2.1.2 Trial Evidence in Migraine
The first drug in this class to be tested clinically was LY334370, which was effective but had off-target toxicity that stopped its development [
33]. Lasmiditan was developed as an orally available ditan [
34,
35]. Its first phase II study was positive [
36], which led to phase III clinical trials of this agent in the acute treatment of migraine [
37,
38]. Lasmiditan at all doses led to an increased rate of headache freedom at 2 h post-doses and freedom from the most bothersome symptom relative to placebo. Interestingly, unlike other acute trials of treatment in migraine, these studies both included patients with coronary artery disease, clinically significant arrhythmia and uncontrolled hypertension and were single attack designs, allowing one or two lasmiditan doses only. The presence of pre-existing vascular risk factors had no impact on treatment efficacy, nor did the drug cause a difference in cardiovascular treatment-emergent adverse events relative to placebo [
39]. Sub-group analysis also suggested efficacy in those who had previously failed triptan therapy [
40,
41], and in those in whom triptans were contraindicated [
42]. In an open-label, phase III study using previously recruited trial patients who continued to use lasmiditan, 100–200 mg was effective in 27–32% of attacks with a consistent response, and was generally well tolerated, with dizziness being the most common side effect, and less common ones including fatigue and paraesthesia [
43]. The dizziness seems to be dose-dependent and of short duration (median 1.5–2 h), without any influence on drug efficacy [
44]. Post-hoc analyses of all three studies have also suggested no increase in adverse events among the elderly compared with younger patients [
45]. Post-hoc safety analyses of a trial of consecutive attacks treated with lasmiditan relative to placebo showed treatment-emergent serious adverse events occurred in only two patients taking 100–200 mg relative to one patient with placebo [
46]. Dizziness, paraesthesia, fatigue, nausea, vertigo and somnolence were the most common events reported, with the vast majority being mild or moderate in severity and the incidence being highest during the first attack and decreasing with subsequent attacks.
In common with triptans [
47], and in contrast to gepants (see below), a second dose of lasmiditan after failure of the initial dose is not more effective than placebo [
48]. Again, consistency of response rates are comparable to triptans at two-thirds having pain relief in ≥ 2/3 attacks with lasmiditan 100 or 200 mg [
49], and sumatriptan 100 mg [
50].
This data has led to the United States Food and Drug Administration (US FDA) approving this drug for the acute treatment of migraine in 2019. Unfortunately, a single dose can lead to an impairment with driving which can be unrecognised by the patient, so patients are forbidden from driving for at least 8 h following drug administration [
51], which makes emergency use of the drug for some patients unfavourable relative to other currently available options.
Studies in the safety of this drug in children are ongoing (ClinicalTrials.gov identifiers: NCT04396236, NCT04396574).
There is a preclinical suggestion that the ditan class may have an MOH effect akin to the triptans [
52], and the potential for this in clinical practice remains to be evaluated as more widespread clinical use of this agent develops.
Serotonin syndrome, an additive effect of alcohol and possible bradycardia with other medications are all drug–drug interactions and risks that will need to be considered as increased prescribing of this drug within clinical practice occurs [
53].
The development of acute migraine therapies that lack vasoconstrictive effects is an appealing therapeutic avenue in migraine, and the ditans hold promise for treatment, particularly in the elderly and those with cardiovascular risk factors.
The phase III clinical trials and sub-studies and their findings for lasmiditan are summarised in Table
1.
Table 1
A summary of the phase III clinical trials and sub-studies of lasmiditan for the acute treatment of migraine, with the salient findings
Kuca et al. (2018) [ 38] (SAMURAI) | Randomised double-blind phase III | Oral | Single attack | 100–200 mg 28.2–32.2% PF2h | 15.3% | |
Goadsby et al. (2019) [ 37] (SPARTAN) | Randomised double-blind phase III | Oral | Single attack | 50–200 mg 28.6–38.8% PF2h | 21.3% | |
Brandes et al. (2019) [ 43] (GLADIATOR) | Randomised open-label phase III | Oral | ≥1 attack | 100–200 mg 26.9–32.4% PF2h | NA | Consistent response across up to 5 attacks in those who treated ≥ 5 |
| Post-hoc analysis of [ 37, 38] | Oral | Single attack | 50–200 mg 28.6–35.6% PF2h 17.4–21.2% PF24h 14.9–18.4% PF48h | 18.3% PF2h 10.3% PF24h 9.6% PF48h | MBS, total migraine-free and disability-free responses more common in treated groups at all doses (21.7–27% vs 12.9%) |
Shapiro et al. (2019) [ 39] | Pooled analysis of [ 37, 38] | Oral | Single attack | | | 0.9% with drug vs 0.4% overall cardiovascular treatment emergent adverse events, independent of previous cardiovascular risk factors and similar efficacy |
| Post-hoc analysis of [ 37, 38] | Oral | Single attack | | | Some efficacy of a second dose of drug for headache recurrence but not ongoing headache |
| Post-hoc analysis of [ 37, 38] | Oral | Single attack | | | No effect of concurrent migraine preventives on drug efficacy or adverse event reporting |
Ashina et al. (2019) [ 153] | Post-hoc analysis of [ 37, 38] | Oral | Single attack | | | Symptom relief of headache and other migraine symptoms can start as early as 30 minutes after dose of 100–200 mg |
Smith et al. (2020) [ 154] | Post-hoc analysis of [ 37, 38, 43] | Oral | Multiple attacks | | | All doses resulted in an improvement in migraine-related disability which was persistent at 48 h |
Tepper et al. (2020) [ 155] | Post-hoc analysis of [ 37, 38] | Oral | Single attack | | | Efficacy of 100–200 mg not influenced by baseline patient characteristics, migraine disease history, delaying treatment > 2 h or co-existent nausea |
Lipton et al. (2021) [ 156] | Pooled analysis from [ 37, 38] | Oral | Single attack | | | Pain freedom relative to mild pain at 2 h is associated with freedom from MBS, lower migraine disability and increased patient global impression of change |
Ashina et al. (2021) [ 49] (CENTURION) | Randomised double-blind phase III | Oral | Four consecutive attacks | 100–200 mg 14.4–24.4% PF2h in ≥ 2 of 3 attacks | 4.3% | Consistent response across attacks with less adverse events after first attack |
Tassorelli et al. (2021) [ 46] | Post-hoc safety analysis of [ 48] | Oral | Four consecutive attacks | NA | NA | Mild to moderate adverse events of short duration, with reducing frequency over subsequent attacks |
Reuter et al. (2022) [ 41] | | Oral | Four consecutive attacks | | | Response independent of previous triptan response |
| | Oral | Single/multiple attacks | | | 2-hour pain relief the same for those with and without triptan contraindications and same safety and tolerability profiles |
2.1.4 Proposed Mode of Action
Whilst it has become well established that blocking the effects of CGRP in migraine has a therapeutic effect, and that CGRP is widely expressed within the central nervous system, including at sites known to be crucial to migraine pathophysiology [
55], the sites of action of the small molecule antagonists or the monoclonal antibodies has not been fully elucidated. It has been suggested that neither the gepants nor the CGRP monoclonal antibodies cross the blood–brain barrier in sufficient quantities, and therefore their migraine effect is mediated peripherally in the trigeminovascular system [
56,
57]. Some sites of action which have been proposed include the most peripheral ends of the C- and Aδ-fibres, in part located in the adventitia of intracranial vessels and on the dura, the trigeminal ganglion and the nodes of Ranvier [
58]. On the other hand, CGRP receptors are well placed in the trigeminocervical complex [
59], ventroposteromedial thalamus [
60] and ventrolateral periaqueductal grey [
61,
62] to have plausible effect in migraine. Moreover, small amounts of monoclonal antibodies enter the cerebrospinal fluid (CSF) [
62], and there is a substantial discrepancy between gepant Ki’s (binding affinity between the small molecule and receptor) and CGRP receptor occupancy on brain penetration studies [
63,
64], whereas their peripheral effect on the forearm blood flow model of CGRP release in humans is mediated via higher receptor occupancy and a concentration-dependant effect [
64].
2.1.5 Trial Evidence in Migraine
Ubrogepant was the first gepant to receive FDA approval in 2019 following two phase III trials demonstrating efficacy relative to placebo with 25–100 mg doses [
65,
66]. The initial studies suggested efficacy and tolerability, and subsequent post-hoc analyses have shown consistent responses in triptan non-responders, insufficient responders and those that are triptan naïve [
67,
68]. In contrast to the triptans and ditans (see above), a second dose of ubrogepant for primary treatment failure is effective [
69]. There seemed to be a favourable side effect profile even amongst those with cardiovascular risk [
70]. The acute headache response also seems sustained at 48 h [
71]. The use of concomitant migraine prevention did not alter efficacy [
72]. Interestingly, a phase III trial assessing the efficacy of ubrogepant in migraine treatment when administered during the prodrome has just been completed, and the results are awaited (NCT04492020). An open-label study is also ongoing looking at the safety of this drug in children and adolescents (NCT05127954). Real-world data are encouraging in terms of efficacy but suggests that adverse events such as fatigue, dry mouth and nausea and vomiting were reported more frequently than in the clinical trials [
73]. The trials of ubrogepant are summarised in Table
2.
Table 2
Summary of the findings of the phase III trials and sub-studies of ubrogepant in the acute treatment of migraine, with the salient findings
Dodick et al. (2019) [ 65] (ACHIEVE-I) | Randomised double-blind phase III | Single attack | 50 or 100 mg 19.2–21.2% PF2h 37.7–38.6% MBS freedom at 2 hours | 11.8% PF2h 27.8% MBS free at 2 hours | Nausea, somnolence, dry mouth | |
Lipton et al. (2019) [ 66] (ACHIEVE-II) | Randomised double-blind phase III | Single attack | 25 or 50 mg 20.7–21.8% PF2h 34.1–38.9% MBS freedom at 2 hours | 14.3% PF2h 27.4% MBS free at 2 hours | Nausea and dizziness | |
Ailani et al. (2020) [ 158] | Randomised open-label phase III | Multiple attacks | | | Upper respiratory tract infection | Long-term use of 50 and 100 mg safe and well tolerated |
Dodick et al. (2020) [ 159] | | Single attack | | | | Increased rates of normal function, medication satisfaction, patient global impression of change scale at all doses relative to placebo |
Goadsby et al. (2021) [ 71] | Post-hoc analysis of [ 65, 66] | Single attack | | | | Drug effect within 1–2 hours post dose with effect persistent at 48 hours |
Hutchinson et al. (2021) [ 70] | Post-hoc analysis of [ 65, 66] | Single attack | | | | No difference in efficacy, adverse events or cardiac events between different cardiovascular risk groups |
Blumenfeld et al. (2021) [ 67] | Post-hoc analysis of [ 65, 66] | Single attack | | | | No difference in efficacy or tolerability regardless of previous triptan exposure or response |
Chiang et al. (2021) [ 73] | Post-market cohort study | Multiple attacks | Headache relief 47.6% Headache freedom 19% | NA | Fatigue, dry mouth, nausea, vomiting, constipation, dizziness | No difference in response amongst those on a CGRP antibody, although higher rates of adverse events, adverse events in general may be higher than suggested in initial trials |
Blumenfeld et al. (2022) [ 72] | Sub-analysis of [ 66, 159] | Single attack | | | | Similar drug response despite migraine prevention, with no significant differences across classes of preventives, and similar adverse events |
Lipton et al. (2022) [ 68] | Post-hoc analysis of [ 65, 66] | Single attack | | | | Increased rates of normal function and treatment satisfaction in those with an insufficient triptan response previously compared with placebo |
Rimegepant has also been FDA approved for use as an orally disintegrating tablet at 75 mg in the acute treatment of migraine, following three randomised, phase III, placebo-controlled trials [
74‐
76], which followed a dose-finding phase IIb study in 2014 [
77]. The agent has since been European Medicines Agency (EMA) approved. This dose was superior to placebo in headache cessation and treatment of the most bothersome symptom, with nausea and urinary tract infection as the most common adverse events. Interestingly, initial concerns regarding liver impairment with the first drugs developed in this class was not born out [
54], with a transaminitis occurring in a single patient in both the active and placebo groups and no elevations in bilirubin more than twice the upper limit of normal reported in one of the rimegepant studies [
74]. A further study showed that the drug could also work in the preventive treatment of migraine with alternate day dosing showing superiority to placebo, without significant adverse events [
78]. This idea that the same drug could work acutely and preventively for migraine has been historically reported with agents like ergotamine, with intranasal and rectal preparations being used acutely [
22], and intravenous dihydroergotamine having a demonstrated preventive effect in migraine [
79], yet this bridge between acute and preventive migraine therapy is emerging again. Whilst the CGRP antibodies currently hold UK licensing and National Institute for Health and Care Excellence (NICE) approval for the prevention of migraine only [
80], there is evidence that if administered intravenously between 1 and 6 h after the onset of a migraine, eptinezumab can be effective at shortening the attack duration relative to placebo [
81], as well as being an effective preventive treatment of migraine [
82,
83]. Recent work also suggests long-term safety of rimegepant use, even in those with moderate to high cardiovascular risk [
84]. An open-label study has suggested a potential preventive effect even with PRN use over a 52-week period with improved quality of life outcomes and no obvious medication overuse effect with more frequent usage of rimegepant [
85]. However, this study was open-label and allowed concomitant use of other migraine preventives (amitriptyline and topiramate being the most common), which could have led to some confounding of the results. The rimegepant studies are summarised in Table
3.
Table 3
Summary of the findings of the phase trials of rimegepant in the acute and preventive treatment of migraine, and the salient findings
Marcus et al. (2014) [ 77] | Randomised phase IIb | Single attack | 75 mg 31.4% 150 mg 32.9% 300 mg 29.7% PF2h | 15.3% PF2h 100 mg sumatriptan 35% PF2h | Nausea and overall adverse event rate comparable to placebo | Sustained pain freedom from 2 to 24 h for all doses relative to placebo |
Lipton et al. (2019) [ 75] | Randomised double-blind phase III | Single attack | 75 mg 19.6% PF2h 37.6% MBS free at 2 hours | 12% PF2h 25.2% MBS free at 2 hours | Nausea and urinary tract infection | Liver toxicity did not seem to be a concern |
| Randomised double-blind phase III | Single attack | 75 mg 21% PF2h 35% MBS free at 2 hours | 11% PF2h 27% MBS free at 2 hours |
| Randomised double-blind phase II/III | Every other day for 12 weeks | 75 mg −4.3 MMD reduction | −3.5 MMD reduction | Nausea, nasopharyngitis, urinary tract infection, upper respiratory tract infection | |
Johnston et al. (2022) [ 85] | Post-hoc analysis of open-label safety study | As needed dosing up to OD for 52 weeks | 75 mg −2 MMD reduction with 2–14 doses/month | NA | NA | Improved quality of life outcomes, no clear impact of frequency of dosing on medication overuse headache |
Atogepant has been specifically investigated for the preventive treatment for migraine rather than the acute treatment of migraine. This has been the latest drug to gain FDA approval in its class in 2021, and is pre-registration for migraine prevention in the EU, Israel, Kuwait and the United Arab Emirates. Two phase III trials have demonstrated efficacy in headache prevention (a reduction in mean monthly migraine days relative to placebo) over 12 weeks at all doses between 10–60 mg, with adverse effects of fatigue, constipation and nausea [
86,
87]. Therapeutic efficacy seems to start early in the course of treatment and is sustained at 12 weeks [
88]. A recent study has demonstrated no clinically significant pharmacokinetic interactions between sumatriptan and atogepant when co-administered [
89]. A further phase III study is examining the efficacy of atogepant in episodic migraine prevention in those who have failed two to four previous preventives (NCT04740827) [
90]. The atogepant studies are summarised in Table
4.
Table 4
Summary of the findings of the phase III and sub-studies trials of atogepant in the preventive treatment of migraine, and the salient findings
Goadsby et al. (2020) [ 86] | Randomised double-blind phase IIb/III | Varying OD or BD dosing for 12 weeks | 10 mg −4 MMD reduction 30 mg −3.8 MMD reduction 60 mg −3.6 MMD reduction 30 mg BD −4.2 MMD reduction 60 mg BD −4.1 MMD reduction | −2.9 MMD reduction | Nausea and fatigue | |
Ailani et al. (2021) [ 87] (ADVANCE) | Randomised double-blind phase III | Varying OD dosing for 12 weeks | 10 mg −3.7 MMD reduction 30 mg −3.9 MMD reduction 60 mg −4.2 MMD reduction | −2.5 MMD reduction | Constipation and nausea | |
Schwedt et al. (2022) [ 88] | Post-hoc analysis of [ 87] | Varying OD dosing for 12 weeks | | | | Efficacy as early as first full day of treatment and sustained monthly across 3 months |
Boinpally et al. (2022) [ 89] | Open-label randomised crossover | Atogepant, sumatriptan or both | | | | No significant pharmacokinetic interactions of clinical relevance between oral sumatriptan and atogepant |
Pozo-Roisch et al. (2022) [ 90] | Randomised double-blind phase III (PROGRESS) | Two doses for 12 weeks | 30 mg BD −7.5 MMD reduction 60 mg QDS −6.9 MMD reduction | −5.1 MMD reduction | Constipation and nausea | ≥ 41% of those treated with atogepant had ≥ 50% reduction in the 3-month MMD compared with 26% in the placebo group. Secondary endpoints of changes in quality of life, acute medication use, performance in daily activities and physical impairment all met with significance for both atogepant doses |
An intranasal gepant, zavegepant, formerly called vazegepant, is under investigation for the acute treatment of migraine (NCT04408794) [
91]. Despite low oral bioavailability in rats, efficacy in the nasal delivery formulation has been demonstrated in unpublished phase II/III data [
92] and approval has been filed at the FDA, with a decision expected early next year. Further work is under way to alter the molecular structure to try to increase oral bioavailability and increase delivery options of this agent [
93]. An oral formulation is currently under investigation (NCT04804033).
Interestingly, preclinical data suggests that targeting the CGRP pathway rather than the serotoninergic one is less likely to lead to medication overuse [
52]. The efficacy of the monoclonal antibodies targeting this pathway despite the presence of medication overuse, compared with other migraine preventives, is interesting and alludes to the role of this system in the mediation of medication overuse [
8]. Again, longer term and more widespread clinical use of these agents will reveal further insights with regard to this in due course. Of note, all the gepants are prone to drug interactions when co-administered with CYP34A inducers or inhibitors; inducers such as phenytoin, St John’s Wort and carbamazepine may lead to reduced gepant serum levels and loss of efficacy and inhibitors such as ketoconazole and clarithromycin may lead to elevated serum gepant levels [
11].
The emergence of these agents in both the acute and preventive treatment of migraine gives us the first targeted oral treatment to use in clinical practice since the development of the triptans in the 1990s. The prospect of these treatments being efficacious, working in the presence of other CGRP-targeted therapies, not interacting with the triptans and not being affected by other migraine prevention, as well as the suggestion that they may not be troublesome in the presence of cardiovascular risk and may not cause medication overuse, provides another novel and exciting treatment opportunity to offer our patients.