Current Series: Chronic Migraine: New Paradigms in Management

Stephen Silberstein, MD:To reiterate what we’ve been talking about, there are now 4 monoclonal antibodies that have been approved or will be approved for the treatment of all migraines in adults. We have galcanezumab and erenumab, which we talked about. Galcanezumab is an antibody against CGRP [calcitonin gene-related peptide], where erenumab is, again, CGRP itself. I’m sorry, the CGRP receptor. Fremanezumab and eptinezumab are both antibodies against CGRP itself. So we have 3 antibodies for CGRP, and one antibody, to what Peter talked about earlier, is the canonical CGRP receptor.

Now let’s talk a little bit about the differences in how they’re given. So fremanezumab can be given monthly or in a triple dose quarterly as a patient option. Erenumab is available as a monthly dosage formulation. Galcanezumab is available monthly. And last but not least, when eptinezumab comes in the market, it’s going to be available as an intravenous formulation, which should be given every 3 months.

We don’t know yet in practice, and correct me if I’m wrong, which is the best approach, and it may be individualized. There are some patients, for example, who do not want to give themselves injections, and if you’re seeing them quarterly, that might be better. Those are patients who don’t want to see us that often and would prefer to do it at home. So I think we have options of drugs with different mechanisms of action, with different groups of administration and with different frequency of administration.

David Dodick, MD: I think your patients would love to see you every quarter, Steve.

Stephen Silberstein, MD: Unfortunately, you’re correct.

Stewart Tepper, MD: And I’ll just mention on dosing in the order in which they were released. So erenumab, the monoclonal antibody against the canonical CGRP receptor, as Steve said, is a subcutaneous, once-a-month injection with an autoinjector, and the dosage can be either 70 or 140 mg monthly. The second released was fremanezumab, and that is a subcutaneous injection in a prefilled syringe, monthly, at 225 mg monthly or 675 mg quarterly, and patients can self-inject that or come in for that injection. And galcanezumab, the third that was released, is available both as a prefilled syringe or as an autoinjector with a 240-mg loading dose and 120 mg monthly thereafter, subcutaneous, and the patient injects that at home. For eptinezumab, we don’t know the dose yet, it’s not FDA approved, but it will be a quarterly infusion. And as Steve mentioned, the latter 3 are against the CGRP peptide or ligand.

Stephen Silberstein, MD: I’d like to mention something that we haven’t thought about in the headache space. When you’re giving an antibody, it lasts for a long time. It has a half-life of about a month. When the patient is getting their second injection, there’s still a significant amount of the previous antibody present. And what’s very interesting to me is the fact that, unlike small molecules, you don’t have to slowly increase the dose. And as long as you’re not taking 100-fold excess of the antibody, you don’t have the same risk of titrating and toxicity.

I think we need to think about one other thing. Peter demonstrated that CGRP is important in migraine. And the first generation of drugs were the small molecule gepants that actually targeted the CGRP receptor. That was the proof of concept to develop monoclonal antibodies. The original gepants were discontinued because of liver function problems. The monoclonal antibodies have clearly shown it’s not related to blocking CGRP, but it was a background in the structure of the molecule. Now we have new drugs in that class. There are 4 gepants being developed by 2 other companies that have clearly shown to be safe and effective for the acute and preventive treatment of migraine. So it’s not a small molecule versus a big molecule, but it’s actually a confluence of ideas of small and big molecules that have led to the revolution in migraine treatment.