Current Series: Chronic Migraine: Current Treatment Options and Recent Advances

Richard B. Lipton, MD: There are currently 4 monoclonal antibodies that target the CGRP system. Three of them are already available and have been approved by the FDA. One of them is in late-stage development—that one is eptinezumab.

Three of the drugs target the CGRP ligand. One of them, erenumab [Aimovig], targets the CGRP receptor. Three of the drugs are given subcutaneously. One of them is given intravenously. I think it’s fair to say when we look at the class of drugs, that they have some important benefits in common. So, they are all very rapidly acting in comparison to conventional oral therapy. They all have very favorable tolerability profiles, in comparison to conventional oral therapy. They’re all relatively easy to use because there’s no need for gradual dose escalation to manage adverse events. So, as a class these 4 agents have much in common. Erenumab is unique in that it is the only drug that binds to the receptor, so there’s a hope that there will be people who respond to receptor targeted therapies who may not respond to ligand-targeted therapies, and vice versa.

An important point of contrast is, do they target the receptor, or do they target the CGRP ligand?

The other important differentiation is, do we give them subcutaneously or intravenously? And eptinezumab is the only drug that’s given intravenously. There is a suggestion and a hope that intravenous administration leads to a more rapid onset of action, although all the drugs work very quickly as preventives in comparison to oral therapies. So, another bright line to draw, in terms of choosing among therapies is whether rapid onset of effect is desirable. And in that context eptinezumab has an advantage.

Peter Goadsby, MBBS: Fremanezumab [Ajovy] is a CGRP peptide monoclonal antibody. It’s been studied in episodic and chronic migraine, and it’s effective in both. It was studied in 2 dosings. One is a subcutaneous monthly dose, and a second [is] a quarterly—you might say, triple dosing every quarter. It’s effective, it’s well-tolerated, and there are no significant adverse events. It’s with regulators at the moment, as I understand, and we should be hearing in the not-too-distant future.

Ubrogepant is a small molecule CGRP receptor antagonist that had a phase II dose ranging study, and it’s had 2 phase III studies called ACHIEVE I and ACHIEVE II, that are both positive across the doses. It’s effective at the 2-hour pain-free mark and effective against most bothersome symptoms. This is where patients pick out nausea, photophobia, or phonophobia, and have to hit that at 2 hours as well. And they’re submitted as a coprimary by the FDA for licensing. So those coprimaries were positive in both of their phase III studies, which were in excess of 500 patients per group, clearly effective and well-tolerated. Really, no particular [adverse] effects of concern and certainly nothing is emerging in terms of abnormal blood tests for liver enzymes in particular.

Richard B. Lipton, MD: We know that galcanezumab [Emgality] has in its label, “improvement in functional status,” using a measure called the Migraine-Specific Quality of Life. As far as I know, fremanezumab doesn’t have quality of life plans and labeling. They use several instruments. They use the Migraine-Specific Quality of Life Questionnaire. And that shows that fremanezumab improves health-related quality of life. They also use the measure called the WPAI [Work Productivity and Activity Impairment], which measures workplace productivity, and using that measure they demonstrated that fremanezumab not only improves quality of life but reduces lost productive time and increases productive time, presumably by decreasing headache frequency. And, of course, it’s important to think about [how we treat for migraine]. It’s not just targeting the disease but targeting the person in all their daily activities and function at work, [which] is very important because migraine is a major cause of workplace disability. So, preventing migraine attacks has as one of its major benefits reducing lost productive time and increasing workplace productivity.

Across the development of CGRP-targeted monoclonal antibodies, sponsors did studies that enrolled patients with episodic migraine and chronic migraine. Episodic migraine, of course, is defined by less than 15 headache days a month, and chronic migraine is defined as 15 or more headache days a month, at least 8 of which shows some link to migraine.

So, for all of the agents across all of the studies, the agents are effective in episodic migraine and they’re effective in chronic migraine as well. The studies did permit people who had tried and failed other preventives. Some of the studies allowed people who are currently taking prior preventives to enroll. And in those ways, the patients are similar to the patients that are seen in clinical practice.
Now one point of departure is that patients who have tried and failed multiple medications, [and] the patient who has suffered for years, who has been treated in subspecialty care for years, might have failed 5 or 10 prior preventives—those patients were ineligible for the study. And, of course, that’s a common design decision that sponsors make running trials, because there’s a fear that if they enroll patients who are refractory to absolutely everything, the patient may be refractory to the study drug as well.

Now as it happens in clinical practice with erenumab, I’m now giving those patients erenumab and seeing results that are gratifyingly positive. So that departure, that disparity between who gets in the trial and who’s in my practice, does not seem to render the trial results inapplicable to the patients I’m treating in practice. And the very refractory patients I’m treating are often, although certainly not inevitably, responding.

Peter Goadsby, MB BS: The studies with galcanezumab, a CGRP monoclonal antibody to the ligand, in an episodic cluster headache—we’ve just seen at the American Headache Society the study was positive. So there’s a clear possibility to use CGRP targeting episodic cluster headache. Interestingly enough, the chronic cluster headache with galcanezumab, and the chronic cluster headache study with fremanezumab seem to have failed. So that’s a differentiation we’re going to have to understand. The upside would be that if one could develop the small molecule receptor antagonists perhaps in an appropriate way for acute treatment. The monoclonal seems to have a short-term preventive effect in episodic cluster headaches. So there does seem to be some headway that we’ll be able to make in cluster headache, episodic cluster headache, with this CGRP mechanism.