Dr Andrew BlumenfeldAndrew Blumenfeld, MD
Ubrogepant, an oral small molecule CGRP receptor antagonist, was shown to result in pain freedom, freedom from the bothersome migraine-associated symptom (MBS), and pain relief for patients with migraine for whom triptans were ineffective, according to a pooled analysis of the phase III ACHIEVE I and II studies.

Presented at the 2019 American Headache Society (AHS) Annual Meeting, July 11-14, 2019, in Philadelphia, Pennsylvania, the data are part of a new drug application for ubrogepant, which was accepted for review by the FDA in March 2019. The FDA is scheduled to make a decision on the application by the end of the year.

To find out more about the gepant, its class of medications, and how it will fit into the migraine treatment landscape if it receives regulatory approval, NeurologyLive® spoke with the lead author of the data, Andrew Blumenfeld, MD, director, Headache Center of Southern California.

NeurologyLive®: Was there anything surprising or unexpected in these data?

Andrew Blumenfeld, MD: No, not really. We know that there are many patients that don’t respond to triptans. Triptans are a big improvement on what we had prior to them, but there are plenty of shortcomings. Triptans don’t get you naturally pain-free within 2 hours and then we also have to deal with all the adverse effect issues, particularly what we call the triptan effects—the flushing, chest discomfort, jaw discomfort, nausea. This has limited how patients will take medications.

Patients will delay taking a triptan because they’re worried about the adverse effects like fatigue, so it’s very beneficial to find a treatment option that’s going to work in a triptan failure that’s either due to a lack of efficacy or intolerability to one of these adverse events. It’s not surprising because with the gepants, like ubrogepant, the mechanism of action was slightly different. You know the triptans block specifically serotonin receptors 5-HT1B and 1D, whereas ubrogepant is a CGRP receptor antagonist specifically blocking a pathway and not a serotonin receptor. The serotonin receptors are on the trigeminal nerve and also on the blood vessels, and they cause vasoconstriction and they stop the nerve from secreting CGRP and other neuropeptides by inhibiting it, but the broader mechanism of action comes with more adverse effects.

If we look at the pivotal data of the ubrogepant response rates, they’re about 20%. The response rates for the triptans for about 2 hours are 33%, so we do get a higher overall response rate for the triptans, but you do pay a price for that which is all the adverse effects that come with it. The interesting thing about ubrogepant is there really aren’t any significant adverse effects—maybe a little bit of nausea in very low numbers. Overall, it’s very well tolerated. No liver toxicity issues that have come to light. It’s an excellent option if there are cardiovascular risks, and certainly, I would think about it in the future, once it's approved, for any patients with triptan adverse effects that are limiting use, and in patients who are not getting enough neural effect form their triptans.

Triptans tend to work best when you take them early in the first hour of the attack, but patients hold off because they’re worried about adverse effects. Although the pivotal data of pain-free results at 2 hours work better, you have to take into account when the patients will take it outside clinical practice. In clinical practice, I think they’ll end up taking ubrogepant much earlier than a triptan and I think we’ll see very good results when they do that. Now, most of the clinical trials are when patients were moderate to severe, so weren’t treating when they were mild. Despite that, we still see that these patients are benefiting even when they failed on a triptan, but not in a surprising way.

How can clinicians judge ubrogepant’s potential in future clinical use? 

We have to look at treatments in a slightly different way to how the FDA approves a drug. When the FDA approves a drug, they’re looking for efficacy relative to placebo. But in clinical practice what we’re looking for is effectiveness, and effectiveness means not only is the product efficacious but that it’s also well tolerated. Tolerability plays a key role in clinical practice because it doesn’t matter if a medicine is super efficacious but you can’t tolerate it—then you don’t take it, so effectiveness should really be the mark that you’re looking to measure a drug in clinical practice, efficacy is just one arm of the equation.

What’s next for ubrogepant in its clinical development? 

I anticipate that by the end of the early next year, ubrogepant will be on the market, but it will be used in patients who have tried and failed in triptans. The American Headache Society (AHS) came out with a guideline for when a new acute treatment should be considered and the guideline was after 2 triptan failures, so I anticipate the insurance companies will pick up on that and see this pattern of use evolving.

The very interesting aspects I think we’re going to see developing next year are first, that ubrogepant does not cause medication overuse headache, so more frequent dosing would not cause an adverse event. With triptans, if you take a triptan more than 9 times in a month—9 days out of a month—say you get to 10-15 days of triptan use, you run the risk of getting an overuse headache pattern secondary to the medication. That pattern is not manifesting with the gepants. The gepants tend to not appear to cause medication overuse headaches, so you could take them up to 15 days a month and there would be no adverse event coming from that.

The long-term adverse safety data with the gepants are showing that when you dose them frequently like that, it doesn’t only work as an acute treatment, but it also starts to work as a preventative treatment. So this intermittent dosing may in the future become a new method of treating migraine because up until now we’ve had these very distinct classes of treatment, acute treatment like a triptan, and preventive treatment like Topamax. But imagine now in the future, instead of having that breakdown, we’d have ubrogepant used up to 15 days, and it will start to act like a preventive. The other patient, the one with frequent headaches, you would be able to get away with just one treatment option. If that comes to bear, that’s going to be very interesting as a new method to approaching migraine. Many patients don’t like to take a medication every day, so if they could just dose when it's bad that could be very positive for them.

Is there anything else you feel is important for clinicians to know?

There’s another key concept in terms of creating a cultural shift and that concept is the one of migraine freedom. So up until now patients, providers, and insurance companies had been very satisfied with reducing headache by 50%. Fifty percent improvement is acceptable as an outcome, but if you were a patient why would you really want to settle for a 50% improvement as an outcome? Most patients would want to be 100%, and certainly so if you look at conditions like epilepsy, where if you only had gotten 50% of the seizures to go away, that’s not a very good job. You’d try to achieve a seizure-free state. The same type of practice needs to be developed for migraine, where you layer different treatments to go on top of this migraine-free state.

This is not a concept that’s readily accepted at this moment. The feeling at the moment is that this is an impossible level to achieve. But the point is, unless you have an aspirational goal of getting to that level, you’ll never achieve it. In some patients, you will and some you won’t, but we need to have an aspirational goal of layering patients on top of each other, building up from a foundation, making sure there are no adverse effects and get the headaches completely under control. This requires this type of layering both for the acute treatment options and the preventative treatment options.

I could see in the future combining ubrogepant with a non-steroidal inflammatory to make it work quicker. I could even see it working with a triptan in some situations to layer on to optimize its effect. We see this on the preventive side where we could be combining Botox and a monoclonal antibody to totally wipe out the headaches and prevent them as much as possible. All of these logistic cocktails need to be developed and practiced, but we need insurance companies to accept that this is a reasonable approach. Insurance companies are very happy with a mono-therapeutic approach with their coverage. They’re OK with saying that 50% is good enough. Patients need to rise up and say we need to be 100% better.

Transcript edited for clarity. For more coverage of AHS 2019, click here.
REFERENCE
Blumenfeld AM, Goadsby PJ, Dodick DW, et al. Ubrogepant is effective for the acute treatment of migraine in patients for whom triptans are ineffective. Presented at: American Headache Society 2019, Philadelphia, PA, July 11-14, 2019.