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REVIEW ARTICLE
Year : 2021  |  Volume : 69  |  Issue : 7  |  Page : 25-42

Acute Treatment of Migraine: What has Changed in Pharmacotherapies?


1 Department of Neurology, Kuang Tien General Hospital; Department of Nutrition, Huang-Kuang University, Taichung, Taiwan
2 Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan
3 Center for Traditional Medicine, Neurological Institute, Taipei Veterans General Hospital; Faculty of Medicine, National Yang Ming Chiao Tung University; Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
4 Department of Healthcare Administration, Asia University, Taichung, Taipei Veterans General Hospital, Taipei, Taiwan
5 Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang Ming Chiao Tung University, School of Medicine; Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan

Date of Submission19-Jan-2021
Date of Decision25-Jan-2021
Date of Acceptance13-Feb-2021
Date of Web Publication14-May-2021

Correspondence Address:
Dr. Shuu-Jiun Wang
Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei - 11217
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.315995

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 » Abstract 


Background: Migraine is the most prevalent neurological disorder and the leading cause of disability in individuals under 50 years of age. Two types of migraine therapies have been defined: acute therapy (abortive or symptomatic treatment), the purpose of which is to interrupt migraine attacks, and preventive treatment (prophylactic treatment), the purpose of which is to reduce the frequency and severity of migraine attacks.
Objective: This paper reviews research advances in new agents for acute therapy of migraine.
Material and Methods: This review provides an overview of emerging new drugs for acute treatment of migraine based on clinical evidence and summarizes the milestones of different stages of clinical development.
Results: Two new formulations of sumatriptan, DFN-11 (3 mg doses of subcutaneous sumatriptan) and DFN-02 (a nasal spray of sumatriptan 10 mg and a permeation-enhancing excipient), have been developed, and both of them showed a fast-onset action with efficacy for acute treatment of migraine with fewer adverse events. New drug discovery programs shifted the focus to the development of ditans, a group of antimigraine drugs targeting 5-HT1F receptors. Only lasmiditan has progressed to phase III clinical trials and was finally approved by the Food and Drug Administration (FDA) for acute migraine treatment. The other target for acute therapy is CGRP receptor antagonists, namely, gepants. Ubrogepant and rimegepant demonstrated statistically significant efficacy, and both were recently approved by the FDA. These 5-HT1F receptor agonists and CGRP receptor antagonists did not cause vasoconstriction, offering advantages over the current mainstay of specific acute migraine treatment.
Conclusions: Overall, these new agents have expanded the available acute therapies for migraine treatment and will likely change the strategy with which we treat patients with migraine in the future.


Keywords: 5-HT1F receptor agonist, acute treatment, CGRP antagonist, migraine
Key Messages: Lasmiditan, a group of antimigraine drugs targeting 5-HT1F receptors, has progressed to phase III clinical trials and was finally approved by the Food and Drug Administration (FDA) for acute migraine treatment. The other target for acute therapy is CGRP receptor antagonists, namely, gepants. Ubrogepant and rimegepant demonstrated statistically significant efficacy, and both were recently approved by the FDA. These 5-HT1F receptor agonists and CGRP receptor antagonists did not cause vasoconstriction, offering advantages over the current mainstay of specific acute migraine treatment.


How to cite this article:
Yang CP, Huang KT, Chang CM, Yang CC, Wang SJ. Acute Treatment of Migraine: What has Changed in Pharmacotherapies?. Neurol India 2021;69, Suppl S1:25-42

How to cite this URL:
Yang CP, Huang KT, Chang CM, Yang CC, Wang SJ. Acute Treatment of Migraine: What has Changed in Pharmacotherapies?. Neurol India [serial online] 2021 [cited 2021 Jun 14];69, Suppl S1:25-42. Available from: https://www.neurologyindia.com/text.asp?2021/69/7/25/315995

Chun-Pai Yang and Kuo-Ting Huang contributed equally to the study




Migraine is one of the most prevalent and disabling diseases and is characterized by recurrent attacks of moderate or severe, unilateral, pulsating headache, which are often accompanied by bothersome symptoms such as nausea, vomiting, photophobia, and phonophobia; approximately one-third of patients experience aura symptoms in some of their migraine attacks.[1],[2]

Two types of migraine therapies have been defined: acute therapy (abortive or symptomatic treatment), the purpose of which is to interrupt acute attacks, and preventive treatment (prophylactic treatment), the purpose of which is to reduce the frequency and severity of migraine attacks. Traditionally, for individuals with mild or moderate symptoms, the first-line medications for acute treatment include acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs), and ergot derivatives alone or in combination with caffeine. For individuals with moderate or severe symptoms, triptans alone or in combination with NSAIDs are recommended. In fact, triptans, i.e., 5-HT1B/1D receptor agonists, currently represent the standard of care for acute migraine treatment. However, the response to these existing triptans was not satisfactory, and only 27%–30% of patients were pain-free as of 2 h after taking triptans; in addition, the triptan discontinuation rate was high, at 55.2%–81.5%.[3] Nonetheless, recent studies have focused on new formulations of triptan therapy, including the delivery of drugs via non-oral routes, such as the subcutaneous (SC) (DFN-11: 3 mg doses of SC sumatriptan) and intranasal routes (DFN-02: a nasal spray of sumatriptan 10 mg and a permeation-enhancing excipient). However, triptans exert a 5-HT1B-mediated vasoconstrictive effect and are therefore contraindicated in patients with uncontrolled hypertension, cardiovascular disease, or cerebrovascular disease[1],[2]

Advances in the understanding of migraine pathophysiology have led to the development of serotoninergic agonists without vasoconstrictive properties; these agonists target 5-HT1D and 5-HT1F receptors. Unfortunately, a phase II trial that investigated the efficacy of 5-HT1D agonists did not meet the primary endpoint; thus, further development was discontinued.[4],[5] Lasmiditan, which belongs to a new class of selective 5-HT1F receptor agonists, is the first medication in this class that has demonstrated statistically significant efficacy; it was approved by the Food and Drug Administration (FDA) in October 2019.[6],[7],[8] Ubrogepant and rimegepant, both CGRP antagonists received FDA approval in December 2019 and February 2020, respectively, for acute treatment of migraine.

This review provides an overview of emerging new drugs for acute treatment of migraine based on clinical evidence and summarizes the milestones of different stages of clinical development.

Objectives and general approaches of acute migraine treatment

The main objective of acute treatment for migraine is to provide rapid relief of headache and decrease functional disability and recurrence while avoiding side effects. There are several general rules to achieve good outcomes through acute treatment: 1) Patients should take acute medication early during the course of an attack or when the pain is still mild, and the primary drug should be taken with drugs with different mechanisms of action or with antiemetics to facilitate the absorption of the primary drugs to enhance pain control. 2) Clinicians should choose the correct drug doses and appropriate routes of administration (e.g., nasal spray, injection, suppository) to improve individual patient outcomes. For example, migraine patients with rapidly escalating headache whose pain peaks rapidly (i.e., within 30 min), those who wake up with a severe migraine, and those with prominent nausea or vomiting nausea during the premonitory period may benefit from non-oral formulations. 3) Patients should be advised to minimize the use of simple analgesics (e.g., non­steroidal anti-inflammatory drugs, paracetamol) to fewer than 15 days per month and to use triptans, ergots, or combination analgesics fewer than 10 days per month to avoid the potential risk of medication-overuse headache (MOH).[9]

In addition, the latest guidelines proposed by the International Headache Society for controlled trials of acute treatment of migraine attacks in adults, published in 2019, suggest that headache-free status at 2 h post-dose should be routinely used as the primary outcome and an absence of the most bothersome migraine-associated symptom (MBS) at 2 h post-dose may be used as a coprimary endpoint.[10] Among others, pain-free status at 2 h with no use of rescue medication or relapse within 24 or 48 hours of the initial treatment; headache relief from moderate or severe at baseline to mild or none at 2 h after treatment and before taking any rescue medication; or an absence of the MBS at 24 or 48 h are also relevant outcome measures.[10] In addition to these parameters being used in the context of clinical trials, they are also equally applicable when assessing the effectiveness of acute treatment in clinical settings.

Serotonin Target

New formulations of intranasal sumatriptan

Sumatriptan, the first triptan, which is widely used clinically, has been available as oral tablets, SC injections, intranasal formulations and, in some countries, rectal suppositories. The nasal spray formulation provides a convenient and a noninvasive method of sumatriptan administration, especially for migraine patients who are needle-averse and unsatisfied with oral treatment or those who suffer from severe nausea or vomiting that preclude the use of oral tablets. Nevertheless, the efficacy of conventional nasal spray sumatriptan 20 mg is limited because of slow absorption (tmax = 0.88-1.75 hours) as well as low bioavailability (~17%), leading to its action being only slightly faster than that of oral sumatriptan (30–45 min vs. 45–60 min).[11],[12] These clinical limitations highlight the unmet need for an effective non-oral acute migraine treatment with a rapid onset of action.[11] Moreover, sumatriptan has a bad, bitter or unpleasant taste, which accounted for 22-27% of subjects using the intranasal formulation in a pooled analysis.[12]

DFN-02 is a novel nasal spray composed of 10 mg sumatriptan plus a permeation-enhancing excipient composed of 0.2% 1-O-n-dodecyl-beta-D-maltopyranoside (DDM), which is designed for rapid sumatriptan absorption within the nasal mucosa into the systemic circulation. The functions of DDM are to loosen cell-cell junctions and facilitate drug transport across the nasal epithelium by altering mucosal viscosity and membrane fluidity.[13] DDM enhances the bioavailability of drugs by serving as a permeation enhancer for medications administered via the nose, mouth, and eyes, including intranasally delivered triptans.[13] A study of DFN-02 bioavailability in healthy subjects showed a more rapid absorption profile after the addition of a permeation enhancer to intranasal sumatriptan 10 mg than with intranasal sumatriptan 20 mg, and systemic exposure from a single dose of administration of DFN-02 was similar to that from a 4 mg dose of SC sumatriptan and one-third lower than that from a 6 mg dose of SC sumatriptan. Moreover, the plasma sumatriptan concentration of DFN-02 peaked rapidly, approximately 10 and 5 min earlier than with 4 mg and 6 mg SC sumatriptan, respectively.[14] In addition to the favorable pharmacokinetics, DFN-02 is safe and well-tolerated. A randomized, double-blind, placebo-controlled study that evaluated the efficacy of DFN-02 in patients with episodic migraine demonstrated significantly higher rates of migraine patients being pain-free at 2 hours post dose in the DFN-02 group than in the placebo group (43.8% vs. 22.5%; P < 0.07).[15] In addition, when compared to placebo, treatment with DFN-02 significantly alleviated the MBS, including nausea, photophobia, and phonophobia (70.7% vs. 39.5% MBS-free at 2 hours post-dose; P < 0.01). Overall, DFN-02 was well-tolerated, with an overall low incidence of treatment-emergent adverse events (TEAEs) (10.0% to 13.5%), a low incidence of dysgeusia (2.0% to 8.1%), and no serious adverse events (SAEs), and no subjects discontinued because of adverse events (AEs).[15] Furthermore, DFN-02 was superior to placebo for reducing the migraine-related functional disability score at 2 h after treatment (−1.2 vs. −0.6, P < 0.001) and provided greater patient satisfaction with acute treatment at 2 h post dose (70.0% vs. 44.2%, P = 0.027).[16] DFN-02 was also well tolerated in a multicenter, open-label, repeat-dose safety and tolerability study over a 6-month treatment period. The study demonstrated that the TEAEs were application-site pain (30.5%) and dysgeusia (21%).[11] The details of phase III clinical trials of DFN-2 are summarized in [Table 1].
Table 1: Summary of phase III clinical trials of serotonin targets: DFN-11 (sumatriptan injection, 3 mg), DFN-02 (intranasal sumatriptan 10 mg), and lasmiditan (5-HT1F receptor agonists)

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The US FDA has approved DFN-02 (Tosymra) for acute treatment of migraine with or without aura in adults (Dr Reddy's Laboratories 2019).[17] For individuals under 18 years of age, it is not known whether DFN-02 is safe and effective.[18],[19] Similar to other sumatriptan products, DFN-02 is contraindicated in those with pre-existing cardiovascular conditions.[18],[19]

New formulations of SC sumatriptan

SC sumatriptan (6 mg) has long been deemed optimal for acute treatment of migraine; it works within 10–15 min and often provides complete relief of the headache and associated symptoms, with approximately 50% of migraine patients with moderate to severe attacks being pain-free at 2 h after dosing.[20] Although 6 mg SC sumatriptan has been considered the most rapid and effective choice for acute treatment of migraine attacks, the tolerability profile is suboptimal because of injection-site reactions or a sudden surge in the sumatriptan level in the blood, which causes obvious triptan sensations (pin-and-needle-like sensations, burning sensations, numbness, tightness in the throat or chest, or temporary worsening of the headache, etc.). The injection-site reaction and triptan sensations occurred at a significantly greater frequency with 6 mg SC sumatriptan than with placebo (injection-site reaction: 59% vs. 24%; triptan sensation: 42% vs. 9%).[21] These side effects have caused two-thirds of migraine patients to delay or avoid using injections.[22]

DFN-11 (Zembrace), a low-dose (3 mg) SC injection of sumatriptan supplied in a single-dose, ready-to-use, disposable autoinjector, was approved by the FDA for acute treatment of migraine in July 2018. A pilot study showed that the 3 mg SC dose and 6 mg SC dose were equally effective, but the 3 mg SC dose showed fewer and shorter triptan sensations with no chest discomfort in patients with episodic migraine.[21] Another multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of DFN-11 (sumatriptan injection, 3 mg) vs. placebo in the treatment of multiple migraine attacks for patients with episodic migraine.[23] The results showed that a significantly higher proportion of patients in the DFN-11 group than in the placebo group (51.0% vs. 30.8%) were pain-free at two hours after dosing (primary outcome). DFN-11 was also significantly superior to placebo for pain relief from 60 min through 2 h post-dose. The most common TEAEs were injection-site reactions, with a higher incidence with DFN-11 than with placebo (23.4% vs. 11.8%). Although the incidence of triptan sensations was low in both groups, patients in the DFN-11 group had a higher rate of triptan sensations than those in the placebo group (7.2% vs. 1.7%). The incidence of chest discomfort was also low in both groups, and interestingly, patients in the DFN-11 group had a lower rate of chest discomfort than those in the placebo group (0.9% vs. 1.7%).[23] Because of the good efficacy and tolerability of 3 mg SC sumatriptan (DFN-11), it could be considered a useful alternative to the 6 mg SC dose of sumatriptan. The details of phase III clinical trials of DFN-11 are summarized in [Table 1].

Serotonin 5-HT1D receptor agonists

To develop serotoninergic agonists without vasoconstrictive properties, studies have shifted the focus to highly selective 5-HT1D and 5-HT1F receptors. In an animal model using guinea pigs for antimigraine drug testing, SC injection of PNU-109291, a selective 5-HT1D receptor agonist successfully reduced dural plasma extravasation evoked by trigeminal ganglion stimulation.[24] However, a randomized, double-blind, placebo-controlled study investigating the efficacy of a 5-HT1D agonist (PNU-142633) demonstrated that there were no statistically significant treatment effects in patients receiving PNU-142633 during acute migraine attacks (headache-free 2 hours after dosing: 8.8% of patients in the PNU-142633 group vs. 5.7% in the placebo group; headache relief 2 hours after dosing: 29.4% of the PNU-142633 group vs. 40.0% of the placebo group).[25] The enthusiasm for 5-HT1D receptor agonists was tempered by this negative finding, and further development was discontinued.

Serotonin 5-HT1F receptor agonists

Similar to other 5-HT1 receptors, 5-HT1F is a protein coupled to Gi/Go and mediates inhibitory neurotransmission of the peripheral as well as central trigeminovascular system, including the trigeminal ganglion, trigeminal cervical complex (TCC), cerebellum, and cortex.[26],[27] In particular, this receptor is found at the prejunctional site of the trigeminal fibers but is lacking in the vascular smooth muscles; therefore, its agonists are postulated to have an antimigraine effect without vasoconstrictive properties.[28] This led to the development of the first 5HT1F agonist, LY334370, which was the first 5-HT1F receptor agonist to be assessed in a phase II trial and proved to be effective for the acute treatment of moderate to severe migraine at 60 mg and 200 mg.[29] Unfortunately, LY334370 phase III trials were halted eventually because of the appearance of frequent AEs such as asthenia, dizziness, somnolence, and liver toxicity in animals.[30]

Following this, lasmiditan (formerly known as LY573144 or COL-144), a more specific 5-HT1F receptor agonist was developed and has been tested in clinical trials for migraine. Since lasmiditan outperformed the placebo in 2 phase II trials, it progressed to phase III trials.[7],[8]

Two pivotal phase III multicenter, randomized, double-blind, placebo-controlled trials (SAMURAI (NCT02439320) and SPARTAN (NCT02605174)) have examined lasmiditan in acute treatment of migraine attacks.[7],[8] Patients with migraine with or without aura were randomized to receive oral lasmiditan 200 mg (n = 745) or 100 mg (n = 744) or placebo (n = 742) in the SAMURAI trial and oral lasmiditan 200 mg (n = 721), 100 mg (n = 721), or 50 mg (n = 716) or placebo (n = 711) in the SPARTAN trial. In SAMURAI, a significantly higher proportion of lasmiditan recipients than placebo recipients were free of headache at 2 hours after dosing (32.2% for 200 mg lasmiditan, 28.2% for 100 mg lasmiditan, and 15.3% for placebo; primary endpoint). Moreover, a significantly higher proportion of lasmiditan recipients than placebo recipients were MBS-free at 2 hours (40.7% for 200 mg lasmiditan, 40.9% for 100 mg lasmiditan, and 29.5% for placebo; key secondary endpoint).[8] In SPARTAN, treatment with lasmiditan at all doses (200 mg, 100 mg, and 50 mg) offered significant benefits over placebo in the proportion of patients who were free of headache at 2 hours after dosing (38.8% with 200 mg lasmiditan, 31.4% with 100 mg lasmiditan, 28.6% with 50 mg lasmiditan, and 21.3% with placebo; primary endpoint) and MBS-free (48.7% with lasmiditan 200 mg, 44.2% with lasmiditan 100 mg, 40.8% with lasmiditan 50 mg, and 33.5% with placebo; key secondary endpoint) at 2 hours after dosing.[7] In pooled data from these two phase III clinical trials, SAMURAI and SPARTAN, lasmiditan significantly improved the proportions of patients who were pain-free and MBS-free (p < 0.05 for all doses vs. placebo) at 2 h.[31] At 24 hours, a significantly higher proportion of lasmiditan recipients than in placebo recipients had sustained pain-free status (21.2% with 200 mg lasmiditan, 16.9% with 100 mg lasmiditan, 17.4% with 50 mg lasmiditan, and 10.3% with placebo). At 48 hours, similar results were observed (18.4% with 200 mg lasmiditan, 15.2% with 100 mg lasmiditan, 14.9% with 50 mg lasmiditan, and 9.6% with placebo).[31]

In a pooled analysis of the safety populations from the SAMURAI and SPARTAN trials (n = 654, 1265, 1258, and 1262 recipients for lasmiditan at 50 mg, 100 mg, and 200 mg and placebo recipients, respectively), TEAEs were reported in 25.4%, 36.2% and 40.5% of patients receiving lasmiditan 50 mg, 100 mg and 200 mg, respectively, vs. 13.8% of patients receiving placebo. Discontinuation due to TEAEs occurred in one patient (a lasmiditan 200 mg recipient, who discontinued due to mild dizziness and fatigue), and serious TEAEs were rarely reported (in 0.2%, 0.1% and 0.2% of patients receiving lasmiditan 50 mg, 100 mg and 200 mg, respectively, vs. 0.2% of patients receiving placebo).[25]

The most common TEAEs of patients receiving any lasmiditan dose were dizziness, somnolence, nausea, fatigue, and paresthesia. The majority of TEAEs were mild or moderate, early-onset (typically < one hour after administration), and more frequent at higher doses of lasmiditan. No incidence of TEAEs related to vasoconstriction, such as angina pectoris, cerebral infarction, or hypertensive crisis was noted, and the incidence of cardiovascular TEAEs (palpitations, tachycardia, bradycardia, etc.) was low (0.2% ~ 0.5%) in both SAMURAI and SPARTAN.[7],[8],[32] Moreover, the efficacy of lasmiditan was not influenced by the presence of cardiovascular risk factors in a post hoc analysis of pooled data from SPARTAN and SAMURAI.[33]

The long-term safety and efficacy of intermittent lasmiditan use (100 mg and 200 mg) in the acute treatment of migraine was sustained over one year in the interim analysis of the patients who had completed either SAMURAI or SPARTAN, known as the GLADIATOR study (NCT02565186). Across 17,295 treated migraine attacks, headache-free status at 2 hours post-dose was achieved in 26.9% of migraine attacks treated with 100 mg lasmiditan and 32.4% of migraine attacks treated with 200 mg lasmiditan. In addition, MBS-free status at 2 h post-dose was achieved in 37.5% of migraine attacks treated with 100 mg lasmiditan and in 40.6% of migraine attacks treated with 200 mg lasmiditan. Furthermore, in the subgroup analysis of patients with ≥5 migraine attacks, the success rate percentages for pain freedom, MBS freedom and pain relief at 2 h post dose were consistent across subsequently treated attacks.[6] In this study, most TEAEs were mild or moderate in intensity, and dizziness was the most frequently reported event. There were no TEAEs related to vasoconstriction, such as angina pectoris, cerebral infarction, or a hypertensive crisis. The details of phase III clinical trials of lasmiditan (5-HT1F receptor agonists) are summarized in [Table 1].

In October 2019, lasmiditan oral tablets were approved by the US FDA for acute treatment of migraine in adults based on the positive results from two pivotal phase III trials.[34] The recommended dose is 50 mg, 100 mg or 200 mg orally as needed, but no more than one dose should be taken in 24 hours because of no further benefit with taking a second dose for the same migraine attack.[35]

CGRP System

The role of CGRP in migraine pathophysiology is well established, and its receptors are widely expressed in peripheral and central regions of the nervous system.[36] CGRP has been the target of extensive investigation to produce drugs for migraine control, from receptor antagonists competing with CGRP at receptor sites for acute treatment to monoclonal antibodies either against CGRP itself or its receptor for preventive treatment.[37],[38] Indeed, the recent development of CGRP receptor antagonists (gepants) represents an important advance in migraine-specific acute treatment.

CGRP receptor antagonists (gepants)

On the basis of the abundance of evidence for the integral role of CGRP in the pathophysiology of migraine, a total of six different small-molecule CGRP receptor antagonists (gepants) were created for acute treatment of migraine attacks. Two of them, ubrogepant and rimegepant, received US FDA approval for the treatment of acute migraine in adults in December 2019 and February 2020, respectively.[39],[40]

Trials for the remaining four including olcegepant, telcagepant, MK-3207, and BI 44370 were halted either because of safety concerns (mostly) due to liver toxicity or because of poor oral availability.[41],[42],[43],[44] Of note, atogepant, another gepant, is intended for migraine prophylaxis rather than acute treatment and is therefore beyond the scope of this review.[45]

Ubrogepant (MK-1602)

Ubrogepant is a novel small-molecule CGRP receptor antagonist and is the first drug in this class approved for acute treatment of migraine.[39] Four clinical studies (ACHIEVE I (NCT02828020; UBR-MD-01), ACHIEVE II (NCT02867709; UBR-MD-02), NCT02873221 (UBR-MD-04) and 3110-105-002) have completed and showed the efficacy, safety and tolerability of orally administered ubrogepant for acute treatment of migraine[46],[47],[48],[49]

NCT01657370, a phase IIb, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial investigated the pharmacokinetics of ubrogepant, as well as the relationship between ubrogepant concentrations and the efficacy of the drug.[50] In another phase IIb trial (a multicenter, randomized, placebo-controlled trial, NCT01613248),[50] a total of 527 migraineurs received one of 5 doses of ubrogepant (1, 20, 25, 40, or 100 mg), and 113 received placebo. The primary efficacy endpoints were pain-free status and pain relief at 2 h post-dose. The trial demonstrated a positive, dose-dependent response for the proportion of patients obtaining pain freedom at 2 h (p < 0.001). Compared to placebo, the 100 mg dose showed a significantly higher proportion of patients with pain freedom at 2 h (8.9% with placebo vs. 25.5% for ubrogepant) but not for coprimary endpoint pain relief (44.6% with placebo vs. 58.8.5% for ubrogepant at 2 h). The 100 mg dose also proved effective in the absence of photophobia and phonophobia at 2 h (though showing no effect on nausea) and sustained pain freedom for up to 48 hours. Efficacy was also present, in terms of pain-free rates, for the 50 (21%) and 25 (21.4%) mg doses for pain scores at 2 h. The overall incidence of AEs, including nausea, fatigue, dizziness, dry mouth, and somnolence, was similar in all groups. Regarding liver toxicity, elevations of hepatic enzymes (at least three times the upper limit of normal (≥ 3 × ULN) for alanine aminotransferase (ALT) or aspartate amino-transferase (AST)) occurred in one patient but finally was judged as 'unlikely' to be related to ubrogepant treatment. The data from these two phase II studies suggested that a dose of ubrogepant of 25 mg or higher was likely to achieve significantly better efficacy than placebo and further supported the ubrogepant dose selection in the pivotal phase III trials.

In the pivotal multicenter, randomized, double-blind, placebo-controlled phase III trials ACHIEVE I (NCT02828020), which investigated 50 and 100 mg doses, and ACHIEVE II (NCT02867709), which investigated 25 and 50 mg doses, both trials assessed the efficacy, safety, and tolerability of two different doses of ubrogepant vs. placebo.[47],[49] In ACHIEVE I, which included 1672 patients, compared to patients receiving placebo, a significantly higher percentage of patients receiving ubrogepant achieved pain freedom at 2 h[49] (11.8% for placebo; 19.2% for 50 mg; 21.2% for 100 mg), and a statistically significant greater percentage of ubrogepant patients achieved the absence of the MBS at 2 h post-dose (27.8% for placebo, 38.6% for 50 mg, and 37.7% for 100 mg, all P < 0.002). In ACHIEVE II (NCT02867709), which included 1686 patients, significantly more patients in the ubrogepant groups than in the placebo group reached pain relief at 2 h after treatment (20.7%, 21.8%, and 14.3% for ubrogepant 25 mg, ubrogepant 50 mg, and placebo, respectively, P < 0.04: 25 mg vs. placebo, P < 0.02: 50 mg vs. placebo).[49] Compared to patients treated with placebo, more patients treated with ubrogepant obtained an absence of the MBS at 2 h after the initial dose (coprimary endpoint) (34.1%, 38.9%, and 27.4% for ubrogepant 25 mg, ubrogepant 50 mg, and placebo, respectively), but the difference was significant only for the 50 mg dose vs. placebo (p < 0.02).[47] Among the total safety population of the two ACHIEVE trials, six cases of ALT or AST elevation ≥3 × ULN occurred in ACHIEVE I and four cases occurred in ACHIEVE II. In ACHIEVE I, four of the six cases (all of which occurred in patients who received ubrogepant) of ALT or AST elevation ≥3 × ULN were adjudicated as unlikely to be related to the study medication; two of the six cases (one in a patient who received ubrogepant and one in a patient who received placebo) of ALT or AST elevation ≥3 × ULN were adjudicated as possibly related to the study medication; and no ALT or AST elevation ≥3 × ULN was adjudicated as probably related to the study medication.[47],[49] In ACHIEVE II, three of the four cases (all of which occurred in patients who received ubrogepant) of ALT or AST elevations ≥3 × ULN were adjudicated as 'unlikely' to be related to the study medication; one of four cases (which occurred in a patient who received placebo) was adjudicated as possibly related to the study medication; and no case of ALT or AST elevation ≥3 × ULN was considered to be treatment-related.[49]

The safety and tolerability of ubrogepant (50 or 100 mg doses) from short-term ACHIEVE I and II trials were maintained during the one-year open-label extension study (UBR-MD-04 (NCT02873221)).[46] The extension study included adult patients with migraine who had been enrolled in and completed one of the previous pivotal studies for ubrogepant: ACHIEVE I or ACHIEVE II. Participants were rerandomized equally to the usual care control arm, in which patients were instructed by the physician to treat their migraine with medication (s) as the standard of care in clinical practice, or the ubrogepant 50 mg or 100 mg arms over the one-year period. In total, 1230 participants (404 in the ubrogepant 50-mg group, 409 in the ubrogepant 100-mg group, and 417 in the usual care group) with 21,454 migraine attacks were treated with 31,968 doses of ubrogepant throughout the year. In this study, long-term intermittent use of ubrogepant was well tolerated, with an AE profile similar to that of the usual care control arm. The most common AEs (>5%) were upper respiratory tract infection, nasopharyngitis, sinusitis, urinary tract infection, and influenza. In terms of hepatic safety, no drug-induced liver injury or hepatic safety concern was observed. Moreover, an average of 23% and 25% of participants treated with ubrogepant at 50 and 100 mg, respectively, reported pain freedom at 2 h. Pain relief at 2 h occurred in 65% and 68% of patients treated with ubrogepant at 50 and 100 mg, respectively.[46]

Particular attention was devoted to liver function since liver toxicity was a concern due to previously investigated gepants. Study 3110-105-002 was conducted based on FDA recommendations to complete a hepatic safety study.[48] This multicenter, randomized, double-blind, placebo-controlled trial included 516 healthy participants (adults ages 18 to 50) and had a duration of eight weeks. Ubrogepant was administered intermittently (two days of ubrogepant 100 mg, alternating with two days of placebo) to reflect the episodic nature of migraine and mimic the way in which patients often experience and treat migraine attacks. In this study, ubrogepant was well tolerated, with an AE profile similar to that of placebo. The most common AEs (>5%) were headache, oropharyngeal pain, and nasopharyngitis. In terms of hepatic safety, a total of seven cases of ALT/AST elevation ≥3 × ULN were reported during the eight weeks of treatment, with two cases reported in the ubrogepant group and five cases occurring in placebo participants. Within the ubrogepant group, both cases were asymptomatic and resolved with continued dosing. No drug-induced liver injury event or hepatic safety concern was observed.

Recently, the data from two phase I trials of ubrogepant demonstrated that single and multiple daily doses of ubrogepant up to the supratherapeutic dose of 400 mg were not associated with clinically meaningful elevations in ALT in healthy men.[51] The absence of hepatotoxicity in these trials and in larger randomized clinical trials and subsequent longer safety studies strongly support the hepatic safety of ubrogepant treatment.

Overall, the available data support the efficacy and consistency of this novel medication for acute treatment of migraine, although data regarding efficacy and safety in subjects in whom triptans are contraindicated are needed to confirm the clinical usage of ubrogepant as an alternative treatment to triptans. The details of phase III clinical trials of ubrogepant are summarized in [Table 2].
Table 2: Summary of phase III clinical trials of CGRP targets: Ubrogepant and Rimegepant

Click here to view


Rimegepant (BMS-927711)


In a phase IIb double-blind randomized, placebo-controlled, dose-finding trial (NCT01430442), a total of 885 patients were recruited to study rimegepant at one of six doses (10, 25, 75, 150, 300, and 600 mg) vs. placebo.[52] Sumatriptan 100 mg in oral formulation was used as an active comparator. Significant differences in the percentage of patients who were pain-free at 2 h post-dose (primary endpoint) were observed for the sumatriptan 100 mg (35%) and rimegepant at 75 mg (31.4%), 150 mg (32.9%) and 300 mg (29.7%) groups when compared to the placebo group (15.3%). However, the higher dose of rimegepant 600 mg had no additional benefit (24.4%). One secondary endpoint evaluating nausea demonstrated that only rimegepant 75 and 300 mg, but not sumatriptan 100 mg, were superior to placebo in achieving nausea freedom within 2 h post-dose. For freedom from photophobia and phonophobia, significant effects were obtained with sumatriptan and rimegepant at 75, 150, 300, and 600 mg at 2 h, and the effect continued until 24 hours post dose. However, sumatriptan 100 mg and rimegepant 75 mg and 300 mg showed the highest percentages of patients with nausea freedom that continued up to 24 hours post dose. Considering the incidence of AEs, the active treatment groups and the placebo group were similar. Regarding the hot topic of hepatotoxicity in gepants, no patients had ALT elevation, that is, ≥3 × ULN, but a mild increase in hepatic enzymes was reported in two patients, one in the placebo group and one in the rimegepant 75 mg group; the ALT elevation in the latter patient occurred on day seven and resolved after 64 days. The results of the study showed that the optimal dose of rimegepant used in the treatment of migraine was 75 mg and led to the selection of a dose of rimegepant of 75 mg for phase III trials (NCT03235479, NCT03237845, NCT03461757) starting in 2017.

In two identically designed, multicenter, double-blind, phase III trials (NCT03235479 (BHV3000-301) and NCT03237845 (BHV3000-302)) in adults with migraine, a single dose of rimegepant 75 mg tablets (BHV-3000) was compared with a single dose of placebo tablets in their ability to achieve the two coprimary endpoints in a single migraine attack.[53],[54] In study NCT03237845 (BHV3000-302), the percentage of patients who were pain-free 2 h (the primary endpoint) after receiving the dose (n = 537 modified intent to treat (mITT)) was 19.6% in the rimegepant group and 12.0% in the placebo group (n = 535), and improvements in the MBS 2 hours after the dose (coprimary endpoint) was achieved in 37.6% of the rimegepant group and 25.2% of the placebo group (all P < 0.001). The most common AEs were nausea and urinary tract infection.[54] In study NCT03235479 (BHV3000-301), for the coprimary endpoints, a significantly (p < 0.03) higher percentage of rimegepant (n = 543 mITT) than placebo (n = 541) recipients achieved pain freedom (19.2 vs. 14.2%) and MBS freedom (36.6 vs. 27.7%) at 2 h post dose.[53]

Study NCT03461757 (BHV3000-303) is a phase III, double-blind, randomized, placebo-controlled, safety and efficacy trial of a rimegepant orally disintegrating tablet (ODT) for acute treatment of migraine involving 1466 participants.[55] At 2 h post-dose, the rimegepant ODT was superior to placebo for freedom from pain (21% vs.vs. 11%, P < 0·0001) and freedom from the MBS (35% vs.vs. 27%, P = 0·0009). The most common AEs were nausea and urinary tract infection (<2%). Treated participants reported no SAEs.[55]

A further open-label, long-term (52 weeks) study (NCT03266588) of the safety and tolerability of a rimegepant 75 mg oral tablet was conducted to evaluate treatment with rimegepant 75 mg as needed up to once daily; the rimegepant 75 mg oral tablet reduced the number of migraine days/month and moderate to severe migraine days/month from baseline at all three-month assessment time points in adults with a history of migraine.[56] Rimegepant recipients experienced improvements in migraine-related disability, as assessed by Migraine Disability Assessment (MIDAS) total scores (mean total score 33.0 at baseline, 21.5 at week 12 and 18.8 at week 24), as well as health-related quality of life from baseline to 3 months, with these benefits sustaining through to week 52. The study results were published as an abstract.[56]

The results from pooled analyses of the one ODT and two conventional oral formulation phase III trials and some individual trials showed consistent efficacy in sustained pain relief and normal function 2–48 h post-dose.[57],[58] Rimegepant had superior efficacy for freedom from pain and nausea at 2 h post-dose and at 2–48 h postdose[59] in patients who were or were not using concurrent preventive migraine medications[60] with low and high attack frequencies.[61] The data are also published as an abstract.

In these trials, rimegepant proved significantly superior to placebo at 2 h post-dose for pain freedom and freedom from the MBS (photophobia, phonophobia, or nausea). The ODT formulation of the drug received FDA approval for acute treatment of migraine in adults in February 2020.[40] The tablet could be disintegrated in saliva and swallowed without additional liquid, and the recommended dose of rimegepant ODT is 75 mg taken as needed, with a maximum dose in a 24-hours period of 75 mg. The details of phase III clinical trials of rimegepant are summarized in [Table 2].


 » Conclusions Top


The favorable results in terms of the efficacy and safety of new formulations of sumatriptan, DFN-02 (sumatriptan 10 mg with permeation enhancer nasal spray) and DFN-11 (sumatriptan injection, 3 mg) suggest that these agents are considered useful alternatives to their conventional forms. Targeting 5-HT1D receptors in acute treatment has ultimately failed. 5-HT1F receptor agonists (lasmiditan) and gepants (ubrogepant and rimegepant) proved their efficacy and received approval for acute treatment of migraine; they have become an option for triptan nonresponders or those with contraindications to the use of triptans. Gepants might be a good candidate for those with triptan-induced MOH. Overall, these new agents have broadened therapies for acute migraine treatment and will likely change the strategy with which we treat migraine in the future. Nevertheless, uncertainties remain regarding the comparative effectiveness and safety of these novel agents alone or in combination with current specific acute medications for migraine attacks. In addition, there is also uncertainty about efficacy overtime or the occurrence of MOH in susceptible individuals when these new agents are used for repeated attacks over the course of years or longer. Further studies are needed to clarify these important issues.

Author contributions

CPY and SJW were responsible for the study concept and design and the review and interpretation of the data. CPY, KTH, CMC, and CCY were responsible for drafting the manuscript. SJW made modifications to the study design and revised the manuscript. CPY, KTH, CMC, and CCY contributed to data collection and analysis. CPY and SJW contributed to the interpretation of the data and revised the manuscript. All authors read and approved the final manuscript.

Acknowledgements

This research was supported by the Ministry of Science and Technology, Taiwan (MOST109-2321-B-010-006-). The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Human and animal rights and informed consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Financial support and sponsorship

This study was supported by a grant from Kuang Tien General Hospital, Taichung, Taiwan, and Taipei Veterans General Hospital, Taipei, Taiwan.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2]



 

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