Using CGRP Antagonists for the Treatment of Migraine


Experts in headache medicine discuss the role of CGRP-based therapy for migraine prevention.

Jessica Ailani, MD: We're talking a lot about new treatment options. We haven't delved into the evidence. Why don't you talk to us about the mechanism of action of our CGRP [calcitonin gene-related peptideantagonist], the gepants looking really focusing on the acute treatment, the ubrogepant, and rimegepant, and how is the mechanism of action of these gepants different from other acute treatment options for me. As has been mentioned migraine-specific therapies. Their small molecule antagonists of the CGRP receptor. They're basically working to block the effects of CGRP. And that's something that has now clearly been shown based on a wide variety of basic and clinical evidence to be a critically important mechanism of migraine. The other acute migraine therapies may also influence CGRP signaling, particularly the triptans. And one of the mechanisms of actions of the triptans is believed to be to block the release of CGRP. In that sense, triptans may be working slightly upstream from the CGRP receptor agonists in terms of their acute effects. And then the other sorts of benefits for example, of the anti-inflammatories or the analgesics, the actual specific mechanisms of action of those are still not clearly understood. But it's been clear based on the response of our patients that these new CGRP-targeted therapies for a subset of people represent a really novel approach, given the different responses that they've had to these compared with anything else they've tried before.

Jessica Ailani, MD: Sait, maybe you can talk to us about CGRP-based therapy focused on the gepants for migraine prevention.

Sait Ashina, MD: Yeah. You’re talking about the small molecule CGRP antagonist?

Jessica Ailani, MD: Yes.

Sait Ashina, MD: There is an idea that they block the CGRP receptor, just like Andy mentioned that they are this way stop patients from developing the migraines because we know that CGRP is one of the key molecules in the development of the migraine involved in the pathological levels. Both at the central level, but also at the peripheral level. We know that CGRP is one of the main neurotransmitters and can be released from first auto neuron and the second auto neuron. But it also is involved in - there is a period release in periphery, which induces the inflammatory reactions. There is a recent study from our group showing that atogepant was working on both A-delta receptors and C receptors. And we know for instance that fremanezumab in the previous studies was only working on A delta receptors. A was working on C receptors. Atogepant in the preclinical models, I would say, offers us unique option of targeting both receptors, which is interesting. In the future, we would need to look to see what are the clinical differences are between the small molecule CGRP antagonists and CGRP monoclonal antibodies.

Jessica Ailani, MD: Clinically, I do believe we're already seeing a difference between patients who perhaps did not respond to a CGRP monoclonal antibody as a preventive and are responding to gepants as preventive. It is nice that we do have some animal model studies or animal mono model studies, but there are others that are somewhat different that are showing there is some difference between these molecules and what those differences might suggest when it comes to migraine pathophysiology, but also, the gepants and the monoclonal should not be considered really the same drug or the same substance.

Transcript Edited for Clarity

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