Qulipta vs. Nurtec for migraine prevention; which wins?

What are the gepants for migraine prevention?

The gepants were the first new migraine abortive (acute) medication class of drugs (CGRP receptor antagonists) since the triptans came to market in 1992 with Sumatriptan. The first to become available was Ubrelvy (Ubrogepant) in January 2020, followed by Nurtec ODT (Rimegepant) in February 2020. These are both pills, although Nurtec is a disintegrating tablet. The first and only gepant abortive nasal spray came to market in July 2023 with Zavzpret (Zavegepant). So initially, the gepants were only FDA approved for migraine abortive use, and these are currently the 3 used for this purpose.

After initially entering the migraine space as abortive only medicines, the gepants then expanded their repertoire to migraine prevention treatment with Nurtec ODT and Qulipta (Atogepant). These 2 preventive gepants will be our focus in today’s blog. A discussion about the abortive gepants above can be found here.

How do the gepants work?

During migraine attacks, the trigeminal nerves release a variety of inflammatory proteins. One of these main proteins is called CGRP (calcitonin gene-related peptide). CGRP causes inflammation around the brain, the arteries in the brain, and in the dural membrane surrounding the brain. It also intensifies and enhances pain signals throughout the brain. CGRP is also a potent vasodilator (makes blood vessels expand) of the arteries through the brain and meninges, and this leads to further increasing pain signals via the trigeminal nerve endings innervating these areas. The end result is intense migraine pain. So, if we can block these steps of migraine pain, the attack should be aborted quickly, and not as severe. If we continue to block these migraine CGRP pain pathways on a continuous basis, then we get the migraine preventive benefits as well. 

The gepants work as CGRP receptor antagonists, which means they directly target and block (antagonist) the CGRP receptor. This “blocks” the CGRP inflammatory protein from sticking to the CGRP receptor to activate it, and thus prevents it from “turning on” these migraine pain pathways. There is also reversal of cerebral blood vessel vasodilation, which decreases the firing of the trigeminal nerves, with cessation of electrical pain signals. Notably, the gepants do this in a way that does not cause vasconstriction, in contrast to the triptans. Thus, they are felt to be safe in those with cardiovascular, cerebrovascular, or peripheral vascular disease (as opposed to the triptans which cannot be used in these patients). 

Ultimately, by blocking the CGRP receptor, you get reversal of the neurogenic inflammation in the brain and around the arteries, you restore normal blood vessel size, and you block the electrical transmission of migraine pain traveling from the trigeminal nerves into the brainstem, and ultimately into the brain.

Gepants for migraine prevention

For many decades up until 2018, there had never been a migraine specific preventive medication created. The preventive migraine treatments we’ve always used have been adopted from and limited to anti-seizure, anti-depressant/anxiety, and anti-blood pressure medications. Although some patients can respond well to these options for preventive treatment of migraine, none of them were scientifically created specifically to target migraine pathways for migraine prevention. Many patients cannot tolerate the side effects of these older medicines or cannot use them due to other medical conditions. 

Then in 2018 the first migraine specific preventive medicine class became available with the CGRP monoclonal antibodies (CGRP mAbs). These were the first CGRP antagonists available. Aimovig (Erenumab) was the first that came to market in 2018 and was followed by 3 more CGRP mAbs; Ajovy (Fremanezumab), Emgality (Galcanezumab), and Vyepti (Eptinezumab). Aimovig, Emgality, and Ajovy are once monthly self injections with an easy to use auto-injector push button device. Vyepti is a once quarterly (every 3 months) 30 minute IV infusion.

The CGRP mAbs were a major step forward for migraine prevention. However, even at that point we still hadn’t had an oral pill developed purely and only for migraine prevention (not “adopted” from a different medicine class such as the anti-seizure, antidepressant, and anti-blood pressure pills). That finally changed with gepant pills, Nurtec and Qulipta, detailed below. 

Nurtec ODT vs. Qulipta for migraine prevention; which is better?

Nurtec ODT (orally disintegrating tablet) and Qulipta are the first and only two oral CGRP migraine preventive medication options. The gepants are CGRP receptor antagonists and are a different type of medicine class compared to the CGRP antagonist mAb injections mentioned above. The gepants offer an oral CGRP preventive alternative to the once monthly CGRP mAb injections. They are both very effective for many patients. If one does not work, it does not mean that the other can not work. It is not uncommon to see someone do very well with one and perhaps not as well with the other.

Compared to standard historical oral preventive options, the gepant preventives Nurtec and Qulipta often work much quicker (within even a day to a week many patients can notice a difference). So you may not have to wait the usual 4-6 weeks to start working and 2-3 months to see full effect as historical oral preventives have typically required. However, it is still recommended that a full trial is at least 3 months.

Let’s discuss them both separately along with their evidence from studies. I will also highlight some important differences between them which may help you and your doctor choose one over the other to try first. Detailed results of the clinical trials comparing Nurtec vs. Qulipta for migraine prevention can be seen at the bottom of this blog.  

Nurtec ODT (Rimegepant ODT)

On 5/27/21, Nurtec ODT received additional FDA approval for episodic migraine (1-14 headache days per month) prevention when taken every other day. This was in addition to its initial FDA approval as an abortive migraine medicine on 2/2020. So it is the only FDA approved oral medication for BOTH abortive and/or preventive migraine treatment simultaneously. Nurtec comes in only one strength, 75 mg.

Nurtec clinical trial results for migraine prevention

Nurtec was studied and published in the preventive treatment of migraine during a 12-week double-blind randomized placebo-controlled trial. Patients included in the study had a baseline frequency of 4-18 migraine days per month. They were randomized to an every other day dose of either Nurtec 75 mg (348 patients) or placebo (347 patients). Nurtec was studied in an every other day dose because in the abortive (acute) migraine trials, many patients received 48 hours of relief after taking it.

Preventive benefits began fast in the trial. Within the 1st week, there was a 30% drop in migraines in the Nurtec group (compared to 9.4% drop in the placebo group). This is important because most preventive migraine medicines typically take 4-6 weeks to start working and 2-3 months until full effect is seen. So to finally have a preventive treatment that can start working fast is a welcome addition!

The primary endpoint of the study was the change in monthly migraine days from baseline compared to weeks 9-12. The study showed a statistically significant reduction in monthly migraine days. Patients receiving Nurtec 75 mg every other day experienced a statistically significant reduction of 4.3 monthly migraine days compared to a 3.5 day reduction in the placebo group.

Secondary endpoints of the study included a number of things. A 50% or more reduction in monthly migraine days in weeks 9-12 was assessed. Nurtec was superior to placebo. 49% of patients taking Nurtec had a 50% or more reduction in monthly migraine days compared to 41% in placebo. There was a consistent trend in reduction of average monthly migraine days month over month from 1 to 3 months.

The change in the average monthly migraine days across the full treatment phase (weeks 1-12) was assessed. Nurtec was superior to placebo. Patients taking Nurtec had 3.6 less monthly migraine days compared to 2.7 less days in the placebo group.

Decrease in rescue medication use days per month in weeks 9-12 was assessed. There were slightly less rescue medication days per month in the Nurtec group (3.7 days) compared to placebo (4 days), but this was not statistically superior.

The change in monthly migraine days in the first 4 treatment weeks (weeks 1-4) was assessed. Nurtec was superior to placebo. Patients taking Nurtec had 2.9 less monthly migraine days compared to 1.7 less days in placebo in the first month alone.

Nurtec ODT side effects

The side effects of Nurtec were similar to placebo in the preventive migraine trial and included nausea 2.7% (vs. 0.8% placebo) and upper abdominal discomfort/indigestion 2.4% (vs. .8% placebo). There were no serious reactions. A 52-week open-label extension phase followed the above main double-blind study. Patients dosed rimegepant 75 mg every other day and were allowed to take up to one dose of rimegepant 75 mg as needed on non-scheduled dosing days to treat migraine attacks as well, and this confirmed benefit with no further safety or side effect concerns of any significance.

Unique clinical benefits of Nurtec

The problem with migraine is that it naturally will fluctuate between periods of time where the frequency and severity is lower, and other times where it is higher. Since Nurtec is FDA approved as either an abortive or preventive medicine, this allows flexibility in that it can just be used as an as-needed basis when the frequency is not high, and can be switched to every other day when migraine frequency is slipping into a higher frequency pattern. Then if it evolves back into a lower frequency migraine pattern, it can then just be used abortively only again.

This flexible dosing option can also be used as a “mini-prophylaxis” within the month. For example, if patients know they are approaching a predictable migraine trigger, such as menstrual migraine, barometric trigger from an airplane trip, upcoming stressful event such as an exam, etc., Nurtec can be taken daily or every other day starting a day or two before the anticipated trigger, and stopping it a day or so after the trigger is no longer present. Unlike other migraine preventive treatments which take 4-6 weeks to start working and 2-3 months to see full effect, Nurtec often works quick, providing faster protection during these short term stretches of migraine flares. Another highlight about the gepants is that there is no rebound headache (medication overuse headache) associated with them, so this is not a concern when used for mini-prophylaxis or even long stretches of daily use.

Lastly, it’s important to know that if your doctor prescribes Nurtec as an every other day preventive and the script is linked to chronic migraine, it will most likely be denied. It’s important to make sure that the prescription is associated with episodic migraine when it is sent in, which is what insurance coverage will allow. If you do have chronic migraine (15-30 headache days per month with at least 8 of them being migraine days), then Qulipta will be the better choice because it is the only pill (and gepant) which has FDA approval for prevention of chronic migraine. So let’s talk about Qulipta next…

Qulipta (Atogepant)

On 9/28/21, Qulipta became the second oral CGRP preventive gepant to receive FDA approval for episodic migraine (1-14 headache days per month) prevention. Then on 4/2023, it was FDA approved for chronic migraine (15-30 headache days per month) as well. Qulipta is the only gepant designed and created purely as a preventive migraine treatment. Qulipta is also unique in that it is the only pill which is FDA approved for both chronic migraine as well as episodic migraine. It is taken once daily and comes in strengths of 10 mg, 30 mg, and 60 mg, although the 60 mg dose is typically considered the starting dose for most patients.

Qulipta clinical trial results for episodic migraine prevention

Qulipta was studied and published in the preventive treatment of episodic migraine during a 12-week double-blind randomized placebo-controlled trial with 10 mg (214 patients), 30 mg (223 patients) and 60 mg (222 patients) doses compared with placebo (214 patients). Patients averaged 4-14 migraine days per month.

The primary endpoint of the study was the change in monthly migraine days from baseline compared to across the 12 week study period. The study showed a statistically significant reduction in monthly migraine days compared to placebo for all doses evaluated across the 12-week treatment period. The average monthly migraine day reduction across the 12 weeks in the Qulipta groups was 3.69 days in the 10 mg group, 3.86 days in the 30 mg group, and 4.2 days in the 60 mg groups compared to 2.48 days in the placebo group. On average across the 12 week trial, patients on the 60 mg dose had a 54% reduction in monthly migraine days compared to 33% reduction in placebo. 

Preventive benefits began very fast in the trial. The day following the first 60 mg dose, patients were 51% less likely to have a migraine. Within the 1st week, there was a 53% drop in migraines in the Qulipta group (compared to 15% drop in the placebo group). Similar to Nurtec, this is important because most preventive migraine medicines typically take 4-6 weeks to start working and 2-3 months until full effect is seen. So having preventive options that can start working quick is really great.

Secondary endpoints of the study included a number of things. A key secondary endpoint measured the number of patients receiving 50% or more reduction in monthly migraine days across the 12-week treatment period. 

The percentage of people in the Qulipta groups receiving 50% or greater monthly migraine day reduction across the 12 week trial was 56% in the 10 mg group, 59% in the 30 mg group, and 61% in the 60 mg groups compared to 29% in the placebo group. 

Reduction in monthly migraine days was compared for each dose between each of the months 1-3, and also further broken down into those receiving 50% or greater reduction in monthly migraine days, 75% or greater reduction in monthly migraine days, and 100% reduction in monthly migraine days. I won’t bore you with every result for each of those categories, but here are few highlights. By weeks 9-12 (3rd month) in the 60 mg dose group, 71% of patients had reduced their monthly migraine days by 50% or more, 50% had reduced their monthly migraine days by 75% or more, and 28% had reduced their monthly migraine days by 100% (yes that means 0 migraine days)!

Patients on the 60 mg Qulipta dose also reported 67% improvement in ability to do work-related and social activities vs. 44% in placebo.

Decrease in rescue medication use days per month across 12 weeks was assessed. There were significantly less rescue medication days per month in the Qulipta group (3.9 days; 57% decrease) compared to placebo (2.4 days; 37% decrease).

Additional results from a 1 year Qulipta trial

After the main trial above was completed, an additional 52 week (1 year) open label trial (patients knew they were taking the medicine) was completed where patients took 60 mg daily. The goal was to assess for further side effects or safety concerns, of which there were none. Across this 1 year trial, there was a month over month decrease in monthly migraine days. Even at the end of the 1 year trial monthly migraine days were still decreasing, although the majority of this overall drop occurred between weeks 1-4. In other words, many patients received a quickly noticeable benefit. By the end of this 1 year trial, patients were averaging 71% less migraine days per month, which equated to 5.2 less migraine days per month on average. At the end of this trial, 84% of all patients had received a 50-100% average monthly migraine day reduction, and 48% received 100% migraine day reduction!

Qulipta clinical trial results for chronic migraine prevention

In April 2023, Qulipta was FDA approved for chronic migraine, in addition to its prior approval for episodic migraine prevention. The Qulipta trial for chronic migraine prevention consisted of a 12-week double-blind randomized placebo-controlled trial with 778 patients. Patients were randomized to either Qulipta 60 mg or placebo once daily, and had a baseline average migraine frequency of just over 19 migraine days per month.

The primary endpoint of the study was the change in monthly migraine days from baseline compared to across the 12 week study period. The study showed a statistically significant reduction in monthly migraine days. Patients receiving Qulipta 60 mg daily experienced a statistically significant reduction of 7 monthly migraine days (36% reduction) compared to a 5.1 day reduction (27%) in the placebo group. So basically patients with chronic migraine were able to eliminate 1 week of migraine days per month on average.

Secondary endpoints showed that with the 60 mg Qulipta dose, patients reported 54% improvement in ability to do work-related and social activities vs. 39% in placebo. Decrease in rescue medication use days per month across 12 weeks was assessed. There were significantly less rescue medication days per month in the Qulipta group (6.2 days; 40% decrease) compared to placebo (4.1 days; 27% decrease).

Qulipta side effects

Across all the Qulipta trials above, no significant safety risks were seen. The most common side effects across the trials were nausea in 5% (10 mg), 6% (30 mg), and 9% (60 mg) vs. 3% in placebo. Constipation occurred in 6% (10 mg), 6% (30 mg), and 8% (60 mg) vs. 2% in placebo. Fatigue occurred in 4% (10 mg), 4% (30 mg), and 5% (60 mg) vs. 4% in placebo. Dizziness occurred in 2% of 10 mg, 30 mg, and placebo groups and 3% in the 60 mg group. 

Decreased appetite occurred in 2% (10 mg), 1% (30 mg), and 3% (60 mg) vs. less than 1% in placebo. Notably, weight was also seen with Qulipta. The proportion of patients with a weight loss of more than 7% at any point was 5.3% for 60 mg, 3.2% for 30 mg, and 3.8% for 10 mg groups compared to 2.5% in placebo.

Unique clinical benefits of Qulipta

Qulipta remains the only gepant created purely as a migraine preventive medicine (not also abortive). Technically, other than Botox injections, Qulipta is the only other treatment and the only pill which is FDA approved specifically for chronic migraine prevention. It is also approved for episodic migraine prevention. So basically, it is approved for any frequency of migraine. This is important to know because if you have a chronic migraine diagnosis linked to your prescription, insurances will usually deny Nurtec ODT if it is written as a preventive medicine (will allow episodic migraine prevention only), but will allow Qulipta for both. So you may want to discuss that with your doctor.

Conclusions

The CGRP receptor antagonist medications were a major step forward for pain relief of migraine symptoms, first with the CGRP mAbs and then the gepants. The gepants initially emerged as new treatment options in the acute treatment of migraine. Then they became available for the prevention of migraine. The preventive gepants (Nurtec, Qulipta) and the preventive CGRP mAb injections (Aimovig, Ajovy, Emgality, Vyepti) are all compared to each other in more detail here in relation to migraine prevention.

These newer prescription drugs for migraine headaches all have much fewer side effects and precisely target the CGRP pathway. Hypersensitivity reactions are infrequent. This makes them a more suitable alternative to older medications (anti-seizure, anti-depressant, anti-blood pressure) which tend to have more drug interactions and adverse effects. The American Headache Society now recommends that CGRP antagonists should be considered as first line migraine preventive options, so it is worth a discussion with your healthcare provider.

IF YOU HAVE HEADACHE, MIGRAINE, OR FACIAL PAIN AND ARE LOOKING FOR ANSWERS ON ANYTHING RELATED TO IT, A HEADACHE SPECIALIST IS HERE TO HELP, FOR FREE!

FIRST, LET’S DECIDE WHERE TO START:

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR THE LATEST INFORMATION, HOT TOPICS, AND TREATMENT TIPS, VISIT OUR FREE BLOG OF HOT TOPICS AND HEADACHE TIPS HERE. THIS IS WHERE I WRITE AND CONDENSE A BROAD VARIETY OF COMMON AND COMPLEX  MIGRAINE AND HEADACHE RELATED TOPICS INTO THE IMPORTANT FACTS AND HIGHLIGHTS YOU NEED TO KNOW, ALONG WITH PROVIDING FIRST HAND CLINICAL EXPERIENCE FROM THE PERSPECTIVE OF A HEADACHE SPECIALIST.

IF YOU DON’T HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR POSSIBLE TYPES OF HEADACHES OR FACIAL PAINS BASED ON YOUR SYMPTOMS, USE THE FREE HEADACHE AND FACIAL PAIN SYMPTOM CHECKER TOOL DEVELOPED BY A HEADACHE SPECIALIST NEUROLOGIST HERE!

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR FURTHER EDUCATION AND SELF-RESEARCH ON YOUR DIAGNOSIS, VISIT OUR FREE EDUCATION CENTER HERE.