Dual Therapy With Anti-CGRP Monoclonal Antibodies and Botulinum Toxin for Migraine Prevention

Is There a Rationale?

Lanfranco Pellesi, MD; Thien P. Do, MD; Håkan Ashina, MD; Messoud Ashina, MD, PhD, DMSc; Rami Burstein, PhD


Headache. 2020;60(6):1056-1065. 

In This Article

Anti-CGRP MABS and the CGRP Pathway

Three humanized antibodies targeting the CGRP peptide (eptinezumab, fremanezumab, and galcanezumab) and a fully human antibody targeting the CGRP receptor (erenumab) were developed to inhibit the CGRP-signaling pathway (Table 1). Due to the relatively large size of these monoclonal antibodies, they most likely inhibit CGRP signaling pathway outside the blood-brain barrier (BBB). In vitro models showed that fremanezumab and erenumab selectively blocked CGRP-mediated vasodilation on intracranial and extracranial human arteries, without impacting vasodilatory responses of other endogenous vasodilators or pharmacological vasoactive substances.[44–47] In order to improve translatability, the mode of action of anti-CGRP mAbs has also been investigated in animal migraine-like pain. In mice, CGRP-induced pain behavior is completely blocked by the pre-administration of eptinezumab while a conventional nonsteroidal anti-inflammatory drug, meloxicam, had no effect.[48] Similarly, eptinezumab and olcegepant alleviated cephalic hypersensitivity and hyperalgesia in a mouse model of glyceryl trinitrate-provoked migraine-like pain and a spontaneous rat model of migraine-like pain.[49] Both drugs displayed a fast onset of action. As olcegepant is thought to poorly penetrate the BBB,[50] it is reasonable to propose that eptinezumab prophylaxis does not depend on the modulation of CGRP signaling in the brain. In accordance, an intravenous infusion of fluorescently conjugated fremanezumab produced intense labeling in the dura and sensory and autonomic ganglia, but not in any CNS structures, that is, in the pia, the TNC, the hypothalamus or the cerebral cortex.[51] Other studies have elaborated on the impact of a single anti-CGRP mAb on the nociceptive trigeminal pathways and their ascending projections to the brainstem.[52,53] Fremanezumab was administered intravenously and tested together with a cortical spreading depression-evoked activation,[54] a cortical event activating both first- and second-order neurons in the trigeminal nociceptive pathway.[55,56] Pre-administration of fremanezumab selectively inhibited the responsiveness of Aδ-, but not C-meningeal nociceptors,[52] and when the focus was turned to the second-order neurons at the TNC, fremanezumab inhibited the activation and sensitization of HT, but not wide-dynamic range (WDR) neurons.[52] Collectively, these findings suggest that fremanezumab is especially effective when meningeal Aδ-fibers and central HT neurons play a critical role in the initiation of headache and the development of allodynia and central sensitization. The selectivity of fremanezumab is consistent with the predominant expression of CGRP receptors on Aδ- but not C-fibers, and their monosynaptic connections with HT, and to a far lesser extent, WDR neurons. Accordingly, it is suggested that at least part of the mechanism of action of fremanezumab (as well as other antibodies targeting the CGRP pathway) in migraine prevention is achieved through its ability to neutralizing dural CGRP before it binds to the CGRP receptors on the Aδ-fibers.[52] Within the node of Ranvier of such fibers, CGRP receptors are implicated in axo-axonal synapses with C-fibers.[17] Nodes of Ranvier are of particular interest, because they are an accessible drug target to antibodies.[57] It was hypothesized that CGRP may be released from C-fibers and axon-axonal synapses occur with Aδ-fibers in the TG and meninges. Such interactions are implicated in regulating the excitability of trigeminal nociceptive afferents, thereby modulating pain transmission.