A discussion on emerging CGRP monoclonal antibodies for the prevention of migraine onset.
Neil Minkoff, MD: We have this emerging class of mostly injectable agents for migraine prevention. There’s a target in the CGRP [calcitonin gene-related peptide] receptor. Dr Dodick, talk about the mechanism of action and how these are different for episodic versus chronic migraine.
David W. Dodick, MD: Yes. There are 4 of these new CGRP monoclonal antibodies. Three of them target the CGRP peptide itself. One of them, erenumab, targets the receptor. Three of them are injected subcutaneously each month, although one of them, fremanezumab, can be injected quarterly. Eptinezumab, which is the most recently approved monoclonal antibody to target the protein, is given intravenously every 3 months.
How do they work? They target CGRP or its receptor, but how does that work? We know that in the trigeminal nerve, which I talked about before, there are 2 different types of pain fibers. There are C fibers and A∂ fibers. Inside of the C fibers, within the trigeminal nerve, is CGRP. When that nerve is activated, it releases CGRP. On the A∂ fiber, which is the other nerve fiber in the trigeminal nerve, sits the CGRP receptor. When CGRP is released from one nerve fiber and binds to the receptor on the other nerve fiber, all within the trigeminal nerve, a pain signal is propagated and sent into the brain. If you were to bind the protein CGRP once it’s released, or block it’s receptor, then you would block the propagation of that pain signal.
I tell patients it’s like a lock and a key. I can either take away your lock and you can’t get in the house, or I can gum up the key and you can’t get the key in the lock, right? That’s one way to think about it, and that’s how these drugs work. Either way, I’m trying to block you from getting into my house. The biological correlate there is propagating a pain signal. That’s the mechanism of action. At least, that’s how we think it works at this point.
Recently, a study was done. A very sophisticated study was done using functional imaging of the living brain. It measured how people responded to erenumab in this case, but I’m sure it’s similar for the other antibodies, as well. When they respond, there is less activation of the area in the brain where we think attacks are generated, called the hypothalamus. When people respond, there is deactivation, or the fire is put out in the hypothalamus. In those who don’t respond, there’s still a fire lit in the hypothalamus. Clearly, these antibodies, which are not thought to cross the blood-brain barrier to any appreciable extent, are having a central effect as well as a peripheral impact on the trigeminal nerve. Whether that’s a direct central effect on the brain, or whether it’s an indirect effect by blocking traffic, it isn’t quite clear at this time.
Neil Minkoff, MD: Could you touch on the difference between the ligand versus the receptor, and what that might mean to the patient?
David W. Dodick, MD: Broadly speaking, whether you target the receptor or whether you target the peptide, the efficacy appears to be similar. Having said that, there are patients who may not respond to an antibody that targets the receptor and may respond to one that targets the peptide, and vice versa. Even though that’s not been shown in clinical trials, our clinical experience is emerging after 2 years to indicate that we might be able to effectively and successfully switch a patient from a receptor- to a peptide-targeted antibody, or vice versa. That’s great news. From an [adverse] effect standpoint, the jury’s still out. The FDA has updated the label of erenumab because it’s been out longer.
Neil Minkoff, MD: Right.
David W. Dodick, MD: But there have been some label updates where hypertension can happen in patients who never had a history of hypertension. In people who have a history of hypertension, it may get worse. That’s generally after the first injection and within the first week. Constipation is an [adverse] effect that can occur. That constipation, not often, but rarely, can be serious and lead to hospitalization. The FDA has updated the label for erenumab.
There may be a difference in the [adverse] effect profile of these antibodies. But it’s going to take a lot more real-world evidence and a lot more time to refine the efficacy and the [adverse] effect spectrum of these antibodies. Unfortunately, to date, if you came into my office today and I was going to start you on one of these antibodies, I can’t tell whether you’re going to respond to a protein-targeted or a receptor-targeted antibody. I can’t tell whether you’re going to respond at all. I can’t tell whether you’re going to respond best to a receptor- or to a peptide-targeted antibody. Unfortunately, there are no biomarkers or clinical features that allow me to predict whether or not you’re going to be a responder, and to which one.