Migraine Headaches

Migraine Headaches: A Pharmacotherapy Update

By: Dr. Kaitlyn Gibson

Introduction

Migraine is a neurological disorder that results in headache attacks characterized by moderate to severe pain. These headaches have a complex pathophysiology with involvement of various neural networks. The pain from an attack is thought to be caused by activation of trigeminal sensory pathways which innervate various intracranial structures, such as the eyes. 1 The typical course of a migraine attack consists of a premonitory phase (in which some individuals may experience aura, which are reversible neurological symptoms), the headache, and a headache resolution phase. Attacks may last anywhere from 4 to 72 hours, during which time many individuals experience disabling symptoms. Among the most common symptoms are photophobia, phonophobia, and gastrointestinal symptoms such as nausea and vomiting; however, individuals can experience a wide variety of other symptoms unique to their migraine attacks. 1

In the 2012 National Health Interview Survey, 14.2% of adults in the United States reported a migraine in the previous 3 months. 2 Migraines are most prevalent in the those who are 18- to 44-years, with females being more affected than males (19.1% vs 9.0% over a 3-month period). 2 Individuals that experience migraine are significantly impacted both physically and financially. Most patients experience some level of functional disability during an attack due to extreme light, sound, touch, or smell sensitivity, visual disturbances, nausea or vomiting, or tingling or numbness in the face or extremities. 3 In the International Burden of Migraine Study (IBMS), 79.8% of patients reported severe to very severe disability due to their migraines. The estimated cost over a 3-month period for the treatment of migraine (not including indirect costs) is around $1,000. 4 This is a huge financial burden to patients and can include visits to providers or emergency departments, diagnostic testing, and medications. 4 In a study published in 2017, 7,671 patients of 857,073 required 2 or more emergency department visits for their migraine and 185,911 saw a neurologist. 5

Treatment recommendations vary depending if an individual is being treated for an acute migraine attack or is taking pre

ventative medications. The 2000 US Headache Consortium guidelines for acute treatment of migraine list triptans as a first-line treatment, with other options with proven clinical benefit being ergotamine derivatives, aspirin, NSAIDs such as ibuprofen and naproxen, and combination products such as acetaminophen/aspirin/caffeine. 6 In the 2012 guideline update for episodic migraine prevention, preferred agents are antiepileptics such as divalproex and topiramate, beta-blockers such as metoprolol and propranolol, and frovatriptan. Other options that can be considered are antidepressants such as amitriptyline and venlafaxine, other beta-blockers such as atenolol and nadolol, and other triptans such as naratriptan and zolmitriptan. 7 Treatment options for both acute management and prevention should be tailored based on patient-specific factors. Since the most recent guideline update, there have been several new classes of medications that have been approved for both acute treatment and prevention. The objective of this review is to evaluate new drug classes for acute treatment or prevention of migraine, examine the evidence supporting their use, and discuss potential future roles in therapy.

New Therapies in Acute Management

Triptans exert their effects via serotonin (5-HT) receptors with a high affinity for 5-HT 1B and 5-HT 1D . 5-HT 1B receptors located on the blood vessels of smooth muscle cells cause cranial vasoconstriction, while 5-HT 1D receptors are in trigeminal nerve terminals and dorsal horn. 5 It is believed that stimulation of these receptors block release of vasoactive peptides and neurotransmitters that convey information to the thalamus leading to a decrease in pain sensation. Due to vasoconstriction, triptans are contraindicated in patients with previous stroke or myocardial infarction, uncontrolled hypertension or ischemic heart disease. 5,8

New therapies target two other receptors, 5-HT 1F and calcitonin gene-related peptide. Patients with a contraindication to a triptan with a higher affinity for 5-HT 1B and 5-HT 1D , may be able to try one of the novel agents since neither of these newer agents cause vasoconstriction. 9-11

Serotonin 5-HT1F Receptor Agonist

Lasmiditan (Reyvow) was approved by the FDA in October 2019 for the acute treatment of migraine with or without aura as a Class V controlled substance. It is the first of a new group of headache medicines called the “ditans.” 9

Lasmiditan is available in 50 mg and 100 mg tablets. Recommended dosing is 50, 100, or 200 mg orally as needed with no more than one dose taken within a 24-hour period. Unlike triptans, a second dose has not been shown to be effective for the same migraine attack. Dose adjustment in the presence of renal or hepatic impairment is not required. Dizziness is the most common adverse event and appears to be dose-related (9% in 50 mg, 15% in 100 mg, 17% in 200 mg). 9 Lasmiditan may also cause driving impairment and CNS depression; therefore, patients should be counseled not to drive until they determine how the medication may affect them. 9

In a phase 3, randomized, double-blinded, placebo-controlled study, lasmiditan was evaluated for efficacy and safety. This research involved 1,856 adults with a diagnosis of migraine for at least 1 year prior to study initiation. Patients were randomized 1:1:1 to receive a first dose of either lasmiditan 200 mg, lasmiditan 100 mg, or placebo. 12 Patients were also randomized to a second dose for rescue treatment for migraine recurrence. Patients in the 200 mg first dose group were randomized 2:1 to lasmiditan 200 mg or placebo. Patients in the 100 mg first dose group were randomized 2:1 to lasmiditan 100 mg or placebo. All patients in the placebo first dose group received placebo as a second dose. The primary efficacy endpoint was a comparison of the proportion of patients in the lasmiditan 200 mg and placebo groups who were headache pain free at 2 hours after the first dose. 12 Key secondary efficacy endpoints included: a comparison in the lasmiditan 200 mg and placebo groups for absence of their most bothersome migraine symptom (either nausea, phonophobia, or photophobia) at 2 hours after the first dose; a comparison in

the lasmiditan 100 mg and placebo groups for freedom from headache pain at 2 hours after the first dose; and a comparison in the lasmiditan 100 mg and placebo groups for absence of their most bothersome migraine symptom. Results showed statistically significantly more patients in the lasmiditan 200 mg group (32.2%, p<0.001) were free from headache pain at 2 hours following the dose compared to placebo (15.3%). 12 Patients in the lasmiditan 100 mg group also showed statistically significance for freedom from headache at 2 hours after the dose compared to placebo (28.2%, p<0.001). 12 Similar results were seen for absence of the most bothersome symptom, with 40.7% (p<0.001) of patients in the lasmiditan 200 mg group having freedom from their most bothersome symptom 2 hours after the dose compared to 29.5% in the placebo group. 12 40.9% (p<0.001) of patients in the lasmiditan 100 mg group showed absence of their most bothersome symptom 2 hours after the dose. The most common adverse event related to the study treatment was dizziness, with 16.3% in the lasmiditan 200 mg group, 12.5% in the lasmiditan 100 mg group, and 3.4% in the placebo group. 12

In a post hoc analysis of pooled data from two phase 3 studies, SAMURAI and SPARTAN, lasmiditan was evaluated for efficacy versus placebo in treating migraine-related headache pain and most bothersome symptom. 13 The use of migraine preventive treatment was allowed if the patient had been on a stable dose at least 3 months prior to screening. Between the two trials, a total of 3,891 adult patients with a diagnosis of episodic migraine with or without aura for at least 1 year were enrolled. In both trials, patients were randomized evenly into the following groups: lasmiditan 100 mg, lasmiditan 200 mg, or placebo. The SPARTAN trial added a fourth group, lasmiditan 50 mg. Patients took their assigned dose during their next migraine attack within 4 hours of pain onset. The primary efficacy outcome for both trials was the proportion of patients that were headache pain-free at 2 hours after the dose. The key secondary efficacy endpoint was the absence of the patient’s most bothersome symptom at 2 hours after the dose. 13 Results were similar to the previous trial; all doses of lasmiditan showed statistically significant (all p-values < 0.05) increases in the percentage of patients who were free from headache pain and had absence of their most bothersome symptom at 2 hours after the dose versus placebo. These two trials also analyzed the efficacy of lasmiditan in patients taking topiramate and propranolol for migraine prevention. Outcomes for the primary and key secondary efficacy endpoint were similar amongst patients using topiramate or propranolol versus patients not taking one of those medications (interaction p-values >0.1). 13 Rates of adverse events were also similar amongst patients using migraine preventive medication versus patients not using migraine preventive medication (14.9% vs 14.6% for dizziness, Oral Calcitonin Gene-Related Peptide Receptor Antagonists

Calcitonin gene-related peptide (CGRP) is a neurotransmitter that is released during a migraine attack and promotes pain transmission in the trigeminovascular system. Oral CGRP receptor antagonists (gepants) antagonize the CGRP receptor to block the action of the neurotransmitter and thus reduce migraine-associated pain during an attack. 10,14 There are currently two medications approved by the FDA in this class: ubrogepant and rimegepant.

Ubrogepant

Ubrogepant (Ubrelvy) was approved in December 2019 for acute treatment of migraine with or without aura in adults. It is available in 50 mg or 100 mg oral tablets, with a recommended dose of 50 or 100 mg as needed for migraine-related headache pain. Patients may take a second dose of ubrogepant at least 2 hours after the initial dose if needed; however, patients should not exceed a total of 200 mg in a 24-hour time period. The recommended dose in severe hepatic impairment (Child-Pugh Class C) is 50 mg for the initial and second doses. Patients with severe renal impairment (CrCl 15-29 mL/min) should also take 50 mg for the initial and second dose. Patients with a CrCl < 15 mL/min should avoid the use of ubrogepant. There is also a dose adjustment for the concomitant use with some medications. Ubrogepant

should be avoided with use of a strong CYP3A4 inhibitor. With the use of moderate CYP3A4 inhibitors, the initial dose of ubrogepant should be 50 mg and a second dose should be avoided within 24 hours. The dose of ubrogepant should be reduced to 50 mg for both the initial and second dose in the presence of weak CYP3A4 inhibitors and BCRP/P-gp inhibitors. The most common adverse events seen in clinical trials, with occurrence >2% and greater than placebo, are nausea and somnolence. 10

In one of the two phase 3 trials conducted for the approval of ubrogepant, a total of 1,672 adults with at least a 1-year history of migraine with or without aura were enrolled. This was a randomized, double-blind, placebo-controlled, parallel-group trial. Patients were randomized 1:1:1 to receive placebo (two tablets of placebo), ubrogepant 50 mg (one tablet of ubrogepant 50 mg and one tablet of placebo), or ubrogepant 100 mg (two tablets of ubrogepant 50 mg). Patients were also randomized for an optional second dose to either the same dose as their initial assignment or placebo. Patients initially in the placebo group also received placebo for the second dose. The coprimary efficacy endpoints were freedom from headache pain and absence of the most bothersome symptom (photophobia, phonophobia, or nausea) at 2 hours after the initial dose. Secondary efficacy endpoints included pain relief at 2 hours after the initial dose, sustained pain relief 2 to 24 hours after the initial dose, freedom from pain 2 to 24 hours after the initial dose, and absence of photophobia, phonophobia, and nausea at 2 hours after the initial dose. Results showed a statistically significant difference versus placebo for the coprimary endpoints for both ubrogepant groups. 11.8% of patients in the placebo group experienced freedom from pain 2 hours after the first dose, compared to 19.2% (P=0.002) in the ubrogepant 50 mg group and 21.2% (P<0.001) in the ubrogepant 100 mg group. Absence of the most bothersome symptom 2 hours after the first dose occurred in 27.8% of patients in the placebo group, compared to 38.6% (P=0.002) in the ubrogepant 50 mg group and 37.7% (P=0.002) in the ubrogepant 100 mg group. Rates of adverse events seem to be dose-related and no patients discontinued the study due to adverse events. Nausea occurred in 1.6% of patients in the placebo group, 1.7% in the ubrogepant 50 mg group, and 4.1% in the ubrogepant 100 mg group. Somnolence occurred in 0.8% of patients in the placebo group, 0.6% in the ubrogepant 50 mg group, and 2.5% in the ubrogepant 100 mg group (no P-values provided). 14

Rimegepant

Rimegepant (Nurtec ODT) was approved in February 2020 for the acute treatment of migraine with or without aura in adults. 11 It is available as a 75 mg orally disintegrating tablet (ODT), with a recommended dose of 75 mg as needed for migraine-related headache. The maximum dose in a 24-hour period is 75 mg. 11 Patients with severe hepatic impairment (Child-Pugh Class C) should not take rimegepant. Concomitant administration with strong CYP3A4 inhibitors, moderate to strong CYP3A inducers, and P-gp or BCRP inhibitors should be avoided. If a patient is also taking a moderate CYP3A4 inhibitor, no more than 1 dose of rimegepant should be administered in a 48-hour period. Severe hypersensitivity reactions, including dyspnea and rash have occurred up to days after administration of rimegepant. Nausea was the most common adverse event reported in clinical trials (≥ 1%). 11

In the trial conducted for FDA approval of the ODT formulation of rimegepant, a total of 1,466 adults with at least a 1-year history of migraine with or without aura were randomized. 15 This was a randomized, double-blind, multicenter, placebo-controlled phase 3 trial. Patients were randomized in a 1:1 fashion to receive either rimegepant 75 mg ODT or placebo. Randomization was stratified based on the patient’s usage of a migraine preventive medication. Coprimary efficacy endpoints were freedom from pain and freedom from the patient’s most bothersome symptom (phonophobia, photophobia, or nausea) at 2 hours after the dose. 15 Twenty-one secondary endpoints were tested, and some include: pain relief, freedom from photophobia, phonophobia, or nausea, and ability to function at 2 hours after the dose; freedom from pain, freedom from the most bothersome symptom, pain relief, and ability to function normally at 90 minutes after the dose; as well as similar endpoints at 24 to 48 hours after the dose. Results showed statis-

tically superior results for coprimary endpoints. 21% of patients in the rimegepant group reported freedom from pain at 2 hours after the dose, compared to 11% in the placebo group (p<0.0001; risk difference 10, 95% CI 6-14). 35% of patients in the rimegepant group experienced freedom from their most bothersome symptom, while 27% in the placebo group reported the same result (p=0.0009; risk difference 8, 95% CI 3-13). Rimegepant was also shown to be superior to placebo for all secondary endpoints besides freedom from nausea and pain relapse. The most common adverse events seen were nausea (2% in the rimegepant group vs <1% in the placebo group) and urinary tract infection (1% in both groups). 15

New Therapies in Preventive Management

Most preventive agents listed in the guidelines are not migraine-specific therapies. Common options include some beta-blockers, antiepileptics, and antidepressants, most of which the mechanism of migraine prevention is not well understood. Each of these classes have their own list of undesirable effects; thus, current preventive migraine management is extremely patient-specific. 7 The new class of medications for migraine prevention, injectable CGRP receptor antagonists, specifically targets a ligand or receptor that is believed to contribute to migraine formation. In addition to a more specific mechanism of action, the medications in this new class are dosed on a monthly basis or longer. 16 Most of the preventive options mentioned in the guidelines must be taken daily to maintain efficacy. 7

Injectable CGRP Receptor Antagonists

This medication class consists of monoclonal antibodies that target and bind to circulating CGRP ligand or its receptor leading to prevention of migraine headaches. 16,17 There are currently four medications approved in this class: galcanezumab, fremanezumab, erenumab, and eptinezumab.

Galcanezumab

Galcanezumab (Emgality) was approved in September 2018 for the preventive treatment of migraine. In June 2019, the FDA approved another indication, treatment of episodic cluster headache. It is a humanized IgG4 monoclonal antibody that targets the CGRP ligand. Galcanezumab is available as a 120 mg/mL single-dose prefilled pen and 100 mg/mL or 120 mg/mL single-dose prefilled syringe. Recommended dosing for migraine prevention is 240 mg (supplied as two consecutive subcutaneous injections of 120 mg each) once as a loading dose, then 120 mg injected subcutaneously once monthly. 17 There are no dosage adjustments recommended by the manufacturer for renal or hepatic impairment. 17 Hypersensitivity reactions have been reported up to days after administration. The most common adverse event reported during clinical trials was injection site reactions. 17 Galcanezumab should be stored in the refrigerator and allowed to sit at room temperature for 30 minutes prior to administration. 17

In the EVOLVE-1 trial, galcanezumab was evaluated for the prevention of episodic migraine. It was a randomized, double-blind, placebo-controlled, multicenter phase 3 study. 18 A total of 862 adults with at least a 1-year history of migraine were randomized 2:1:1 to receive placebo, galcanezumab 120 mg, or galcanezumab 240 mg, all once monthly. The primary endpoint was to determine the superiority of at least 1 dose of galcanezumab versus placebo for mean change from baseline in the number of monthly migraine headache days (MHDs). 18 Secondary outcomes included proportion of patients with reduction in monthly MHDs, MHDs with acute medication use, Patient Global Impression of Severity scores (a 7-point scale that ranks severity of illness from normal to severely ill), and Migraine Disability Assessment scores (ranks days missed in school, work, activities, et cetera to provide a score range of little or no disability to severe disability due to migraine). 18 Both the 120 mg dose and 240 mg dose of galcanezumab achieved the primary endpoint, with a reduction in 1.9 MHDs in the 120 mg group and a reduction of 1.8 MHDs in the 240 mg group (both P-values < 0.001). 18 Galcanezumab 120 mg and 240 mg both also achieved a statistically significantly greater improvement from baseline versus placebo in scores for both Patient Global Impression of Severity and Migraine Disability Assessment. 18 The most frequently reported adverse event in all groups was injection site pain,

with rates similar between all groups. Adverse events that had higher rates of occurrence in the galcanezumab groups compared to placebo were injection site erythema, injection site pruritis, and injection site reaction (all >2% in both galcanezumab groups). 18

After the publication of the EVOLVE-1 trial, a study was conducted to evaluate the long-term safety of galcanezumab. This was a randomized, multicenter, open-label phase 3 trial that randomized a total of 270 adults with at least a 1-year history of migraine headaches. 19 Patients were randomized 1:1 to receive either galcanezumab 120 mg or galcanezumab 240 mg. To achieve the primary objective of long-term safety evaluation of galcanezumab, the study assessed serious adverse events, treatment-emergent adverse events, discontinuation rates, vital signs and weight, electrocardiograms, laboratory measurements, suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale, and incidence of treatment-emergent anti-drug antibodies. 19 Secondary objectives included the evaluation of efficacy measures to fully assess the long-term effectiveness of galcanezumab. 19 77.8% of patients completed the study over a total of 12 months of treatment. Less than 5% of patients discontinued the trial due to adverse events. The most common adverse events reported were similar to those of previous trials; injection site pain, reaction, or erythema frequency between the two dosage groups were not statistically different. Overall mean reduction in MHDs over the 12-month treatment period was 2.2 days in the 120 mg Fremanezumab

Fremanezumab (Ajovy) was FDA approved in September 2018 for the preventive treatment of migraine. It is a fully humanized IgG2Δa/kappa monoclonal antibody that targets the CGRP ligand. 20 Fremanezumab is available in a single-dose prefilled syringe as 225 mg/1.5 mL solution. Recommended dosing is 225 mg injected subcutaneously once monthly or 675 mg every 3 months (three consecutive 225 mg subcutaneous injections). 20 There are no dosage adjustments recommended by the manufacturer for renal or hepatic impairment. Fremanezumab should be stored in the refrigerator and allowed to sit at room temperature 30 minutes prior to administration. Hypersensitivity reactions, including rash, pruritis, drug hypersensitivity, and urticaria have been reported from within hours to one month after administration. 20 The most common adverse event reported in clinical trials was injection site reactions (incidence >5% and greater than placebo). 20

In a phase 3 trial that evaluated the efficacy, safety, and side effect profile of two doses of fremanezumab, a total of 1,130 adults with a history of migraine for at least 12 months were enrolled. This was a randomized, double-blind, placebo-controlled, parallel-group trial. Patients were randomized 1:1:1 to receive either placebo, fremanezumab monthly injections, or fremanezumab quarterly injections. All patients received three injections at baseline and one injection at weeks 4 and 8 with doses varying depending on group assignments. The primary endpoint was the mean change in average number of headache days. Secondary endpoints included the mean change from baseline in the average number of migraine days per month, the percentage of patients with a reduction of at least 50% in the average number of headache days per month, and the mean change from baseline in the average number of days per month in which acute headache medication was used in the 12- week period after the first day. 21 Results showed a significant decrease in the number of headache days per month for both fremanezumab groups. The number of headache days per month was reduced by a mean of 4.3 days in the quarterly group, 4.6 days in the monthly group, and 2.5 days in the placebo group (P<0.001 for both groups compared to placebo). There was also a significant reduction in the number of days per month in which acute headache medication was used for both fremanezumab groups compared to placebo (mean of 3.7 days in the quarterly group, 4.2 in the monthly group, and 1.9 in the placebo group, P<0.001 for both groups compared to placebo). One of the most commonly reported adverse events was injection site reactions, with a frequency of 40% the placebo group, 47% in the quarterly group (P=0.08), and 47% in the monthly group (P=0.03). 21

Erenumab

Erenumab (Aimovig) was approved in May 2018 for preventive treatment of migraine. It is a

human IgG2 monoclonal antibody that binds to the CGRP receptor with high affinity. Erenumab is available in a 70 mg/mL single-dose prefilled autoinjector and syringe. 22 The needle shield and needle cap of the prefilled syringe dosage form contain a derivative of latex and may cause allergic reaction in patients with latex sensitivities. 22 Recommended dosing is 70 mg injected subcutaneously once a month; however, some patients may benefit from 140 mg injected subcutaneously once a month (two consecutive injections of 70 mg each). No dose adjustments for renal or hepatic impairment are recommended by the manufacturer. Erenumab should be stored in the refrigerator and allowed to sit at room temperature for 30 minutes prior to administration. The most common adverse events seen in clinical trials were injection site reactions and constipation (frequency at least 3% and more often than placebo). 22

In the ARISE study, erenumab was evaluated for efficacy and safety in migraine prevention. It was a randomized, double-blind, placebo-controlled, parallel-group, multicenter phase 3 trial. A total of 547 adults with at least a 12-month history of episodic migraine with or without aura were enrolled. Patients were randomized 1:1 to receive erenumab 70 mg monthly subcutaneous injections or placebo for 12 weeks. 23 The primary endpoint was change from baseline in monthly migraine days in month 3 of the treatment phase. Secondary endpoints included achievement of more than 50% reduction from baseline in monthly migraine days, change from baseline in monthly acute migraine-specific medication treatment days, achievement of at least a 5-point reduction in monthly average Migraine Physical Function Impact Diary score, and achievement of at least a 5-point reduction in monthly average Impact on Everyday Activities score. 23 At week 12, patients in the erenumab group reported a mean reduction of 2.9 monthly migraine days, compared to a mean reduction of 1.8 days in the placebo group (p<0.001). 23 Erenumab was also statistically superior to placebo for most secondary endpoints with the exception of the change in scores for the Migraine Physical Function Impact Diary and Impact on Everyday Activities. Adverse events reported that had a frequency >2% and higher than placebo were upper respiratory tract infection, injection site pain, and fatigue (no p-values reported). 23

Eptinezumab

The newest addition to this drug class, eptinezumab (Vyepti), was approved in February 2020 for the prevention of migraine. It is a humanized IgG1 monoclonal antibody that binds to the CGRP ligand. Administration for eptinezumab is intravenous infusion only, rather than a subcutaneous injection like the other injectable CGRP receptor antagonists. It requires dilution with 100 mL 0.9% Sodium Chloride Injection, USP prior to administration. Single-dose vials are 100 mg/mL, and recommended administration is 100 mg intravenous infusion over 30 minutes every 3 months. Some patients may benefit from 300 mg IV infusion every 3 month. There are no preservatives in the vials and any unused portion remaining in the vial should be discarded. 24 There are no dose adjustments recommended by the manufacturer for renal or hepatic impairment. 24 Hypersensitivity reactions such as angioedema, urticaria, facial flushing, and rash have occurred mainly during infusion. The most common adverse events reported in clinical trials (frequency greater than 2%, and 2% or greater than placebo) were nasopharyngitis and hypersensitivity. 24

In the PROMISE-1 trial, eptinezumab was evaluated for efficacy, safety, and pharmacokinetics for prevention of episodic migraine. 25 Chronic migraine patients were included in the PROMISE-2 study. PROMISE-1 was a parallel-group, double-blind, randomized, placebo-controlled, multicenter phase 3 study. A total of 898 adults with at least a 12-month history of migraine with at least 4 migraine days per month in the 3 months prior to screening were enrolled in the trial. 25 Patients were randomized 1:1:1:1 to receive either eptinezumab 30 mg, 100 mg, 300 mg, or placebo for 4 treatments (primary efficacy analysis was completed through the second treatment). The primary efficacy endpoint was the change from baseline in monthly migraine days over weeks 1-12, assessed by eDiary data. 25 Key secondary efficacy endpoints included a 75% migraine responder rate over weeks 1-4 and weeks 1-12, a 50% migraine responder rate over weeks 1-12, and percentage of patients with a migraine on the day after dosing. 25 Results

revealed a statistically significant reduction from baseline in the frequency of migraine days during weeks 1-12 versus placebo for the eptinezumab 100 mg and 300 mg groups. 25 Patients in the placebo group had a reduction of 3.2 monthly migraine days, in the eptinezumab 30 mg group patients experienced a reduction of 4.0 monthly migraine days (unadjusted p=0.0046; not statistically significant per the testing hierarchy). Patients in the eptinezumab 100 mg group reported a reduction of 3.9 monthly migraine days (unadjusted p=0.0182) and patients in the 300 mg group experienced a reduction of 4.3 monthly migraine days (unadjusted p=0.0001), both of which were considered statistically significant per the testing hierarchy. 25 Adverse events that had a frequency higher than placebo included upper respiratory tract infection, nasopharyngitis, and fatigue. 25

Conclusion

With no updated guidelines yet to reflect the addition of novel therapies or head-to-head trials comparing new therapies to the gold standards, it is difficult to determine the place in therapy for lasmiditan and the CGRP receptor antagonists. Current published phase 3 trials demonstrate short-term efficacy and safety of these novel agents; however, there are very few long-term studies available yet since most of the drugs were approved within the previous two years. Despite a wide array of data that accompanies more traditional therapies, such as triptans, many patients may benefit from these novel agents, such as those with contraindications or failure to traditional migraine treatments. A potential barrier to novel agents for many patients is cost (see Table 1). Many manufacturers are offering coupon cards to reduce the cost to patients, but not everyone is eligible, and they are typically valid only for a set amount of time. Despite the lack of longterm data and cost, these newly approved drugs with different mechanisms of action for acute or preventive treatment of migraine are a much-needed addition to the arsenal of treatment options for patients suffering from migraine headaches.

Author: Dr. Kaitlyn Gibson is a recent graduate of the Campbell University College of Pharmacy & Health Sciences. kagibson0830@ email.campbell.edu>

References

1.Dodick DW. Migraine. Lancet. 2018;391(10127):1315-30. 2. Burch RC, Loder S, Loder E, Smitherman TA. The Prevalence and Burden of Migraine and Severe Headache in the United States: Updated Statistics from Government Health Surveillance Studies. Headache. 2015;55(1):21-34. 3. Migraine Research Foundation. About Migraine. Available at: https:// migraineresearchfoundation.org/ about-migraine/migraine-facts/. Accessed 4/28/2020. 4. Stokes M, Becker WJ, Lipton RB, et al. Cost of Health Care Among Patients with Chronic and Episodic Migraine in Canada and the USA: Results From the International Burden of Migraine Study (IBMS). Headache. 2011;51(7):1058-77. 5. Bonafede M, Cai Q, Cappell K, et al. Factors Associated with Direct Health Care Costs Among Patients with Migraine. JMCP. 2017;23(11):1169-76. 6. Silberstein SD. Practice Parameter: Evidence-Based Guidelines for Migraine Headache (An Evidence-Based Review). Neurology. 2000;55(6):754-62. 7. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults. Neurology. 2012;78:1337-45. 8. The role of triptans in the treatment of migraine in adults. BMJ. 2014;62:28-36. 9. Reyvow (lasmiditan) [prescribing information]. Indianapolis, IN: Lilly USA, LLC; October 2019. 10. Ubrelvy (ubrogepant) [prescribing information]. Madison, NJ: Allergan USA, Inc; December 2019. 11. Nurtec ODT (rimegepant) [prescribing information]. New Haven, CT: Biohaven Pharmaceuticals, Inc; February 2020. 12. Kuca B, Silberstein SD, Wietecha L, Berg PH, Dozier G, Lipton RB. Lasmiditan is an effective acute treatment for migraine. Neurology. 2018;91:e2222-32. 13. Loo LS, Ailani J, Schim J, Baygani S, Hundemer H, Port M, Krege JH. Efficacy and safety of lasmiditan in patients using concomitant migraine preventive medications: findings from SAMURAI and SPARTAN, two randomized phase 3 trials. The Journal of Headache and Pain. 2019;20(84). 14. Dodick D, Lipton R, Ailani J, Lu K, Finnegan M, Trugman J, Szegedi A. Ubrogepant for the Treatment of Migraine. N Engl J Med. 2019;381(23):2230-41. 15. Croop R, Goadsby PJ, Stock DA, et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomized, phase 3, double-blind, placebo-controlled trial. Lancet. 2019;394(10200):737-45. 16. Scuteri D, Adornetto A, Rom-

bolà L, et al. New Trends in Migraine Pharmacology: Targeting Calcitonin Gene-Related Peptide (CGRP) With Monoclonal Antibodies. Front Pharmacol. 2019;10(363). 17. Emgality (galcanezumab) [prescribing information]. Indianapolis, IN: Eli Lilly and Company; September 2018. 18. Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial. JAMA Neurol. 2018;75(9):1080-88. 19. Camporeale A, Kudrow D, Sides R, Wang S, Van Dycke A, Selzler KJ, Stauffer VL. A phase 3, long-term, open-label safety study of Galcanezumab in patients with migraine. BMC Neurol. 2018;18(188). 20. Ajovy (fremanezumab) [prescribing information]. North Wales, PA: Teva Pharmaceuticals USA, Inc; September 2018. 21. Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the Preventive Treatment of Chronic Migraine. N Engl J Med. 2017;377(22):2113-22. 22. Aimovig (erenumab) [prescribing information]. Thousand Oaks, CA: Amgen Inc; May 2018. 23. Dodick DW, Ashina M, Brandes JL, et al. ARISE: A Phase 3 randomized trial of erenumab for episodic migraine. Cephalagia. 2018;38(6):1026-37. 24. Vyepti (eptinezumab) [prescribing information]. Bothell, WA: Lundbeck Seattle BioPharmaceuticals, Inc; February 2020. 25. Ashina M, Saper J, Cady R, et al. Eptinezumab in episodic migraine: A randomized, double-blind, placebo-controlled study (PROMISE-1). Cephalagia. 2020;40(3):241-54. 26. GoodRx.com; Pricing information. Accessed 4/30/2020.

Table 1: Summary of monthly costs for novel drugs for migraine acute or preventive treatment 26

Drug

Average Monthly Cost* Lasmiditan Ubrogepant Rimegepant Galcanezumab

$640 (#8 100-mg tablets)

$850 (#10 50-mg tablets)

$850 (1 dose pack of 8 ODT)

$560 (1 single-dose pen)

Fremanezumab

$600 (1 single-dose syringe)

Erenumab

$600 (1 single-dose pen)

Eptinezumab

$500 (1 single-use vial is $1,500 and is a 3-month supply)

*Prices do not reflect any available manufacturer coupons or insurance prices that could provide additional savings to patients