Migraine monoclonal antibodies against CGRP change brain activity depending on ligand or receptor target – an fMRI study

Abstract

Background:Monoclonal antibodies (mAbs) against calcitonin gene-related peptides (CGRP) are novel treatments for migraine prevention. Based on a previous functional imaging study which investigated the CGRP receptor mAb (erenumab), we hypothesized that (i) the CGRP ligand mAb galcanezumab would alter central trigeminal pain processing; (ii) responders to galcanezumab treatment would show specific hypothalamic modulation in contrast to non-responders; and (iii) the ligand and the receptor antibody differ in brain responses.Methods:Using an established trigeminal nociceptive functional magnetic imaging paradigm, 26 migraine patients were subsequently scanned twice: before and 2–3 weeks after administration of galcanezumab.Results:We found that galcanezumab decreases hypothalamic activation in all patients and that the reduction was stronger in responders than in non-responders. Contrasting erenumab and galcanezumab showed that both antibodies activate a distinct network. We also found that pre-treatment activity of the spinal trigeminal nucleus (STN) and coupling between the STN and the hypothalamus covariates with the response to galcanezumab.Conclusions:These data suggest that despite relative impermeability of the blood-brain barrier for CGRP mAb, mAb treatment induces certain and highly specific brain effects which may be part of the mechanism of their efficacy in migraine treatment.Funding:This work was supported by the German Ministry of Education and Research (BMBF) of ERA-Net Neuron under the project code BIOMIGA (01EW2002 to AM) and by the German Research Foundation (SFB936-178316478-A5 to AM). The funding sources did not influence study conduction in any way.Clinical trial number:The basic science study was preregistered in the Open Science Framework (https://osf.io/m2rc6).

Longitudinal changes in functional connectivity and pain-induced brain activations in patients with migraine: a functional MRI study pre- and post- treatment with Erenumab

“…Acupuncture treatment has been associated with an increase in periaqueductal gray functional connectivity with anterior cingulate cortex among individuals who have migraine without aura [63]. A pre-treatment and 2-3 week posttreatment study of galcanezumab, a CGRP ligand mAB, for migraine demonstrated that galcanezumab decreased hypothalamic activation in response to nociceptive trigeminal stimulation to a greater extent in galcanezumab-responders vs. non-responders [12]. There were also responder-specific decreases in BOLD activation in the inferior parietal lobule, insula and parahippocampal gyrus.…”

“…Other studies have demonstrated cycling activity and functional connectivity of brain regions such as the hypothalamus, pons, and trigeminal nucleus, that correlate with the occurrence of migraine attacks [3,4,7]. Only a few studies have investigated changes in resting-state functional connectivity or paininduced brain activations associated with response to migraine preventive treatment [8][9][10][11][12]. These publications demonstrate that migraine preventive treatments, even those that are unlikely to directly access the brain, may be associated with changes in brain functional connectivity and pain-induced activations.…”

“…A previously published functional magnetic resonance imaging (fMRI) study demonstrated that erenumab treatment is associated with changes in central processing of trigeminal pain and brain resting state functional connectivity at 2 weeks after starting treatment [10]. Another study investigated the impact of treatment with galcanezumab, another anti-CGRP pathway mAb, on brain activation in response to trigeminal nociception measured 2-3 weeks after starting galcanezumab [12]. The objective of our study was to determine if participants with migraine who respond to erenumab, an anti-CGRP pathway mAb targeting the receptor, have post-treatment changes in functional connectivity and pain-induced brain activations that differ from erenumab non-responders.…”

Epigenetic Connection of the Calcitonin Gene-Related Peptide and Its Potential in Migraine

“…The ongoing BIOmarkers of MIGrAine based on the stratification of responders to CGRP monoclonal antibodies (BIOMIGA) proof of concept study (NCT04503083) includes the assessment of DNA methylation levels in migraine subjects as compared to non-migraineur controls ( , accessed on 10 May 2022). It is expected that the results of the project will be related to the epigenetic regulation of CGRP [ 63 ].…”

Anticuerpos monoclonales anti-PRGC y modificación de la historia natural de la migraña

“…-De forma similar, el mismo grupo realizó un estudio con 26 pacientes tratados con galcanezumab. En estos se observó, tras 2-3 semanas de tratamiento, una reducción de la activación hipotalámica, más intensa en los respondedores, pero apreciada en el global de pacientes 30 . Sin embargo, el resto de los cambios a nivel central (tálamo, giro temporal, opér-culo…) objetivados con erenumab 29 no fueron demostrables en este estudio.…”