Onset of migraine preventive effects with rimegepant


The pharmacotherapy of migraine is commonly classified into two types: acute treatments for relief of attacks during their occurrence, and preventive treatments to reduce attack frequency and severity. Rimegepant is an orally administered calcitonin gene-related peptide (CGRP) receptor antagonist approved by the US Food and Drug Administration (FDA) for the acute treatment of migraine with or without aura and the preventive treatment of episodic migraine in adults, making it the first approved medication for both the acute and preventive treatment setting.1

The FDA approval of rimegepant for the preventive setting was based on a multicenter, Phase II/III, randomized, double-blind, placebo-controlled trial (NCT03732638) that compared the efficacy of rimegepant 75 mg dosed every other day with placebo for preventive treatment of migraine. The primary efficacy endpoint was the change in the mean number of migraine days per month during weeks 9–12. Results demonstrated that rimegepant was superior to placebo, reducing the monthly migraine days by 4.3 days per month after three months of treatment while placebo reduced the monthly migraine days by 3.5 days. The least-squares mean (LSM) difference between rimegepant and placebo groups was -0.8 days (95% CI, -1.46 to -0.20; P=0.0099).1

At the International Headache Congress 2021, Christopher Jensen, PharmD, MBA, Biohaven Pharmaceuticals, New Haven, CT, presented a post-hoc analysis of the Phase II/III trial assessing the onset of migraine preventive treatment efficacy with rimegepant during the first four weeks of treatment in patients treated every other day. Results from this analysis demonstrate that rimegepant 75 mg was more effective than placebo during week 1 (−0.7 vs. −0.3, P=0.0003).2


Within the first week of treatment, rimegepant-treated participants had a 30% reduction (95% CI, –36.1 to –23.9) in weekly migraine days compared with a 9.4% reduction (95% CI, –17.1. to –1.8) for placebo-treated participants. Rimegepant continued to show more efficacy than placebo in the following weeks. However, in week 4, the differences were no longer significant (−0.8 vs. −0.6, P=0.1275).2

Overall, the analysis showed that the onset of preventive treatment effects is relatively rapid with oral rimegepant, with significant effects within the first week of treatment. As rimegepant is also effective in the acute treatment of migraine, it is an option that offers flexibility and the ability to create individualized treatment approaches depending on the patient’s acute and/or preventive treatment needs.

CEFALY device for acute migraine treatment


Currently, treatments available for migraine mainly include pharmacological approaches, which have numerous side effects, contraindications, and incomplete efficacy. Thus, there is an urgent need for new alternative non-pharmacological treatment strategies.3

Trigeminal neurostimulation with a supraorbital transcutaneous stimulator is an alternative strategy that has demonstrated safety and efficacy in preventing migraine. The CEFALY device is an external trigeminal nerve stimulator (e-TNS) that superficially stimulates the supraorbital nerve in the forehead, a branch of the trigeminal nerve known to play a key role in migraine pathophysiology.3


CEFALY was the first e-TNS approved by the US Food and Drug Administration (FDA) for use before the onset of a migraine, as a preventive treatment for migraine headaches, in patients 18 or older.4 More recently, studies have been exploring its use in the acute treatment of migraine.

Deena Kuruvilla, MD, Westport Headache Institute, Westport, CT, discusses the findings of the randomized, double-blind, sham-controlled, multicenter, Phase III TEAM study (NCT03465904), assessing the efficacy of the CEFALY device in the acute treatment of migraine. A total of 538 adults diagnosed with 2–8 migraine headache days per month were randomized to active or sham stimulation. Neurostimulation was applied at home for 2 hours continuously to treat a migraine attack.5 Patients were instructed to use the device when the pain was moderate to severe.

The TEAM study met its two primary endpoints; CEFALY was superior to the sham device in providing 2-hour pain freedom with a therapeutic gain of 7.2% (25.5% versus 18.3%, p=0.043) and was also more effective than sham in achieving freedom from the most bothersome migraine-associated symptom (MBS) at 2 hours (56.4% versus 42.3%, p= 0.001).5 The results demonstrated by CEFALY in the TEAM trial suggest it may represent a non-invasive and non-pharmacological alternative to current acute migraine treatments.

Phenome-wide analysis reveals putative causal relationships between migraine and other complex traits


Migraine is a complex and debilitating neurological disorder. It has been established that there is a significant genetic component to migraine, with heritability estimates of up to 60%. Genome-wide association studies (GWAS) have provided valuable insights into the genetic etiology of migraine.6,7 Over 40 genomic risk loci have been identified as well as the genetic overlap between migraine and other phenotypes such as epilepsy, stroke and coronary artery disease. However, the existence of shared genetic associations between traits does not indicate a causal relationship.

One phenome-wide study investigated the potential causal relationships between self-reported migraine and other complex traits, using genetic data and a hypothesis-free approach. Luis Marco García-Marín, Biotechnology Engineer, PhD student in Statistical Genetics, QIMR Berghofer Medical Research Institute & The University of Queensland, Brisbane, Australia, shares the findings from the study, which used data from GWAS of 1,504 phenotypes. In total, 510 genetic correlations were identified, of which 17 were explained by a potential causal association with self-reported migraine.7

Phenotypes of conditions causing abdominal pain discomfort, such as diaphragmatic hernia, ventral hernia, and benign neoplasm of colon, rectum, anus, and anal canal, posed a putative causal effect increasing self-reported migraine. Similarly, self-reports of pulmonary embolism and deep venous thrombosis and traits diagnosed by a doctor, such as a blood clot in the leg, increased self-reported migraine risk. In particular, hypertension and blood clot formations were causally associated with an increased migraine risk, possibly through vasoconstriction and platelet clumping.7


The study also investigated occupational and environmental factors such as work environments where individuals are exposed to paints, thinner, glues, or diesel exhaust, which were causally associated with self-reported migraine. Finally, psychiatric-related phenotypes, including stressful life events, can potentially influence an increase in self-reported migraine. While ever feeling unenthusiastic or disinterested for a whole week, a phenotype related to the psychological well-being of individuals was identified as a potential consequence of self-reported migraine.7

Altogether, these findings validate various causal associations reported in previous studies, which could be used as testable hypotheses in future studies. Better insights into the relationship between migraine and other traits can inform the design of novel interventions for the acute and preventive treatment of migraine.7

Written by Marta Palhas


  1. R Croop, RB Lipton, D Kudrow, et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet. Jan 2021;397(10268):51-60.
  2. RB Lipton, D Kudrow, T Smith, et al. AL053 Onset of Migraine Preventive Effects With Rimegepant in a Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Trial. The International Headache Congress – IHS and EHF joint congress 2021. J Headache Pain. Sep 2021;22,103.
  3. DE Chou, M Shnayderman Yugrakh, D Winegarner, et al. Acute migraine therapy with external trigeminal neurostimulation (ACME): A randomized controlled trial. Cephalalgia. Jan 2019;39(1):3-14.
  4. FDA: Treating Migraines: More Ways to Fight the Pain. Available from: https://www.fda.gov/consumers/consumer-updates/treating-migraines-more-ways-fight-pain Last accessed: 11/10/2021.
  5. D Kuruvilla, A Starling, SJ Tepper, et al. AL059 A Phase 3 randomized, double-blind, sham-controlled Trial of e-TNS for the Acute treatment of Migraine (TEAM). The International Headache Congress – IHS and EHF joint congress 2021. J Headache Pain. Sep 2021;22,103.
  6. C Bron, HG Sutherland, LR Griffiths. Exploring the Hereditary Nature of Migraine. Neuropsychiatr Dis Treat. Apr 2021;17:1183-1194.
  7. LM García-Marín, AI Campos, NG Martin, et al. Phenome-wide analysis highlights putative causal relationships between self-reported migraine and other complex traits. J Headache Pain. Jul 2021;22,66.