Preventative Migraine Treatment: Injectable CGRP Antagonists


David Kudrow, MD, reviews the available FDA-approved injectable CGRP antagonists for preventive migraine treatment.

David Kudrow, MD: Let’s talk about the injectable CGRP antagonists for migraine prevention. We’ll touch a little on their efficacy, safety, and dosing. The idea is that all of these injectable CGRP antagonist medications are monoclonal antibodies. The safety and efficacy have all been established with these medications in phase 2 and phase 3 clinical trials. The clinical trials were designed pretty much the same. The inclusion and exclusion criteria were pretty much the same. In the end, efficacy, as defined by reduction in mean monthly migraine days, a 50% responder rate, and quality-of-life improvement in both episodic and chronic migraine were pretty similar across the board. The adverse effect profiles differed a little. The pharmacology differs a little from one monoclonal antibody to the next.

With that respect, I’ll say a little about each of them. First, eptinezumab is a monoclonal antibody and the only one administered by intravenous infusion of the 4 in the class. It’s dosed at 100 or 300 mg infused over 30 minutes quarterly, so once every 3 months. Patients get 4 doses per year. The most common adverse events reported with eptinezumab seem to be hypersensitivity reactions.

Erenumab is another medication. This was the first drug approved in the class in May of 2018. It’s a subcutaneous injection that is done monthly by the patient. It’s an autoinjector of either 70 or 140 mg per month. The most common adverse events in clinical trials included injection site reactions, which typically means pain, redness, or swelling. There could be a localized hypersensitivity reaction. In clinical trials, about 3% of patients on the 140-mg dose experienced constipation. Two percent of patients had muscle spasm.

In post-marketing surveillance, there have been reports of more severe cases of constipation, in some cases requiring hospitalization, and even a handful of cases requiring surgical intervention. That’s pretty rare. Also in post-marketing surveillance, there have been some reports of hypertension that we didn’t see in any of the clinical trials. All of the phase 2 and phase 3 studies were looked at for cardiovascular safety, and hypertension didn’t come up as an event occurring more often than with the placebo in any of the trials or with any of the doses. It’s unclear how or why some of these cases are popping up, and it’s actively being looked at. In some cases, patients have a history of hypertension. Otherwise, it’s unknown who might be at risk. In any case, it’s recommended that patients be followed. Blood pressure should be followed after they’re started on medication, at least initially.

Fremanezumab, another of the monoclonal antibodies, is also a monthly subcutaneous injection that’s available by autoinjector. The dose can be either 225 mg per month or 675 mg every 3 months, or quarterly. The most common adverse events occurring in clinical trials with fremanezumab are injection site reactions. Galcanezumab, another monoclonal antibody directed against CGRP, is another monthly subcutaneous injection with initially a loading dose of 240 mg, which is 2 injections of 120 mg, followed by monthly injections of 120 mg. That’s the only one of the medications that has a loading dose.

I should go back and add that the mechanistic difference between these medications is that erenumab is the only one of the monoclonal antibodies that is directed against the CGRP receptor, while eptinezumab, fremanezumab, and galcanezumab are monoclonal antibodies directed against the CGRP ligand. That may be important to remember while considering mechanistic differences between these medications. Why might that be important? CGRP is a ubiquitous potent vasodilator that exists in the central nervous system, the peripheral nervous system, and the enteric nervous system. It obviously binds to its own CGRP receptor, but it also binds to 2 other receptors: the amylin and adrenomedullin receptors. From a mechanistic standpoint, erenumab, which is a receptor blocker, will only block CGRP at the CGRP receptor and not at the other 2 receptors, while the ligand-directed monoclonal antibodies will prevent CGRP from binding to any of the receptors, including the CGRP receptor, amylin receptor, and adrenomedullin receptor.

Transcript edited for clarity.

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