The Significance of 5-HT1F Agonist Approval


A discussion on the significance of the approval of a 5-HT1F agonist, with special consideration of the safety and efficacy from the respective clinical trial.

Amaal J. Starling, MD: For many years from an acute migraine treatment perspective, especially from an oral migraine treatment perspective, we had only 1 migraine-specific option, and those were our triptan medications. In general, they did work well for many of our patients. But unfortunately, based on trials, for 30% to 40% of patients, it did not work for them. It was either ineffective or it resulted in a lot of adverse effects. A lot of people call these the triptan sensations, where people will have a lot of neck tightness, chest tightness or heaviness, or people would feel like their hair is on fire. Some patients would even describe it to me as, “The migraine attack is awful, but the adverse effects that I’m experiencing from the triptan medication are even worse than the migraine attack itself, so I can’t take it.” Some people would even have jaw pain to the point where they can’t move their jaw because it almost locks into place.

Then there were other patients for whom I was unable to use triptan medications because of a history of severe cardiovascular disease, heart attacks, strokes, angina, TIAs [transient ischemic attacks], or even peripheral vascular disease. We really didn’t have a lot of options for those individuals. However, with the FDA approval of lasmiditan, it was something we were looking forward to because we have known for a long time that the 5-HT1B, 1D, 1F receptor located on the trigeminovascular system is important for migraine. If we could activate that receptor without activating the 5-HT1B/1D receptor on blood vessels, then we could benefit acute migraine attacks without the adverse effect of constricting blood vessels in the brain and on the heart. Then we might be able to use these medications for patients who have had a history of heart disease and cerebrovascular disease, and maybe these medications would be better tolerated in patients who have these severe adverse effects from triptan medications. That’s what we were looking forward to with the FDA approval of this medication.

I also appreciate that the pivotal trials that led up to the FDA approval did include these at-risk populations to make sure that they were investigated, and that there wasn’t an increased risk of having cardiovascular and cerebrovascular events. Because those are the populations for which there are gaps that we need to fill. We have options for them now. Even beyond those populations, we said there are 30% to 40% of patients for whom triptans were simply not effective, and it’s important that we have a different option that isn’t a triptan that we can use for those patients. I’m appreciative that we have lasmiditan for those patients.

From a safety perspective, from the clinical trials, as far as having increased risk of cardiovascular or cerebrovascular events, the safety data looked good. There was an increased adverse event profile of dizziness with lasmiditan, as well as some sedation. If we look back at other acute migraine medications, we have some adverse events in some of those trials, perhaps not as high as lasmiditan. But for example, in the rizatriptan trials, there is some dizziness present. In addition, if you look at our patients with migraine, even in the absence of medications, some will have some fatigue, somnolence, or dizziness associated with their migraine attack. 

I’m not saying that lasmiditan does not have those potential adverse effects with our patient population, but I also don’t want those to make us shy away from prescribing these medications for our patients. We need to inform our patients that these were adverse events in the clinical trials, but we also need to allow our patients to experience these medications, see if they tolerate it. I have many patients who have tolerated the medications very well with minimal adverse effects, with good efficacy. And I have some patients who have not tolerated the medication and have preferred to go on other treatment options.

That’s the key in migraine, whether we’re talking about acute therapies or even preventive therapies, that migraine is a very heterogenetic disease. In the last review article I read, there were over 100 genetic mutations that have been identified that give migraine vulnerability to people with this disease. Everyone’s migraine disease is a little bit different, so we should not expect that the treatment is going to be a one-size-fits-all. What we need as headache treatment providers and as neurologists is a lot of options in our toolbox. It is wonderful to have lasmiditan as a 5-HT1F agonist as an option in our toolbox that we can use in our patients for whom triptan medications were either ineffective, contraindicated, or simply not tolerated.

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