A multicenter,open-label long-term safety study of rimegepant for the acute treatment of migraine

Abstract

Background

The present study evaluated the long-term safety and tolerability of rimegepant, an orally administered small molecule calcitonin gene-related peptide receptor antagonist, in people with migraine.

Methods

This multicenter, long-term, open-label safety study included adults (≥18 years) with ≥1 year history of migraine who were sequentially enrolled into three groups: participants in the first two groups had either 2–8 or 9–14 moderate to severe migraine attacks per month by history and treated as needed (pro re nata [PRN]) with one rimegepant 75 mg oral tablet up to once per calendar day for 52 weeks (PRN 2–8 and PRN 9–14); a third group, included to collect safety data during higher-frequency dosing, had 4–14 moderate to severe migraine attacks per month by history and who took one rimegepant tablet every other day as scheduled dosing plus PRN dosing of one rimegepant tablet for migraine attacks of any severity on nonscheduled dosing days for 12 weeks (every other day (EOD) + PRN).

Results

Overall, 1800 participants self-administered rimegepant (PRN 2–8: n = 1033; PRN 9–14: n = 481; EOD + PRN: n = 286). The most common on-treatment adverse events (AEs) were upper respiratory tract infection (8.8%), nasopharyngitis (6.8%) and sinusitis (5.1%). Most AEs were mild or moderate and considered unrelated to rimegepant. Serious AEs considered possibly (n = 1) or unlikely (n = 9) related to rimegepant were reported in ten (0.6%) participants. No signal of drug-induced liver injury because of rimegepant was identified.

Conclusions

Rimegepant 75 mg up to once per day as EOD + PRN for 12 weeks or PRN for up to 52 weeks was safe and well tolerated. No signal of hepatotoxicity, potential drug abuse, or medication-overuse headache was identified.

Trial registration: Clinicaltrials.gov: NCT03266588.

Keywords

Adults as needed CGRP every other day gepants tolerability

Introduction

The safety and tolerability of medications used for the acute treatment of migraine remains a persistent issue in clinical practice. Non-steroidal anti-inflammatory drugs (NSAIDs) can be associated with serious gastrointestinal and cardiovascular adverse events (AEs) (1 –3), and the recommendation to use them for the shortest duration and the lowest possible dose (4) complicates long-term use. Triptans cause AEs in up to 52% of users (5), and contraindications limit their utility in individuals with coronary artery disease, peripheral vascular disease, cerebrovascular disease and uncontrolled hypertension (6). In people with frequent migraine attacks, both NSAIDs and triptans may lead to medication overuse (regular use on ≥10 or ≥15 days per month depending on the medication (7)), medication-overuse headache (headache occurring ≥15 days/month as a result of medication overuse for >3 months (7)) and chronic migraine (8).

Medications targeting the calcitonin gene-related peptide (CGRP) receptor are an important alternative to traditional acute migraine treatments (9). Rimegepant is an orally administered small molecule CGRP receptor antagonist indicated for the acute treatment of migraine and the preventive treatment of episodic migraine in the USA, European Union and UK. Although rimegepant 75 mg has demonstrated efficacy, safety and tolerability in the acute treatment of migraine in five randomized, controlled single-attack clinical trials (10 –14), its long-term safety has not previously been assessed in the context of acute use. Every other day (EOD) dosing has been evaluated in a 12-week, placebo-controlled phase 2/3 prevention trial (15).

The primary objective of this trial was to evaluate the long-term safety and tolerability of rimegepant for the acute treatment of migraine. Secondary objectives included evaluating the frequency of elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3× upper limit of normal (ULN) with concurrent elevations in bilirubin >2× ULN and the frequency and severity of hepatic-related AEs and the frequency of hepatic-related treatment discontinuations.

Methods

Ethics

This clinical trial (NCT03266588) was conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Conference on Harmonisation Harmonized Tripartite Guideline and all local laws and regulations. Before any study-related procedures were undertaken, investigators at each study center obtained Institutional Review Board/Independent Ethics Committee approval of the protocol and study-related materials, and participants provided written informed consent.

Study conduct

This multicenter, open-label, long-term safety study of rimegepant 75 mg oral tablets was conducted at 103 sites in the USA. Adults with migraine were sequentially enrolled into three groups. Those in the first two enrollment groups had self-reported history of either two to eight or nine to 14 moderate to severe migraine attacks per month and were allowed to treat migraine attacks of any severity (mild, moderate or severe headache pain intensity) as needed (pro re nata [PRN]) with up to one rimegepant 75 mg oral tablet per calendar day for 52 weeks (PRN 2–8 and PRN 9–14). Participants in the third group had a self-reported history of four to 14 moderate to severe migraine attacks per month; they were instructed to take one rimegepant 75 mg oral tablet every other day (EOD) as scheduled dosing plus as needed (PRN) dosing of one rimegepant 75 mg oral tablet for migraine attacks of any severity on non-scheduled dosing days for 12 weeks (EOD + PRN). The maximum daily dose of study medication for all enrollment groups was one rimegepant 75 mg oral tablet. The purpose of the 12-week EOD + PRN enrollment group was to collect safety data during higher-frequency dosing.

The study included three periods: a screening visit/observation period of 30 days, a long-term treatment period of 12 or 52 weeks and a follow-up safety visit 14 ± 2 days after the end of treatment (Figure 1). Participants who remained eligible after screening were provided an electronic diary (eDiary; eResearch Technology, Philadelphia, PA, USA) to document study drug usage, as well as a paper diary to record use of their usual migraine medication(s) throughout the study, including the 30-day observation period. After completing the observation period, participants returned to the study site for the baseline visit, which included a review of the eDiary and paper diary to ensure compliance with study requirements. Participants who continued to meet all inclusion/exclusion criteria and were compliant with the eDiary could enter the long-term treatment period. They were given a bottle containing a 30-day supply of study medication (i.e. 30 rimegepant 75 mg uncoated oral tablets) and were instructed not to begin taking study medication until baseline laboratory results confirmed their continued eligibility. During the long-term treatment period, participants visited the study site approximately every two weeks during the first month and then every four weeks until week 12 or week 52 for assessment of study medication compliance and monitoring of tolerability and safety (including vital signs, laboratory tests and electrocardiograms (ECG)). At the end of week 12 (EOD + PRN group) or week 52 (both PRN groups), participants returned to the study site for review of the eDiary and assessments of medication compliance and tolerability and safety. After 14 ± 2 days, participants returned to the study site for a follow-up safety visit that included collection of laboratory tests, vital signs, ECG and AEs.

Figure 1.

Study design. PRN 2–8 = self-reported history of two to eight moderate to severe migraine attacks per month who treated migraine attacks of any severity (mild, moderate or severe headache pain intensity) as needed with up to one rimegepant tablet per calendar day for 52 weeks; PRN 9–14 = self-reported history of nine to 14 moderate to severe migraine attacks per month who treated migraine attacks of any severity (mild, moderate or severe headache pain intensity) as needed with up to one rimegepant tablet per calendar day for 52 weeks; EOD + PRN = history of four to 14 moderate to severe attacks per month who took one rimegepant tablet every other day as scheduled dosing plus as needed dosing of one rimegepant tablet for migraine attacks of any severity on nonscheduled dosing days for 12 weeks. ^aMaximum daily dose of one rimegepant 75 mg oral tablet.

Participants

Eligible participants included adults aged 18 years and older who had migraine with or without aura according to the criteria of the International Classification of Headache Disorders, 3rd edition, beta version (16); a one-year history of migraine attacks lasting about 4–72 hours if untreated, with the age of onset prior to 50 years of age; two to 14 moderate or severe migraine attacks per month within the three months before screening; and two or more migraine days requiring treatment during the observation period. Participants also had to be able to distinguish migraine attacks from attacks of tension-type headache and cluster headache. Those taking preventive migraine medication were permitted to remain on therapy if they were on a stable dose for at least three months (which was reduced to two months in a protocol amendment on 22 June 2018) prior to the baseline visit, and the dose was not expected to change during the course of the study. Participants were permitted to take the following previously prescribed standard of care medications: aspirin; ibuprofen; acetaminophen up to 1000 mg/day for a maximum of two consecutive days at a time (including Excedrin Migraine, Haleon plc, Weybridge, UK); any NSAID; antiemetics (e.g. metoclopramide or promethazine); or baclofen during the course of the study. Participants with a contraindication to triptans could participate if they satisfied all other inclusion criteria. Use of triptans by participants without a contraindication was allowed only during the 30-day screening visit/observation period. Use of triptans was prohibited during the long-term treatment phase. With the exception of triptans and acetaminophen, as described above, participants were allowed to take standard of care migraine treatment, if needed, during the course of the study.

Participants were excluded if they had a history of migraine with brainstem aura or hemiplegic migraine; human immunodeficiency virus disease; Gilbert’s syndrome or active hepatic or biliary disease; AST, ALT or serum bilirubin (total, direct, or indirect) >1× ULN; diseases or conditions causing malabsorption; and alcohol or drug abuse within the past 12 months. Participants with the following current conditions were also excluded: uncontrolled, unstable or recently diagnosed cardiovascular disease; uncontrolled hypertension; uncontrolled diabetes; body mass index ≥30 kg/m²; unstable medical conditions; diagnosis of major depressive disorder, pain syndromes, psychiatric conditions or significant neurological disorders; current diagnosis of schizophrenia, major depressive disorder requiring treatment with atypical antipsychotics, bipolar disorder or borderline personality disorder; and medically significant positive drug screen for drugs of abuse. Concomitant use of strong cytochrome 3A4 inhibitors or inducers with rimegepant was prohibited during the study.

Assessments

Efficacy

Exploratory efficacy assessments were performed on the endpoints of migraine-related quality of life, preference of medication, satisfaction with medication and total improvement relative to baseline. Results are reported in the supplementary material.

Safety

Safety assessments included AEs (non-serious and serious AEs), vital signs (seated arterial systolic and diastolic blood pressure, radial artery pulse rate, respiratory rate and body temperature) and physical measurements (height, weight); ECGs; physical examinations; clinical laboratory test evaluations (hematology, serum chemistry/electrolyte, liver function tests [LFTs], lipid panel, estimated glomerular filtration rate, urinalysis, urine drug screen and follicle-stimulating hormone); pregnancy tests (serum or urine); and the Sheehan Suicidality Tracking Scale (17).

For clinical laboratory test evaluations, participants were instructed to fast for a minimum of eight hours prior to blood draws at baseline, week 4, week 12 (EOD + PRN only), week 24 and week 52. If a participant had not fasted before a given visit, the blood draw was still performed.

Statistical analysis

Populations for analysis

Analysis sets included screened participants (signed informed consent and assigned to an enrollment group), enrolled participants (screened and enrolled in long-term treatment) and treated participants (took any amount of rimegepant).

Endpoints

The primary safety and tolerability endpoints were the frequency (i.e. number and percentage of participants) of AEs occurring in ≥5% of treated participants by severity, serious AEs, AEs leading to study drug discontinuation and laboratory test abnormalities by toxicity grade. The 5% threshold on AEs applied to the percentage of participants with a preferred term in any enrollment group, regardless of severity. Investigators determined the severity (e.g. mild, moderate, severe) of AEs and the relationship of AEs to study drug; their terms were coded and grouped by system organ class and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). In analyses of AEs by severity, the highest severity on treatment was reported for each preferred term. Laboratory test results were graded according to numeric laboratory test criteria (18,19). The worst (highest) toxicity grade on treatment was reported for each test.

Secondary safety endpoints included the frequencies of the following events or findings on treatment: elevations of AST or ALT >3× ULN concurrent with total bilirubin >2× ULN (where concurrent was defined as the same collection date); hepatic-related AEs (which were AEs of special interest); and hepatic-related AEs leading to study drug discontinuation.

Additional safety endpoints included the frequencies of AEs related to study drug and AEs of special interest on treatment. The AEs of special interest (hepatic-related AEs, potential drug abuse AEs, cardiovascular AEs and suicidality AEs (completed, attempted, ideation)) were prespecified in the statistical analysis plan and identified primarily from standardized MedDRA queries (SMQs) and relevant preferred terms. The SMQs were aligned with the version of MedDRA used for analyses.

In addition, medication-overuse headache was assessed using medical history and medication-overuse headache AEs, which were identified from the preferred term of medication overuse headache or the lowest level term of rebound headache using MedDRA.

Safety endpoints were assessed on treatment. AEs with onset date on or after the study drug start date through the study drug end date plus seven days were considered on treatment. Findings measured after the study drug start date through the study drug end date plus seven days were considered on treatment.

Statistical approaches used to assess exploratory endpoints are included in the supplementary material.

Sample size

Enrollment of up to approximately 2800 individuals was planned in order to assign up to approximately 2000 participants to rimegepant in order to enhance the clinical value and generalizability of results. With a sample size of approximately 2000 subjects, and with no events observed, the upper bound of a one-sided 95% confidence interval for zero observations is approximately 0.0015. Hence, this sample size was sufficently large to rule out events that occur at rates greater than 15 cases per 10,000 patients.

Results

Participants

The first participant was enrolled into the study on August 30, 2017, and the last participant completed the study on 15 July 2019. Of the 3019 participants who were screened (Table 1), 1908 (63.2%) were enrolled, and 1800 (59.6%) were treated with rimegepant (PRN, n = 1514; EOD + PRN, n = 286). Approximately half (51%; 918/1800) of the treated participants had participated in a previous rimegepant study.

Table 1.

Disposition of screened participants.

	PRN 2–8(52 weeks)n = 1646	PRN 9–14(52 weeks)n = 862	EOD + PRN(12 weeks)n = 511	OverallN = 3019
Enrolled in the long-term treatment period, n (%)	1089 (66.2)	511 (59.3)	308 (60.3)	1908 (63.2)
Not treated	56 (5.1)	30 (5.9)	22 (7.1)	108 (5.7)
Screen failure	29 (2.7)	15 (2.9)	15 (4.9)	59 (3.1)
Withdrawal by participant	11 (1.0)	7 (1.4)	2 (0.6)	20 (1.0)
Protocol deviation	2 (0.2)	4 (0.8)	3 (1.0)	9 (0.5)
Lost to follow-up	6 (0.6)	0	2 (0.6)	8 (0.4)
Non-compliance	4 (0.4)	2 (0.4)	0	6 (0.3)
No qualifying migraine attack by week 8 visit	1 (0.1)	2 (0.4)	0	3 (0.2)
Adverse event	2 (0.2)	0	0	2 (0.1)
Pregnancy	1 (0.1)	0	0	1 (0.1)
Treated (analyzed for safety)	1033 (94.9)	481 (94.1)	286 (92.9)	1800 (94.3)
Participated in previous rimegepant trial	799 (77.3)	10 (2.1)	109 (38.1)	918 (51.0)
Completed the study	683 (66.1)	271 (56.3)	243 (85.0)	1197 (66.5)
Discontinued the study	350 (33.9)	210 (43.7)	43 (15.0)	603 (33.5)
Non-compliance	122 (11.8)	55 (11.4)	7 (2.4)	184 (10.2)
Withdrawal by participant	89 (8.6)	56 (11.6)	14 (4.9)	159 (8.8)
Lack of efficacy	41 (4.0)	31 (6.4)	5 (1.7)	77 (4.3)
Lost to follow-up	33 (3.2)	37 (7.7)	6 (2.1)	76 (4.2)
Adverse event	31 (3.0)	17 (3.5)	8 (2.8)	56 (3.1)
Protocol deviation	15 (1.5)	6 (1.2)	1 (0.3)	22 (1.2)
Pregnancy	10 (1.0)	5 (1.0)	0	15 (0.8)
Screen failure	4 (0.4)	2 (0.4)	2 (0.7)	8 (0.4)
Other	5 (0.5)	0	0	5 (0.3)
Positive Sheehan-STS score	0	1 (0.2)	0	1 (0.1)

PRN 2–8 = self-reported history of two to eight moderate to severe migraine attacks per month who treated migraine attacks of any severity (mild, moderate or severe headache pain intensity) as needed with up to one rimegepant tablet per calendar day for 52 weeks; PRN 9–14 = self-reported history of nine to 14 moderate to severe migraine attacks per month who treated migraine attacks of any severity (mild, moderate or severe headache pain intensity) as needed with up to one rimegepant tablet per calendar day for 52 weeks; EOD + PRN = history of four to 14 moderate to severe attacks per month who took one rimegepant tablet every other day as scheduled dosing plus as needed dosing of one rimegepant tablet for migraine attacks of any severity on nonscheduled dosing days for 12 weeks; STS, Suicidality Tracking Scale.

As shown in Table 2, treated participants had a mean ± SD age of 43.1 ± 12.2 years, with 66 (3.7%) participants aged ≥65 years; 1609 (89.4%) participants were female and 1475 (81.9%) were White. The mean ±SD age at migraine onset was 20.6 ± 10.2 years, the mean ± SD average duration of untreated migraine attacks was 33.9 ± 22.3 hours and the mean ± SD number of moderate to severe migraine attacks per month was 6.7 ± 3.1.

Table 2.

Demographics and baseline characteristics of treated participants.

	PRN 2–8(52 weeks)n = 1033	PRN 9–14(52 weeks)n = 481	EOD + PRN(12 weeks)n = 286	OverallN = 1800
Age (years), mean ± SD	44.0 ± 11.8	42.4 ± 12.4	41.1 ± 12.7	43.1 ± 12.2
<40	402 ± 38.9	213 ± 44.3	144 ± 50.3	759 ± 42.2
≥40	631 ± 61.1	268 ± 55.7	142 ± 49.7	1041 ± 57.8
<65	998 ± 96.6	463 ± 96.3	273 ± 95.5	1734 ± 96.3
≥65	35 ± 3.4	18 ± 3.7	13 ± 4.5	66 ± 3.7
Sex, n (%)
Female	917 (88.8)	444 (92.3)	248 (86.7)	1609 (89.4)
Male	116 (11.2)	37 (7.7)	38 (13.3)	191 (10.6)
Race, n (%)
White	847 (82.0)	394 (81.9)	234 (81.8)	1475 (81.9)
Black or African American	149 (14.4)	66 (13.7)	35 (12.2)	250 (13.9)
Other^a	37 (3.6)	21 (4.4)	17 (5.9)	75 (4.2)
Weight (kg), mean ± SD	83.6 ± 22.0	81.7 ± 22.9	69.8 ± 11.7	80.9 ± 21.5
Body mass index (kg/m²), mean ± SD	30.4 ± 7.8	29.7 ± 7.7	25.2 ± 3.5	29.4 ± 7.5
Moderate-severe migraine attacks (per month), mean ± SD^b	4.9 ± 1.8	10.8 ± 1.6	6.8 ± 2.6	6.7 ± 3.1
Duration of untreated migraine attacks (hours), mean ± SD^b	33.7 ± 22.2	34.5 ± 21.9	33.5 ± 23.2	33.9 ± 22.3
Primary migraine type, n (%)^b
Without aura	674 (65.2)	311 (64.7)	215 (75.2)	1200 (66.7)
With aura	359 (34.8)	170 (35.3)	71 (24.8)	600 (33.3)
Taking preventive migraine medication, n (%)	136 (13.2)	76 (15.8)	32 (11.2)	244 (13.6)

Includes American Indian or Alaska Native, Asian, Multiple and Native Hawaiian or Other Pacific Islander.

Historical.

The mean ± SD numbers of tablets taken per month were 5.6 ± 3.5, 8.5 ± 4.2 and 13.7 ± 2.9 in the PRN 2–8, PRN 9–14 and EOD + PRN enrollment groups, respectively (Table 3). Among participants in the EOD + PRN group, 88.8% (254/286) were ≥80% compliant with EOD dosing and 80.1% (229/286) were ≥90% compliant with EOD dosing. The median (range) number of weeks in the long-term treatment period were 52.0 (1.0–57.0), 51.6 (1.6–55.6) and 12.1 (1.0–18.1) in the PRN 2–8, PRN 9–14 and EOD + PRN groups, respectively.

Table 3.

Time in long-term treatment period and average rimegepant exposure of treated participants.

	PRN 2–8(52 weeks)n = 1033	PRN 9–14(52 weeks)n = 481	EOD + PRN(12 weeks)n = 286	OverallN = 1800
Time in the long-term treatment period (weeks),
mean ± SD	42.1 ± 16.5	38.0 ± 18.6	11.3 ± 2.9	36.1 ± 19.2
Median (minimum, maximum)	52.0 (1.0, 57.0)	51.6 (1.6, 55.6)	12.1 (1.0, 18.1)	51.1 (1.0, 57.0)
Average rimegepant exposure, tablets per month,
mean ± SD^a	5.6 ± 3.5	8.5 ± 4.2	13.7 ± 2.9	7.7 ± 4.6
Median (minimum, maximum)	4.9 (0.2, 27.6)	7.8 (0.7, 26.6)	14.2 (0.3, 22.0)	6.5 (0.2, 27.6)

Four-week (28-day) interval.

Safety

As shown in the Table 4, 60.4% (1088/1800) of treated participants had at least one AE on treatment; most (78.2%) AEs were mild or moderate and few (20%; 360/1800) were judged by investigators to be related to study drug. In total, 2.7% (48/1800) of treated participants had an AE leading to study drug discontinuation, and 2.6% (47/1800) experienced a serious AE. The only serious AEs reported in more than one participant were accidental overdose, appendicitis, osteoarthritis, pulmonary embolism (three participants (0.2%) each), constipation, pneumonia and sepsis (two participants (0.1%) each). Serious AEs considered by the investigator to be possibly (one serious AE) or unlikely (nine serious AEs) related to study drug were reported in 10 (0.6%) participants (see supplementary Table 1). All other serious AEs were considered by the investigators to be unrelated to rimegepant.

Table 4.

Adverse events on treatment in treated participants

	PRN 2–8(52 weeks)n = 1033	PRN 9–14(52 weeks)n = 481	EOD + PRN(12 weeks)n = 286	OverallN = 1800
Participants with ≥1 AE, n (%)	664 (64.3)	315 (65.5)	109 (38.1)	1088 (60.4)
Mild^a	484 (46.9)	226 (47.0)	66 (23.1)	776 (43.1)
Moderate^a	398 (38.5)	191 (39.7)	53 (18.5)	642 (35.7)
Severe^a	55 (5.3)	21 (4.4)	3 (1.0)	79 (4.4)
AEs related to study drug, n (%)	191 (18.5)	123 (25.6)	46 (16.1)	360 (20.0)
AEs leading to study drug discontinuation, n (%)	24 (2.3)	16 (3.3)	8 (2.8)	48 (2.7)
Hepatic-related AEs leading to study drug discontinuation, n (%)	3 (0.3)	3 (0.6)	0	6 (0.3)
ALT increased	0	3 (0.6)	0	3 (0.2)
AST increased	0	3 (0.6)	0	3 (0.2)
Gamma-glutamyltransferase increased	0	1 (0.2)	0	1 (<0.1)
Liver function test increased	1 (<0.1)	0	0	1 (<0.1)
Transaminases increased	1 (<0.1)	0	0	1 (<0.1)
Hepatic cyst	1 (<0.1)	0	0	1 (<0.1)
Serious AE, n (%)	28 (2.7)	16 (3.3)	3 (1.0)	47 (2.6)
AEs in ≥2% of participants in any enrollment group, n (%)	378 (36.6)	163 (33.9)	53 (18.5)	594 (33.0)
Upper respiratory tract infection	108 (10.5)	38 (7.9)	12 (4.2)	158 (8.8)
Nasopharyngitis	72 (7.0)	41 (8.5)	9 (3.1)	122 (6.8)
Sinusitis	57 (5.5)	28 (5.8)	7 (2.4)	92 (5.1)
Urinary tract infection	40 (3.9)	21 (4.4)	8 (2.8)	69 (3.8)
Influenza	49 (4.7)	9 (1.9)	1 (0.3)	59 (3.3)
Back pain	36 (3.5)	14 (2.9)	6 (2.1)	56 (3.1)
Bronchitis	35 (3.4)	14 (2.9)	4 (1.4)	53 (2.9)
Nausea	33 (3.2)	15 (3.1)	3 (1.0)	51 (2.8)
Dizziness	26 (2.5)	13 (2.7)	3 (1.0)	42 (2.3)
Arthralgia	25 (2.4)	9 (1.9)	2 (0.7)	36 (2.0)
Diarrhea	17 (1.6)	12 (2.5)	5 (1.7)	34 (1.9)
Muscle strain	8 (0.8)	10 (2.1)	0	18 (1.0)
Acute sinusitis	6 (0.6)	10 (2.1)	0	16 (0.9)

Worst severity on treatment for each AE term.

Among the 1762 participants with LFT data on treatment, elevations >ULN were reported for ALT (159 participants; 9.0%), AST (119 participants; 6.8%), ALT or AST (196 participants; 11.1%) and total bilirubin (30 participants; 1.7%); LFT elevations >3× ULN were reported for ALT (12 participants; 0.7%), AST (14 participants; 0.8%) and ALT or AST (18 participants; 1.0%). No participants in the EOD + PRN enrollment group had ALT or AST >3× ULN or total bilirubin >2× ULN. Based on local laboratory tests, one participant (0.1%) had concurrent elevations of ALT or AST >3× ULN and total bilirubin >2× ULN. Total bilirubin elevation >2× ULN was observed once; bilirubin results obtained the next day and subsequently all were within the reference range. The case was assessed as being unlikely related to rimegepant by an independent panel of hepatologists and as clinically and biochemically most consistent with passing a gallstone. A second participant had non-concurrent elevations of ALT or AST >3× ULN and total bilirubin >2× ULN; total bilirubin elevation >2× ULN was observed once and found to be normal at the next determination 12 days later. The panel assessed the case as being unlikely related to rimegepant and most likely as a result of mercaptopurine that the subject was taking concomitantly for the treatment of ulcerative colitis.

Hepatic-related on-treatment AEs were reported in 26 (1.4%) of the 1800 treated participants, all in the PRN groups. The majority of these AEs were mild or moderate; they were assessed as severe in two (0.1%) participants. The first participant with a severe hepatic-related AE had elevated transaminases, alkaline phosphatase and gamma-glutamyltransferase, with normal bilirubin, the day after receiving intravenous ketorolac, morphine, ondansetron and promethazine in an emergency room (ER) for treatment of left lower quadrant abdominal pain. LFTs in the ER before this treatment were unremarkable and the study site investigator attributed the AE (drug-induced liver injury) to ketorolac and/or morphine. The second participant was found to have asymptomatic transaminase elevations (AE: transaminases increased), with normal bilirubin, alkaline phosphatase and gamma-glutamyltransferase, and a positive antinuclear antibody result. She also had a body mass index of 42.6 kg/m² at study entry and a medical history notable for idiopathic diabetes insipidus, type 2 diabetes mellitus and hypothyroidism, among multiple medical conditions. As shown in Table 4, six (0.3%) participants had hepatic-related AEs leading to study drug discontinuation, and the majority of these were LFT-related AEs.

Overall, 6.0% (108/1800) of participants had at least one on-treatment AE categorized as associated with potential drug abuse (Table 5). The most frequent of these (≥1% of participants in any enrollment group) were fatigue (1.4%; 25/1800), somnolence (1.3%; 23/1800) and insomnia (0.9%; 16/1800), all of which were mild in the majority of cases.

Table 5.

Potential drug abuse adverse events on treatment in ≥1% of treated participants in any enrollment group.

	PRN 2–8(52 weeks)n = 1033	PRN 9–14(52 weeks)n = 481	EOD + PRN(12 weeks)n = 286	OverallN = 1800
At least one AE, n (%)	65 (6.3)	36 (7.5)	7 (2.4)	108 (6.0)
Fatigue	14 (1.4)	8 (1.7)	3 (1.0)	25 (1.4)
Somnolence	15 (1.5)	6 (1.2)	2 (0.7)	23 (1.3)
Insomnia	10 (1.0)	4 (0.8)	2 (0.7)	16 (0.9)

The most frequently reported laboratory abnormalities on treatment in treated participants were related to lipid elevations: low-density lipoprotein (LDL)-cholesterol, fasting ≥8 hours (38.9%; 316/813); cholesterol high (37.8%; 584/1546); LDL-cholesterol (37.3% 577/1546); hypertriglyceridemia, not fasting ≥8 hours (i.e. fasting <8 hours or not fasting; 36.5%; 330/903); LDL-cholesterol, not fasting ≥8 hours (33.3%; 301/903); hypertriglyceridemia (31.8%; 492/1546); and hypertriglyceridemia, fasting ≥8 hours (23.1%; 188/813). Pretreatment lipid elevations (i.e. >Grade 0) were also observed among treated participants: LDL-cholesterol, fasting ≥8 hours (36.5%); cholesterol (35.2%); LDL-cholesterol (35.0%); LDL-cholesterol, not fasting ≥8 hours (32.9%); triglycerides, not fasting ≥8 hours (32.3%); triglycerides (27.6%); and triglycerides, fasting ≥8 hours (22.6%).

Discussion

The present study was conducted to evaluate the safety and tolerability of up to 1 year of rimegepant 75 mg oral tablets taken up to once daily, to determine the frequency of elevations in ALT or AST >3× ULN with concurrent elevations in bilirubin >2× ULN, and to assess the frequency and severity of hepatic-related AEs and hepatic-related AEs leading to study drug discontinuation. Exploratory endpoints evaluated the treatment effects of rimegepant on migraine-specific quality of life, preference of medication, satisfaction with medication and clinical improvement.

The results showed that rimegepant 75 mg oral tablet, self-administered up to once daily for up to 52 weeks by adults with migraine, was well tolerated and safe. Consistent with findings from previous research with rimegepant (10 –13), most AEs were mild or moderate in severity and were judged by the investigator to be unrelated to rimegepant. In the PRN enrollment groups, four-week exposure was in accordance with the historical frequency of migraine attacks (i.e. higher in participants with nine to 14 attacks per month than in participants with two to eight attacks per month). No signal of potential drug abuse, medication-overuse headache or hepatotoxicity because of rimegepant was identified during up to 52 weeks of dosing.

Most hepatic-related AEs were mild or moderate, and few hepatic-related AEs led to study drug discontinuation. On-treatment ALT and/or AST elevations >3× ULN were reported in approximately 1% of treated participants, with none in the EOD + PRN group, and there was no pattern of elevations associated with dosing duration or dosing frequency (i.e. no signal that elevations were associated with higher-frequency dosing, dosing duration or higher cumulative exposure). These elevations were typically asymptomatic and transient and were identified by the frequent protocol-specified lab collections. Two treated participants experienced ALT or AST >3× ULN and total bilirubin >2× ULN; both cases were assessed as being unlikely related to rimegepant by an independent panel of hepatologists. No signal of drug-induced liver disease because of rimegepant was identified during higher-frequency EOD + PRN scheduled dosing (at least every other day) or up to one year of PRN dosing (up to daily).

Clinical laboratory test evaluations were generally unremarkable. The most frequent laboratory test abnormalities on treatment were lipid elevations (cholesterol 35.1%, fasting LDL cholesterol 36.9% and triglycerides 27.7%) that were also present at baseline. It is likely these results were obtained because the protocol did not require fasting blood collections at any timepoint, and they were not controlled for fasting.

Rimegepant 75 mg, whether dosed PRN for 52 weeks or every other day plus PRN for 12 weeks, conferred long-term improvement in quality of life, with observed improvements exceeding the minimum clinically important difference across all domains and dosing regimens from week 12 through week 52. Participants also expressed a preference for rimegepant over their previous migraine medication and had high rates of satisfaction with rimegepant at weeks 12 and 52. Investigators considered a large majority of rimegepant-treated participants improved versus baseline, confirming the positive perceptions of rimegepant’s treatment effects provided by study participants. Rimegepant has a unique clinical utility as the only currently available migraine medication indicated for clinical use as an acute and a preventive treatment. This utility may underlie the favorable results in these endpoints.

The strengths of the present study include employing novel dosing regimens, including a large, balanced and representative (20,21) sample, as well as using a validated instrument to assess quality of life (22). Limitations include the open-label design and eligibility criteria that excluded comorbid conditions likely to be present in uncontrolled settings, both of which reduce the generalizability of its findings. The fact that 51.0% of treated participants had participated in a previous blinded rimegepant study may have introduced some selection bias because patients who had already participated in a clinical trial with rimegepant perhaps had different motivations than those without prior participation. Whether these participants, who had previously received blinded placebo or rimegepant, were potentially less likely to experience and report safety concerns is unknown. The lack of an active comparator limits understanding of the benefits of rimegepant relative to other migraine drugs.

Conclusions

Rimegepant, administered up to once per day as EOD + PRN for 12 weeks or PRN for up to 52 weeks, was safe and well tolerated in the acute treatment of migraine across a variety of safety endpoints, including AE assessments, clinical laboratory and LFTs, vital signs and ECGs. The results were consistent with the favorable safety and tolerability profiles observed in previous studies of rimegepant.

Clinical implications

A multicenter, open-label, long-term safety study evaluated the safety and tolerability of rimegepant in the acute treatment of migraine.

Rimegepant 75 mg administered up to once per day as EOD + PRN for 12 weeks or PRN for up to 52 weeks in adults with migraine was well tolerated, and its safety was consistent with the favorable profile observed in previous research.

During up to 52 weeks of dosing, no signal of potential drug abuse, medication-overuse headache or hepatotoxicity because of rimegepant was identified.

Supplemental Material

sj-pdf-1-cep-10.1177_03331024241232944 - Supplemental material for A multicenter, open-label long-term safety study of rimegepant for the acute treatment of migraine

Supplemental material, sj-pdf-1-cep-10.1177_03331024241232944 for A multicenter, open-label long-term safety study of rimegepant for the acute treatment of migraine by Robert Croop, Gary Berman, David Kudrow, Kathleen Mullin, Alexandra Thiry, Meghan Lovegren, Gilbert L’Italien and Richard B Lipton in Cephalalgia

Footnotes

Acknowledgments

We thank the participants and investigative staff at the study centers. Medical writing services were provided by Christopher Caiazza at Polymedia Corporation and funded by Pfizer.

Declaration of conflicting interests

Robert Croop was an employee of Biohaven Pharmaceuticals, owns stock in Biohaven Ltd, was an employee of Pfizer, has received research payments from Pfizer, and provides services to Collima LLC, which has had consulting agreements with Pfizer, Aptose Biosciences Inc., Manistee Therapeutics and Vida Ventures Management Co., LLC.

Gary Berman, MD, has received speaker fees from Amgen, Lilly, Allergan and Teva. He has received research support from Amgen, Lilly, Allergan, Teva, Biohaven, Alder and Novartis.

David Kudrow, MD, has received fees for advisory board from Alder, Biohaven, Eli Lilly, Amgen and Xoc, and for speaker’s bureau from Xoc, Teva, Amgen, Novartis and Eli Lilly. He has also received research support from Amgen, Novartis, Eli Lilly, Teva, Alder, Biohaven, Biogen and Roche-Genentech.

Kathleen Mullin serves as a consultant, advisory board member or has received honoraria from Amgen, Teva, Theranica, Vorso, Biohaven, electroCore and Eli Lilly.

Alexandra Thiry is employed by Pfizer and own stock/stock options in Biohaven Pharmaceuticals and Pfizer.

Meghan Lovegren and Gilbert L’Italien are employed by and own stock/stock options in Biohaven Pharmaceuticals.

Richard B. Lipton serves on the editorial board of Neurology and as senior advisor to Headache but is not paid for his roles on these journals. He has received research support from the NIH. He also receives support from the National Headache Foundation. He receives research grants from Allergan/AbbVie, Amgen, Dr. Reddy’s Laboratories and Novartis. He has reviewed for the NIA and NINDS and serves as consultant, advisory board member or has received honoraria from Allergan/AbbVie, Amgen, Biohaven, Dr Reddy’s Laboratories, electroCore, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Teva and Vedanta. He receives royalties from Wolff’s Headache (8th edition, Oxford University Press, 2009) and Informa. He holds stock options in Biohaven Pharmaceuticals and Manistee.

Data availability

Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de-identified participant data. For more information, see .

Ethical statement

This clinical trial was conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Conference on Harmonisation Harmonized Tripartite Guideline and all local laws and regulations. Before any study-related procedures were undertaken, investigators at each study center obtained Institutional Review Board/Independent Ethics Committee approval of the protocol and study-related materials, and participants provided written informed consent.

Funding

This study was sponsored by Biohaven, which was acquired by Pfizer in October 2022.

ORCID iD

Richard B. Lipton

Supplemental material

Supplemental material for this article is available online.

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