Safety of Anti-CGRP Migraine Therapeutics in Ischemic Stroke

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Small molecule calcitonin gene-related peptide (CGRP) receptor antagonists (“gepants”) and anti-CGRP or anti- CGRP-receptor monoclonal antibodies (“nezumabs”) are novel treatments for migraine. However, endogenous CGRP is among the most potent vasodilator molecules, and CGRP-mediated vasodilation is a critical rescue mechanism in cerebral ischemia. Therefore, CGRP antagonism may increase cerebrovascular event risk in migraineurs. Despite this obvious concern, the magnitude of unmet need in the migraine field has propelled the clinical development of CGRP antagonists despite case reports of vascular complications. We recently reported that gepants worsen the outcome after brief middle cerebral artery occlusion (MCAO) mimicking transient ischemic attack in mice (Mulder et al. Ann Neurol, 2020). Gepant arm was significantly more likely to develop infarcts compared with controls. Upon longer MCAO, infarct volumes, neurological deficits and mortality were also higher in the gepant arm. Worse cerebral blood flow (CBF) deficits during MCAO implicated impaired collateral function. These data strongly suggest that CGRP antagonists might exacerbate coincidental or superimposed ischemic events, especially in migraineurs on chronic prophylaxis. Therefore, our overarching goal is to define the cerebrovascular safety of CGRP antagonism and refine the target population to mitigate the risk. To this end, we propose to examine the risk increment with CGRP antagonism in focal cerebral ischemia in the absence (Aim 1) or presence of vascular risk factors (Aim 2), and elucidate the mechanisms (Aim 3). Aim 1 will test whether a gepant and an anti-CGRP monoclonal antibody worsen focal cerebral ischemic outcomes after various durations of MCAO in mice. We will establish the dose-response, the duration of effect, and the effect of prolonged CGRP antagonism. Aim 2 will test whether comorbid vascular risk factors (aging, diabetes, hypertension, migraine with aura) exacerbate the risk of CGRP antagonism. We will also determine blood-brain barrier penetration of the anti-CGRP monoclonal antibody. Aim 3 will test whether CGRP antagonism impairs cerebral collaterals and pial and penetrating arterial function, in vivo, using cutting-edge optical imaging tools (laser speckle flowmetry, dynamic light scattering optical coherence tomography, two-photon microscopy). All experiments will use both males and females with particular emphasis on rigor and reproducibility. Millions of migraineurs are soon going to be receiving CGRP antagonists. It is imperative to better understand the cerebrovascular risk associated with this class of drugs in an objective, bias-free manner. This is a mission unlikely to be carried out or funded by the industry and should be trusted into the hands of NIH-funded labs with no conflict of interest. Our laboratory has a long track record in both migraine and stroke. The investigative team includes experts in MRI, optical imaging and migraine pathophysiology and therapies. All proposed methods are in daily use. Therefore, we believe we are uniquely positioned to address this urgent unmet need.