Oral Gepants: Christopher Gottschalk, MD Tells the Origin Story, Highlights Broad Efficacy

The migraine-specific oral gepants are proving effective across the continuum of migraine frequency. Dr Gottschalk talks about their shaky start.

The discovery of calcitonin gene-related peptide (CGRP) and its role in migraine physiology has resulted in an array of new highly effective acute and preventive therapies for the headaches.

In a recent interview with Patient Care, Chris Gottschalk, MD, a prominent migraine researcher and professor of clinical neruology, director of headache medicine, and section chief, general neurology, at the Yale School of Medicine, expalined that while earlier oral CGRP inhibitor formualtions were shelved after reports of liver toxicity, the modified agents, the gepants, are quite successful and proving effective along the continuum of migraine headache frequency.


Christopher H. Gottschalk, MD, is professor of clinical neurology, director of headache medicine, and section chief, general neurology, at the Yale School of Medicine in New Havent, CT. Gottschalk is also current president of the Alliance for Headache Disorders Advocacy.


The following has been lightly edited for clarity and style.

The success of those monoclonal therapies [injectable CGRP inhibitors] rekindled interest in the gepant class, and several older chemicals were either revived or modified further, to try to find acute therapies that would effectively treat attacks with minimal side effects, and also without having the liver toxicity, and several of those succeeded. One of them is now being used exclusively for acute attacks, ubrogepant; one of them has been developed as both an acute or a preventive option, rimegepant. And the third one was developed and approved solely for prevention, atogepant. So we now have monthly injectable, quarterly injectable options, we have oral therapies for acute or preventive treatment, all of which developed out of the discovery of CGRP and its essential role in migraine physiology.

The last drug, the ditan, is really based on the idea that we could target something almost the same as a triptan does. So in the 1990s, when sumatriptan and its relatives, the other 6 agents in that class were developed and discovered, it was based on the understanding that a serotonin agonist, in this case with the triptans of the 5-HT1B and HT1D receptors, would be an effective acute therapy. But they have some limitations because they do cause a degree of vasoconstriction, which at the time was believed to be why they are helpful for migraine. We have since proven that that is not the case. But the fact that the triptans do cause any vasoconstriction leaves people with some hesitation about prescribing for those people with any kind of cardiovascular disease.

So the 5-HT1F receptor, which is closely related and follows some of the same pathways in terms of where it appears in the trigeminal vascular system, was expected to be a good alternative to the triptan target, but would have little or none of the vasoconstrictive properties of the triptans and, sure enough. So we now have one agent that is kind of a one-off of a triptan and has certainly proven to be an effective therapy, although some of its side effects have led to labeling which makes it a little bit more cumbersome to use in regular practice.