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CONy 2021 | Comparing CGRP ligand- and receptor-directed antibody treatments in migraine

Piero Barbanti, MD, PhD, IRCCS San Raffaele Pisana, Rome, Italy, compares monoclonal antibody treatments targeting the CGRP receptor and ligand in migraine. There is a lack of clear evidence on the comparative efficacy and safety of CGRP receptor and ligand-directed therapies; however, there is some evidence regarding tolerability. Around 10–15% of patients in real-life settings that receive anti-CGRP receptor antibodies such as erenumab experience constipation. This might be explained by the dose-related ability of CGRP receptor antibodies to pervade gastrointestinal tract tissue to inhibit local CGRP receptors, compared to CGRP ligand-directed antibodies, which remain in circulation. Some evidence also suggests that CGRP ligand antibodies are more likely to be effective with fewer side-effects in episodic migraine. Overall, clinical trials directly comparing CGRP receptor and ligand-directed antibodies are required, and a better understanding of the implications of blocking CGRP-mediated activation of the amylin-1 receptor is required. This interview was conducted during the virtual 2021 CONy meeting.

Transcript (edited for clarity)

Because we know, we now know that the CGRP acts on more than one receptor. CGRP interacts with its own receptor, which is called obviously CGRP receptor, but also on amylin receptor, amylin-1 receptor. So, probably CGRP is involved in migraine pathophysiology, but other members, at least amylin of the so-called calcitonin peptide family are also involved. So, by acting only on the receptor, you completely block CGRP effects on its own receptor...

Because we know, we now know that the CGRP acts on more than one receptor. CGRP interacts with its own receptor, which is called obviously CGRP receptor, but also on amylin receptor, amylin-1 receptor. So, probably CGRP is involved in migraine pathophysiology, but other members, at least amylin of the so-called calcitonin peptide family are also involved. So, by acting only on the receptor, you completely block CGRP effects on its own receptor. But amylin-1 receptor is free of working as usual. If you block the ligand, if you block CGRP, you dramatically reduce its activity on both CGRP and amylin-1 receptors.

I think that we do not have any definite information on the difference in safety, but we do have in terms of tolerability, why? Because CGRP is present in our brain, but also in the gastrointestinal tract. And we know that by blocking the receptor with, for example, we can have constipation in roughly 3-4% in randomized control trials, and 10-15% in real-life studies. And, the reason is this: usually, monoclonal antibodies targeting the ligand are confined to circulation and have a negligible effect on amylin-1 receptors, which are located in the area postrema. And these receptors mediate nausea and mediate also reduce peristalsis in the gastrointestinal tract. Conversely, if we block the receptor, the monoclonal antibodies blocking the receptor are dosed to reach the tissue and they block CGRP locally in the gastrointestinal tract. So, constipation may occur. And also they have a clear action on CGRP, which is somehow free of working on amylin-1 receptor, further increases the constipation and probably nausea in the area postrema.

We lack this kind of studies. And so our reasoning is hypothetical. And we should have had to head comparative studies, but we still lack. And as far as I know, they are not planned in the next future. However, some papers have been published. One in particular, looking at the likelihood of being helped or harmed using monoclonal antibodies, targeting the ligand on the receptor. And, in episodic migraine, the monoclonal antibodies who performed better in terms of likelihood of being helped or harmed is a mono antibodies targeting the ligand, not the receptor, the likelihood of being help or harm measures the probability of the patient to improve without having adverse event and without discontinuing, due to adverse events.

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Disclosures

Advisory board, speaker bureau, investigational studies: Angelini, Assosalute, Bayer, Eli-Lilly, Lundbeck, Lusofarmaco, 1MED, MSD, Noema Pharma, Novartis, Teva, Visufarma, Zambon.