Posts Tagged "gepants"


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!

@Neuralgroover

BACKGROUND

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

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

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…

 

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.

 

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING TO ASK QUESTIONS TO A HEADACHE SPECIALIST OR OTHER HEADACHE, MIGRAINE, AND FACIAL PAIN WEBSITE MEMBERS, VISIT OUR FREE DISCUSSION FORUMS HERE.

 

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Last updated on April 9th, 2021 at 12:43 am

UBRELVY (UBROGEPANT) vs. NURTEC ODT (RIMEGEPANT) vs. REYVOW (LASMIDITAN) vs. TRIPTANS. NEW MIGRAINE ABORTIVE OPTIONS ARE FINALLY HERE, BUT WHAT ARE THE DIFFERENCES AND IS ONE BEST FOR YOU?

@Neuralgroover

BACKGROUND

Ubrelvy vs. Nurtec, Ubrelvy vs. triptans, Nurtec vs. triptans, Ubrelvy vs. Reyvow, Nurtec vs. Reyvow, Reyvow vs. triptans, Rimegepant vs. Ubrogepant, Ubrogepepant vs. triptans, Rimegepant vs. triptans, Lasmiditan vs. Ubrelvy, Nurtec vs. Lasmiditan, Lasmiditan vs. triptans, Ubrogepant vs. Lasmiditan, Rimegepant vs. Lasmiditan. How do you know which one to pick??? Let’s discuss how to pick the best one for you.

 

First off, these medications are all migraine specific abortive/acute (as needed) options. The goal of migraine abortive treatments 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 rather than having to go lay down and miss the whole day in bed. This is in contrast to migraine preventive treatments which are a continuous treatment. Preventive treatments include a daily pill, a monthly/quarterly treatment such as CGRP monoclonal antibodies (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 these options 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.

 

Since the development and availability of sumatriptan in 1992, the primary migraine specific abortive/acute (as needed) option available has been the triptans. Triptans (Imitrex, Maxalt, etc.) work great for a lot of people. However, about 30% of patients do not respond to triptans. Others cannot tolerate side effects, or they cannot use them because of medical contraindications (such as coronary artery disease, peripheral artery disease, cerebrovascular disease, stroke, etc.). Triptans are also contraindicated in patients with visual snow, persistent migraine aura, and migrainous stroke (infarction). They have been historically contraindicated in hemiplegic migraine or basilar migraine (now called migraine with brainstem aura) due to theoretical concerns of vasoconstriction potentially causing stroke. When the triptan studies were done previously, they excluded patients with these forms of migraine due to the ongoing vascular theory of migraine at that time. The vascular theory of migraine assumed that vasoconstriction and lack of blood flow was the cause of aura and neurologic features with migraine. So the thinking was that if you cause further vasoconstriction with a triptan, you may cause stroke. However, we now know that these phenomenon are primarily of an electrical basis and not a vascular basis. Therefore many specialists have gotten more liberal with the use of triptans in patients with hemiplegic or basilar migraine, and there have been a number of case series and case reports of these patients using triptans without any problems.

 

The alternatives to triptans have historically been the ergots (ergotamine, DHE) which can be complicated to use, tend to have an excess of side effects for many, and have the same medical contraindications as triptans. NSAIDs and over the counter analgesics are also commonly used, although many do not respond to or cannot take them due to other medical conditions. Even worse are opiates/opioids and butalbital medications such as fioricet, both of which (as do excess triptans, NSAIDS, OTCs) have a high risk of leading to medication overuse headache (rebound headache), as discussed here.  For close to 3 decades, these have remained the only limited options of acute/abortive migraine treatment, despite migraine being such a widespread common disorder! More recently, neuromodulation devices have also become available as abortive options.

 

Thankfully, these limited options have now expanded to 3 new migraine abortive options in adults between 2 new classes which became available commercially in 2020; the gepants and the ditans. These medications can be used SAFELY in all of the medical contraindications mentioned above! These 3 new abortive medications are compared and contrasted with one another, as well as with the triptans in the table which I constructed below.

 

GEPANTS

The gepants were the first to emerge as new migraine abortive options, first with Ubrogepant (Ubrelvy) which became available from Allergan in January 2020 and then Rimegepant (Nurtec ODT (orally dissolvable tablet)) became available by Biohaven in February 2020.

 

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.

 

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 pain. So, you get reversal of cerebral vasodilation, which decreases the firing off of the trigeminal nerves. 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.

 

The side effect profile of the gepants is minimal and similar to placebo compared to the triptans and their alternatives.  This is really great to have new options with much less side effect potential. In addition, there is no interaction with using them and triptans, NSAIDs, or other acute meds in case they happen to be taken close together. These medications are not associated with addiction potential, and do not cause medication overuse headache (rebound), which is great! Compared to the triptans and ergots, these medications are NOT contraindicated in patients with stable cardiovascular or peripheral vascular disease or risk factors because they do not cause vasoconstriction (narrowing) of the arteries, which is a HUGE benefit. There are many patients who have been stuck in limbo unable to use standard therapies such as triptans due to other medical problems such as heart disease, so we finally have a safe alternative for them, which is another highlight of these medications. Safety of these medications in pregnancy or breastfeeding is unknown because they haven’t been studied, and therefore are not recommended. The primary drug interactions to be aware of with these medications are when used with other medications that are metabolized by the liver enzyme system called CYP3A4. Many commonly used medications are metabolized by this system. Strong or moderate inhibitors of CYP3A4 (which slow down the metabolism activity) will cause an increase in gepant exposure. Strong or moderate inducers of CYP3A4 (which increase the metabolism activity) will cause a decrease in gepant exposure and possibly decreased effectiveness. These medications should be avoided in patients with severe liver disease or end stage kidney disease such as those on dialysis.

 

Many patients use once monthly CGRP antagonist monoclonal antibody (mAbs) self-injections (autoinjection devices) which are FDA approved for migraine prevention (Aimovig (Erenumab), Ajovy (Fremanezumab), Emgality (Galcanezumab), and Vyepti (Eptinezumab), which is a once quarterly 30 minute IV infusion). The CGRP mAbs are discussed in much greater detail and compared with one another here. These have little to no drug interactions and do not affect the liver or kidneys. However, patients often ask if these medications can be used with the gepants given similar mechanisms of action (although much different structure, molecule size, and metabolism). Further confirmatory research is needed, but it is theorized that these medicines can likely be used safely together, and they are metabolized by completely different mechanisms. The gepants are metabolized in the liver, while the CGRP mAbs are metabolized and cleared in the reticuloendothelial system. Furthermore, there is limited evidence suggesting that they may even provide a synergistic effect by working together, but more evidence is needed to confirm this. 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, despite 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 had added erenumab (Aimovig). The combination of both successfully aborted 100% of their acute migraine attacks. Certainly we need need larger studies to confirm the suspicion that they likely work together synergistically.

 

Given that Ubrelvy and Nurtec ODT are of the same gepant class, they each have their own marketing pitch to differentiate them, although the bottom line is that they are both excellent options. Although they are both very effective for most patients, I commonly see patients who may respond to one better than the other. So if one of them does not help, it is worth trying the other one as well.

 

Ubrelvy (Ubrogepant)

Allergan markets Ubrelvy as quickly relieving migraine pain within 2 hours with just one dose, and that complete elimination of migraine pain with one dose is possible. Furthermore, they highlight that they provide the option of being able to repeat a 2nd dose if needed (similar to how triptans are dosed), with a higher proportion of patients achieving pain freedom 2 hours after taking the optional second dose. They also claim effective relief whether Ubrelvy was taken right away at migraine onset or within 4 hours. The half life is 5-7 hours, so duration of effect is extended compared to many options that we had up to this point. The clinical data highlights of Ubrelvy are that at 1 hour Ubrelvy 50 mg becomes statistically superior to placebo for pain relief, and at 2 hours the 100 mg dose also becomes statistically superior to placebo for pain relief. At 2 hours, both the 50 mg and 100 mg doses become statistically superior to placebo for pain freedom as well as freedom from most bothersome migraine symptom (nausea, photophobia or phonophobia). These benefits could extend into 24 and even 48 hours. In patients who received pain relief with the 1st dose and took an optional 2nd dose of 50 mg, 55% went on to become pain free 2 hours from that point.

Side effects were similar to placebo and the most common were nausea (placebo 2%, Ubrelvy 50 mg 2%, Ubrelvy 100 mg 4%), and somnolence (sleepiness) (placebo 1%, Ubrelvy 50 mg 2%, Ubrelvy 100 mg 3%).

They currently have a savings card program which should work with commercial insurances for $10 per month, which works out to $1 per pill (10 pills per month). You can get a digital copy of this savings card on your phone to show to the pharmacist if you text UBRELVY to 48764.

 

Nurtec ODT (Rimegepant)

Biohaven boasts that Nurtec ODT 75 mg dissolves under or on the tongue in seconds, and starts working in minutes (15 minutes in some patients). They highlight that it does not require water or other liquids to take with the dose, so it can be taken anytime and anywhere. It is taken as a simple single strength single dose. They also point out that pain relief and pain freedom lasts up to 48 hours for many patients, which makes sense because it has the longest half-life (11 hours). The clinical data highlights of Nurtec ODT are that at 15 minutes, you get separation from placebo of both pain relief and return to normal function (but not yet statistically superior). At 1 hour, pain relief and return to normal function become statistically superior to placebo. At 1.5 hours, you get additional statistical superiority over placebo of pain freedom and freedom from most bothersome migraine symptom (nausea, photophobia or phonophobia). For the vast majority of patients, the superiority of all of these trial endpoints over placebo remain sustained through 48 hours.

Side effects were similar to placebo and the most common was nausea (placebo 0.4%, Nurtec 2%).

They currently have a savings card program which should work with commercial insurances for $0 per month (8 pills per month). You can get a digital copy of this savings card on your phone to show to the pharmacist if you text NSAVE to 26789.

Notably, Biohaven submitted a request to the FDA in October 2020 to approve Rimegepant as a preventive migraine treatment as discussed further here, in addition to its current migraine abortive FDA approved indication. This decision is pending. This move followed clinical trials showing that patients taking 75 mg of Rimegepant every other day experienced a 4.3 day reduction from baseline in monthly migraine days.

 

DITANS

Reyvow (Lasmiditan)

The ditans are another new class of migraine abortive, premiering with Lasmiditan (Reyvow) in January 2020 from Eli Lilly. Lasmiditan acts as a high affinity 5-HT1F (serotonin 1F) receptor agonist. The result of its action is a decrease in the release of inflammatory pain producing neurotransmitters and neuropeptides including CGRP from the trigeminal nerves during a migraine attack. These receptors are also involved in modulating other pain signals and blocking (inhibiting) other pain pathways. Notably, like the gepants, they also do not cause arterial vasoconstriction. Again, this is a tremendous benefit and another great option in patients who may not be able to use triptans due to medical contraindications such as coronary or peripheral vascular disease. Caution should be used with other serotonergic drugs given a potential for serotonin syndrome, which was reported in clinical trials.

Similar to the gepants, the Reyvow clinical data highlights showed superiority over placebo at trial endpoints of 2 hour pain freedom, freedom from most bothersome migraine symptom (nausea, photophobia or phonophobia), and pain relief.

In a driving study, 50 mg, 100 mg, or 200 mg doses of Lasmiditan significantly impaired subjects’ ability to drive, and more sleepiness was reported at 8 hours following a single dose compared to placebo. Therefore, patients should wait at least 8 hours between dosing and driving or operating machinery. This can certainly be a drawback in terms of being a treatment option for many patients as the goal of abortive therapy is partly to be able to maintain and restore function in order to not disrupt work, plans, etc. However, if you are in a position where this would not be an issue for you, it could certainly be a valid option to have in your migraine war chest. It should also be used with caution in combination with alcohol or other central nervous system depressants.

Notably, Lasmiditan is a Schedule V controlled substance compared to the other abortive options. Schedule V represents the lowest abuse potential category from the DEA. The reason is because in a human abuse potential study, doses of 100 mg, 200 mg, and a supratherapeutic dose of 400 mg were associated with statistically significantly higher “drug liking” scores than placebo, indicating possible abuse potential. However, it had statistically significantly lower “drug liking” scores compared to alprazolam 2 mg. Lasmiditan also produced adverse events of euphoria and hallucinations to a greater extent than placebo, although it was a low frequency (about 1% of patients). They currently have a savings card program which should work with commercial insurances for $0 per month (4 pills per month).

 

SUMMARY

The chart below compares and contrasts the treatment outcomes data between Rimegepant, Ubrogepant, Lasmiditan, and Sumatriptan (as representative of the triptan class since it was the first developed). The source of the data comes from the key trials of each medication, as well as some data obtained directly from the pharmaceutical companies. It’s important to note that the trials for each medication did not all include the same data point evaluations, so not all of the comparison data is available across the medications to compare. Also, this data is not reflective of head to head trials between these medications. The data is derived from separate independent trials, many times of which there were variations in study design and endpoints. So, they should not be thought of as head to head comparisons necessarily. In addition, the original triptan studies did not include many of the treatment outcome data points that have become more commonly used since they were developed such as 8 hour data, 2-48 hour data, most bothersome symptom, etc. Therefore, many of these data points within the columns of the different medications may be labeled by N/A (not available).

 

Overall, these are all very effective and useful medications to keep in mind for your migraine abortive war chest. They are all a welcome and much needed option for the abortive (acute) treatment of migraine. Notably, Ubrelvy, Nurtec ODT, and Reyvow were all proven to be statistically superior to placebo at 2 hours post-dose (some sooner) in terms of pain freedom, pain relief, and freedom from most bothersome migraine symptom (nausea, sensitivity to light (photophobia) or sensitivity to sound (phonophobia)). So there is no “bad” option. Many of the data points are fairly similar with some slight variations, and some data points weren’t compared. Regardless, I have highlighted some of the key differences to take note of in bold print. I hope this data can provide some guidance on some of the differences in these medications which may help to better select them based on the treatment goals, setting of use, and other patient characteristics.

 

Rimegepant Ubrogepant Lasmiditan Sumatriptan (100 mg)
Class Gepant Gepant Ditan Triptan
Mechanism of Action CGRP receptor antagonist CGRP receptor antagonist 5HT1F agonist 5HT1B and 5HT1Dagonist
Available dosing 75 mg orally dissolvable tablet 50 mg, 100 mg pill 50 mg, 100 mg, 200 mg (100 mg x 2) pill 25 mg, 50 mg, 100 mg pill; 3 mg, 4 mg, 6 mg injection; 5 mg, 10 mg, 20 mg nasal spray
Max dose per 24 hours 75 mg 200 mg 200 mg 200 mg
Pills per prescription (standard, may be more depending on insurance) 8 10 8 9
Dosing frequency 1 dose/24 hours Dose can repeated once in 2 hours; 2 doses/24 hours 1 dose/24 hours Dose can repeated once in 2 hours; 2 doses/24 hours
Suggested number of migraine attacks treated per 30 days 15 (however, currently also being studied as a daily preventive) 8 4 10
Time to reach statistically significant pain relief 60 minutes (however, there was a 15 minute measured clinical beneficial effect) 60 minutes with 50 mg or higher doses 30 minutes with 100 mg or higher doses;

60 minutes with 50 mg dose

30 minutes with 50 mg or higher doses
1 hour significant pain relief 37%

31% (placebo)

43% (50 mg)

N/A (100 mg)

36.7% (placebo)

37.3% (50 mg)

»41% (100 mg)

»46% (200 mg)

30.6% (placebo)

20-35% (100 mg)

12-21% (placebo)

Differences in pain relief at 15 minutes 8%

5% (placebo)

N/A N/A N/A
Differences in pain relief at 30 minutes 19%

17% (placebo)

19% (50 mg)

N/A (100 mg)

20% (placebo)

»15% (50 mg)

17.5% (100 mg)

19.1% (200 mg)

13.4% (placebo)

11% (100 mg)

12% (placebo)

2 hour pain relief 59%

43% (placebo)

61.7% (50 mg)

61.4% (100 mg)

48.7% (placebo)

59% (50 mg)

59.4-64.8% (100 mg)

59.5-65% (200 mg)

42.2-47.7% (placebo)

46-67% (100 mg)

18-44% (placebo)

2 hour pain freedom 21%

11% (placebo)

20.5% (50 mg)

21.2% (100 mg)

13% (placebo)

28% (50 mg)

28-31% (100 mg)

32-39% (200 mg)

15-21% (placebo)

22-33% (100 mg)

3-13% (placebo)

8 hour pain freedom with 1 dose 56%

33% (placebo)

82.3% (50 mg)

82.7% (100 mg)

69.8% (placebo)

N/A N/A
8 hour pain relief with 1 dose 74%

56% (placebo)

92% (50 mg)

N/A (100 mg)

82% (placebo)

N/A N/A
% of patients with 1st dose pain relief who achieved pain freedom after 2nddose N/A 54.7% (50 mg/50 mg)

33.3% (50 mg/placebo)

51.6% (100 mg/100 mg)

33.3% (100 mg/placebo)

N/A N/A
Sustained pain freedom 2-24 hours 15.7%

5.6% (placebo)

13.6% (50 mg)

15.4% (100 mg)

8.4% (placebo)

17.2% (50 mg)

14.8-17.9% (100 mg)

18.6-22.7% (200 mg)

7.6-13.4% (placebo)

N/A
Sustained pain relief 2-48 hours 47.8%

27.7% (placebo)

31.5% (50 mg)

34% (100 mg)

17.5% (placebo)

N/A N/A
2 hour absence of most bothersome migraine symptom 35%

27% (placebo)

38.7% (50 mg)

37.7% (100 mg)

27.6% (placebo)

41% (50 mg)

41-44% (100 mg)

41-49% (200 mg)

30-33% (placebo)

N/A
8 hour absence of most bothersome migraine symptom N/A 90.9% (50 mg)

92.4% (100 mg)

77.7% (placebo)

N/A N/A
Time to peak plasma concentration TMAX 1.5 hours 1.5 hours 1.8 hours 1.5-2.5 hours
½ life 11 hours 5-7 hours 5.7 hours 2-2.5 hours
Time to reach pharmacologically active concentration 15 minutes Within 11 minutes N/A N/A
Time the pharmacologically active concentration is maintained 48 hours 12 hours N/A N/A
Notable side effects Nausea

2%

0.4% (placebo)

Nausea

2% (50 mg)

4% (100 mg)

2% (placebo)

 

Somnolence/Sedation

2% (50 mg)

3% (100 mg)

1% (placebo)

Nausea

3% (50 mg)

4% (100 mg)

4% (200 mg)

2% (placebo)

 

Somnolence/Sedation

6% (50 mg)

6% (100 mg)

7% (200 mg)

2% (placebo)

 

Dizziness

9% (50 mg)

15% (100 mg)

17% (200 mg)

3% (placebo)

 

Paresthesias

3% (50 mg)

7% (100 mg)

9% (200 mg)

2% (placebo)

Widely variable, most common: Dizziness, fatigue, paresthesias, sedation, nausea, palpitations, anxiety, muscle tightness sensation in chest/neck/throat

 

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