In a NeurologyLive® Peer Exchange, a panel of migraine specialists discussed the novel therapies in development and those entering the market for the treatment of acute migraine.
Expectations for acute migraine treatment are increasing due to the recent uptick in both approved and investigational therapies. With more confidence in the ability to effectively treat acute migraine has come an opportunity to reevaluate how success is measured, with more focus on patient-centered outcomes.
Although conversations in this space have been dominated by the progress and success of the calcitonin gene-related peptide (CGRP)–targeted monoclonal antibodies and the small-molecule gepants, more novel therapies are making their way toward regulatory evaluation. As such, headache and migraine specialists are proceeding with enthusiasm, with the hope of maintaining a reflective approach to gain insights into the possibilities of these new therapies.
In a recent NeurologyLive® Peer Exchange, “Advances in the Management of Acute Treatment of Migraine,” a panel of experts led by Peter J. Goadsby, MD, PhD, DSc, professor of neurology at the University of California, Los Angeles, Goldberg Migraine Program, discussed the mechanisms of action, efficacy, and safety of therapies in the acute migraine treatment armamentarium.
In October 2019, the United States Food and Drug Administration (FDA) approved the first member of the ditan class, lasmiditan (Reyvow; Eli Lilly), an oral, central nervous system (CNS)–penetrating agent that selectively targets the 5-HT1F receptor. This is in contrast with the triptan class, which targets the serotonin 5-HT1B/1D receptors, though Goadsby noted that some agents, such as naratriptan and sumatriptan, act on the 5-HT1F receptor.
Triptans, which have been available since the early 1990s, can be challenging to use, as they bind to 5-HT1B and blood vessels, causing vasoconstriction. Jelena Pavlovic, MD, PhD, associate professor of neurology at the Albert Einstein College of Medicine and faculty at Montefiore Headache Center, noted that the high selectivity of lasmiditan offers a unique mechanism of action. “It’s the antagonist of 5-HT1F, and it has much higher selectivity for that receptor than the triptans have for the 5-HT1B/1D. Therefore, it has no vasoconstriction properties, which have been the primary challenge with triptans,” she explained.
Pavlovic added that 5-HT1 receptors are found at a number of locations in the trigeminovascular system but do not exist on the blood vessels. The current understanding is that they operate on the level of the trigeminal ganglion, trigeminal nucleus caudalis, cerebral vessels, neocortex, and hippocampus—putting forth multiple pathways in the activation of migraine pain.
Although study results showed success with lasmiditan in providing freedom from pain within 2 hours (across 2 clinical trials with the 3 doses of 50 mg, 100 mg, and 200 mg, 28% to 39% of patients achieved complete resolution of migraine pain at 2 hours), the agent’s CNS penetration occasionally leads to adverse effects.1
“The FDA required additional studies for lasmiditan for this reason, including a study showing potential for addiction,” Pavlovic said. “They finally awarded a controlled substance Schedule V rating to lasmiditan, so it is a controlled substance at this point. There is an 8-hour driving restriction, given the cognitive impairment seen after dosing. The recommendation is not to drive for 8 hours or operate heavy machinery.”
Goadsby added that having this selectivity over the 5-HT1B/1D receptors has been an extraordinary development in the treatment of migraine. It may not be perfect, he noted, but it certainly offers clinicians an option to avoid the 5-HT1B effects.
“Let me just add that one of the reasons I like lasmiditan in my practice is that it does have some ability to lower CGRP concentration in the periphery,” Wade M. Cooper, DO, associate professor of neurology at Michigan Medicine Headache & Neuropathic Pain Clinic, said. “There is a peripheral anti-CGRP effect. The effect is not strong, but it’s one of the few FDA-approved medicines for migraine that goes centrally. That’s what defines it and separates it from some of the other agents out there.”
Cooper and Goadsby then turned to the small-molecule CGRP receptor antagonists, focusing on the 2 approved agents, rimegepant (Nurtec ODT; Biohaven) and ubrogepant (Ubrelvy; AbbVie). Cooper described the mechanistic qualities of these therapies, which work mostly in the periphery, blocking the inflammatory signal coming from the pain-sensitive nerves. Both drugs also suppress inflammation of the meninges.
Additionally, these therapies focus on receptors missed by triptans, in similar fashion to the ditans, making them promising treatments for those who cannot be prescribed triptans or do not derive benefit, which Paul G. Mathew, MD, assistant professor of neurology at Brigham and Women’s Hospital and Harvard Medical School, noted earlier in the discussion.
“What’s also cool about these is that they tend to work relatively quickly,” Cooper said. “Most remarkable from my perspective is their almost complete lack of adverse effects. When you compare the gepants class medicines with the triptan adverse effects, it’s quite phenomenal. Nausea seems to be a reported adverse effect in the clinical trials. I’ve had 1 or 2 people with some pretty severe nausea from it, but as a whole, it’s really well tolerated.”
"These are complex [processes] with many neurotransmitters involved, and when someone knows a bit of what is going on, they’re going to be more comfortable [with their treatment]."— DAWN C. BUSE, PHD
As for dosing, rimegepant has a set dose of 75 mg while ubrogepant is available in a small range of doses. Pavlovic noted that rimegepant, which comes as an orally disintegrating tablet, provides an appealing ease of administration. Due to the tolerability of these therapies, Cooper noted that he begins dosing at the upper end of the dose range, aiming for the highest efficacy. In comparison, as Pavlovic noted, lasmiditan dosing often requires a “go low, start slow” approach.
“I start at 50 mg in patients who feel relief and may have a lower adverse-effect profile. If they can’t achieve pain freedom completely, then because there is an additive effect to a higher dose, I will increase the dose at that point,” she explained.
Mathew concurred, noting that if a patient easily tolerates 50-mg lasmiditan, he’ll suggest they take a double dose before prescribing 100 mg. “I will do the same thing with ubrogepant, with the instructions that if they tolerate the 50 mg just fine and find it partially effective, try taking 2 of them, then let my office know, and I’ll call in a refill for the 100 mg of that medication as well,” he said.
In addition to the ditans and gepants, there has recently been an attempt to reformulate dihydroergotamine (DHE), a therapy that has been in use since the 1940s. It exists in a number of available formulations, including intravenous, intramuscular, subcutaneous, and inhaled. Mathew noted that DHE causes significant nausea, so it often has to be codosed with an antiemetic, giving it a bit of a “bad name.”
“The 2 newer forms of DHE are both intranasal,” he explained. “One of them is a proprietary pump, which squirts the DHE into a particular part of the nose where it’s able to get absorbed much more consistently. It’s still in liquid formulation. The other is a small vial; you squeeze it, and a powder form of DHE is injected into the nose.”
Mathew noted that these delivery systems are encouraging, in part because of their ability to reach plasma levels lower than the inject-able formulations, which helps to avoid some of the associated adverse effects while maintaining a consistent dose.
“Nerve blocks are something you can consider in the office, urgent care, or emergency department,” Mathew said. “But if either of these formulations gets approved, there may potentially be a DHE protocol in which you give the patient a prescription and they can take 1 of these 2 intranasal formulations for a few days. That’s going to be potentially useful for when someone has status migrainosus [and] nothing else is working.”
Dawn C. Buse, PhD, clinical professor of neurology at Albert Einstein College of Medicine, inquired about the potential of DHE as a therapy for women of child-bearing age, and if extra education and caution is required in that population.
“Regarding pregnancy, the advice I give many of my patients is that—this is just my view—getting pregnant can take weeks, months, or even years,” Mathew said. “To discontinue someone’s medications because they’re trying to get pregnant can really limit their ability to get pregnant and can lead to a lot of migraines and unnecessary suffering. My advice to these patients is, the minute you become pregnant, call your doctor. We’ll rapidly wean you off everything.”
Buse noted that in the CaMEO study, investigators found that 10% of women with chronic migraine chose not to have children or delayed having children because of concerns associated with their migraine care—either that they would pass on their disease, that they would have to stop their medications, or that their migraine would get worse.
“Anything we can do to treat them as well as possible, keep them comfortable, and allow them to make those lifestyle choices— including reproductive choices, which are core to being human— is important,” she explained. “We also need to think about how, as women age out of childbearing age and get older, their risk for cardiac events might increase again. We may need to think about a woman who’s maybe been on a triptan for decades, since she was a teen or a young adult. It may be time to reconsider her options as she ages into the postmenopausal age bracket.”
Pavlovic noted that, similar to triptans, registries accounting for the use of the new medications during pregnancy are needed to help build our understanding. “We know that women will inadvertently use them in early pregnancy before awareness that they are pregnant. These medications will be used, and having registries that are active and already started will be very helpful,” she said.
Goadsby then probed the group about their views of the adverse-effect profiles of these agents, as well as compared with those for older medications. Mathew noted that if the patient is taking a CGRP monoclonal antibody, he may be swayed toward prescribing a ditan over a gepant due to its different mechanism of action.
“It’s certainly mechanistically attractive to think that if you have a CGRP blockade, the ditan will come along and block other things that are prejunctionally and presynaptically released,” Goadsby said. “Glutamate is the obvious thing, and perhaps it blocks other peptides. The multi- mechanistic side is useful. Colleagues are also finding that there’s room still to push on the CGRP mechanism, even in people taking monoclonal antibodies. We have a lot of things to learn practically.”
Mathew noted that he offers this simplified description of that process to his patients: The antibody is lowering the overall level of CGRP, so if they happen to experience a migraine, they will have an episodic burst of CGRP, which the gepant can then suppress. He suggested that giving the patient a better understanding of these processes can also improve adherence to treatment, with which Buse agreed.
“These are complex [processes] with many neurotransmitters involved, and when someone knows a bit of what is going on, they’re going to be more comfortable,” Buse said. “They’re going to tolerate any adverse effects that might arise early a bit better, and they’re going to tend to be more adherent. They’re also going to have more comfort with their provider when they’re told in advance what to expect.”
To watch the entire series, click here.