Stephen Silberstein, MD: CGRP, or calcitonin gene-related peptide, is a neuropeptide which occurs throughout the body and in the nerves innervating the face and the head. The original observation was made a long time ago that during a migraine attack, a patients’ CGRP levels go up and if you treat them with a triptan, they go down. Then other investigators found that if you infuse CGRP, it produces a migraine headache in patients with migraine. Based on this small molecule, CGRP antagonists were made called gepants, and they were shown to be effective in the acute and, in addition, the preventative treatment of migraine. But the early ones were discontinued because of liver toxicity.
Richard B. Lipton, MD: The development of the CGRP-targeted therapies is incredibly exciting. We’ve known for years that CGRP was a molecule involved in migraines. We’ve known that because CGRP is elevated in the blood of people who have migraines, CGRP levels go up during migraine attacks. They go down after successful treatment of migraine attacks, and if we infuse CGRP, that induces a migraine attack. If we give drugs that block CGRP, either by binding the receptor or binding the CGRP molecule itself, that effectively treats migraine acutely and preventatively, depending on how the drug is used.
So, the first thing that’s exciting about the advent of CGRP-targeted therapies simply is that it confirms the science linking CGRP to migraine, and in many ways, these are the first mechanism-based targeted therapies for migraine.
Another reason they’re exciting is because these treatments have advantages over existing therapies. So, for the monoclonal antibodies that are used preventatively for migraine, they have a very rapid onset of action. You can begin at a maximum dose, the optimal dose, without engaging at a period of dose titration. And the drugs have benefits that kick in relatively quickly, and, as a consequence they’re easy to use. They also had very favorable side effect profiles. So, the monoclonal antibodies are a therapeutic advance.
In addition, there are a number of people who are what we call “CGRP super responders.” I’ve treated patients who I’ve struggled for years to help get their headaches in control, and after a single treatment, they just never have another headache. So, the antibodies are advantageous as preventives, but, of course, they’re all injectable. The oral agents are being developed both as acute treatments and preventive treatments. There are 2 acute treatments—rimegepant, ubrogepant [MK-1602]–and 2 preventive treatments, because rimegepant is also being developed as a preventive, as is atogepant.
These agents, again, have advantages on the acute treatment side that are several-fold. They’re very well tolerated, and they produce very reasonable headache response rates at 2 hours. They don’t carry the cardiovascular liability of [triptans], and we have as a hope, that they won’t cause medication overuse syndromes the way so many other acute treatments do. That hope is based on the fact that the same molecule that we can use as an acute treatment, we also use as a preventive treatment without an acceleration of headaches. So, having a cardiovascularly safe, effective, acute treatment that doesn’t cause medication overuse or rebound headache, [is a huge advantage].