Fremanezumab—A Humanized Monoclonal Anti-CGRP Antibody—Inhibits Thinly Myelinated (Aδ) But Not Unmyelinated (C) Meningeal Nociceptors

Abstract

Calcitonin gene-related peptide (CGRP), the most abundant neuropeptide in primary afferent sensory neurons, is strongly implicated in the pathophysiology of migraine headache, but its role in migraine is still equivocal. As a new approach to migraine treatment, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs) were developed to reduce the availability of CGRP, and were found effective in reducing the frequency of chronic and episodic migraine. We recently tested the effect of fremanezumab (TEV-48125), a CGRP-mAb, on the activity of second-order trigeminovascular dorsal horn neurons that receive peripheral input from the cranial dura, and found a selective inhibition of high-threshold but not wide-dynamic range class of neurons. To investigate the basis for this selective inhibitory effect, and further explore the mechanism of action of CGRP-mAbs, we tested the effect of fremanezumab on the cortical spreading depression-evoked activation of mechanosensitive primary afferent meningeal nociceptors that innervate the cranial dura, using single-unit recording in the trigeminal ganglion of anesthetized male rats. Fremanezumab pretreatment selectively inhibited the responsiveness of Aδ neurons, but not C-fiber neurons, as reflected in a decrease in the percentage of neurons that showed activation by cortical spreading depression. These findings identify Aδ meningeal nociceptors as a likely site of action of fremanezumab in the prevention of headache. The selectivity in its peripheral inhibitory action may partly account for fremanezumab's selective inhibition of high-threshold, as a result of a predominant A-δ input to high-threshold neurons, but not wide dynamic-range dorsal horn neurons, and why it may not be effective in all migraine patients. Recently, we reported that humanized CGRP monoclonal antibodies (CGRP-mAbs) prevent activation and sensitization of high-threshold (HT) but not wide-dynamic range trigeminovascular neurons by cortical spreading depression (CSD). In the current paper, we report that CGRP-mAbs prevent the activation of Aδ but not C-type meningeal nociceptors by CSD. This is the first identification of an anti-migraine drug that appears to be selective for Aδ-fibers (peripherally) and HT neurons (centrally). As the main CGRP-mAb site of action appears to be situated outside the brain, we conclude that the initiation of the headache phase of migraine depends on activation of meningeal nociceptors, and that for selected patients, activation of the Aδ-HT pain pathway may be sufficient for the generation of headache perception.

Calcitonin Gene‐Related Peptide Modulators – The History and Renaissance of a New Migraine Drug Class

“…There is no doubt that CGRP released or applied centrally will activate trigeminal neurons, but clinically IV CGRP triggers migraine, and it is unlikely to have penetrated from the blood to central CGRP receptors on sensory neurons in the brain stem to exert sensitizing effects. In contrast to their original suggestion, the same laboratory showed that pretreatment with the CGRP mAb fremanezumab, which does not cross the blood‐brain barrier, selectively inhibited the responsiveness of neurons receiving input from thinly myelinated Aδ fibers, but not neurons receiving input from neurons receiving input from unmyelinated C‐fibers neurons, as measured by a decrease in the percentage of neurons that showed activation by CSD . In an accompanying study, single‐unit recording was used to assess the effects of fremanezumab on spontaneous and evoked activity in naive and CSD‐sensitized trigeminovascular neurons in the spinal trigeminal nucleus of anesthetized male and female rats.…”

Novel Medications for the Treatment of Migraine

“…21 CGRP is a 37-amino acid neuropeptide, first described in 1983. [26][27][28][29][30] About 50% of the neurons in the trigeminal ganglion is CGRP-immunoreactive. 22 Neuropeptides are proteinaceous substances that are synthesized in the nucleus of the neuron and released from dense core vesicles.…”

“…Due to their large size, they must be given via parenteral routes of administration (intravenous, subcutaneous, or intramuscular). 29 This inhibits the Aδ input to high-threshold neurons that transduce mechanical stimuli into nociceptive signals. 63 They remain in the vasculature and likely reach their targets through extravasation.…”

“…62 Antibodies are metabolized by the reticuloendothelial system as well as in the skin, muscle, and gut, rather than by the liver. 29,30 Three CGRP mAbs have been approved for preventive treatment of migraine. 64 Antibody binding to cell-surface receptor proteins or to the ligand prevents binding between the receptor and the ligand, inhibiting downstream processes.…”

A Popperian View on Anti‐CGRP Biologics in Migraine

“…Seminal work by the Burstein's laboratory in a rat model of migraine with aura shows that fremanezumab counteracts neurotransmission of Aδ trigeminal afferents with a dural receptive field, 38,39 thereby providing the first hint on how anti-CGRP biologics counteract trigeminal pain in the periphery. Seminal work by the Burstein's laboratory in a rat model of migraine with aura shows that fremanezumab counteracts neurotransmission of Aδ trigeminal afferents with a dural receptive field, 38,39 thereby providing the first hint on how anti-CGRP biologics counteract trigeminal pain in the periphery.…”