Abstract
Background
Long-term data helps assess the consistency of efficacy, tolerability, and safety of acute treatment over repeated use for different attacks. Real-world studies help assess tolerability, safety, and efficacy in patients with possibly refractory chronic migraine, more comorbidities, other diseases such as cardiovascular diseases, and polypharmacy.
Methods
This is a narrative review of the long-term open-label and real-world studies of lasmiditan, ubrogepant, and rimegepant for the acute treatment of migraine. Both manuscripts and abstracts were reviewed.
Results
The efficacy and tolerability of lasmiditan, ubrogepant, and rimegepant are maintained over time. No significant cardiovascular adverse events were thought to be related to any of these medications. The rare instances of palpitations and/or tachycardia occurred within 48 hours of lasmiditan. One participant with a history of supraventricular tachycardia had sinus tachycardia thought to be related to ubrogepant which did not recur despite continued use. One case of thrombocytopenia and two cases of increased aspartate aminotransferase and alanine transaminase were thought to be possibly related, but the alanine transaminase and aspartate aminotransferase levels normalized despite continued use of ubrogepant. A case of first-degree atrioventricular block was considered possibly related to rimegepant. Acute use of rimegepant was associated with a decrease in monthly migraine days over time. The three medications were associated with improvement in function and/or productivity.
Conclusion
Long-term and real-world data of tolerability, safety and efficacy of lasmiditan, ubrogepant, and rimegepant is thus far consistent with prior studies, but more longitudinal data that clarifies long-term safety as well as consistency and predictors of response is needed.
Introduction
Well-designed, open-label extension studies may provide important data on the long-term safety and tolerability of new acute medications and help with the medication licensing application (1). Tolerability (i.e. the incidence of adverse events such as paresthesia that may not preclude patients from continuing to take the medication) has to be distinguished from safety (i.e. the incidence of serious adverse events such as a clinically significant laboratory abnormality) (2). Extension safety studies may help confirm the incidence of adverse events found in the Phase II and III clinical trials, as well as the overall spectrum of adverse events, especially when the participants are still randomly allocated into a medication and a control group (3). The lack of control group in some extension trials limits the value of the incidence of adverse events as there may be confounding factors such as concurrent treatments and comorbid diseases (3).
Since migraine is a chronic disease with attacks that may vary in severity, intensity, associated symptoms, triggers, and aggravating factors, it is helpful to gather multi-attack efficacy data of new acute treatments over the long-term. However, it is important to be aware of the inherent selection bias of extension studies as participants who found a benefit from the study drug and/or tolerated it well, are more likely to enroll in the extension phase and only participants who completed the randomized phase are recruited for the extension phase (4). When trying to assess for selection bias, the reader can look for any demographic discrepancies between the participants of the randomized versus the extension phase and look at the numbers of participants in the original versus extension trials, as well as at the proportion of extension phase participants who found the study drug effective and tolerable compared to the randomized phase (4).
More emphasis has been placed on real world evidence (RWE) since the 21st Century Cures Act (Cures Act) was signed in 2016 and the subsequent Food Drug Administration (FDA) framework for assessing the role of RWE in regulatory decision-making (5). Real world studies provide important additional information since clinical trial participants may not be representative of the diverse patient population seen in clinical practice and the clinical trial exclusion criteria and restrictions on medication use limit their generalizability (6). Efficacy and safety data is needed for people with chronic migraine as acute treatment trials have been performed only in people with episodic migraine. In addition, efficacy and safety data is required for those with complex comorbidities, multiple ineffective acute and preventive treatment trials, and concomitant use of other acute and preventive medications. The patient experience is also different as study participants have regular study appointments, required detailed data entry, and specific (and sometimes limiting) treatment instructions (7). Obtaining real-world data may also come with some methodological challenges such as missing data, selection bias, measurement bias, lack of a control group, data safety, and multiple hypotheses being tested (6).
Post-marketing safety surveillance systems are still needed to detect unpredictable and rare serious events that may not have presented in open-label extension trials nor single-center relatively small real-world studies (3). Lasmiditan is a highly selective 5-HT1F agonist with an affinity for the 5-HT1F receptor, 470 times higher than for the vasoconstrictive 5-HT1B receptor that was developed for patients who have cardiovascular contraindications or intolerable side effects from triptans (8). Gepants are oral small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (9). The first gepant, olcegepant, was effective in the acute treatment of migraine, but its development was stopped because it was given intravenously and had poor oral bioavailability (9). The development of the first two oral gepants (telcagepant - MK-0974 and MK-3207) was stopped due to concern of liver test abnormalities attributed to molecule-specific metabolites, and not to CGRP inhibition (9–12). Ubrogepant and atogepant were then chemically engineered to hopefully avoid hepatoxicity (9).
As a point of reference, there were three one-year open-label studies that assessed the long-term efficacy, safety, and tolerability of sumatriptan 100 mg oral or sumatriptan 6 mg subcutaneous (13). Preventive treatments, if any, had to be discontinued prior to enrollment in these studies (13). The efficacy of sumatriptan was maintained over time (13). A total of 849 patients treated 24,907 migraine attacks with sumatriptan and adverse events were noted for 3892 (16%) attacks (13). Common adverse events included malaise/fatigue, dizziness/vertigo, nausea, emesis, heaviness or pressure in a body part, neck pain/stiffness and occurred within two hours of taking oral sumatriptan (13). There were no serious treatment-related adverse events in those three long-term studies (13). Less than 10% of patients discontinued sumatriptan due to adverse events (13).
This is a narrative review of the long-term open-label and real-world studies of lasmiditan, rimegepant, and ubrogepant for the acute treatment of migraine attacks. Each medication will be discussed with a similar structure: the studies available to date, the medication tolerability and safety, its efficacy, impact on disability/function/work productivity, and patients’ satisfaction if available. Table 1 summarizes the demographics, clinical characteristics, and exclusion criteria of each study to provide an overview.
Some highlights about the studies discussed in terms of demographics, clinical characteristics, and exclusion criteria.
Methods
This is a narrative review of the long-term open-label and real-world studies of lasmiditan, ubrogepant, and rimegepant for the acute treatment of migraine attacks as there are currently not enough trials and studies on the topic to do a meta-analysis. On 10 January 2022, a PubMed search for “Lasmiditan” led to 135 articles (four were relevant to this review [14–17]), “Ubrogepant” led to 95 articles (one was relevant to this review [18]), “Rimegepant” led to 91 articles (none were relevant to this review). The abstracts of the American Academy of Neurology Annual Meeting in 2021 and 2022, International Headache Congress in 2021, and American Headache Society annual scientific meetings from June 2020 and June 2021 were searched for relevant data. Of the 157 headache-related abstracts presented at the American Academy of Neurology Annual Meeting in 2021, thirteen were relevant (19–31). Of the headache-related abstracts presented at the American Academy of Neurology Annual Meeting in 2022, four were relevant (32–35). Of the abstracts presented at the International Headache Congress 2021, thirteen were relevant AL060, P0258, P0382, P0232, P0266, P0259, P0269, P0271, P0281, P0272, P0275, P0278, P0282 (36). Of the abstracts presented at the 62nd Annual Scientific Meeting American Headache Society in June 2020, 15 were relevant (two regarding lasmiditan, 12 regarding rimegepant all related to study 201, and one regarding ubrogepant) (37). Of the abstracts presented at the 63rd Annual Scientific Meeting American Headache Society in June 2021, 12 were relevant (one regarding lasmiditan, seven regarding rimegepant all related to study 201, and four regarding ubrogepant) (38).
Some of the abstracts were presented at multiple conferences. To ensure all relevant data was captured, Representatives at Lilly, Abbvie, and Biohaven were contacted to inquire about their library of data that has been published in abstract, pre-print, or full publication on those medications. The bibliographic information was recorded with Zotero.
Findings
Lasmiditan
Studies
As of May 2022, two open-label studies investigating the efficacy of lasmiditan have been conducted.
The first study is the ‘lonG-term safety study of
The second is the Functional REstoration with rEyvow (FREE): a US-based observational cross-sectional survey of patients taking lasmiditan in the real-world (36,42). This study aimed to assess the ability to return to usual activities and the level of impairment of those activities following acute migraine treatment with lasmiditan. Patients were recruited through a US patient support program, given a saving card, and treated for at least one migraine attack with lasmiditan within the prior month.
Safety and tolerability
In the GLADIATOR study, treatment-emergent adverse events (TEAEs) were reported by 45.1% for the lasmiditan 100 mg group and 52.5% for the lasmiditan 200 mg group (7). The most frequently reported treatment-emergent adverse events were dizziness (18.5% total, 15.7% in the 100 mg group vs 21.2% in the 200 mg group), somnolence (8.5% total, 7.8% in the 100 mg group vs 9.1% in the 200 mg group), and paresthesia (6.8% total, 5.3% in the 100 mg group vs 8.3% in the 200 mg group), which were thought to be related to the central nervous system (7). Most TEAEs were mild-to-moderate in severity (7). Encouragingly, the incidence of TEAEs decreased across treated attacks 1–5 in patients who were treated for ≥5 attacks (7). Even if 82% of participants had at least one cardiovascular risk factor, there was no treatment-related treatment-emergent serious adverse events including cardiovascular TEAEs that could be attributed to vasoconstriction, such as angina pectoris, uncontrolled hypertension, ischemic stroke, or death for the 19,879 migraine attacks treated with lasmiditan by 2030 patients (7). Treatment-related cardiovascular events such as palpitations and tachycardia tended to happen within 48 hours of the dose (43). There was no pattern of baseline-to-endpoint changes in laboratory parameters, vital signs, or ECGs that were considered clinically meaningful (7). Adverse events accounted for about one-eighth (12.9%) of study discontinuation (7).
A post hoc analysis examined lasmiditan tolerability and safety in the 4.2% of the GLADIATOR participants aged ≥65 years (16). The incidence of TEAEs was lower in that group compared to the younger group (37.6% vs. 49.4%) (16). Dizziness and paresthesia occurred more frequently, while fatigue and somnolence occurred less frequently in the participants ≥65 years-old (16). Cardiovascular events were not reported in the elderly population, but the number was small; therefore, further research is necessary (16).
Efficacy
Lasmiditan efficacy was found to be consistent over time (7). Even if lasmiditan seems to have relatively higher efficacy for attacks of mild pain intensity, it has significant efficacy for moderate to severe attacks (7,15,31,39).
Overall in the GLADIATOR study, two-hour pain freedom was observed in 26.7% of attacks treated with lasmiditan 100 mg, and 32.2% of attacks treated with lasmiditan 200 mg (7). The results were similar across all four quarters of the study, and for the first five consecutive attacks in patients who received ≥5 attacks (7). MBS freedom was observed in 37.2% and 40.5% of patients treated with lasmiditan 100 mg and 200 mg respectively (7). A post hoc analysis assessed lasmiditan efficacy in migraine attacks with mild pain as 273 (1.5%) treated attacks were of mild pain intensity (31,39) despite instructions to administer while pain was moderate or severe. There was a relatively greater proportion of attacks with two-hour pain freedom if treated while pain was mild compared to moderate and severe pain (mild: 100 mg/200 mg: 33.6%/54.8%; moderate: 29.7%/36.2%; severe: 17.9%/19.4%) (31,39). Similar trends were seen for the 24-hour sustained pain freedom endpoint. These data suggest that earlier dosing with lasmiditan while pain is mild intensity may be more beneficial (31,39).
In the real-world Functional REstoration with rEyvow (FREE) study, lasmiditan doses of 50 mg, 100 mg, and 200 mg were used in 35%, 63%, and 3% of participants, respectively. Lasmiditan was taken within 30 min of onset 17% of the time, and from 30 min to 2 h after onset 55% of the time (36,42). At the time of lasmiditan dosing, 49% of the patients had severe pain and 45% had moderate pain (36,42). A total of 64.1% and 29.5% achieved two-hour pain relief and two-hour pain freedom respectively (36,42). These efficacy results are similar to the results from the randomized studies (two-hour pain freedom in 26.7% of attacks treated with lasmiditan 100 mg in the GLADIATOR study, in 28.2% in the SPARTAN study, 31.4% in the SAMURAI study) (40,41).
Function and patient satisfaction
The mean MIDAS scores for the 100 mg and 200 mg groups were 29.4 and 28.9 at baseline, respectively, and decreased by 12.5 and 12.2 points respectively, at 12 months (14). About half of participants (49% and 53%) achieved at least 50% reduction in MIDAS scores (14). The proportion of patients with at least a 50% decrease in the MIDAS scores from baseline increased steadily from ≥30% at 3 months to ≥49% at 12 months (14). Both doses exerted positive effects on absenteeism, presenteeism, monthly headache days, and mean headache pain intensity at all time points for up to one year (14).
As a post hoc analysis, first-attack data of the GLADIATOR were assessed with migraine-related functional disability at time points. The percentage of patients free from migraine-related functional disability increased over time (17).
In the real-world Functional REstoration with rEyvow (FREE) study, 45–75% of participants returned to their current/planned activities after lasmiditan, except for planned activities outside the home (22%) (36). Most respondents (76.9%) were satisfied with lasmiditan and able to return to their usual activities with no or some degree of impairment (61.5%) (36).
Ubrogepant
Studies
Allergan plc sponsored a Phase III, multicenter, randomized, 52‐week trial as an extension to the two randomized, double‐blind, placebo‐controlled, single‐attack, Phase III trials ACHIEVE I, NCT02828020 and ACHIEVE II, NCT02867709 to assess the safety and tolerability of ubrogepant use long-term as an acute treatment for migraine (18). After completing either ACHIEVE I or ACHIEVE II, 1254 participants selected were re‐randomized 1:1:1 to usual care (using the same acute treatment as before the trial), ubrogepant 50 mg, or ubrogepant 100 mg (18). ACHIEVE I had 1672 participants with two-hour pain freedom of 11.8% in the placebo group, 19.2% in the 50 mg ubrogepant group, and 21.2% in the 100 mg ubrogepant group (44). ACHIEVE II had 1686 participants with two-hour pain freedom of 14.3% in the placebo group, 21.8% in the 50 mg ubrogepant group, and 20.7% in the 25 mg ubrogepant group (45). Participants were blinded to the dose of ubrogepant they were receiving (18). They could treat up to eight migraine attacks per month with ubrogepant (18). However, the average monthly use in the study was much lower (18). Among the 1230 participants included in the safety population, the average number of doses taken per participant per month was 3.2 doses for ubrogepant 50 mg and 3.35 doses for ubrogepant 100 mg (18). The participants were instructed to take ubrogepant within four hours of the headache start and for attacks preceded by 48 hours of pain freedom (18).
To our knowledge, there were two real-world studies, one at a tertiary headache center and one that used the Migraine Buddy application data (22,32,33,36). In the tertiary center real-world study, among all patients who were prescribed ubrogepant at their visit to a headache clinic between 20 January 2020 to 12 June 2020, 106 completed a survey about their experience (22). On average, participants had tried seven (0–34) preventive medications and five (0–32) acute medications, which provided insufficient or no relief (22). The most common comorbidities were anxiety (25.5%), depression (20.8%), postural orthostatic tachycardia syndrome (13.2%), hypertension (15.1%), and hyperlipidemia (13.2%) (22). There was a prospective observational real-world study using the Migraine Buddy application with 245 participants who used ubrogepant as acute treatment while also being on an anti-CGRP monoclonal antibody for prevention (33,36).
Safety and tolerability
Ubrogepant is well-tolerated in long-term and real-world studies with most common side effects being nausea, somnolence, dizziness, dry mouth, constipation, resulting in low discontinuation rate due to side effects, and low rate of serious adverse events (18,22). People with cardiovascular disease were excluded from the extension trial too, limiting the generalizability of the study results to this population (18).
In the Phase III extension trial, treatment‐related adverse events occurred in 42 (10.4%) and 43 (10.5%) of participants in the ubrogepant 50 mg and ubrogepant 100 mg groups respectively (18). The most common treatment‐related adverse events were nausea (1.5 and 1.7% with ubrogepant 50 and 100 mg, respectively), somnolence (1.5 and 1.2%), dizziness (0.5 and 1.5%), ALT increases (0.7 and 1.0%), and AST increases (0.5 and 1.0%) (18). Severe treatment-emergent adverse effects were reported for 6.2 and 8.1% of participants in ubrogepant 50 mg and ubrogepant 100 mg groups, respectively, the most common were influenza, migraine, nausea, AST increase, cholelithiasis, nephrolithiasis, pneumonia, and sinusitis (18). Of the serious adverse events reported in 2% and 3% of participants in the ubrogepant 50 mg and 100 mg groups, one and possibly two were thought to be treatment-related (18). The sinus tachycardia in a patient with a history of supraventricular tachycardia who underwent ablation and continued to take ubrogepant without further adverse events was thought to be related (18). The occurrence of thrombocytopenia in another participant may have been related too (18). No myocardial infarction or stroke related to ubrogepant were reported (18). Two cases (both ubrogepant 50 mg) of ALT or AST levels becoming ≥3× upper limit of normal were thought to be possibly related with confounding factors of increased alcohol and acetaminophen use for one and dilated bile duct for the other; one such case (ubrogepant 100 mg) was thought to be probably related with confounding factor of prednisone use for exacerbation of psoriasis prior to rise in ALT/AST (18). All ALT or AST levels normalized in those who continued ubrogepant dosing (18). The discontinuation rate due to adverse events was very low (2.2% for the 50 mg and 2.7% for the 100 mg groups) (18).
In the real-world study at a tertiary headache center, ubrogepant side effects reported included fatigue (27.4%), dry mouth (7.5%), nausea/vomiting (6.6%), constipation (4.7%), and dizziness (2.8%) (22). Other adverse events were reported such as brain freeze, feeling “spacey,” panic attack, warmth in the entire body, tongue numbness, and worsening headache, each by one participant (22). Most adverse events were mild (65%); the rest (35%) were rated as moderate (22). The adverse event rates were similar between the participants on CGRP monoclonal antibodies for prevention and those who were not, but there was a higher proportion of moderate adverse events in the CGRP monoclonal antibody group (22). The adverse event rates were similar between the participants on onabotulinumtoxinA for prevention and those who were not (22). Age, headache frequency, years lived with migraine, comorbidities, response to prior acute and preventive treatment trials, response to triptans, and response to OnabotulinumtoxinA or a CGRP monoclonal antibodies were not associated with ubrogepant-related adverse events (22). No worsening of blood pressure was observed using chart review for the participants with hypertension (22).
Efficacy
Ubrogepant has been found to remain effective over time, to have good within-person consistency, and to be effective in the acute treatment of perimenstrual migraine attacks in the extensions of the clinical trials (18,21,34). Most of participants used another acute treatment two hours after ubrogepant (18). The efficacy results regarding ubrogepant efficacy for mild attacks were similar in a real-world study of patients with mostly chronic migraine, 41.1% of participants in the real-world study achieved two-hour pain freedom for ≥75% of mild attacks compared to 39% and 43% of patients in the 50 and 100 mg groups (22,36,46).
The primary outcomes of the extension of the ACHIEVE I and ACHIEVE II trials were related to safety and tolerability (18). Nevertheless, efficacy was maintained at one year with two-hour pain freedom for about one in four attacks (23% and 25% of attacks treated with ubrogepant 50 mg and 100 mg respectively), and two-hour pain relief for about two third of attacks (65% and 68% of attacks respectively) (18). It is worth noting that nearly all participants (99.5%) needed to use at least another acute treatment such as ibuprofen (54.5%), combination aspirin‐acetaminophen‐caffeine (36.4%), sumatriptan (27.6%), and acetaminophen (25.6%) two hours after using ubrogepant (18). Ubrogepant efficacy was better when attacks were mild; a higher proportion of mild attacks achieved two-hour pain freedom compared to moderate/severe attacks (50 mg: 57.1% vs 30.9%; 100 mg: 51.1% vs 27.2%), which suggested a benefit in treating attacks early when still mild in severity (36,46). Treatment success was also measured using latent class modeling (LCM) with five efficacy measures at two hours: pain intensity, functional disability, and presence of nausea, photophobia, and phonophobia (34). For 490 participants, the estimated consistency between the first three treated attacks for two-hour treatment success was 55.9%; 27.3% of participants achieved two-hour treatment success for two thirds of attacks and 28.6% of participants achieved two-hour treatment success for all attacks (34).
Among the 808 ubrogepant participants in the modified intent-to-treat population of the extension trial, nearly half (43.8%) were menstruating women of whom the majority (78.5%) treated at least one perimenstrual migraine attack (attack that started on or between two days before and three days after the start of menses) with ubrogepant (21). The two-hour pain freedom was similar for perimenstrual attacks (28.7% and 29.7% [50 mg and 100 mg group respectively]) and non-perimenstrual migraine attacks (22.3% and 24.8%), p = 0.046 and p = 0.406 for the 50 mg and 100 mg ubrogepant groups respectively (21). The two-hour pain relief was also similar between perimenstrual attacks (64.8% and 67.1% for the 50 mg and 100 mg doses) and non-perimenstrual attacks (64.9% and 67.8% for the 50 mg and 100 mg groups), p = 0.396 and p = 0.253 for the 50 mg and 100 mg groups respectively (21).
In a real-world study, nearly two thirds of participants never experienced headache freedom at two hours (60.0%), 8.6% experienced two-hour pain freedom less than 50% of the time, 12.4% between 50 and 75%, 6.6% between 75 and 100% of the time, and 12.4% of patients said they experienced headache freedom at two hours for all attacks treated with ubrogepant (22). Regarding pain relief at two hours, more than a quarter of participants never experienced pain relief at two hours (26.7%), 14.3% experienced two-hour pain relief less than 50% of the time, 11.4% between 50 and 75% of the time, 17.1% between 75 and 100% of the time, and 30.5% of patients said they experienced headache freedom at two hours for all attacks treated with ubrogepant (22). When using an 11-point visual analog scale, ubrogepant was able to provide ≥3 and ≥6 points reduction in pain intensity for the treated attacks in 74.7% and 21.8% patients, respectively (22). The response rates were similar between the participants on CGRP monoclonal antibodies for prevention and those who were not and between the participants on onabotulinumtoxinA for prevention and those who were not (22).
Positive factors of response to ubrogepant included migraine with aura (OR: 2.27, CI: 1.01–5.12, p = 0.048), <5 unsuccessful preventive and acute medication treatment trials (preventive OR: 2.98, CI: 1.30–6.86, p = 0.010, acute OR: 2.42, CI: 1.10–5.30, p = 0.028), prior response to CGRP monoclonal antibodies (OR: 4.5, CI: 1.45–13.95, p = 0.009) (22). Negative factors of response to ubrogepant included chronic migraine (OR: 0.205, CI: 0.05–0.78, p = 0.021), no response to onabotulinumtoxinA (OR: 0.369, CI: 0.14–0.95, p = 0.04) (22). Age, headache frequency, years lived with migraine, comorbidities, and response to triptans were not associated with response to ubrogepant (22)
In the prospective observational real-world study using the Migraine Buddy application, for the first treated attack, 61.6% and 80.4% of participants had meaningful pain relief at two- and four-hours post-dose respectively, and 34.7% and 55.5% of participants had return to normal function at two- and four-hours post-dose respectively (33,36). For the 10 ubrogepant-treated attacks, 51.3% and 73.5% of participants had meaningful pain relief at two- and four-hours post-dose respectively (33,36).
Function and patient satisfaction
In prospective observational real-world study using the Migraine Buddy application of patients using ubrogepant as acute treatment and on CGRP monoclonal antibody for migraine prevention, 32.2% and 53.2% of participants had return to normal function at two- and four-hours post-dose respectively (33,36). Out of 264 participants who reported using ubrogepant due to insufficient response to other acute treatments, 76.1% had two-hour pain relief, 85.2% were satisfied with their ability to think clearly, and 84.8% were satisfied with their return to normal function (32,36). Using ubrogepant as an acute treatment was associated with reduced use of other treatments such as opioids (−28%), barbiturates (−25%), ergots (−15%), triptans (−55%), nonsteroidal anti-inflammatory drugs (−38%) (32,36).
In a real-world study at a tertiary center, 30.2% of participants were not satisfied at all, 38.7% were somewhat satisfied, and 31.1% were very satisfied (22). In the real-world study of patients already on anti-CGRP monoclonal antibody for prevention, most (91.7%) of 264 participants who had insufficient response to other prior acute treatments said they were likely to continue ubrogepant use (32,36).
Rimegepant
Studies
There was a multicenter, open-label, long-term safety study of rimegepant for the acute treatment of migraine (study 201) with primary outcomes of number of participants who discontinued the medication due to adverse events and the number of participants who developed clinically significant laboratory abnormalities (19,20,24–30,35,47–51). The 1800 participants could receive one of two dosing regimens: 1. rimegepant 75 mg as needed for 52 weeks to treat attacks of any pain intensity (1514 participants) and 2. every other day as prevention plus as needed as acute treatment for 12 weeks (286 participants) (19,20,24,47). Patients who completed any randomized trial of rimegepant for the acute treatment of migraine could participate in study 401 which provided them with continued access to rimegepant while monitoring its safety until its regulatory approval (52). Of the 77 participants, most (84%) came directly from study 201, continued rimegepant for a mean (SD) time of 20.6 (11.6) weeks with about 6.4 doses per month.
Safety and tolerability
In the multicenter, open-label, Phase II/III, long-term safety study of rimegepant for the acute treatment of migraine, a little less than two third of participants (59.5%) experienced at least one adverse event, most were mild or moderate in intensity (48). Only 2.7% of participants stopped taking rimegepant due to an adverse event (48). The most common adverse events included upper respiratory tract infection (URI) (8.5%), nasopharyngitis (6.4%), and sinusitis (4.8%) (48). Serious adverse events happened in nine participants including one that was possibly related to rimegepant (48). No clinically significant laboratory abnormalities were found (48). Rimegepant was also found to be well-tolerated in the subgroup of 246 (13.7%) with a baseline of ≥15 migraine days per month with a discontinuation rate due to adverse events of 4.9% and no serious adverse events thought to be related to rimegepant (27). Of the 1800 participants, 546 (30.3%) stopped using 1 triptan due to inadequate efficacy or lack of tolerability and 246 (13.7%) stopped ≥2 triptans for the same reasons (25). Rimegepant was found to be well tolerated in this subgroup of participants who did not experience efficacy or tolerability from triptans (25). Rimegepant was stopped due to adverse events in 1.6% and 2.0% of participants who discontinued 1 or ≥2 triptans, respectively (25). Serious adverse events happened in 3.7% and 2.4% of participants who discontinued 1 or ≥2 triptans, respectively; none were thought to be related to rimegepant (25). The majority of patients who participated in study 401 completed 201, so it is not surprising that the most common side effects (nasopharyngitis [9.1%], influenza [7.8%], and sinusitis [6.5%]) were similar, but it provided some longer-term data (52). All adverse events were of mild to moderate intensity, and none were thought to be related to rimegepant nor led to discontinuation (52).
Cardiovascular safety
Among the 1800 participants, 28.8% and 12.1%, respectively, had 1 or ≥2 cardiovascular risk factors including 7% with a moderate to high 10-year Framingham cardiovascular risk (20). There was no difference in the rate of serious adverse events based on cardiovascular risk factor and no serious adverse events were deemed to be related to rimegepant (20). A 53-year-old man who had a history of angina pectoris had another episode of angina pectoris during the study which was not considered to be related to rimegepant (20).
Tolerability and safety with other treatments
Rimegepant was tolerated in patients taking preventive medications such as topiramate, amitriptyline, botulinum toxin type A, and CGRP monoclonal antibodies (19,47). The proportions of participants who developed adverse events were 68.7% vs 59.2% and the proportions of participants who discontinued rimegepant due to adverse events were 4.5% vs 2.4% in the groups using preventive treatment concomitantly vs not on preventive treatment (19). In a 12-week sub-study of 13 participants using rimegepant as needed as acute migraine treatment and a CGRP monoclonal antibody (erenumab, fremanezumab, or galcanezumab) as a preventive treatment, five (38%) participants reported at least one adverse event, most commonly nasopharyngitis (2/13 [15%]) (47). All other adverse events (back pain, myalgia, contusion, dizziness, viral gastroenteritis, sinusitis, and first-degree atrioventricular block) each affected one participant and none of them were serious (47). A 30-year-old woman who was concomitantly on erenumab developed first-degree atrioventricular block, which was considered possibly related to treatment (47). A 58-year-old woman experienced mild dizziness, which was considered possibly related to treatment (47).
Since there has been a theoretical concern for serotonin syndrome with the coadministration of triptans (and ditans) with antidepressants which has not been a major concern in clinical practice (53), the tolerability and safety of rimegepant were assessed in the subgroup of participants on antidepressants (50). Of the 1800 participants, 181 (10.1%) were using an SSRI (mostly citalopram [3.4%], sertraline [2.4%], and fluoxetine [2.3%]) and 195 (10.8%) were using another antidepressant (mostly bupropion [4.5%], venlafaxine [3.0%], and trazodone [2.1%]) (50). On average, participants on SSRI tended to use rimegepant as needed a little more (8.3 [SD 4.8] vs 7.6 [SD 4.6] days/month) (50). The rates of adverse events were slightly higher in the SSRI (23.8% on SSRI vs 19.6% not on SSRI) and other antidepressant (20.2% on other antidepressant vs 17.9% not on antidepressant) groups compared to those not on any antidepressants, but most were mild to moderate (50). The rates of serious adverse events were 3.3% in the SSRI group and 5.1% in the other antidepressant group, but none of them were considered to be related to rimegepant (50). It may be helpful to get more data on rates of adverse events for patients on amitriptyline is one of the first line migraine preventive medications (54).
Efficacy
A decrease in migraine frequency was observed in the long-term study of rimegepant as an acute treatment, which is both encouraging for its use as a preventive treatment and supports that rimegepant is not associated with medication overexposure headache (MOH) (49). In a post-hoc analysis of study 201 including 1044 participants with ≥6 monthly migraine days (MMD) at baseline, the median time to ≥30% reduction of baseline MMD was 12 weeks (IQR; 4–40 weeks) and the median time to ≥50% MMD reduction was 32 weeks (IQR; 12-NR weeks) (49). At one year, 78.6% of participants noted a ≥30% reduction of baseline MMD and 63.3% of participants noted a ≥50% MMD reduction (49). Lower baseline migraine frequency was associated with faster time to reach a significant MMD reduction (49). Participants with ≥14 migraine days per month at baseline who took rimegepant as needed for migraine attacks had a six-day reduction in monthly migraine days at one year (48). Of note, if these participants treated every attack with rimegepant, their rimegepant as needed use may be close to every other day preventive use.
The majority (87.5%) of participants in the subgroup of 246 (13.7%) with a baseline of ≥15 migraine days per month had improvement in their clinical global impression of change at one year (27).
Function
The baseline MIDAS was 32.8 (SD 33.1) with 12.7 reduction at 12 weeks (95%CI −14.6, −10.8) for the group who tolerated and had a sufficient response to triptans, 34.5 (SD 31.8) with 12.5 (95% CI −15.1, −10.0) reduction at 12 weeks for the group who did not tolerate or did not benefit from a sufficient response to 1 triptan, and 36.9 (SD 32.0) with −12.0 (−15.9, −8.1) weeks for the group who did not tolerate or did not benefit from a sufficient response to ≥2 triptans (35).
Using the first two questions of the Migraine Disability Assessment (MIDAS), absences decreased by 7.9 (95%CI −9, −6.8) in the last three months (ABS), days worked with ≥50% decreased productivity due to headaches decreased by 6.9 (95%CI −7.8, −5.9) in the last three months (PRE), and lost productive time (LPT = ABS + PREx0.5) decreased by 11.3 days (95%CI −12.8, −9.9) in the last three months between baseline and one-year assessments (55). For the participants who used rimegepant two to eight days per month as needed, their lost productive time decreased from 28.2 days in the last three months at baseline to 16.1 days in the last three months at one year (mean %change was −43%, 95% CI [−56%, −30%]) (28). For the participants who used rimegepant nine to 14 days per month as needed, their lost productive time decreased from 46.6 days in the last three months at baseline to 20.9 in the last three months at one year (mean % change was −47%, 95% CI [−57%, −37%]) (28).
Quality of life
All domains of the migraine-specific quality of life questionnaire (MSQv2) improved between baseline and one-year assessments; even more so for those who experienced a decrease in monthly migraine days (51,56). At the one-year assessment, the EuroQol-5 Dimensions-3 Level (EQ-5D-3L) utilities increased to 0.75, 0.73, and 0.77 for the groups with 2-8 MMD with as needed use of rimegepant, 9–14 MMD with as needed use of rimegepant, and 4–14 MMD in the every other day preventive use + as needed use of rimegepant respectively, representing changes from baseline of +0.09, +0.10, and +0.12, respectively (51). This was also found for the participants who had discontinued triptans due to inadequate efficacy or lack of tolerability (30). Baseline Role-Restrictive (RR), Role Preventative (RP), and Emotional Role (ER) were 53.6, 69.4, and 62.5 for the participants who stopped 1 triptan (n = 546) and 51.5, 66.7, and 56.2 for the participants who stopped ≥2 triptans (n = 246) (30). One-year improvements in RR, RP, and ER, respectively, were +16.0, +12.5, +15.7 for the participants who stopped 1 triptan and +15.8, +13.0, +16.8 for the participants who stopped ≥2 triptans (30).
Decreased use of other acute treatments
Over time with use of rimegepant as needed, the use of acetaminophen, combination analgesics, NSAIDs (ibuprofen, naproxen), and antiemetics (ondansetron, promethazine, dimenhydrinate, meclizine, and prochlorperazine) decreased from 80.1% of participants using them initially to 32.4% of participants using them at weeks 49–52 (24).
Patient satisfaction
Among participants who had stopped triptans due to inadequate efficacy or lack of tolerability, 77.0% (71.6, 81.6) and 82.0% (74.5, 87.6) preferred rimegepant compared to their prior acute treatment at one-year for the group who stopped using 1 triptan and the group who stopped ≥2 triptans respectively (29), which suggests that rimegepant may be helping to fill the need for acute treatments in patients for whom triptans have inadequate efficacy and/or poor tolerability.
Discussion
The long-term extension trials and real-world evidence available to date support the results of the Phase III trials in terms of tolerability, safety, and efficacy of lasmiditan, ubrogepant, and rimegepant and show consistency over time (7,18,22,34,47). Table 2 summarizes most common side effects, efficacy, and function outcomes. Side effects were less frequent in participants of at least 65 years of age and tended to decrease with use of lasmiditan (7,16). Ubrogepant was not used frequently in the extension trial, about 3.2 to 3.35 doses per month (18).
Summary of tolerability and efficacy.
Regarding efficacy, it is worth noting that most participants (99.5%) had to use another acute rescue treatment after ubrogepant (18). Yet, overall, ubrogepant and rimegepant were associated with reduction in the use of other acute treatments such as triptans and NSAIDs (24,32). Treating attacks early while pain is of mild intensity may be beneficial (6,46). Lasmiditan appears to have slightly higher efficacy when used while pain is mild compared to moderate or severe. (7). Ubrogepant efficacy was substantially higher when treating attacks of mild intensity (46).
To our knowledge, there is no long-term data on the two-hour pain freedom, pain relief, and relief from the most bothersome symptom for rimegepant. Interestingly, the long-term study of rimegepant as acute treatment for migraine showed a decrease in monthly migraine days over time (49).
Although there are some guidelines available (considering ditan or gepants as acute treatment if there is insufficient response or contraindication to triptans), two studies evaluated the factors that played a role in the choice of acute treatment for migraine: 1. A retrospective cross-sectional online survey of 214 US neurologists and migraine specialists and chart review completed in September 2020 looked at the data regarding 1048 patients prescribed lasmiditan (n = 243), ubrogepant (n = 417), or rimegepant (n = 389) within the last three months (54,57) and 2. An observational study using IBM® MarketScan® Early View commercial database looking at adults with a claim for lasmiditan, rimegepant or ubrogepant between 1 January 2020 and 31 August 2020 (58). Patients prescribed lasmiditan were more likely to have a history of insufficient response to a prior acute therapy compared to patients prescribed a gepant (50% vs. 40%; p < 0.05) (58). The main reason to change acute therapy was efficacy concern such as persistent or worsening migraine attacks, prolonged time to return to function, lack of two-hour pain freedom (58). So many factors play a role in prescription decision such as the medication mechanism of action (lasmiditan: 47%, ubrogepant: 45%, rimegepant: 51%), physician comfort/familiarity (lasmiditan: 46%, ubrogepant: 49% vs rimegepant: 39%; p < 0.05), expectations of two-hour pain freedom (rimegepant: 48% vs. ubrogepant: 36%, lasmiditan: 32%; p < 0.05), expected time for return to normal function (rimegepant: 47% vs. ubrogepant: 38%, lasmiditan: 37%; p < 0.05), expected low need for redosing/use of rescue medications (rimegepant: 23% vs. ubrogepant: 14%, lasmiditan: 14%; p < 0.05), preference for dosing formulation (rimegepant: 16% vs. ubrogepant: 5%, lasmiditan: 9%; p < 0.05 – contrary to ubrogepant or lasmiditan, rimegepant was not studied to be potentially redosed within 24-hour of use (57,59). Using the data from the same study, patients with moderate or high risk of complications/death if infected with the coronavirus were more likely to be prescribed rimegepant (2% vs. <1%), and less likely to be prescribed a triptan (41% vs. 48%) or prescription strength NSAID (20% vs. 27%) compared to patients with a low risk of coronavirus complications (60). Looking at claims from January 2020 to August 2020, 6964 patients (88.1% women with mean age of 45.0) started a new acute treatment for migraine: 4498 (64.6%) ubrogepant, 2308 (33.1%) an oral triptan, 2205 (31.7%) rimegepant, 543 (7.8%) a non-oral triptan, and 234 (3.4%) lasmiditan (58). Contraindication to triptans was a major driver of prescribing novel acute treatments; of the patients who were prescribed lasmiditan, ubrogepant, or lasmiditan, 23.4% and 53.8% had at least one cardiovascular contraindication to triptan in the prior year and in their entire pre-index insurance history (median of seven years) respectively (58).
Limitations
Lasmiditan, ubrogepant, and rimegepant have not been available for long, which limits the number of long-term and/or real-world studies to date. To date, most of the data is available in the form of posters presented at conference and has not been published in peer-reviewed journals yet. Most studies were conducted by pharmaceutical companies; only a minority were done by independent researchers (22). Studies on diverse and more representative patient population are needed as in the studies described above, the great majority of participants (usually more than 80%) are white and the participants’ ethnicities are not reported. The GLADIATOR extension trial from SAMURAI and SPARTAN did not include a control group in their randomization (7), contrary to the ubrogepant extension study which had a group randomized to usual care (18). Participants with some of the contraindications to triptans (basilar or hemiplegic migraine, uncontrolled hypertension, significant cardiovascular or cerebrovascular disease or myocardial infarction, transient ischemic attack, or stroke within six months) were excluded from the ubrogepant and rimegepant trial, limiting the evaluation of its cardiovascular safety (18,48), but 15% of participants had hypertension in the real-world study of ubrogepant use at a tertiary headache center (22). The Food and Drug Administration approved lasmiditan in October 2019, ubrogepant in December 2019, and rimegepant in February 2020. At the time this manuscript is written, these medications are not available yet in most countries.
Further studies
Currently, much of the data is only available in the form of abstract poster presentations. More information will be available once all the available data is published in manuscript form. Real-world evidence studies on more demographically and clinically diverse patient populations are needed. It would be helpful to have more data on the cardiovascular safety of gepants for people with cardiovascular risk factors; consistency of response across attacks; safety of using triptans and gepants after two hours from each other; and on the safety and tolerability of lasmiditan used in close temporal relation to a gepant and/or being on a CGRP monoclonal antibody for prevention. Given that ubrogepant and rimegepant both block the CGRP and amylin 1 receptors like erenumab and that erenumab had a Federal Drug Administration (FDA) warning regarding new-onset hypertension or worsening of hypertension, it will be important to evaluate whether gepants (used acutely or preventively) are associated with hypertension (61). Triptans were allowed as a rescue starting two hours after ubrogepant use in the ubrogepant extension study (18), but not in the lasmiditan GLADIATOR study (7,15). To our knowledge, it is unclear whether triptan use was allowed as a rescue in the rimegepant study 201. Triptans were not part of the rescue options allowed after two hours in the Phase III study of rimegepant for the acute treatment of migraine (62), but triptans were allowed as a rescue (not rimegepant) in the Phase II/III, randomized, double-blind, placebo-controlled trial of rimegepant for the prevention of migraine (63). Post-marketing real-world safety surveillance is also important to detect any potential rare adverse event.
Conclusion
The tolerability, safety, and efficacy results of long-term trials and real-world studies of lasmiditan, ubrogepant, and rimegepant are consistent with Phase III studies. Patients with cardiovascular risk factors were not excluded from the lasmiditan studies and no significant cardiovascular adverse events were found. Lasmiditan side effects tended to lessen over time and included dizziness, somnolence, and paresthesias. Ubrogepant and rimegepant were well-tolerated with low discontinuation rate. Treating migraine attacks when they are mild may be beneficial in terms of efficacy for lasmiditan and especially for ubrogepant. Lasmiditan, ubrogepant, and rimegepant were all associated with improvement in function and/or work productivity.
Article highlights
Lasmiditan, ubrogepant, and rimegepant are associated with improvement in function and/or work productivity in terms of both presenteeism and abstenteeism. Treating migraine attacks early while pain intensity is mild may achieve better outcomes. Rimegepant used as an acute treatment as needed is associated with a decrease in monthly migraine days over time.
Footnotes
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: OBdD serves as an Executive Editor for the Pain Medicine Journal and as a Consultant for Neurolytic Healthcare.
TT reports being an advisor for Eli Lilly Japan, Otsuka and Amgen. TT received speaker’s fees from Eli Lilly Japan, Daiichi Sankyo, Otsuka, Amgen, Kowa, Kyowa Kirin, Eisai, UCB Japan and Santen Pharmaceutical, and research fund from Tsumura outside the submitted work.
DWD reports the following conflicts: Consulting: Amgen, CapiThera, Cerecin, Ceruvia Lifesciences, Cooltech, Ctrl M, Allergan, Abbvie, Biohaven, GSK, Lundbeck, Eli Lilly, Novartis, Impel, Satsuma, Theranica, WL Gore, Genentech, Nocira, Perfood, Praxis, Pfizer, AYYA Biosciences, Revance. Honoraria/expense reimbursement/royalties: American Academy of Neurology, Headache Cooperative of the Pacific, MF Med Ed Research, Biopharm Communications, CEA Group Holding Company (Clinical Education Alliance LLC), Teva (speaking), Amgen (speaking), Eli Lilly (Speaking), Lundbeck (Speaking), Vector psychometric Group, Clinical Care Solutions, CME Outfitters, Curry Rockefeller Group, DeepBench, Global Access Meetings, KLJ Associates, Academy for Continued Healthcare Learning, Majallin LLC, Medlogix Communications, Medica Communications LLC, MJH Lifesciences, Miller Medical Communications, Synapse, WebMD Health/Medscape, Wolters Kluwer, Oxford University Press, Cambridge University Press. Non-profit board membership: American Brain Foundation, American Migraine Foundation, ONE Neurology, Precon Health Foundation, International Headache Society Global Patient Advocacy Coalition, Atria Health Collaborative, Domestic Violence HOPE Foundation/Panfila, CSF Leak Foundation. Research Support: Department of Defense, National Institutes of Health, Henry Jackson Foundation, Sperling Foundation, American Migraine Foundation, Patient Centered Outcomes Research Institute (PCORI). Stock Options/Shareholder/Patents/Board of Directors: Ctrl M (options), Aural analytics (options), ExSano (options), Palion (options), Healint (Options), Theranica (Options), Second Opinion/Mobile Health (Options), Epien (Options/Board), Nocira (options), Matterhorn (Shares/Board), Ontologics (Shares/Board), King-Devick Technologies (Options/Board), Precon Health (Options/Board), AYYA Biosciences (Options), Axon Therapeutics (Options/Board), Cephalgia Group (Options/Board), Atria Health (Options/salary). Patent 17189376.1-1466:vTitle: Botulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis (No fee/compensation/royalty).
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The publication of this article was supported by JSPS KAKENHI (grant number 22K15693 to Tsubasa Takizawa).