These therapies now include several large-molecule monoclonal antibodies, including Emgality (galcanezumab), Ajovy (fremanezumab), and Aimovig (erenumab). In December 2019, the list of CGRP inhibitors expanded with the introduction of a small-molecule antagonist called Ubrelvy (ubrogepant), and in February 2020, the U.S. Food and Drug Administration (FDA) approved the intravenously delivered CGRP inhibitor Vyepti (eptinezumab). Most recently, at the end of February, the FDA greenlighted another CGRP antagonist called Nurtec ODT (rimegepant), a fast-acting orally disintegrating tablet that can alleviate symptoms within one hour and potentially deliver sustained results for up to 48 hours. Biohaven Pharmaceuticals, which manufactures the drug, says Nurtec ODT should be available to consumers this month.
What’s So Special About CGRP Inhibitors?
During a migraine attack, levels of CGRP increase and trigger intense inflammation around the brain, according to the American Migraine Foundation. These monoclonal antibodies (sometimes called “mabs”) and the antagonists (called “gepants”) work differently, but both block a pain pathway associated with the CGRP protein. “If you are one of those people who is suffering from migraines and have been disappointed in the past, this might be the time to go back to the doctor and see if you might be a candidate for one of the new and emerging treatment options that have been helping so many people,” says Richard Lipton, MD, director of the Montefiore Headache Center in the Bronx, New York, and a leading researcher on CGRP inhibitors.
An Alternative for Immediate Relief
People with migraine already have a broad selection of medication to choose from to reduce symptoms when signs of an attack first come on. These include over-the-counter pain relievers like aspirin or ibuprofen (Advil, Motrin), as well as opioid medication and anti-nausea drugs. Triptans have become the most widely used class of prescription drugs for migraine, according to Dr. Lipton. First introduced in the 1990s, several brand-name triptans are now on the market, including Axert (almotriptan), Relpax (eletriptan), Frova (frovatriptan), Amerge (naratriptan), Maxalt (rizatriptan), Imitrex (sumatriptan), and Zomig (zolmitriptan). Lipton says that Imitrex is probably the best known, and Maxalt is probably the second most widely used. Triptans work by stimulating serotonin, a neurotransmitter found in the brain. The American Migraine Foundation points out that these drugs also wind up inhibiting the release of CGRP, but through a different mechanism than the mabs and gepants, which act directly on CGRP or its receptor.
Some Possible Advantages of CGRP Inhibitors Over Triptans
While triptans effectively reduce migraine symptoms for many people, Lipton notes that they aren’t a good choice for everyone with migraine. “All triptans constrict blood vessels, so they can’t be used safely in people who have had heart attack, stroke, or other vascular complications,” he says. “So one big advantage of rimegepant is that it can be used safely by the three million Americans with migraine who have cardiovascular contraindications or precautions regarding the use of triptans.” Lipton also notes that CGRP inhibitors have few side effects. “A disadvantage of triptans is that they produce a variety of side effects — flushing, tingling, chest pressure,” he says. “The side effect profile of rimegepant is really remarkably clean.” One more check in the positive column is an indication that overuse is less likely with rimegepant. Some people with migraine take a drug excessively for acute treatment, and this misuse can lead to a drug-induced headache and liver toxicity, according to the American Migraine Foundation. “Researchers found that patients who took rimegepant did not really need to take additional doses, which suggests that there was not medication overuse with it as has been seen with the triptans,” says Robert Cowan, MD, professor of neurology and chief of the division of headache medicine at Stanford University in Palo Alto, California.
One Drawback: Nurtec Will Almost Certainly Cost More Than Triptans
Triptans are currently available as low-cost generics, and Nurtec is a new branded treatment that is likely to cost much more. “Given the economic reality, rimegepant will most likely be a second-line treatment, prescribed after triptans have failed,” says Dr. Cowan. “Will you have to have tried one triptan, or two or three, before insurance will approve [coverage for] rimegepant? We will have to see.”
Latest Research Shows Short-Term and Long-Term Results
The FDA approval of rimegepant for immediate migraine relief hinged on results from a phase 3 trial involving 1,351 people, which showed the medication to be more effective than placebo. All study participants were being treated for an average of at least two migraine days per month. The study, published in August 2019 in The Lancet, noted that this fast-acting formulation demonstrated superiority over placebo in 21 specific measures, and it had an earlier onset of action — as much as 30 minutes — compared with a standard tablet formulation of rimegepant. The paper highlighted that 21 percent of the participants who received a 75-milligram dose of the drug were pain-free two hours after taking it, compared with 11 percent in the placebo group. In addition, 35 percent of people who took rimegepant were free of their most bothersome symptoms (such as nausea, sensitivity to light, and sensitivity to sound) at the two-hour point, compared with 27 percent in the placebo group. (Similar results were reported in research published in July 2019 in The New England Journal of Medicine.) Those taking rimegepant ODT also demonstrated statistically significant pain relief 48 hours after taking the treatment. “Those are not super-high numbers, because that means 80 percent still aren’t pain-free,” says Lipton, who was senior author on the investigation. “The really interesting thing is, if you look at the proportion of people who go from moderate or severe pain to mild pain, that’s over 60 percent of people. The reality is that when people go from moderate or severe pain to mild pain, that’s often associated with the ability to work and function normally or nearly normally. ” Although rimegepant is only FDA-approved for acute migraine at this point, Lipton and colleagues are completing research looking into potential benefits of repeated dosing of up to once daily to prevent chronic migraine. Most recently, the CGRP monoclonal antibodies, such as Vyepti, have been producing promising outcomes for those with chronic migraine. Cowan points out that some doctors may already be prescribing rimegepant as a preventive treatment. “The FDA indication doesn’t necessarily have a big impact on prescribing, knowing that it is safe,” he says. “Biohaven can’t market it as preventive at this time, but most headache specialists are aware of the potential for it to be a preventive.”
As Treatment Options Grow, So Does Hope for Migraine Relief
The Migraine Research Foundation estimates that migraine affects 39 million men, women, and children in the United States. Most have attacks once or twice a month, and a significant proportion (about four million) have chronic migraine, meaning they have at least 15 migraine days per month. More than 90 percent of people with migraine are unable to work or function normally during an attack. For all of these people, a new generation of treatments offers great potential to get their migraine symptoms under control. “There are one billion people with migraines globally, and it’s the second leading cause of lost time due to disability,” says Lipton. “Today, we have an incredible array of new treatments that give us insight into the fundamental mechanisms of migraine, and I think they will help a lot of people.”
