Ge-Bu Indication
What is Ge-Bu’s opinion?
- The percentage of patients who are free of pain 2 hours after an attack of migraine is significantly higher among those using rimegepant than among those using placebo. The ‘number needed to treat’ is 10 to 13.
- However, a network meta-analysis including only indirect comparisons indicates that its efficacy appears to be lower than that of most triptans.
- So far, no cardiovascular adverse effects have been reported to be associated with the use of rimegepant. Unlike the triptans, rimegepant is not contraindicated in the presence of cardiovascular disorders.
- The use of rimegepant for migraine attacks is appropriate as an alternative to paracetamol, NSAIDs or triptans, in case these drugs are insufficiently effective, are contraindicated or have bothersome or serious adverse effects.
New drugs for migraine attacks
Since 1991, migraine attacks have been treated not only with paracetamol and NSAIDs, but also with triptans. After almost 30 years, two new classes of drugs have now been added to the therapeutic armoury for migraine attacks, the 5HT1F receptor agonists and the small-molecule CGRP (calcitonin gene-related peptide) antagonists. The literature also refers to the 5HT1F agonists as ‘ditans’ and to the small-molecule CGRP antagonists as ‘gepants’, referring to the last part of the drug names. There is also a group of large-molecule CGRP antagonists. These monoclonal antibodies, such as erenumab, have been authorised for the prophylaxis of migraine.
The first representative of the 5HT1F agonists is lasmiditan. This drug was authorised in the United States in 2019, and the CHMP (Committee for Medicinal Products for Human Use) of the EMA gave it a favourable recommendation for authorisation in Europe on 23 June 2022.1 This drug is beyond the scope of this article.
Rimegepant (Vydura®) has recently become the first ‘gepant’ to be authorised in Europe for the treatment of migraine, but the drug is not yet on the market in the Netherlands. It has been authorised for the acute and prophylactic treatment of migraine. Its use as a prophylactic drug is not discussed here, as it was investigated only recently. Vydura® is an orodispersible tablet, which disintegrates in the mouth and can be taken without fluids.2 Rimegepant is significantly more effective in halting a migraine attack than placebo, in terms of the percentage of patients who are free of pain after 2 hours. The NNT is 10 to 13. The most bothersome symptom of migraine (such as photophobia, phonophobia or nausea) disappears within 2 hours among significantly more patients in the rimegepant group than in the placebo group (NNT 8 to 12). No cardiovascular or hepatotoxic adverse effects have so far been reported, even after 1 year of rimegepant use.
Efficacy compared to placebo
Study design
For the purpose of registration, two randomised double-blind controlled phase 3 studies have been conducted into the efficacy of rimegepant.3,4 Both registration studies included patients experiencing two to eight moderate to severe migraine episodes a month. The use of preventive migraine medication was permitted if this use had started at least 3 months before the study. Patients were issued 1 tablet of rimegepant or placebo, which they had to take in case of a migraine attack with moderate to severe pain. The first study used an ordinary tablet, while the second one used an orodispersible tablet. There were two primary outcome measures: freedom from pain after 2 hours, and disappearance of the ‘most bothersome symptom’ (MBS) after 2 hours. Adverse effects were also recorded.
Results
In the first study, 1072 patients were randomised to a rimegepant group (n = 537) or a placebo group (n = 535). The average age of the participants was 40.6 years, and most of them were female (88.7%). The participants had an average of 4.6 migraine attacks a month, involving photophobia (51.9%), nausea (29.6%) or phonophobia (15,3%) as the most bothersome migraine symptom.3
Patient characteristics in the second study were comparable; 1351 patients were included, 669 in the rimegepant group and 682 in the placebo group. The average age was 40.2 years, and 85% were female. They too had an average of 4.6 migraine attacks a month, with photophobia (57%), nausea (23%) or phonophobia (15%) as the most bothersome migraine symptom.4
Table 1 shows the results for the primary outcome measures.
Table 1. Study findings regarding the primary outcome measures for rimegepant compared to placebo
|
| Study 1 | Study 2 | ||||
|---|---|---|---|---|---|---|
|
| rimegepant 75 mg (%) | placebo (%) | difference (%) (95% CI) | rimegepant 75 mg ODT (%) | placebo (%) | difference (%) (95% CI) |
| Pain-free after 2 hours | 19.6 | 12.0 | 7.6 (3.3-11.9) | 21.2 | 10.9 | 10.4 (6.5-14.2) |
| No MBS after 2 hours | 37.6 | 25.2 | 12.4 (6.9-17.9) | 35.1 | 26.8 | 8.3 (3.4-13.2) |
ODT: orodispersible tablet, MBS: most bothersome migraine symptom, CI: confidence interval
Both studies found that significantly more patients in the rimegepant group than in the placebo group were free of pain after 2 hours (NNT 10 to 13) or free of the most bothersome migraine symptom (NNT 8 tot 12).
Efficacy compared to triptans
A network meta-analysis compared rimegepant with triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan).5
The literature was searched for randomised double-blind studies regarding drugs specifically used for migraine attacks. The primary outcome measure was freedom from pain after 2 hours.
Results
The review included 64 randomised studies, including two using rimegepant and three using ubrogepant (which is authorised in the US). The total number of participants was 46,442, with the percentage of women ranging from 74% to 87% and ages ranging from 36 to 43 years.
Table 2 lists the odds ratios for the primary outcome measure, i.e. freedom from pain after 2 hours, of all triptans and CGRP antagonists investigated, at their authorised dosage. The drugs were compared with placebo and with rimegepant.
Table 2. Study findings for the primary outcome measure of freedom from pain after 2 hours
|
| Pain-free after 2 hours OR (95% CI) vs. placebo | Pain-free after 2 hours OR (95% CI) vs. rimegepant |
|---|---|---|
| Almotriptan 12.5 mg | 2.80 (2.23-3.52) | 1.58 (1.07-2.33) |
| Eletriptan 40 mg | 5.68 (4.66-6.91) | 3.13 (2.16-4.52) |
| Frovatriptan 2.5 mg | 4.55 (1.73-11.95) | 2.55 (0.90-7.18) ns |
| Naratriptan 2.5 mg | 1.74 (1.17-2.58) | 0.97 (0.58-1.63) ns |
| Rizatriptan 10 mg | 4.78 (3.79-6.01) | 2.73 (1.85-4.02) |
| Sumatriptan 50 mg | 3.46 (2.83-4.23) | 1.93 (1.33-2.80) |
| Sumatriptan 100 mg | 4.37 (3.57-5.36) | 2.48 (1.71-3.59) |
| Zolmitriptan 2.5 mg | 3.37 (2.78-4.09) | 1.90 (1.31-2.74) |
| Rimegepant 75 mg | 1.79 (1.37-2.33) | - |
| Ubrogepant 50 mg | 1.81 (1.32-2.50) | 1.04 (0.79-1.37) ns |
| Ubrogepant 100 mg | 2.18 (1.48-3.20) | 1.02 (0.74-1.40) ns |
OR: odds ratio, CI: confidence interval, ns: non-significant.
The odds ratio of all drugs investigated compared to placebo is higher than 1 for the primary outcome measure of freedom from pain after 2 hours. The probability of a patient no longer experiencing migraine-related pain after 2 hours is statistically significantly greater when using a triptan or a CGRP antagonist than when using a placebo. The odds ratio for most of the triptans (except frovatriptan and naratriptan) compared to rimegepant is also statistically significantly greater than 1. This means that the probability of these triptans being effective is significantly greater than that for rimegepant. The odds ratios for rimegepant and ubrogepant are not significantly different.
Discussion
Most of the studies included in the network meta-analysis investigated the effects of administration of the drug after the start of a single migraine attack. It remains unclear whether the effects persist after multiple treatments. Furthermore, no randomised studies have been conducted in which the CGRP antagonists were compared with triptans, so that the evidence from the network meta-analysis rests solely on indirect comparisons.
Adverse effects
Registration studies
Nausea as an adverse effect was reported in the registration studies in both the rimegepant group (1.8 to 2%) and the placebo group (0 to 1.1%), as was urinary tract infection (1.5% and 0.6 to 1.1%, respectively). Laboratory studies have found no evidence of hepatotoxicity.3,4
The long-term adverse effects (6 to 12 months) have been assessed in two studies including a total of 2402 patients. They found no serious adverse effects.2
Network meta-analysis
The network meta-analysis comparing rimegepant with the triptans used the number of adverse effects that had occurred as a secondary outcome measure. The findings for this secondary outcome measure are shown in Table 3.
Table 3. Odds ratios of the adverse effects found in the study of triptans and CGRP antagonists compared to placebo
|
| Adverse effects OR (95% CI) compared to placebo |
|---|---|
| Almotriptan 12.5 mg | 1.16 (0.78-1.72) ns |
| Eletriptan 40 mg | 1.31 (0.97-1.78) ns |
| Frovatriptan 2.5 mg | 1.51 (0.74-3.05) ns |
| Naratriptan 2.5 mg | 1.06 (0.75-1.50) ns |
| Rizatriptan 10 mg | 1.89 (1.36-2.45) |
| Sumatriptan 50 mg | 1.77 (1.39-2.36) |
| Sumatriptan 100 mg | 1.71 (1.32-2.22) |
| Zolmitriptan 2.5 mg | 2.26 (1.76-2.90) |
| Rimegepant 75 mg | 1.25 (0.85-1.84) ns |
| Ubrogepant 50 mg | 0.93 (0.60-1.43) ns |
| Ubrogepant 100 mg | 1.42 (0.86-2.35) ns |
OR: odds ratio, CI: confidence interval, ns: non-significant.
De odds ratios for rimegepant or ubrogepant do not differ significantly from that for placebo. The odds ratio for some of the triptans (rizatriptan 10 mg, sumatriptan 50 mg and 100 mg and zolmitriptan 2.5 mg) is significantly higher than 1, due to adverse effects in the chest, such as pain and oppressive, heavy or tight feelings in the chest (6.7% to 9.0%).
Background information
Further information about the prevalence, symptoms and pathophysiology of migraine can be found in the recent Ge-Bu article ‘Nieuwe geneesmiddelen voor migraineprofylaxe’.6
Treatment of a migraine attack
The drugs of first choice for the acute treatment of a migraine attack are paracetamol, NSAIDs and triptans.7,8 The use of NSAIDs results in 9% to 20% (NNT 5 to 11) more patients being free of pain within 2 hours than with placebo. The figure for diclofenac 50 mg and ibuprofen 400 mg is 14% (NNT 7). The corresponding figures for the various triptans range from 16% to 32%; for sumatriptan 50 mg this is 16.9% (NNT 6) and for sumatriptan 100 mg 21.4% (NNT 5).9,10,11 Triptans are ineffective in 30% of patients, and in 25% of patients they cause adverse effects like an oppressed feeling (in the chest or at other sites), drowsiness, flushing and tingling sensations. In addition, triptans are contraindicated in the presence of ischaemic heart conditions, coronary vessel spasms, peripheral vascular disorders, hypertension and previous myocardial infarction, stroke or transient ischaemic attack (TIA).9
Acute treatment with paracetamol, NSAIDs and triptans is ineffective in a considerable proportion of patients. In addition, long-term use of these drugs can lead to medication overuse headache (MOH). This type of headache, which occurs during 15 days or more per month, can arise after using analgesics for 15 days or more, or in the case of triptans for 10 days or more. It is as yet unclear whether the long-term use of rimegepant is also associated with the development of MOH.
Mode of action of migraine-specific acute medication
The triptans act as 5HT1B/1D receptor agonists. These drugs induce vasoconstriction of the cranial vessels and inhibit the activated nociceptive neurons, which leads to pain relief.12 Rimegepant is a ‘calcitonin gene-related peptide’ (CGRP) receptor antagonist. It blocks the action of CGRP, which is released during a migraine attack, thereby inhibiting neurogenic inflammation (dilation of intracranial arteries and extravasation) and the activation of nociceptors on the trigeminal nerve (which are responsible for the perception of the pain in migraine).12 Under normal physiological conditions, the potent vasodilator CGRP plays a major role in the cardiovascular homeostasis in the body.
Conducting migraine research
The Clinical Trials Subcommittee of the International Headache Society (IHS) has formulated guidelines for conducting research into the acute treatment of migraine.13 The following primary clinical outcome measures have been defined for clinical studies of the acute treatment of migraine:
- Free of pain within 2 hours after the start of the treatment, expressed as the percentage of patients going from moderate or severe pain to no pain. The intensity of the headache is assessed using a four-point scale: 0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain.
- Disappearance of the ‘most bothersome symptom’ (MBS) (nausea, vomiting, photophobia or phonophobia) within 2 hours after the start of the treatment, expressed as the percentage of the total number of patients.
Rimegepant
Rimegepant is a small-molecule CGRP antagonist. It has been authorised for the ‘acute treatment of migraine with or without aura in adults’. In addition, it has been authorised for the ‘preventive treatment of episodic migraine in adults who have at least 4 migraine attacks per month’.14,2
Rimegepant (Vydura®) is produced as a 75 mg orodispersible tablet, which disintegrates below or on top of the tongue under the influence of saliva and is absorbed at a tmax of 1.48 hours. The maximum dosage is 75 mg per 24 hours. The presence of fatty food in the stomach extends the tmax by 1 hour, and reduces the maximum concentration by 36% to 53%. The extended absorption time after consumption of fatty food does not suggest a major role of oromucosal absorption. Rimegepant is mainly metabolised by CYP3A4, and to a lower degree by CYP2C9. Simultaneous use of rimegepant and strong CYP3A4 inhibitors or moderate to strong CYP3A4 inductors is not recommended. The half-life is 10 to 12 hours. Rimegepant is also under investigation for the treatment of trigeminal neuralgia.15,14 Rimegepant is not yet on the market in the Netherlands, and its price is not yet known.
Other CGRP antagonists for migraine
While only rimegepant has currently been authorised in Europe, other CGRP antagonists are already known. The first CGRP antagonist to be investigated is olcegepant, but the development of this drug was terminated as oral administration resulted in insufficient uptake into the body for a useful therapeutic effect.16 The development of telcagepant has also been terminated, as this drug proved to be hepatotoxic in chronic use.16 Ubrogepant was authorised in the US in late 2019 for the treatment of migraine attacks. In addition to rimegepant, atogepant was also authorised by the FDA in 2021 for migraine prophylaxis. Zavegepant is currently being investigated for migraine prophylaxis.17
Details of the studies discussed
Registration study 1 3
Inclusion criteria: patients who have had migraine for longer than 1 year, have 2 to 8 migraine attacks of moderate to severe intensity a month; stable preventive migraine medication allowed
Main exclusion criterion: an unstable medical condition such as a cardiovascular disorder, which may influence the efficacy or adverse effects
Intervention: rimegepant 75 mg tablet versus placebo when having a migraine attack
Primary endpoints and study duration: freedom from pain after 2 hours and disappearance of most bothersome migraine symptom after 2 hours; 45 days
Intended number of patients and power: 1100 patients, 95% power
Randomisation: 1:1, using an interactive web response system
Blinding: double-blind
Population analysed: modified intention-to-treat (patients who had correctly taken the medication after a migraine attack, and had subsequently had at least one efficacy assessment)
Number of patients included and patient characteristics: 1072 in total, 88.7% female, average age 40.6 years
Trial registration: NCT03237845
Funding: Biohaven Pharmaceuticals
Conflicts of interest: 9 of the 10 authors
Registration study 2 4
Inclusion criteria: patients who have had migraine for longer than 1 year, have 2 to 8 migraine attacks of moderate to severe intensity a month; stable preventive migraine medication allowed
Main exclusion criterion: an unstable medical condition such as a cardiovascular disorder, which may influence the efficacy or adverse effects
Intervention: rimegepant 75 mg orodispersible tablet versus placebo when having a migraine attack
Primary endpoints and trial duration: freedom from pain after 2 hours and disappearance of most bothersome migraine symptom after 2 hours; 45 days
Intended number of patients and power: 1200, 95% power
Randomisation: 1:1, using an interactive web response system and stratification for use or non-use of preventive migraine medication
Blinding: double-blind
Population analysed: modified intention-to-treat (patients who had correctly taken the medication after a migraine attack, and had subsequently had at least one efficacy assessment)
Number of patients included and patient characteristics: 1351, 85% female, average age 40.2 years
Trial registration: NCT03461757
Funding: Biohaven Pharmaceuticals
Conflicts of interest: all 8 authors
Network meta-analysis 5
Primary endpoint: freedom from pain after 2 hours
Major secondary endpoints: pain relief after 2 hours and adverse effects
Inclusion criteria: double-blind randomised studies of migraine-specific acute medication
Major exclusion criteria: studies of one drug administered via different routes
Number of articles analysed: 8488, 62 of which were included, 2 concerning rimegepant
Number of patients: 46,442, 1206 of whom used rimegepant
Quality standards applied: PRISMA
Method used to asses risk of bias: Cochrane risk of bias tool for randomised trials version 2
Limitations reported by authors: only short-term effects were studied, study designs differed (migraine with or without aura, migraine prophylaxis or not). Analysis depends on high-quality studies, but number of studies with high risk of bias was low. Many indirect comparisons, which cannot replace a direct comparison
Funding: Ministry of Science and Technology, and Ministry of Education, Taiwan
Conflicts of interest: 1 of the 8 authors
Literature references
- Committee for Medicinal Products for Human Use. Summary of opinion (initial authorisation). Rayvow. Lasmiditan. Available from: https://www.ema.europa.eu/en/documents/smop-initial/chmp-summary-positive-opinion-rayvow_en.pdf. Accessed 23 July 2022.
- EMA. Product information for Vydura®. Available from: https://www.ema.europa.eu/en/documents/assessment-report/vydura-epar-public-assessment-report_en.pdf. Accessed 1 June 2022.
- Lipton RB, Croop R, Stock EG, Stock DA, Morris BA, Frost M, et al. Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine. N Engl J Med. 2019 Jul 11;381(2):142-149. doi: 10.1056/NEJMoa1811090.
- Croop R, Goadsby PJ, Stock DA, Conway CM, Forshaw M, Stock EG, et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. Lancet. 2019 Aug 31;394(10200):737-745. doi: 10.1016/S0140-6736(19)31606-X.
- Yang CP, Liang CS, Chang CM, Yang CC, Shih PH, Yau YC, et al. Comparison of New Pharmacologic Agents With Triptans for Treatment of Migraine: A Systematic Review and Meta-analysis. JAMA Netw Open. 2021 Oct 1;4(10):e2128544. doi: 10.1001/jamanetworkopen.2021.28544.
- Schwarz EP. Nieuwe geneesmiddelen voor migraineprofylaxe. Gebu. 2022;56(1):1-8.
- NHG-Standaard Hoofdpijn. Versie 5.0 september 2021. Utrecht: Nederlands Huisartsen Genootschap, 2021. Available from: https://richtlijnen.nhg.org/standaarden/hoofdpijn.
- Nederlandse Vereniging voor Neurologie. Richtlijn Medicamenteuze behandeling migraine en MOH. 2017. Available from: https://richtlijnendatabase.nl/richtlijn/medicamenteuze_behandeling_migraine_en_moh/profylactische_behandeling_migraine.html
- Robbins MS. Diagnosis and Management of Headache: A Review. JAMA. 2021 May 11;325(18):1874-1885. doi: 10.1001/jama.2021.1640.
- VanderPluym JH, Halker Singh RB, Urtecho M, Morrow AS, Nayfeh T, Torres Roldan VD, et al. Acute Treatments for Episodic Migraine in Adults: A Systematic Review and Meta-analysis. JAMA. 2021 Jun 15;325(23):2357-2369. doi: 10.1001/jama.2021.7939.
- Ashina M. Migraine. N Engl J Med. 2020 Nov 5;383(19):1866-1876. doi: 10.1056/NEJMra1915327.
- Ashina M, Hansen JM, Do TP, Melo-Carrillo A, Burstein R, Moskowitz MA. Migraine and the trigeminovascular system-40 years and counting. Lancet Neurol. 2019 Aug;18(8):795-804. doi: 10.1016/S1474-4422(19)30185-1.
- Diener HC, Tassorelli C, Dodick DW, Silberstein SD, Lipton RB, Ashina M, et al. International Headache Society Clinical Trials Standing Committee. Guidelines of the International Headache Society for controlled trials of acute treatment of migraine attacks in adults: Fourth edition. Cephalalgia. 2019 May;39(6):687-710. doi: 10.1177/0333102419828967.
- CBG-MEB. Productinformatie Vydura®. Available from : www.cbg-meb.nl. Accessed 1 June 2022.
- Scott LJ. Rimegepant: First Approval. Drugs. 2020 May;80(7):741-746. doi: 10.1007/s40265-020-01301-3.
- Hargreaves R, Olesen J. Calcitonin Gene-Related Peptide Modulators - The History and Renaissance of a New Migraine Drug Class. Headache. 2019 Jun;59(6):951-970. doi: 10.1111/head.13510.
- Cohen F, Yuan H, Silberstein SD. Calcitonin Gene-Related Peptide (CGRP)-Targeted Monoclonal Antibodies and Antagonists in Migraine: Current Evidence and Rationale. BioDrugs. 2022 May;36(3):341-358. doi: 10.1007/s40259-022-00530-0.
