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ipsen. Dr. Burstein has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurolief. Dr. Burstein has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Percept. Dr. Burstein has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. Dr. Burstein has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Theranica. The institution of Dr. Burstein has received research support from Allergan. The institution of Dr. Burstein has received research support from Teva. The institution of Dr. Burstein has received research support from Eli Lilly. The institution of Dr. Burstein has received research support from Dr. Reddy.
No disclosure on file
Agustin Melo Carrillo (Beth Israel Deaconess Medical Center. Harvard Medical School) Dr. Melo Carrillo has nothing to disclose.
No disclosure on file
Aubrey Adams Dr. Manack Adams has received personal compensation for serving as an employee of Abbvie. Dr. Manack Adams has stock in Abbvie.
Mitchell Brin (Abbvie / UC Irvine) Dr. Brin has received personal compensation for serving as an employee of Allergan. Dr. Brin has stock in Allergan.