| Article Access Statistics|
| Viewed||420 |
| Printed||18 |
| Emailed||0 |
| PDF Downloaded||11 |
| Comments ||[Add] |
Click on image for details.
|Year : 2021 | Volume
| Issue : 6 | Page : 1759-1762
Newer Horizon for Treatment of Acute Attack of Migraine: Lasmiditan and Ubrogepant
Arpita Maitra1, Sabyasachi Mukhopadhyay2, Abhijit Das1, Shouvik Choudhury1
1 Department of Pharmacology, Burdwan Medical College, Kolkata, West Bengal, India
2 Department of Neonatology, AMRI Hospital, Kolkata, West Bengal, India
|Date of Submission||24-Apr-2020|
|Date of Decision||08-Jul-2020|
|Date of Acceptance||15-May-2021|
|Date of Web Publication||23-Dec-2021|
Dr. Shouvik Choudhury
Department of Pharmacology, Burdwan Medical College, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
Migraine is characterized by severe, intermittent headache attacks with associated symptoms including nausea, vomiting, phonophobia, and photophobia. Still Triptans (selective 5-HT1B/D agonists) are considered as the first-line therapy in acute attack of migraine. Recently two new drugs Lasmiditan and Ubrogepant were approved by United States Food and Drug Administration in acute attack of migraine with or without aura in adults. Lasmiditan is a highly selective 5-HT1F receptor agonist which demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed phase-3 trials, SAMURAI and SPARTAN. Ubrogepant is a novel small molecule oral calcitonin gene-related peptide receptor antagonist. The approval was supported by two pivotal phase-3, randomized, double-blind, placebo-controlled trials (ACHIEVE I and ACHIEVE II) that evaluated the efficacy, safety, tolerability. Hopefully, these two drugs may soon be a new addition to the mounting armory of drugs against migraine and may fulfill a substantial unmet need.
Keywords: Headache, lasmiditan, migraine, ubrogepant
Key Messages: Triptans are still used as the first-line drug in acute migraine headache with some limitations. Lasmiditan, highly selective 5-HT1F receptor agonist and Ubrogepant, oral CGRP antagonist are recently USFDA approved drugs which show the promising result in treating acute migraine attacks.
|How to cite this article:|
Maitra A, Mukhopadhyay S, Das A, Choudhury S. Newer Horizon for Treatment of Acute Attack of Migraine: Lasmiditan and Ubrogepant. Neurol India 2021;69:1759-62
Migraine is ranked as the world's second leading cause of disability by the World Health Organization. It is characterized by severe, intermittent headache attacks with associated symptoms including nausea, vomiting, phonophobia, and photophobia which can be chronic and disabling. Migraine is a neurological and disabling disease with an estimated global prevalence of approximately 12%. The main target of therapy is to relieve pain, to restore normal functions, to reduce headache frequency and consequently to get rid of migraine-related symptoms. Treatment options can be broadly classified into two types of therapy: prophylactic to prevent migraine attack and drugs used to terminate acute attack. Still Triptans (selective 5-HT1B/D agonists) are considered as the first-line therapy in acute attack of migraine. Seven triptan molecules are available and each of them has a specific pharmacokinetic and pharmacodynamic features. But triptans have some limitations both regarding efficacy and safety. A considerable number of patients fail to respond to triptans, and also these drugs are contraindicated in cardiovascular (CV) diseases due to vasoconstrictive actions. Thus, the search for new drugs with novel mechanisms are need of the hour. Recently, two new drugs Lasmiditan and Ubrogepant were approved by United States Food and Drug Administration (USFDA) in acute attack of migraine which may open a new horizon.
| » Recent View about Migraine Pathophysiology|| |
Migraine was thought to be a type of vascular headache which suggests that migraine headache was caused by meningeal vessel dilatation. Migraine is a pathophysiologically complex disease. Recent evidence suggests that migraine is a neuronal process involving activation and sensitization of the trigeminal nociceptors and the trigeminocervical complex, as well as cortical spreading depression and abnormal brainstem activity. During a migraine, there is also meningeal vessel dilatation, but it is now thought to be an epiphenomenon. Triptans bind nonspecifically to 5-HT1B and 5-HT1D receptors and cause direct vasoconstriction to relieve the acute attack. They also have some affinity over 5-HT1F receptors. But according to current theory, trigeminal activation triggers the release of signaling proteins including calcitonin gene-related peptide (CGRP), causing secondary cerebral vessel dilation, plasma protein extravasations, and mast cell degranulation. Lasmiditan acts as specific 5-HT1F receptor agonist and Ubrogepant acts as oral CGRP receptor antagonist.
| » Lasmiditan|| |
Lasmiditan was approved by USFDA on October 11, 2019 in acute attack of migraine with or without aura in adults. This “ditan” molecule is classified as “neurally acting antimigraine agents” due to its mechanism of action. Lasmiditan is a highly selective 5-HT1F agonist, having a greater than 450-fold increased affinity for 5-HT1F over 5-HT1A, 5-HT1B, and 5-HT1D receptors. In triptans, an indole structure that closely resembles the 5-HT receptor is present, which is replaced with a pyridine-piperidine scaffold in ditan. Lasmiditan lowers plasma protein extravasations decreasing the neurogenic inflammation of the dura and suppresses neuronal firing within the trigeminal nucleus caudalis. Also, 5HT1F agonists have shown to decrease c-fos activity within trigeminal nucleus, thereby reducing the level of synaptic activation. The 5-HT1F receptors are found in high density in the neurons of the trigeminal ganglion. Neurogenic inflammation is a significant cause of pain and pain provoking stimuli like CGRP and substance-P are released from presynaptic membrane by plasma protein extravasations. It is blocked by lasmiditan. C-fos protein regulates the transcription rate of genes and is used as an indicator of the level of synaptic activation. Lasmiditan is found to decrease C-fos expression in nucleus caudalis.
The drug is absorbed rapidly after oral ingestion irrespective of food intake. It is metabolized hepatically and extrahepatically, primarily by noncytochrome P450 (CYP) enzymes and eliminated via metabolism, with the major pathway being ketone reduction. Pharmacokinetics is not significantly affected by age, sex, ethnicity, or body weight. Few common adverse effects are dizziness, fatigue, paresthesia, sleepiness, and rarely serotonin syndrome. Drug is available in 50mg, 100mg, and 200mg tablet form for use as and when required basis.
| » Clinical Trial Data|| |
The approval was based on data from two double-blind placebo-controlled phase-3 clinical trials: Trial 1 (# NCT02439320, SAMURAI) and Trial 2 (#NCT02605174, SPARTAN) of 4439 patients with migraine headaches with or without aura. Trials were conducted at 224 sites in the United States, the United Kingdom, and Germany. Trial participants were male or female, ≥18 years, with a diagnosis of episodic migraine with three to eight migraine attacks per month with or without aura, fulfilling the International Classification of Headache Disorders-II (ICD) diagnostic criteria 1.1 or 1.2.1. All enrolled patients had experienced migraine for at least 1 year and had a Migraine Disability Assessment (MIDAS) total score ≥11. Study designs were similar for both trials. Patients were distributed into three treatment groups evenly for SAMURAI: Lasmiditan 100 mg, lasmiditan 200 mg, and placebo. In SPARTAN, a fourth group was also added with lasmiditan 50 mg. They were asked to treat their next migraine attack with study drug within 4 h of pain onset. Primary and key secondary outcomes to evaluate the efficacy of lasmiditan were pain-free and MBS-free (most bothersome migraine-associated symptoms) at 2 h. In all doses, lasmiditan showed better efficacy result. Safety result was also similar for patients using and not using preventive medications. Though both trials included patients with CVrisk factors, SPARTAN also included patients with preexisting CV diseases. Another long-term, open-label, prospective, randomized trial (GLADIATOR) is going on to evaluate the safety and tolerability of long-term (12 months) intermittent use of lasmiditan 100 and 200 mg and also long-term efficacy of drug. Treatment emerging adverse effects were commonly dizziness, somnolence, paresthesia, etc.
| » Ongoing Trials|| |
Another randomized, double-blind, placebo-controlled, multinational phase-III trial (NCT03670810) is going on to evaluate the efficacy and safety of lasmiditan. In Japanese population, a randomized, double-blind, placebo-controlled, phase-II MONONOFU trial (NCT03962738) is also currently recruiting patients to assess the efficacy and safety. A phase-I study (NCT03988088) to examine the pharmacokinetics, safety, and tolerability of lasmiditan in children is currently recruiting pediatric patients aged 6–17 years.
Due to its overall efficacy and unique mechanism with minimal CVadverse effects (unlike triptans), lasmiditan may soon become an important addition to the migraine therapy.
| » Ubrogepant|| |
Ubrogepant, a novel small molecule oral CGRP receptor antagonist was approved on December 23, 2019 in acute attack of migraine with or without aura in adults. CGRP, a vasodilatory neuropeptide is involved in nociceptive transmission and modulation. CGRP receptors are widely expressed both in central and peripheral nervous system (mostly in trigeminal ganglia and nerve terminals, spinal nuclei and thalamus, and extracerebral blood vessels). Ubrogepant does not induce major vasoconstriction in cerebral, coronary, or middle meningeal arteries. It shows competitive inhibition of α-CGRP-induced relaxations, with antagonism of CGRP-induced relaxation more potent for cranial arteries.
α-CGRP is the main isoform in trigeminovascular system and brain. CGRP binds to a G-protein coupled receptor formed by two subunits: Calcitonin receptor-like receptor and receptor activity-modifying protein 1. Along with being a potent vasodilator, CGRP also plays a role in migraine pathophysiology. During spontaneous migraine attacks, CGRP concentrations measured from the external jugular vein rise. Several antagonists like olcegepant, telcagepant, ubregepant, atogepant, etc., have been tried. Four monoclonal antibodies are also currently in development for migraine prevention: three against CGRP itself: Galcanezumab, eptinezumab Eptinezumab, and fremanezumab Fremanezumab and one against the CGRP receptor erenumab.Hence, CGRP antagonism pathway promises a new ray of hope in treatment.
Ubrogepant is rapidly absorbed after oral administration, with peak plasma concentrations attained at ≈1.5hand does not have any effect over food. It is primarily metabolized by CYP3A4 and eliminated by biliary/fecalroute. Elimination half-life is 5–7 h. No clinically relevant effects of age, sex, race, bodyweight, mild or moderate renal impairment, and mild or moderate hepatic impairment are found on the pharmacokinetics of ubrogepant. The recommended dose is 50mg or 100mg, one tablet, when needed and one second dose may be repeated if required after 2 h.
| » Clinical Trial Data|| |
The FDA approval was based on evidence from two multicenter, randomized, double-blind, placebo-controlled, parallel-group, single-attack phase-3 trials conducted in the United States (Trial 1/NCT02828020, ACHIEVE I) and (Trial 2/NCT02867709, ACHIEVE II). Eligible participants were 18–75 years of age, with a history of migraine with or without aura for at least 1 year consistent with a diagnosis according to ICD criteria. Where in ACHIEVE I, participants were randomized 1:1:1 to placebo, ubrogepant 50 mg, or ubrogepant 100 mg, but in ACHIEVE II, participants were randomized 1:1:1 to placebo, ubrogepant 25 mg, or ubrogepant 50 mg. In the result of these two trials, percentages of participants with headache pain freedom 2 h post dose and absence of the most bothersome migraine-associated symptom were significantly superior with ubrogepant. Functional Disability Scale [40%–42% patients at 2 h, 60%–62% at 4 h reported no disability after ubrogepant intake], participant satisfaction with study medication, and Patient Global Impression of Change scale were used in these trials. Ubrogepant also shows restoration and maintenance participants' ability to function in daily activities. ACHIEVE Itrial was done on 1672 patients. Higher percentage of patients responded better to ubrogepant. Common adverse effects were found to be nausea, somnolence, and dry mouth. But though rare (0.2%), some serious adverse effects occurred from 48 h to 30 days of therapy as appendicitis, pericardial effusion, spontaneous abortion, and seizure. Very few patients were also found to have elevated liver enzymes but all are not associated to trial-relatedcause.ACHIEVE II trial was conducted at 99 sites including 1686 patients. Two primary outcomes were pain freedom and absence of MBS. Secondary outcomes were immediate and sustained pain relief, associated symptoms (photophobia, phonophobia, nausea) relief. Result indicated 50mg tablet was ideal to address key treatment goals. Pain freedom at 2 h was reported by 22% and absence of MBS at hours by 39% patients, which was better than placebo, but not superior to conventional drugs. A meta-analysis done by Yang et al. has published data of three trials of 3326 patients. It also shows the use of ubrogepant to be effective. Short-term use was not also associated with increased risk of adverse effects. Safety endpoints demonstrated no significant difference in treatment-related adverse events reported within 48 h and within 30 days post-dose compared with placebo. The trials pooled in meta-analysis had no reported CVadverse events, but included participants with CVrisks. The drug was very well tolerated and no signal of hepatotoxicity was also found. Overall, it suggests ubrogepant has a lower pain-abortion effect but better safety profile compared with triptans and lasmiditan. But still no clinical trial was conducted directly comparing with triptans.
| » Ongoing Clinical Trials|| |
A randomized, open-label, phase-I trial (NCT04179474) was initiated to evaluate the potential for a pharmacokinetic interaction and the safety and tolerability of ubrogepant when ubrogepant and erenumab or galcanezumab are coadministered.
Hopefully, these two drugs may soon be a new addition to the mounting armory of drugs against migraine and may fulfill the substantial unmet need. The authors do not have any firsthand experience using these drugs. Both the drugs have been just launched in market and only lasmiditan is now available in India. Recently another “gepant” molecule, Rimegepant is also approved by FDA on 27 February, 2020 for treatment in acute migraine. Both of these lasmiditan and ubrogepant are first in class approved drug from their respective groups. These novel mechanisms of action like selective 5-HT1F agonism or CGRP receptor antagonism have opened a complete new pathway regarding fight against such common global disease like migraine. Overall efficacy, tolerability, and safety data seems to be promising in both cases. But there is a lack of head to head trial data against commonly used drugs like triptans or NSAIDs. Another major drawback of these molecules may be the high cost of therapy. The Institute for Clinical and Economic Review report suggested that lasmiditan exceeds commonly accepted thresholds for long term cost-effectiveness per quality-adjusted life year, where ubrogepant falls below threshold. In a view of cost effectiveness, triptans are less expensive compared with Ubrogepant and Lasmiditan. In a view of cost effectiveness, triptans are less expensive compared with Ubrogepant and Lasmiditan. Finally, the panelists opined that the “gepants” and lasmiditan offered a novel mechanism of action or approach that will allow successful treatment of many patients for whom other treatments have failed and adequate evidence to demonstrate a net health benefit for treatment with lasmiditan, rimegepant, or ubrogepant compared with no treatment.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: A systematic analysis for the Global burden of disease study 2016. Lancet 2017;390:1211-59.
Sutherland HG, Albury CL, Griffiths LR. Advances in genetics of migraine. J Headache Pain 2019;20:72.
Pomes LM, Guglielmetti M, Bertamino E, Simmaco M, Borro M, Martelletti P. Optimising migraine treatment: From drug-drug interactions to personalized medicine. J Headache Pain 2019;20:56.
Oswald JC, Schuster NM. Lasmiditan for the treatment of acute migraine: A review and potential role in clinical practice. J Pain Res 2018;11:2221-27.
US Food and Drug Administration (FDA). FDA approves new treatment for patients with migraine [media release]. 11 Oct 2019. http://www.fda.gov
Curto M, Cipolla F, Cisale GY, Capi M, Spuntarelli V, Guglielmetti M, et al
. Profiling lasmiditan as a treatment option for migraine. Expert Opin Pharmacother 2020;21:147-53.
Lamb YN. Lasmiditan: First approval. Drugs 2019;79:1989-96.
Loo LS, Ailani J, Schim J, Baygani S, Hundemer H-P, Port M, et al
. Efficacy and safety of lasmiditan in patients using concomitant migraine preventive medications: Findings from SAMURAI and SPARTAN, two randomized phase 3 trials. J Headache Pain 2019;20:84.
Scott LJ. Ubrogepant: First approval. Drugs 2020;80:323-8.
Tso AR, Goadsby PJ. Anti-CGRP monoclonal antibodies: The next era of migraine prevention? Curr Treat Options Neurol 2017;19:27.
Dodick DW, Lipton RB, Ailani J, Singh RB, Shewale AR, Zhao S, et al
. Ubrogepant, an acute treatment for migraine, improved patient-reported functional disability and satisfaction in 2 single-attack phase 3 randomized trials, ACHIEVE I and II. Headache 2020;60:686-700.
Dodick DW, Lipton RB, Ailani J, Lu K, Finnegan M, Trugman JM, et al
. Ubrogepantfor the treatment of migraine. N Engl J Med 2019;381:2230-41.
Lipton RB, Dodick DW, Ailani J, Lu K, Finnegan M, Szegedi A, et al
. Effect of ubrogepantvs placebo on pain and the most bothersome associated symptom in the acute treatment of migraine: The ACHIEVE II randomized clinical trial. JAMA 2019;322:1887-98.
Yang Y, Chen M, Sun Y, Gao B, Chen Z, Wang Z. Safety and efficacy of ubrogepantfor the acute treatment of episodic migraine: A meta-analysis of randomized clinical trials. CNS Drugs2020;34:463-71.
ICER. Acute Migraine: Report-at-a-Glance. ICER website. Published February 25, 2020. [Last accessed 2020 Mar 10]. icer-review.org/wp-content/uploads/2019/06/Acute-Migraine-RAAG-022420.pdf.