David W. Dodick, MD: In terms of recent advances when it comes to acute medications for migraine, there are basically 2 classes that have recently become available, FDA approved, and commercially available for prescription. The first class is comprised of the so-called gepants. They're called gepants because the suffix in the name ends in gepant—ubrogepant and rimegepant. The other class is called the ditan class, and it's called that because the suffix in the name is a ditan—lasmiditan. I guess we should call them gepants and ditans because that's the way they are pronounced when you spell the name, when you say the word. Anyway, ditans and gepants.
There are 2 approved gepants—rimegepant and ubrogepant—and 1 approved ditan—lasmiditan. The gepants are antagonists to CGRP [calcitonin gene-related peptide], so they are CGRP receptor antagonists.
CGRP is a molecule that, since the 1980s, we knew was involved in the pathophysiology or pathogenesis of migraine. It plays an important role. It's a signaling neuropeptide, so it seems to propagate pain signals along sensory nerves, particularly the trigeminal nerve, which is responsible for migraine. It seemed clear that if you could block that protein, either bind it up so that it doesn't get to its receptor or lock it from attaching to its receptor, you could inhibit the propagation of pain signals. That's what these gepants do. They bind to the receptor for CGRP on trigeminal nerves and block its ability to signal along that pain nerve.
These 2 gepants were shown to be effective and well-tolerated during their pivotal trials. There were 2 pivotal trials for ubrogepant, and same for rimegepant. Both were shown to be effective, with pain freedom rates around 20%—19% to 21%, but suffice it to say that around 20% of patients achieved freedom from pain at 2 hours.
They were also effective in relieving patients' most bothersome symptom. We talked earlier about the fact that migraine is not just head pain. There are a variety of other symptoms that come with migraine. And so, patients were able to select the symptom. They may have 10 symptoms, but 1 may be most bothersome to them. Maybe it's nausea. Maybe it's sensitivity to light, what have you. And so, in these trials, it was assessed the extent to which they relieved both the pain as well as the most bothersome symptom.
Both of those gepants showed statistical superiority over placebo in the extent to which they both rendered the patient free from pain in 2 hours as well as free from the most bothersome symptom.
There were a variety of other secondary end points that these 2 drugs also achieved, or were separated from placebo. We've talked a bit about the difference between pain-free and headache relief. From a headache relief standpoint, 58% to 62% of patients achieved relief from pain. In other words, they were either pain free or they still had mild pain. And so, the 2 looked very similar in terms of efficacy, and they looked fairly similar in terms of tolerability as well. There didn't appear to be any serious safety concerns with either of the medications in the clinical trials.
One of the benefits of this class of medication, beyond the triptans that have been available now for 3 decades, is that they don't constrict blood vessels. They block a protein, CGRP, that dilates blood vessels, but they don't directly constrict the blood vessel like triptans do. From that perspective, they may be used in patients for whom triptans were otherwise contraindicated. So if you had a bypass surgery, for example, for coronary artery disease, or you had hardening of your carotid artery that might have led to a stroke in the past, you couldn't take a triptan. However, you could take these medications because they don't constrict blood vessels. That's one of the major advantages of these medications.
The other major advantage of these medications is that they don't cause, or don't appear to cause medication overuse headaches. There's this phenomenon known as rebound or medication overuse headache in that the more you use an acute medicine, the more likely it is that you're going to increase the frequency. It's kind of short-term gain for long-term pain, if you will. The more you take, the more attacks you get. That's true with triptans, it's true with over-the-counter analgesics, and it's true with pretty much every acute medicine we use for migraine, except the gepants. Now there are gepants in development that, if you take them every day or every other day, actually show a reduction in the frequency. And since medication overuse headache or this rebound phenomenon appears to be mediated by CGRP, blocking CGRP could actually prevent and treat medication overuse headache.
That's one of the other differences with the gepants: There may be no limit to the use of them, other than cost and access to the number of tablets when it comes to the fear of and the propensity with which you can induce medication overuse headache. That's the other advantage, I think.
Lasmiditan is not a gepant, obviously. It's a selective 5-HT1F receptor agonist. What does that mean? Well, triptans bind to 3 different serotonin receptors. Serotonin is abbreviated by 5-HT. So, when I say 5-HT, I really mean serotonin. Triptans bind to 5-HT1B—B for blood vessel, because those receptors are on blood vessels; 5-HT1D—D for dendrite, because they're on nerves; and a couple of them find the 1F receptor, which is also on nerve endings and not on blood vessels. So ideally, if you developed a molecule like a triptan that bound to either the 1D or the 1F receptor but not to the 1B receptor, because then you wouldn't constrict blood vessels, you would only bind to receptors that are located on nerves and not on blood vessels. And so, that's what this group does. They developed a selective 5-HT1F receptor agonist. So this molecule binds to the 1F receptor on nerves, trigeminal nerves, and, again, prevents the propagation of pain signals. And so, it too, like the gepants, does not constrict blood vessels. That’s a good thing. You can use it in people who would otherwise not be able to use triptans.
The pain-free rates with lasmiditan were somewhere, depending on the dose, between 28% and 38%. So, higher than we saw with gepants. The headache relief rates were similar. About 60% or so had relief of headache. And like gepants, lasmiditan led to the complete relief of patients' most bothersome symptom. It was superior to placebo at 2 hours. So lasmiditan was approved by the FDA for the acute treatment of migraine as well.
The adverse effect profile of lasmiditan appears to be different then it is for gepants. Because it's a centrally penetrant drug—it crosses the blood-brain barrier and gets into the brain more easily—it can cause adverse events like dizziness, sedation, fatigue, or lethargy, and those sorts of things. Because of the propensity with which you could develop some sedation, it's a Schedule V substance. This means you can't operate heavy machinery or operate a motor vehicle within 8 hours of taking the drug because of the probability or propensity of it causing some sedation or a drop in reaction time and things like that.
So the adverse effect profile of lasmiditan looks different than the gepants, at least in clinical trials.