RIMEGEPANT (NURTEC ODT) VS. ATOGEPANT FOR MIGRAINE PREVENTION. THE GEPANTS AREN’T JUST FOR ABORTIVE TREATMENT ANYMORE!
Last updated on April 9th, 2021 at 12:47 am
RIMEGEPANT (NURTEC ODT) VS. ATOGEPANT FOR MIGRAINE PREVENTION. THE GEPANTS AREN’T JUST FOR ABORTIVE TREATMENT ANYMORE!
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!
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). 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 in contrast to migraine preventive treatments which are a continuous treatment (not just taken as needed). Preventive treatments include a daily pill, a monthly/quarterly treatment such as CGRP mAbs (Aimovig, Ajovy, Emgality, Vyepti), or neuromodulation devices. 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. 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 Eptinizumab (Vyepti).
The CGRP mAbs were 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). That was until now. These new gepant medications will be the first in history to assume this new role.
As mentioned earlier, the worlds of the gepants, abortive and preventive treatments are all colliding. There are 2 gepants which have been submitted to the FDA for their pending approval as migraine preventives, and both seem very effective!! As of now, neither has officially received FDA approval for migraine prevention yet. Stay tuned to this blog for developments in FDA approval, further data and information.
These gepants are Rimegepant (Nurtec ODT, but unknown if the preventive name will be different) from Biohaven and Atogepant (brand name currently unknown) from Allergan/Abbvie. Notably, Rimegepant would be FDA approved as both an abortive and preventive medicine simultaneously, which would be a first ever. Yes, I know your mind has just been blown. Let’s discuss them and the currently available data, which can be found on each company’s website.
Rimegepant 75 mg every other day was studied 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. 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 for preventive purposes during the study. 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.
A 52-week open-label extension phase was also conducted in which 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. The data from this will be forthcoming.
The primary endpoint of this study measured the change from baseline in mean number of migraine days per month in weeks 9-12. Secondary endpoints included achievement of at least a 50% reduction in the mean number of moderate to severe migraine days per month during weeks 9-12, change in the mean number of migraine days per month across the full treatment phase (Weeks 1-12), mean number of rescue medication days per month during weeks 9-12, and change in the mean number of migraine days per month in the first 4 weeks (Weeks 1-4). 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).
Rimegepant was more effective than placebo regarding the percent of participants with at least a 50% reduction in the mean number of moderate to severe migraine days per month during weeks 9-12. Rimegepant was also superior to placebo for the mean change in mean number of total migraine days per month over the 3-month treatment period. The rimegepant and placebo treatment groups were not statistically different with respect to the mean days of rescue medication per month during weeks 9-12.
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, nausea, urinary tract infection, and upper respiratory tract infection. 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.
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. 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, respectively, all compared to patients in the placebo arm, who experienced a decrease of 2.48 days.
Atogepant also showed statistically significant improvements in six secondary endpoints in the 30 mg and 60 mg once-daily treatment arms. A key secondary endpoint measured the proportion of patients that achieved at least a 50% reduction in mean monthly migraine days across the 12-week treatment period. Results showed that 55.6%/58.7%/60.8% of patients in the 10 mg/30 mg/60 mg atogepant arms, respectively, achieved at least a 50% reduction, compared to 29.0% of patients in the placebo arm. Additional secondary endpoints measured across the 12-week treatment period included change from baseline in mean 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.
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.
Stay tuned! As more information, data, and official FDA approval is granted for each medication, this blog will continue to be updated…
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