Dr Richard B LiptonRichard B. Lipton, MD
For years, no therapeutic area had been as ripe for new drug development as headache. Now, with a host of highly effective preventive therapies on the market, including anti–calcitonin gene-related peptide (CGRP) agents, clinicians are turning their attention to acute treatments, where cracks in the foundations of go-to OTC analgesics and triptans are hard to ignore. In an interview with NeurologyLive™, Richard B. Lipton, MD, the Edwin S. Lowe Professor and vice chair of neurology, a professor of epidemiology and population health, and a professor of psychiatry and behavioral sciences at the Albert Einstein College of Medicine, and director of the Montefiore Headache Center, both in Bronx, New York, detailed the most urgent needs in migraine treatment and provided perspective on what will likely be another practice-changing period for the headache specialty.

Q:What makes headache and migraine in particular targets for safer, more effective therapies when several good treatment options are already available?

According to the Global Burden of Disease studies, migraine is the second-most-disabling disorder in the world, as measured by disability-adjusted life-years. The reason migraine plays such a prominent role in disability is because, first of all, it’s so common: Forty million Americans have migraine, and more than 1 billion people worldwide have migraine. Migraine produces so much disability because it’s a condition of long duration that affects people during their peak productive years. Migraine most often begins in adolescence or early adult life and may persist for many years. It produces a lot of interference with education and the workplace in the form of both absenteeism—missing work—and presenteeism—being at work while ill but unable to function with full effectiveness. In addition, migraine has an enormous burden on families because, again, it’s a disorder that’s very common in early and middle adult life.

There’s no question that since the early 1990s, we’ve made tremendous progress in migraine treatments, and there’s no question that triptans have been a major boon to people with migraine, but the triptans have limitations that we’ve become increasingly aware of the longer we’ve used them.

Although triptans have made a tremendous difference in migraine therapy, they certainly have limitations. One is that they produce a set of adverse effects that are called triptan sensations, which include flushing, sweating, and occasionally chest pressure. For some people, those adverse effects are difficult to tolerate and in turn limit use. A second limitation of triptans and, for that matter, all migraine therapies is that they don’t work for everyone. With so many millions of people with migraine, we believe there’s some diversity in terms of migraine mechanisms. The triptan mechanism works for a lot of people with migraine but not everyone. The final and perhaps most notable limitation of triptans is that they are vasoconstrictive agents, and [because] of that, the FDA label for triptans prohibits use in people who have had heart attacks, stroke, angina, claudication, ischemic colitis, and a variety of other disorders and recommends caution in people who are at high risk for those sorts of events.

Those contraindications have played out in 2 ways: In one way, people who have those triptan restrictions may well not be treated, but in addition, the real issues of cardiovascular safety have limited use among even people who might be able to safely take triptans. As a consequence, nearly 30 years into the triptan era, only something like a quarter of all migraine attacks treated with prescription drugs are treated with triptans. So triptans are underused and leave people with unmet needs for a number of reasons. Another issue with triptans is that they cause a phenomenon called rebound headache, or medication overuse headache. As triptans wear off, they may actually trigger headache, and if triptans are taken too often, that may make headaches worse. And that’s yet another important limitation for people with frequent migraine attacks. 

Ironically, I currently treat some people with disabling migraine with triptans despite concerns about cardiovascular safety, largely because I don’t have a good alternative. I think in a world where medications that don’t pose any cardiovascular risk [increasingly] become available, I think I will use triptans where they’re safe and effective. In cases where their safety is marginal or questionable, I think I’ll be more likely to use drugs that don’t constrict blood vessels, like the gepants or the ditans. 

Q: What is unique about these second-generation CGRP antagonists and ditans that might make them better suited for treatment of acute migraine? 

Over the past couple of years, there’s been an increasing emphasis on CGRP-targeted therapies, and we’ve known that CGRP plays an important role in migraine for a long time. We know that during migraine attack, CGRP is elevated in jugular blood. We know that successful treatment of migraine attacks results in reduction of CGRP levels in jugular blood. We know that CGRP, which is a peptide neural transmitter, is found in the pathways that play an important role in migraine, including the trigeminal nerve and the trigeminal nucleus caudalis. We know that if we give CGRP to people with migraine, that actually triggers a migraine attack, and we know that if we block CGRP with either monoclonal antibodies or small molecules, that relieves migraine attacks. So there’s abundant evidence that CGRP plays a crucial role in the pathophysiology of migraine. Of course, the wonderful thing about the emerging and already-arrived treatments that target CGRP is that they’re very much designer drugs for migraine; they are very much agents that were developed to target a specific neurotransmitter system or the receptors that that neurotransmitter binds to. There’s now abundant evidence that that’s a highly effective therapeutic strategy. So it’s a great example of translational research in which human science and animal science demonstrate a mechanism of disease, namely involvement of CGRP, and then new therapeutics emerge that target a relatively novel molecular mechanism. 

One of the advantages of CGRP-targeted therapies is that they are not vasoconstrictors, and similarly, ditans, which are 5HT1F [5-hydroxytryptamine receptor 1F] blockers, are also free of vasoconstrictive adverse effects. On that basis, we believe that gepants and ditans are likely to be free of the cardiovascular issues that have limited the use of triptans. 

Q: How has our clinical trial evaluation of migraine therapies evolved with these new drugs, and what do the results suggest? 

As acute treatments, the 2 gepants that are furthest along, ubrogepant and rimegepant, are being developed as oral, small molecule, CGRP receptor blockers. There is a phase 2 study and 2 large-scale phase 3 studies for ubrogepant; for rimegepant, there is a phase 2 study and 3 large-scale phase 3 studies. Both development programs have as their co-primary efficacy end points pain freedom at 2 hours and freedom from most bothersome symptom at 2 hours. Freedom from most bothersome symptom is a relatively new end point in the migraine world. In the past, because we understood that migraine was a symptom complex, the FDA wanted acute treatments for migraine to relieve pain and relieve the cardinal associated symptoms of migraine, including nausea, photophobia, and phonophobia. The challenge we faced in trials was that perhaps 60% of patients had nausea with a particular attack. Relieving nausea in people who don’t have nausea is a somewhat difficult job, and when acute treatment trials failed, they usually failed on nausea simply because nausea was the least common of the cardinal associated symptoms. So as an alternative regulatory pathway, the way most bothersome symptom works is that immediately before treatment, patients designate which symptom—nausea, photophobia, phonophobia— is most bothersome to them. Then we’re guaranteed that they have the symptom we’re trying to relieve, and we simply measure the proportion of people who are free of that patient-designated most bothersome symptom 2 hours after taking therapy. Both the ubrogepant and rimegepant trials use 2-hour pain freedom and 2-hour freedom from most bothersome symptom as their primary end points. 

AS A CONSEQUENCE [OF CONTRAINDICATIONS], NEARLY 30 YEARS INTO THE TRIPTAN ERA...TRIPTANS ARE UNDERUSED AND LEAVE PEOPLE WITH UNMENT NEEDS FOR A NUMBER OF REASONS. 
— RICHARD B. LIPTON, MD


In all the studies, highly statistically significant results were achieved. For both drugs, the level of freedom from pain at 2 hours is relatively modest, in about the 20% range. Some people have said, “If only 20% of people become pain free, is the drug worth using?” And I would point out several things. First, from the triptan trials, for the most part, the primary end point wasn’t freedom from pain at 2 hours; it was relief of pain at 2 hours. In the trials, freedom from pain means that you go from moderate or severe pain to pain that is absent. Relief means that you go from moderate or severe pain to pain that is mild or absent. When we look at pain relief rates, they are much higher [with the gepants], and when we look at relief of disability and restoration of function, that tends to travel with relief of pain and is achieved well before pain freedom is achieved. My belief is that 2-hour pain freedom is very useful as a regulatory end point, but it doesn’t fully reflect the benefits of treatment, which I think are better reflected by headache relief measures and by measures of restoration of function. 

Of course, cross-study comparisons are always hazardous, but lasmiditan actually achieved higher pain-free rates than ubrogepant or rimegepant. But one of the strengths of ubrogepant and rimegepant is that those medications are really highly tolerable. There are relatively few adverse effects, and with lasmiditan, there was some sedation [and] some dizziness observed in the trials and also an issue with driving. There was a study showing that after you take lasmiditan, ability to drive is impaired for up to 8 hours. So on the one hand, I think lasmiditan is probably a bit more effective than the gepants, but on the other hand, I also think it causes more adverse effects. When you’re looking for a drug that works through a mechanism different [from that of] triptans for those who don’t respond to triptans, when you’re looking for drugs for people who can’t tolerate triptans, or when you’re looking for a drug that doesn’t have the cardiovascular contraindications of triptans, my best guess is that we will end up using gepants before we use lasmiditan simply because of its better tolerability profile. 

That said, I think lasmiditan will be the treatment of choice particularly for people who have migraine at night that interferes with sleep. If you have a migraine and it’s bedtime and you want a little relief of headache, you won’t really mind taking a drug that might cause a little bit of sedation because you’ll sleep 8 hours and wake up in the morning and be able to drive to work. So I think lasmiditan will certainly play an important role in people for whom gepants don’t work, and I think it will play an important role for people who have migraine at night or are in a position where they can take a migraine medication and then take a nap and don’t need to drive to or stay at work. But I think for most patients, gepants will likely be used first. 

Q: Data from some of the trials of the preventive anti-CGRP therapies suggest a cumulative benefit of the drugs over time. Has there been any indication in the acute treatment trials of a similar effect? 

I think it’s important to note that in the past, we really drew a bright line between acute and preventive treatments. But the reality is that the distinction between acute and preventive treatment is being blurred. We know that CGRP-targeted therapies work acutely when they’re given in the form of gepants. We know they work very well in the form of monoclonal antibodies, and we actually also know that gepants, if given frequently enough, have a preventive effect. A third gepant that we haven’t talked about yet is atogepant. Allergan, [the manufacturer of atogepant], has a phase 2 study [whose results] show that in comparison to a placebo-treated group, atogepant is effective as a preventive treatment for migraine. And with [its agent] rimegepant in the long-term safety studies, Biohaven has shown that frequent use of rimegepant as an acute treatment actually reduces the number of monthly migraine days that treated patients experience. The fascinating thing for me is that if you take triptans too often, they may make your headaches worse, but if you take gepants quite often, they may work acutely and may deliver preventive benefits as well. How that plays out in practice I think remains to be seen, but certainly not causing medication overuse and not making headaches worse are big advantages, and potentially making headaches better with frequent use is an even bigger advantage. 

Q: Are there any dosing or administration advantages between the gepants, and has there been any indication that the therapies for acute migraine might be effective when used in conjunction with preventives? 

Ubrogepant and rimegepant were both studied as tablets, but rimegepant was also studied in an ODT [orally dissolving tablet] formulation. The ODT pivotal efficacy study was recently published in Lancet, and broadly speaking, the expectation was that the ODT formulation might work quicker because one of the ways to predict treatment response is the Tmax [time to maximum plasma concentration]. The Tmax for the ODT formulation is 30 minutes faster than the Tmax for the rimegepant tablet formulation, and overall, though there are no head-to-head data, it seems that the ODT formulation shows statistically significant differences relative to placebo at earlier points than the tablets, so the ODT formulation may be an advantage for rimegepant in terms of both convenience and rapidity of onset. 

In terms of conjunctive use, there are preliminary indications that they work. I was a coauthor on a study in which we evaluated patients who took rimegepant on top of a couple of different monoclonal antibodies, and we found that they consistently delivered pain relief on top of the monoclonal antibody. That’s interesting because some people predicted it wouldn’t work, essentially saying, “Well, if you block CGRP and then you get a migraine, something else must be going on. Therefore, incremental CGRP blockade shouldn’t deliver incremental benefit.” But the anecdotal experience that we have thus far suggests that gepants will work on top of monoclonal antibodies, and based on open-label treatment trials, they seem to really work quite well. In a way, that’s not surprising because what it suggests is that the antibodies don’t produce complete 100% blockade of CGRP, and so maybe in the setting of partial blockade, it could be that gepants will work even better because there’s less CGRP around to mop up. 

Q: Do you foresee any particular barriers that would prevent you from prescribing gepants as first-line treatment versus trying out treatment with a triptan or other acute medication first? 

I think the biggest barrier to using the newer therapies will be access and reimbursement. Triptans are now generic drugs, although they’re not tremendously inexpensive, nor are they tremendously expensive. Undoubtedly, gepants and ditans will be at a higher price point than triptans. I imagine that managed care will in some way impose guidelines that limit the use of gepants and ditans to people who have failed triptans for tolerability or efficacy or people who can’t take triptans because of cardiovascular adverse effects. What’s concerning right now is that there is evidence, some of which was recently reported at the American Headache Society meeting in July, that when people get triptans and choose not to continue them, they are most frequently prescribed opioids next, and the difficulty with that is that opioids make pain worse on a long-term basis and are associated with risk for transitioning from episodic to chronic migraine. So I think in headache specialty practice right now, if somebody fails one triptan, generally what we do is understand the nature of that failure and switch to another triptan. But most triptans are prescribed in primary care, and the predominant pattern is that if the triptan fails, [patients] go to an opioid. Honestly, I find that practice pattern worrisome because we know opioids make migraine worse in the long run. 

My hope is that if there’s an alternative to triptans that is safe and effective and that doesn’t put people at risk of medication overuse the way both triptans and opioids do, access will be relatively easy, though managed care ultimately will write step therapy guidelines that will determine who has access and who doesn’t. My hope is that the American Headache Society has a position paper that basically recommends the use of gepants and ditans in people who have tried and failed a couple of triptans for tolerability or efficacy and in people who have cardiovascular risk factors that would make triptans less than safe. I would add that if someone has very frequent headaches, gepants in particular might be better a choice because of that characteristic of [cumulative] treatment resulting in a reduction of monthly headache days. So the more you take the drug, maybe the less you need the drug, and in that way, gepants may be partially self-limited, which may be attractive to managed care. 

All 3 of the drugs that are closest to approval are important tools that I think will make life better for people with migraine. The reality is, with 40 million Americans with migraine, there’s certainly no 1-size-fits-all solution on the one hand, but on the other hand, it’s great having new options emerge. This is definitely an exciting time for clinicians who treat migraine, for scientists who study it, and for people who are seeking relief.