The gepants were the first to emerge as new migraine abortive options, and the first new migraine specific abortive class since the triptans came to market in 1992. The first to become available was Ubrogepant (Ubrelvy) from Allergan in January 2020. Then Rimegepant (Nurtec ODT (orally dissolvable tablet)) became available by Biohaven shortly after in February 2020. The gepants have been game changers in the migraine abortive arena. However, they are now bringing their benefits to the migraine preventive realm, following a mind-blowing trifecta collision of the worlds of gepants, abortive and preventive therapy with Rimegepant (Nurtec ODT) and Atogepant (Qulipta)! These two medications are compared head to head in the table below.
On 5/27/21, Nurtec ODT made history as the first and only FDA approved medication for BOTH abortive and preventive migraine treatment simultaneously, and the only option with this flexibility! More recently, on 9/28/21, Qulipta (Atogepant) became the second oral CGRP preventive gepant medication to become FDA approved for migraine prevention. It is taken once daily. So these 2 options have become the first oral CGRP preventive medication options. They are both of the gepant medication family, which is different than the CGRP mAb family, but none the less now offer an oral alternative to once monthly CGRP monoclonal antibody injections.
I can hear you now. Rimegepant (Nurtec ODT) for migraine prevention? Atogepant for migraine prevention? Yes, you heard correctly. Are these available yet? We’ll discuss this and these new options a bit further down.
HOW DO THE GEPANTS WORK?
To review, during a migraine attack, the trigeminal nerves release a variety of inflammatory proteins. One of the main proteins is called CGRP (calcitonin gene related peptide). CGRP causes inflammation around the brain and cerebral arteries (“sterile inflammation”) in the dural membrane surrounding the brain, intensified pain signals, enhanced transmission of pain signals through the trigeminal nerves into the brainstem and into the brain, and dilation of the cerebral arteries through the dural membrane, which in turn leads to further increasing pain signals via the trigeminal nerve endings covering the cerebral arteries. The result is intense migraine pain (as you are unfortunately very familiar with). So, if we can block these steps of migraine pain, the attack should be aborted quickly, and not as severe. That’s the thinking here, and that’s where the CGRP medications (gepants and CGRP monoclonal antibodies) come into play.
The gepants work as CGRP receptor antagonists, which means they directly target and block (antagonist) the CGRP receptor. This results in the medication “blocking” the CGRP inflammatory protein from sticking to the CGRP receptor to activate it, and thus prevents it from “turning on” these pathways of migraine pain. So, you get reversal of cerebral vasodilation, which decreases the firing off of the trigeminal nerves, and 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 or cerebrovascular disease (as opposed to the triptans which can not be used in these patients). By blocking the CGRP receptor, you also get reversal of the neurogenic inflammation going on through the brain and around the arteries, and you block the electrical transmission of migraine pain from traveling from the trigeminal nerves into the brainstem, and ultimately into the brain.
GEPANTS FOR MIGRAINE PREVENTION
Rimegepant (Nurtec ODT) and Ubrogepant (Ubrelvy) were created and FDA approved for the abortive (as needed) treatment of migraine in 2020. The goal of migraine abortive treatment is to stop individual migraine attacks at onset so the migraine does not reach full severity, ends quickly, and your function is restored and maintained. We want you to avoid having to go lay down and miss that family/social event, work meeting, or whatever else you had planned, and instead end up spending the whole day in a dark quiet bedroom. As opposed to conventional migraine abortives such as triptans, NSAIDs, and other analgesics, the gepants have the unique characteristic that they do not cause rebound headache (medication overuse headache), which is why they have also been evaluated as daily preventive medications as we’ll discuss below.
Abortive treatments are different than migraine preventive treatments, which are a continuous treatment (not just taken as needed) meant to lessen the frequency and/or severity of migraine attacks (hopefully both). Conventional preventive treatment options include a daily pill, a monthly/quarterly CGRP monoclonal antibody (mAb) (Aimovig, Ajovy, Emgality, Vyepti) injection, neuromodulation devices, Botox injections, or alternative treatments such as vitamins and supplements, acupuncture, acupressure and pressure points, or yoga and meditation. The goal of migraine preventive treatment is to lessen the frequency and/or severity of migraine attacks and are discussed in more detail here. If you have migraine, you want to have both a good abortive and preventive treatment plan to lessen migraine’s nasty habit of interfering and disrupting life and function.
Notably, for many decades, we have never had migraine specific preventive treatment. What I mean is that the treatments we have always used have been adopted from and limited to medications including antiseizure, antidepressant/anxiety, and blood pressure medications. Although many patients certainly do well with these preventive options, none of these medicines have been scientifically engineered and created specifically to target migraine pathophysiology for migraine prevention. In addition, many patients do not tolerate the side effects or cannot use many of these medications due to other medical conditions. So a lot of patients have been stuck without adequate preventive migraine therapy. That was until 2018 with the first once monthly self-injection CGRP monoclonal antibody (mAb) Erenumab (Aimovig) came to market, and was followed by 3 more CGRP mAbs; Fremanazumab (Ajovy), Galcanezumab (Emgality), and Eptinezumab (Vyepti).
The CGRP mAbs have been a major step forward for migraine prevention. However, up to this point, we still have not had an oral pill that has been engineered and created 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 was until now. These new oral gepant medications will be the first in history to assume this new role, finally giving migraine patients a new unique treatment option to add to their war chest.
The two gepants being targeted for preventive migraine therapy are Rimegepant (Nurtec ODT) from Biohaven and Atogepant (Qulipta) from Allergan/Abbvie. On 5/27/21, Nurtec ODT made history as the first and only FDA approved medication for BOTH abortive and preventive migraine treatment simultaneously, and the only option with this flexibility! The perspective and reasoning behind this is that migraine is truly a fluid and variable disease, commonly fluctuating between periods of episodic migraine (1-14 headache days per month), and other periods of chronic migraine (15 or more headache days per month). So having a medicine that can function as both types of treatment, depending on what type of phase the migraine is in (episodic or chronic) opens up an entirely new flexible treatment paradigm and approach which we have never had up to this point.
More recently, on 9/28/21, Qulipta (Atogepant) became the second oral CGRP preventive gepant medication to become FDA approved for migraine prevention (not dually approved for both abortive and preventive). It is the first gepant that was designed and studied purely for only migraine prevention. It is taken once daily. So, Nurtec ODT and Qulipta have become the first oral CGRP preventive medication options. They are both of the gepant medication family, which is different than the CGRP mAb family, but none the less now offer an oral alternative to once monthly injections.
Compared to standard historical oral preventive options, the gepant preventives Nurtec and Qulipta work extremely quick (within even a day!) as detailed below. So you are not having to wait the usual 4-6 weeks to start working and 2-3 months to see full effect as oral preventives have typically required.
Yes, I know your mind has just been blown. Let’s discuss them both and the currently available data, which can be found on each company’s website.
RIMEGEPANT ODT (Nurtec ODT)
Rimegepant ODT 75 mg every other day was studied and published in the preventive treatment of both episodic (4-14 days per month) and chronic migraine (15-30 days per month) during a 12-week double-blind randomized placebo-controlled treatment which included 747 patients. Migraine frequency was first observed and tracked for 4 weeks. Then, the 12 week treatment phase began. Patients were allowed to take 1 preventive migraine medication, (excluding CGRP receptor antagonists and CGRP monoclonal antibodies), as long as they were on a stable dose for at least 3 months and did not change it during the study. Patients were instructed to take 1 tablet every other day (which was either rimegepant or placebo) for migraine prevention. They were allowed to use rescue medications including triptans, nonsteroidal anti-inflammatory drugs (NSAIDs), and other typical analgesics. Rimegepant was not permitted as a rescue medication during the 12-week double-blind treatment phase. Migraine preventive benefits were seen in patients with episodic migraine, as well as those with and without a history of chronic migraine. Detailed results can be seen in the table below comparing Nurtec vs. Qulipta for migraine prevention.
The primary endpoint of this study:
-Change in monthly migraine days from the observation baseline compared to weeks 9-12. The study met its primary endpoint, demonstrating a statistically significant reduction from baseline in monthly migraine days in patients treated with Rimegepant compared with placebo. Patients receiving rimegepant 75 mg every other day (N=348) experienced a statistically significant reduction of 4.3 monthly migraine days for Rimegepant compared to a 3.5 day reduction in the placebo group (N=347).
Secondary endpoints included:
-50% or more reduction in monthly moderate to severe migraine days in weeks 9-12. Rimegepant was superior to placebo. 49% of patients taking Rimegepant had a 50% or more reduction in moderate to severe migraine days compared to 41% in placebo.
-Change in the mean monthly migraine days across the full treatment phase (weeks 1-12). Rimegepant was superior to placebo. Patients taking Rimegepant had 3.6 less monthly migraine days compared to 2.7 less days in placebo.
-Rescue medication days per month in weeks 9-12. There were slightly less rescue medication days per month in the Rimegepant group (3.7 days) compared to placebo (4 days), but this was not statistically superior.
-Change in monthly migraine days in the first 4 treatment weeks (weeks 1-4). Rimegepant was superior to placebo. Patients taking Rimegepant had 2.9 less monthly migraine days compared to 1.7 less days in placebo.
Preventive benefits began fast. Within the 1st week, there was a 30% drop in migraines (compared to 9.4% drop in the placebo group).
The safety and tolerability of rimegepant across the 12-week double-blind treatment phase was similar to that of placebo. Adverse events (AEs) occurring in greater than 2% of participants in the rimegepant treated group were nasopharyngitis (4%), nausea (3%), urinary tract infection (2%), and upper respiratory tract infection (2%). Nearly all AEs were mild or moderate in intensity. No treatment-related serious AEs were reported in the rimegepant group. Discontinuations due to an AE were low in both groups (rimegepant 2% and placebo 1%). Four (1%) participants who were treated with rimegepant and 2 (1%) participants who were treated with placebo experienced transaminase (ALT or AST) elevations greater than 3x upper limit of normal (ULN). One participant in the rimegepant group had asymptomatic elevation of transaminases with ALT greater than 10x ULN; alkaline phosphatase and bilirubin levels remained within normal limits. One participant in the rimegepant group had bilirubin levels greater than 2x ULN and was diagnosed with Gilbert’s syndrome after genomic testing.
A 52-week open-label extension phase followed the above 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. The data from this will be forthcoming.
Personally, I think this opens many treatment possibilities that we haven’t had available up to this point. For one thing, taking it every other day could be used as an ongoing daily preventive strategy (the long half life allows for this spread out dosing) when the migraine is in a high frequency to chronic migraine phase. If it evolves back into a lower frequency episodic migraine pattern, it can then just be used abortively only when needed for a migraine attack. This new flexible dosing option could 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., the medication could possibly be taken daily or every other day starting a few days 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, the gepants work fast and this would allow this potential treatment option to work. Headache specialists often do this “mini-prophylaxis” for the above mentioned scenarios with long acting triptans such as Frovatriptan and Naratriptan. However, for some people, this could lead to having to use it more than 10 days per month on average, which could then start to fuel rebound headache (medication overuse headache). The nice thing about the gepants is that there is no rebound headache associated with them, so this would also not be a risk when used for mini-prophylaxis.
Atogepant 10 mg, 30 mg and 60 mg doses once daily were studied in the preventive treatment of episodic migraine (4-14 days per month) during a 12-week double-blind randomized placebo-controlled treatment which included 910 patients. Detailed results can be seen in the table below.
Atogepant met the primary endpoint of statistically significant reduction from baseline in mean monthly migraine days, compared to placebo, for all doses evaluated across the 12-week treatment period. Patients treated in the 10 mg/30 mg/60 mg atogepant arms experienced a decrease of 3.69/3.86/4.2 days per month averaged over the 12 weeks, respectively, compared to placebo at 2.48 days less. By weeks 9-12, there was a 4-4 day reduction in migraine days with 60 mg. On average across the 12 week trial, patients on the 60 mg dose had a 54% reduction in monthly migraine days!
It worked very fast as well. 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% reduction in migraines (compared to 15% in placebo)!
Atogepant also showed statistically significant improvements in six secondary endpoints in the 30 mg and 60 mg once-daily treatment arms. Additional secondary endpoints measured across the 12-week treatment period included change from baseline in monthly headache days, mean monthly acute-medication use days, and mean monthly performance of daily activities and physical impairment domain scores. The 30 mg and 60 mg doses resulted in statistically significant improvements in all secondary endpoints, while treatment with the 10 mg dose resulted in statistically significant improvements in four out of the six secondary endpoints.
A key secondary endpoint measured the proportion of patients that achieved at least a 50% reduction in monthly migraine days across the 12-week treatment period. Results showed that across the 12 week trial, 56%/59%/61% of patients in the 10 mg/30 mg/60 mg atogepant arms, respectively, achieved a 50% or more reduction in migraine days compared to 29.0% of patients in the placebo arm. By weeks 9-12, 71% of patients on 60 mg had reduced their monthly migraine days by 50% or more!!
The trial also assessed the proportion of patients that achieved a 75% or more reduction in monthly migraine days across the 12-week treatment period. Results showed that 30%/30%/38% of patients in the 10 mg/30 mg/60 mg atogepant arms, respectively, achieved a 75% or more reduction in monthly migraine days, compared to 11% of patients in the placebo arm. By weeks 9-12, 50% of patients on 60 mg had reduced their monthly migraine days by 75% or more!!
And they didn’t stop there. The trial then assessed the proportion of patients that achieved a 100% reduction in monthly migraine days across the 12-week treatment period. Yes, you read that correctly, they went to 0 migraines per month. Results showed that 8%/5%/8% of patients in the 10 mg/30 mg/60 mg atogepant arms, respectively, achieved a 100% reduction in monthly migraine days, compared to 1% of patients in the placebo arm. By weeks 9-12, 28% of patients on 60 mg had 100% reduction in monthly migraine days… complete resolution!! Amazing. We just aren’t used to seeing these kinds of results.
After the main trials were completed, they began a 52 week (1 year) open label trial (patients knew they were taking the medicine) where patients took 60 mg daily. The goal was to assess for further side effects or safety concerns, of which there were none. By the end of the trial, and after a continued decline in migraines, patients were averaging 71% less migraine days per month, which equated to 5.2 less migraine days per month on average.
No significant safety risks were observed. Serious adverse events occurred in 0.9% of patients treated in the atogepant 10 mg arm compared to 0.9% of patients in the placebo arm (so basically, no difference). No patients in the atogepant 30 mg or 60 mg treatment arms experienced a serious adverse event. The most common adverse events reported with a frequency ≥ 5% in at least one atogepant treatment arm, and greater than placebo, were constipation (6.9-7.7% across all doses vs. 0.5% for placebo), nausea (4.4-6.1% across all doses vs. 1.8% for placebo), and upper respiratory tract infection (3.9-5.7% across all doses vs. 4.5% for placebo). The majority of cases of constipation, nausea and upper respiratory tract infection were mild or moderate in severity and did not lead to discontinuation. There were no hepatic safety issues identified in the trial.
The gepants (Nurtec, Qulipta) and the CGRP mAbs (Aimovig, Ajovy, Emgality, Vyepti) are all compared to each other in more detail here.
Nurtec ODT vs. Qulipta are compared in the following table. As I obtain additional data, this table will continue to be updated.
|Nurtec ODT (Rimegepant)||Qulipta (Atogepant)|
|Mechanism of Action||CGRP receptor antagonist||CGRP receptor antagonist|
|Available dosing||75 mg orally dissolvable tablet||10 mg, 30 mg, 60 mg pill|
|Pills per prescription (standard, may be more depending on insurance)||16||30|
|Dosing frequency||1 dose every other day||1 dose daily|
|Reduction of monthly migraine days across weeks 1-12||Averaged weeks 9-12:
75 mg: -4.3
Averaged weeks 1-12:
75 mg: -3.6
|Averaged weeks 9-12:
10 mg: -4.24
30 mg: -4.25
60 mg: -4.44
Averaged weeks 1-12:
10 mg: -3.7
30 mg: -3.9
60 mg: -4.2
|% reduction of migraine days in week 1||75 mg: 30%
|10 mg: N/A
30 mg: N/A
60 mg: 53%
|% reduction of migraine days in weeks 1-12||75 mg: N/A
|10 mg: N/A
30 mg: N/A
60 mg: 54%
|% of patients with a 50% or more decrease in monthly migraine days across weeks 1-12||75 mg: 49%*
*Assessed during weeks 9-12 only, not weeks 1-12
|10 mg: 56%
30 mg: 59%
60 mg: 61%
-Weeks 1-4: 61%
-Weeks 5-8: 66%
-Weeks 9-12: 71%
|% of patients with a 75% or more decrease in monthly migraine days across weeks 1-12||75 mg: N/A
|10 mg: 30%
30 mg: 30%
60 mg: 38%
-Weeks 1-4: 39%
-Weeks 5-8: 41%
-Weeks 9-12: 50%
|% of patients with a 100% decrease in monthly migraine days across weeks 1-12||75 mg: N/A
|10 mg: 8%
30 mg: 5%
60 mg: 8%
-Weeks 1-4: 19%
-Weeks 5-8: 24%
-Weeks 9-12: 28%
|Time to peak plasma concentration TMAX||90 minutes||60-120 minutes|
|½ life||11 hours||11 hours|
|Notable side effects||Nausea
75 mg: 2.7%
75 mg: 2.4%
10 mg: 5%
30 mg: 6%
60 mg: 9%
10 mg: 6%
30 mg: 6%
60 mg: 9%
10 mg: 4%
30 mg: 4%
60 mg: 6%
10 mg: 2%
30 mg: 1%
60 mg: 2%
% of Patients with Weight Loss of 7% or More
10 mg: 3.8%
30 mg: 3.2%
60 mg: 4.9%
Can I use a CGRP monoclonal antibody (mAb) (Aimovig, Ajovy, Emgality, Vyepti) with the gepants (Nurtec, Ubrelvy)?
An insurance battle often ensues when trying to use the large molecule preventive CGRP mAbs with the small molecule abortive gepant medications (Nurtec, Ubrelvy), which also work by a CGRP mechanism. Insurance companies will often not allow these to be used together, but again, no good scientific basis. Actually, there is some limited evidence showing that these medications can work synergistically together, which would make sense when taking their mechanisms of action into account. Specifically, there was a publication of data from only a 2-patient cohort showing that the use of these acute and preventive CGRP migraine therapies together can be successful and safe. These two patients had been using rimegepant (Nurtec) in a long-term safety study and they had added erenumab (Aimovig) once monthly injection as a preventive treatment. After Aimovig was added, patient 1 had 100% relief for 7 of 7 acute migraine attacks treated with Nurtec. Patient 2 had 100% relief for 9 of 9 acute migraine attacks treated with Nurtec. So, the combination of using Nurtec abortively in addition to using Aimovig preventively appeared to provide an even more effective acute migraine response. Theoretically, it would make sense that benefit would be greater with both classes of medicines combined because they are entirely different types of medications targeting aspects of the same migraine pathway simultaneously (either targeting the CGRP receptor or the CGRP ligand protein). Larger studies to confirm the suspicion that they likely work together synergistically will be helpful.
There was a larger safety study publication which evaluated the acute treatment of migraine with Rimegepant while using a CGRP monoclonal antibody for the prevention of migraine. The CGRP mAbs used were Erenumab (Aimovig) (7 patients), Fremanezumab (Ajovy) (4 patients), and Galcanezumab (Emgality) (2 patients). The study determined that Rimegepant used as an acute migraine treatment in combination with CGRP mAbs for migraine prevention was well tolerated with no safety issues identified. The researchers concluded that the probability between these 2 classes (gepants and CGRP mAbs) was low, especially because they have entirely different pathways of drug metabolism. They also concluded that existing evidence supports the safety of combined use, although further larger research was warranted.
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