One of the most exciting and promising areas of current migraine research is a new class of medications that target the calcitonin gene-related peptide (CGRP). These medications are being studied for use as acute medications to be taken when we get a migraine and as preventive medications.
What Is CGRP?
CGRP is a naturally occurring substance found in many organs in the body, including the brain. Depending on its target it has multiple effects. When CGRP is released around the nerves most associated with migraine, it makes blood vessels expand and causes inflammation. Although research has shown that this expansion of blood vessels doesn't always occur during a migraine attack, when it does, it can contribute to migraine pain, as does inflammation.
When we have a migraine attack, our levels of CGRP rise significantly resulting in a constellation of symptoms including head pain, photophobia, phonophobia, nausea and more. Blocking the CGRP receptors or gathering most of the CGRP circulating in the blood system appears to greatly reduce migraine and migraine symptoms.
Two Groups of CGRP Medications:
There are two different groups of CGRP medications in development:
- The group with the larger sized molecule is monoclonal antibodies (Mabs). Mabs are intended for migraine prevention. Unlike most migraine preventive medications, they aren't given daily. They're given every two weeks, monthly, or less frequently. Thus far in the clinical trials, these medications have shown no major side effects. What's not know yet is what, if any, problems there may be with blocking CGRP on a long-term basis.
- The group with the smaller sized molecules is sometimes called "gepants," and the clinical trials of them have mostly been for acute treatment of migraine, when an attack occurs. You may remember one called telcagepant that was in clinical trials a few years ago, but was withdrawn when it was found to cause liver problems. In clinical trials thus far, they seem to be working as well as triptans (Imitrex, Maxalt, Zomig, etc.), but without some of the potential side effects of triptans.
CGRP Monoclonal Antibodies for Prevention:
Currently, there are four GCRP monoclonal antibody medications (Mabs) in development:
- ALD403 collects or takes out the CGRP itself and is administered via IV injection. At 1,000 mg, in clinical trials, it has produced approximately a 20 percent reduction in migraine and headache days when compared with placebo.
- LY2951742 collects or takes out the CGRP itself. Injected subcutaneously every two weeks for 12 weeks in clinical trials, produced a 25 percent reduction in migraine and headache days compared with placebo. It's also being investigated for preventing cluster headaches.
- TEV-48125 collects or takes out the CGRP itself, and is administered monthly via subcutaneous injection. In clinical trials, it has been found beneficial for both episodic and chronic migraine.
- AMG 334 targets the CGRP receptors and is administered monthly via subcutaneous injection. Statistics from clinical trials are not yet available.
CGRP Receptor Antagonists for Aborting Migraine:
Currently, there are three GCRP receptor antagonist (blocker) medications (gepants) in development. They work by competing with CGRP for space on CGRP receptors, blocking the CGRP.
The molecule of these medications is small enough to cross into the blood around the brain, directly blocking pain transmission to the trigeminal nerve and the blood vessels surrounding it. The potential risk for these medications is possibly affecting other organs. This is what happened when telcagepant affected the liver. These new gepants are being tested for safety. There are three of these being tested currently.
What's All the Excitement?
At this point, there are no medications on the market that were originally developed for migraine prevention. Not even one. All of those we use are hand-me-down medications that were originally developed for other conditions, then found to help with migraine. When it comes to acute migraine-specific medications, we have the triptans, ergotamines, and the Midrin equivalent medications.
In clinical trials, the Mab medications have decreased migraine frequency by at least 50 percent for some patients. Amazingly, about 16 percent of study patients, had no migraines at all for three months or longer.
Thus far in the clinical trials of these CGRP medications, the side effects profile has been very low, lower than many of the medications we use now. Additionally, when used as migraine abortives, these new medications may be safe for patients for whom current triptan and ergotamine abortive medications are contraindicated - patients with a history of uncontrolled hypertension, heart attack and coronary artery disease, and stroke.
Summary and Implications for Patients:
These GCRP medications offer great hope for the future for everyone with migraine. Although there are more clinical trials to be done, and it will be a few years before we see any of them approved by the FDA, those few years pale when compared to the years many of us have been living with migraine disease.
On the preventive front, the GCRP monoclonal antibody medications may prove more effective for people who have problems remembering to take daily oral medications since they're taken every two weeks to 30 days.
On the abortive front, having options that aren't contraindicated for those with blood pressure, heart, or stroke issues would be a gigantic step forward.