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Emerging Therapies for Patients With Difficult-to-Treat Migraine

Troy Kish PharmD, BCPS

Migraine is a debilitating neurological disorder that affects over one billion individuals worldwide and is the second most common condition when ranked by years living with disability.1 In the United States, data from the National Health Interview Survey in 2015 show that 20% of women and 9.7% of men over the age of 18 experienced a severe headache or migraine in the previous three months. Rates of severe headache or migraine are highest among individuals aged 18–44 years and subsequently decline with advancing age in both men and women.2

Diagnosis of migraine requires patients to have at least five headache attacks that meet the following criteria: lasting 4–72 hours; the presence of nausea and/ or vomiting or photophobia and phonophobia; they must be present in a unilateral location, accompanied by moderate to severe pain, possess a pulsating quality, or be aggravated by or cause the patient to avoid physical activity.3 Migraine patients may also experience prodromal symptoms such as fatigue, neck stiffness, or cognitive impairment, which can begin hours to days before the onset of the headache.3 Some patients may also experience aura symptoms prior to or shortly after migraine onset.3 Auras are usually present with visual disturbances but sensory and/or speech/ language symptoms may also occur.3 Most patients experience emergent migraines (EMs) that occur periodically, while other patients suffer from chronic migraines (CMs), defined as experiencing at least 15 headaches, with eight being migraines, monthly for three months.3 When compared to patients with EM, patients with CM utilize more health care resources through increased visits to primary care offices, emergency rooms, and specialists, as well as an increased need and use for acute or prophylactic medications.4 Patients with migraine also suffer from reduced productivity and higher absenteeism, leading to higher indirect costs associated with this condition.5

Knowledge of the complex patho-physiology involved in migraine development is constantly growing. The once-held theory that vasodilation was responsible for migraines has largely been debunked.6 Two key targets that are the focus of new drug development are serotonin and calcitonin-gene-related peptide (CGRP). Serotonin has been well documented to contribute to the development of migraines; however, the exact mechanism(s) through which it does so remains unclear. Triptans, which work by stimulating the 5HT1B/D receptor, are the most effective acute treatment while medications inhibiting serotonin reuptake, such as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), have proven efficacy in migraine prevention.7 CGRP is the most abundant neuropeptide found in the trigeminal nerve and is involved in promoting vasodilation and neurogenic inflammation.8 Circulating levels of CGRP are increased during episodes of migraine and an injection of CGRP can induce migraine headaches in patients with a history of migraine but not in healthy volunteers.9 Emergent migraines are treated with a variety of medications from differing classes ranging from simple over-the-counter analgesics to prescription agents. Patients with CM may regularly take prophylactic medications to reduce their frequency of attacks. Table 1 provides an overview of common medications used in the acute treatment as well as chronic prevention of migraines.

Despite the variety of agents available, there are still limitations in the ability to treat some patients. Areas of unmet need are medications that are safe for patients with cardiovascular disease as well as agents with novel and more targeted mechanisms of action for both prevention and treatment of acute episodes.11 This article will highlight, in no particular order, medications recently approved by the FDA or those in late-stage development that are intended to fill those treatment gaps. A summary of these medications can also be found in Table 2.

Erenumab

Erenumab is a monoclonal antibody (mAb) that binds to and inhibits CGRP, and which was recently approved by the FDA in May, 2018 for the prevention of episodic migraines. It is available as an auto-injector, which patients can self-administer at doses of 70 or 140 mg subcutaneously monthly.13

STRIVE was a randomized, 24-week, double-blind placebo-controlled trial that enrolled 995 patients suffering from episodic migraines to receive monthly subcutaneous injections of 70 mg or 140 mg of erenumab or placebo. At baseline, enrolled patients experienced an average of 8.3 migraines per month. Results of this trial showed a decrease of 3.2 and 3.7 migraines per month in the 70-mg and 140-mg arms, respectively, as compared to a decrease of 1.8 migraines in the placebo arm. The secondary endpoint evaluating a 50% or greater reduction in monthly migraine days (MMD) was observed in 43.3% and 50% of patients receiving 70 or 140 mg, respectively, as compared to 26.6% of placebo patients.14

The ARISE trial was a phase 3, randomized, double-blind, placebo-controlled trial to evaluate the use of erenumab for the prevention of episodic migraine. Five-hundred seventy-seven patients were randomized to 70 mg of erenumab or placebo and followed for three months. Patients receiving erenumab noted a reduction of 2.9 MMD while placebo patients reported a 1.9 MMD decrease. Nearly 40% of treatment patients experienced a 50% reduction in MMD, and 29.5% of placebo patients reported the same.15

A third trial enrolled patients with chronic migraine to assess erenumab as a preventative medication. A total of 667 patients were divided into groups receiving subcutaneous injections of 70 mg or 140 mg of erenumab or placebo monthly for three months. At baseline, patients reported an average of 18 MMD and patients in both treatment groups reported a decline of 6.6 MMD while placebo patients reported a decrease of 4.2 MMD. Similar to the other trials, 39–41% of treatment patients achieved a 50% reduction in MMD; this was seen in only 23.5% of placebo patients.16 Patients who completed this trial were eligible to enroll in a 52-week, open-label follow-up study to assess long-term safety and efficacy. Twenty-four out of the 609 patients who continued in the study experienced a severe adverse effect, and ultimately 16 patients discontinued treatment following an adverse reaction. Non-serious adverse effects included viral upper respiratory tract infection (15.8%), upper respiratory tract infection (7.4%), and sinusitis (7.2%). Evaluation of efficacy at Week 52 showed a 9.3-day reduction in the mean number of MMD in participants who continued treatment.17

During these trials, patients were permitted to continue using other therapies such as nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, or ergotamine products. In addition, patients with a major cardiovascular event or procedure (myocardial infarction, unstable angina, transient ischemic attack, revascularization procedures) in the preceding 12 months were excluded. The compiled adverse effects from these 3 trials show erenumab to be well tolerated with the most commonly reported adverse effects being injection-site reactions (5–6%), including injection-site pain or erythema, constipation (1–3%), or cramps or muscle spasms (<1–2%) for both the 70-mg and 140-mg doses.13

Fremanezumab

Fremanezumab is a CGRP mAb under development from Teva Pharmaceuticals. In clinical trials, patients received subcutaneous injections of either 675 mg quarterly or 225 mg monthly following a 675-mg initial dose. The possibility of quarterly dosing helps to set fremanezumab apart from other CGRP mAbs in development. Results of two large clinical trials involving fremanezumab have been published, with one focusing on prevention of episodic migraine and the other on prevention of chronic migraine.18,19

The phase 3 clinical trial focusing on prevention of episodic migraine enrolled patients experiencing 6–14 MMD with at least four days being categorized as migraine days. Ultimately, 875 patients were randomized to receive either a single 675-mg injection followed by placebo injections at weeks 4 and 8, a 675-mg injection followed by 225-mg injections at weeks 4 and 8, or placebo. Overall, patients receiving monthly active treatment demonstrated a 3.7-day reduction in least-squares mean MMD, patients receiving quarterly fremanezumab reported a 3.4-day reduction, and placebo patients reported a 2.2-day reduction. Among patients who experienced a 50% reduction in MMD, 47.7% of patients were receiving monthly fremanezumab, 44.4% were receiving quarterly fremanezumab, and 27.9% received placebo.18

A separate clinical trial evaluating patients with chronic migraine was also conducted with 1,130 patients receiving the same dosing protocol as in the previous trial. The primary outcome was a reduction in the mean number of headache days per month, which was defined as any headache lasting at least four consecutive hours and reaching moderate pain levels, or a headache for which a migraine-specific medication (triptan or ergot derivative) was used for treatment. The number of headache days at baseline was ~13 across all groups. At 12 weeks, the least-square mean change from baseline was a reduction of 4.3 days and 4.6 days for patients receiving quarterly and monthly fremanezumab, respectively, while placebo patients reported a 2.5-day reduction. Only 18% of placebo patients reported a 50% reduction in average headache days per month as compared to 38–41% of fremanezumab patients.19

Rates of adverse effects in both of the above trials were similar between the patients receiving fremanezumab and placebo. The most commonly reported events in the fremanezumab groups included: injection-site reactions (26–30%) such as pain, induration, erythema, or hemorrhage; infections (1–5%) such as nasopharyngitis, upper respiratory tract infections, or sinusitis; dizziness (2– 3%) or nausea (1–2%).18,19

Galcanezumab

Galcanezumab is another CGRP mAb in development for the prevention of episodic migraines; its efficacy has been supported by two large trials. EVOLVE-1 was a randomized, double-blind, placebo- controlled trial that enrolled 1,671 participants who experienced 4–14 migraines or probable migraine headaches per month and two migraine attacks in the baseline evaluation. Patients in the active treatment arms received a loading dose of 240 mg, followed by either 120 mg or 240 mg monthly via subcutaneous injection. Patients receiving 120 mg and 240 mg reported a 4.7-day and 4.6-day reduction, respectively, in the number of monthly headaches while placebo patients reported a 2.8-day reduction. Rates of serious adverse effects were similar in both treatment and placebo groups, and none were attributed to galcanezumab. Adverse effects seen more frequently in the galcanezumab groups included injection-site pruritus (4.4–4.6%), injection-site reactions (3.4–5.5%), and generalized pruritus (1–2.7%).20 The EVOLVE-2 trial had the same inclusion criteria and treatment doses as EVOLVE-1 and enrolled 1,696 patients. Galcanezumab-treated patients saw a similar reduction of 4.3 and 4.2 migraine days for 120 mg and 240 mg, respectively, while placebo patients reported a 2.3-day reduction. Again, injection-site reactions (3.1–7.9% vs. 0%) and injection-site pruritus (2.7 – 3.1% vs. 0%) were the only adverse effects reported at a higher frequency than placebo.21

The REGAIN trial followed 1,117 patients with chronic migraine who received either 120 mg or 240 mg of galcanezumab monthly or placebo. At the 3-month follow-up, patients in the 120-mg and 240-mg groups reported a 4.8 and 4.6 least-squares mean decrease in the number of MMD, respectively, while placebo patients noted a 2.7-day decrease. Twenty-seven percent of patients receiving either dose of galcanezumab experienced a 50% reduction in MMD as compared to 15% of placebo patients. The only adverse effects to occur more frequently in the treatment groups were injection-site reactions (4.1%) and injection-site erythema (3.1%), while other common adverse effects such as nasopharyngitis (4.7%), upper respiratory tract infection (3.2%), and sinusitis (2.2%) were at a rate similar to that seen in the placebo arm.22

Eptinezumab

Eptinezumab is a CGRP mAb under development from Alder Biopharmaceuticals. Eptinezumab will provide a convenient dosing schedule, as it can be administered every 12 weeks; however, it is administered via intravenous infusion, which can limit its utility. The PROMISE 1 trial evaluated three doses of eptinezumab intravenous infusion (30, 100, and 300 mg) given every 12 weeks versus placebo in patients with frequent episodic migraines. The primary endpoint was a reduction in MMD at week 12 with additional outcomes extending to 24 weeks. At 12 weeks, a MMD reduction of 4.3 days and 3.9 days was seen in the 300-mg and 100-mg groups, respectively, while placebo patients recorded a 3.2-day reduction. At week 12, 56.3% of patients who received 300 mg and 49.8% of patients who received 100 mg reported a 50% reduction in MMD as compared to 37.4% of placebo patients. The frequency of adverse effects was similar between all treatment and placebo groups with the most commonly reported events being nasopharyngitis (6–7%), sinusitis (2–4%), and upper respiratory tract infection (9–10%).23

The PROMISE 2 trial evaluated infusions of 100 mg or 300 mg given in 12-week intervals for patients with chronic migraines versus placebo. At baseline, patients had an average of 16.1 MMD, and treatment with eptinezumab resulted in a 7.7-day and 8.2-day reduction in MMD for 100 mg and 300 mg, respectively, from weeks 1 to 12. Patients receiving placebo reported a 5.6-day reduction in MMD. Overall, 58 – 61% of eptinezumab patients achieved a 50% reduction in their reported migraine days during the first 12 weeks. Safety data were consistent with the previous PROMISE 1 findings and were similar between both the treatment and placebo arms.24 Currently, there is an ongoing, open-label safety trial assessing the use of eptinezumab in chronic migraine patients for up to 56 weeks.25

Ubrogepant

Ubrogepant is a CGRP antagonist that is being developed for the acute treatment of migraine. The ACHIEVE I study evaluated ubrogepant doses of 50 mg or 100 mg to resolve acute migraine symptoms versus placebo in 1,672 enrolled patients. The percentage of patients who reported being pain-free at two hours was significantly higher in both treatment groups with 19.2% of 50-mg patients and 21.2% of 100-mg patients reporting resolution as compared to 11.8% of placebo patients. Resolution of their most bothersome symptom (MBS), characterized as nausea, phonophobia, or photophobia, was also higher in the ubrogepant patients, at 38.6% and 37.7% for the 50- and 100-mg arms, respectively, compared to 27.8% of placebo patients. The most commonly reported adverse effects were nausea, somnolence, and dry mouth. Although there were six reports of elevated liver enzymes, the liver safety adjudication board found none of these to be related to the study medication.26 Additional positive results were released from the ACHIEVE II trial, which evaluated 1,686 patients receiving doses of 25 mg or 50 mg of ubrogepant or placebo in the treatment of acute migraine. Two hours following their initial dose, patients were able to receive a second dose of active treatment or placebo if symptoms persisted. The percentages of patients who reported being pain-free at two hours were 20.7% with 25 mg and 21.8% with 50-mg doses as compared to 14.3% of patients receiving placebo. Patients receiving 50 mg also had a higher resolution of MBS when compared to placebo (38.9% vs. 27.4%) while no significant reduction in MBS was seen in the 25-mg group. Nausea and dizziness were the most commonly noted adverse effects in the treatment arms but occurred at a frequency of < 2.5%. All cases of elevated liver enzymes were determined by a designated liver safety board not to be associated with the treatment medication.27

Atogepant

Allergan’s second CGRP antagonist, atogepant, is being evaluated for use in the prevention of migraine, as it possesses a longer half-life and is more potent than ubrogepant. Recent results from a phase 2b/3 clinical trial provided initial efficacy and safety information for atogepant in migraine prevention. This trial evaluated multiple doses and regimens in 834 patients with episodic migraines over a 12-week period. Patients were randomized to receive either daily doses of 10, 30, or 60 mg or twice daily doses of 30 or 60 mg, or placebo. All atogepant treatment groups noted a significant decrease in their mean monthly migraine/probable migraine headache days when compared to placebo. The most commonly observed adverse effects included nausea, fatigue, constipation, nasopharyngitis, and urinary tract infection. In addition, the frequency of liver enzyme elevation was similar in both the placebo and treatment arms.28

When compared to CGRP mAbs, these agents have the advantage of being orally administered and will likely have a lower price point. Drugs in this class do not carry any cardiovascular warnings, which may make them an option in patients for whom triptans are contraindicated. Long-term safety may be a concern, as a previous CGRP receptor antagonist, telcagepant, stopped early clinical trials following concerns about liver damage.29 Atogepant and ubrogepant belong to a different chemical series than telcagepant and have thus far not demonstrated increased liver toxicity, but data from larger and long-term clinical studies is still desired.

Lasmiditan

Lasmiditan is a novel migraine therapy that works upon the 5-HT1F receptors along the trigeminal nerve, ultimately blocking the transmission of migraine pain sensations. Some advantages of lasmiditan over the triptan class include its lack of cardiovascular effects and the ability to target receptors both within the periphery and the brain.30 The phase 3 SAMURAI trial evaluated the ability of lasmiditan oral tablets to reduce migraine pain at two hours compared to placebo. There were 630 and 609 patients in the lasmiditan 100-mg and 200-mg groups, respectively, while 617 patients received a placebo. Patients enrolled were mostly Caucasian females with a mean migraine history of 19 years, an average age of 41.6 years, and an average Migraine Disability Assessment (MIDAS) score of 31. Cardiovascular risk factors were present in 82% of enrollees, and patients with established cardiovascular disease were also included.31 At two hours, 28.2% and 32.2% of patients receiving lasmiditan 100 mg and 200 mg, respectively, reported being pain-free as compared to 15.3% of placebo patients. In addition, ~40–41% of patients receiving lasmiditan reported resolution of their MBS as compared to 29.5% of placebo patients. Adverse effects were mostly described as being mild to moderate and typically affected the nervous system. The most frequently described adverse effects in the treatment arms were dizziness (11.9–15.4%), paresthesia (5.7–7.6%), somnolence (5.2–5.3%), nausea (2.5–4.8%), fatigue (3.8–3.0%), lethargy (1.9–2.3%), and vertigo (0.3–1%). No serious cardiovascular effects were reported in any group.31

Eli Lilly released results from the second phase 3 trial, SPARTAN, which evaluated three doses of lasmiditan versus placebo. Resolution of migraine-associated pain at two hours was reported in 28.6%, 31.4%, and 38.8% of patients receiving 50 mg, 100 mg, and 200 mg of lasmiditan, respectively, and in 21.3% of patients receiving placebo. In addition, 40.8–48.7% of patients receiving lasmiditan reported resolution of their MBS at two hours compared to 33.5% of placebo patients. Adverse effects were similar to those described in SAMURAI; however, their frequency was not reported.32 An ongoing, open-label trial known as GLADIATOR is designed to evaluated the long-term safety and efficacy of lasmiditan 100 mg and 200 mg for acute migraine treatment with an anticipated completion date of August 2019.33 Lasmiditan will be the first medication from the ditan class to enter the market and will serve as an option for patients in whom triptans are either ineffective or contraindicated. A current lack of head-to-head comparative trials and long-term safety data along with prohibitive medication pricing may serve as barriers for lasmiditan.

CONCLUSION

The landscape of migraine therapy is set to change with these new classes of medications that are poised to enter the market soon. These therapies will provide options for patients who previously did not respond to or were contraindicated to receive existing medications; however, given the comparatively low-cost generic status of most existing migraine therapies, the pricing of these novel agents will likely be a key determinant in the extent of their use in clinical practice.

Tables

Common Therapies Used for Acute and Preventative Management of Migraine10

Medication Class Available Products How Supplied Limitations of Medication Class Generic Status
Acute Therapies
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
  • Aspirin
  • Diclofenac
  • Naproxen
  • Ibuprofen
  • Tablet, suppository, caplet
  • Tablet, oral solution, capsule
  • Tablet, capsule, ER and DR tablet
  • Tablet, capsule
May increase risk of bleeding or formation of gastric ulcers, concerns with renal disease Generics available
Triptans
  • Almotriptan (Axert)
  • Eletriptan (Relpax)
  • Frovatriptan (Frova)
  • Naratriptan (Amerge)
  • Rizatriptan (Maxalt)
  • Sumatriptan (Imitrex)
  • Zolmitriptan (Zomig)
  • Tablet
  • Tablet
  • Tablet
  • Tablet
  • Tablet, ODT
  • Tablet, SQ injection, NS
  • Tablet, ODT, NS
Cannot be used in patients with history of ischemic cardiovascular disease or cerebrovascular disease Generics available
Ergot Alkaloids
  • Ergotamine
  • Ergotamine with caffeine
  • Dihydroergotamine
  • Sublingual tablet
  • Tablet, suppository
  • NS, SQ or IM injection
Cannot be used in patients with history of cardiovascular disease Generics available
Preventative Therapies*
Botulinum Toxin Type A
  • Onabotulinum toxin A (Botox)
  • IM injection by physician
Cost, need for injections No generic available
Beta Blockers
  • Atenolol (Tenormin)
  • Metoprolol (Toprol)
  • Propranolol (Inderal)
  • Timolol (Blocadren)
  • Tablet
  • Tablet
  • Tablet, oral solution, ER capsule
  • Tablet
Bradycardia, bronchospasm, increased fatigue or lethargy Generics available
Antidepressants
  • Amitriptyline (Elavil)
  • Venlafaxine (Effexor)
  • Tablet
  • Tablet, ER tablet, ER capsule
  • Anticholinergic effects, orthostatic hypotension
  • Insomnia, dizziness, drowsiness
Generics available
Calcium-channel Blockers
  • Verapamil (Calan; Verelan)
  • Tablet, ER tablet, ER capsule
  • Constipation, potential drug–drug interactions
Generics available
Anticonvulsants
  • Valproic acid (Depakote)
  • Topiramate (Topamax)
  • ER and DR tablet, oral solution, taste disturbances
  • Tablet, ER tablet, ER capsule, sprinkle capsule
  • Avoid in pregnancy, nausea, drowsiness, insomnia, alopecia
  • Cognitive dysfunction, sedation, taste disturbances
Generics available

DR= delayed release; ER= extended release; IM= intramuscular; NS= nasal spray; ODT= orally dissolving tablet; SQ= subcutaneous.

*Not a comprehensive listing.

Therapies in Late-Stage Development for Migraine11,12

Medication Developer(s) Mechanism of Action Targeted Indication/ Population Route and Dose* Current or Expected Pricing Strategy FDA Approval or Anticipated Launch Date (United States)
Lasmiditan
Eli Lilly & Company
5-HT1F receptor agonist Patients with CV disease or those who are unresponsive to triptans 50-mg, 100-mg, or 200-mg oral tablets 10% premium to Imitrex tablets 2019
Erenumab-aooe (Aimovig)
Amgen Novartis
Monoclonal antibody against CGRP Preventative therapy for patients with chronic migraine 70 mg or 140 mg subcutaneously monthly AWP: $690 for 70-mg or 140-mg dose Approved May 2018
Fremanezumab
Teva Pharmaceutical Industries
Monoclonal antibody against CGRP Preventative therapy for patients with chronic migraine 225 mg or 675 mg intravenously or subcutaneously monthly or every 12 weeks 20% premium to Praluent 2018
Galcanezumab
Eli Lilly & Company
Monoclonal antibody against CGRP Preventative therapy for patients with chronic migraine 120 mg subcutaneously monthly 20% premium to Praluent 2018
Eptinezumab
Alder
Biopharmaceuticals
Monoclonal antibody against CGRP Preventative therapy for patients with chronic migraine 100 mg or 300 mg intravenously every 12 weeks 20% premium to Praluent 2019
Ubrogepant
Allergan
CGRP antagonist Acute treatment of episodic migraine 25-mg, 50-mg tablets at migraine onset 20% premium to Imitrex tablets 2020
Atogepant
Allergan
CGRP antagonist Preventative therapy for patients with episodic migraine 10-mg, 30-mg, or 60-mg capsule once or twice daily 30% premium to Topamax tablets 2022

*Doses listed reflect those evaluated in clinical trials, FDA-approved doses and routes may change.

AWP= Average wholesale price; CV= cardiovascular.

Author bio: 
Dr. Kish is an Associate Professor of Pharmacy Practice at Long Island University, LIU Pharmacy (Arnold and Marie Schwartz College of Pharmacy and Health Sciences), in Brooklyn, New York.

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  33. ClinicalTrials.gov. An open-label, long-term, safety study of lasmiditan for the acute treatment of migraine (GLADIATOR)  Updated July 23, 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT02565186. Accessed July 27, 2018