A 52‐week open‐label extension study to evaluate the safety and efficacy of oral rimegepant for the preventive treatment of migraine

Abstract

Objective

To assess the safety, tolerability, and treatment effects of rimegepant 75 mg every other calendar day (EOD) for the preventive treatment of migraine in a 52‐week, open‐label extension (OLE) study.

Background

Rimegepant is an oral small molecule calcitonin gene–related peptide receptor antagonist approved for the acute treatment of migraine and the preventive treatment of episodic migraine in adults. The efficacy and safety of rimegepant for preventive treatment of migraine was demonstrated in a 12‐week, phase 2/3, randomized, double‐blind (DB), placebo‐controlled trial in which rimegepant treatment produced significant improvement in the number of monthly migraine days (MMDs) with a safety profile similar to placebo.

Methods

In the DB trial period, an initial 4‐week observation period was followed by a randomized, DB, 12‐week treatment period. This was an optional 52‐week OLE following the initial DB study for adults who completed the DB period. Participants were instructed to take one tablet of rimegepant 75 mg EOD for 52 weeks. If participants required an acute treatment of migraine on a non‐scheduled dosing day, they could take one tablet of rimegepant 75 mg on that day (as‐needed dosing). Secondary endpoints evaluated the safety and tolerability of rimegepant, including the frequencies of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3× upper limit of normal (ULN) concurrent with total bilirubin (TBIL) > 2× ULN, hepatic‐related adverse events (AEs), and hepatic‐related AEs leading to rimegepant discontinuation. Exploratory endpoints included the mean reduction in the number of MMDs. The study (DB and OLE) was conducted from November 2018 to February 2021.

Results

Of 603 participants who entered the OLE period, 428 (71.0%) completed the study. Overall, 312 (51.7%) participants reported at least one on‐study AE and most events were mild in severity. Severe AEs were reported in 14 (2.3%) participants. Serious AEs were reported in 13 participants (2.2%); none were liver related. AEs considered related to rimegepant were reported in 91 (15.1%) participants; the most frequently reported were constipation (n = 6, 1.0%), upper respiratory tract infection (n = 5, 0.8%), nausea, migraine, ALT increased, AST increased, and weight increased (n = 4, 0.7% each). Hepatic‐related AEs occurred with low frequency (n = 11, 1.8%). AEs leading to rimegepant discontinuation were also uncommon (n = 17, 2.8%); two (0.3%) discontinued due to liver enzyme–related AEs. No participant had ALT or AST > 3× ULN concurrent with TBIL > 2× ULN. Over the OLE period, there was a mean (standard deviation) decrease of 6.2 (3.81) days in the number of MMDs. Mean MMDs and participants achieving categorical response rates improved over the OLE period, without any evidence of a diminution of effect.

Conclusions

The OLE data showed favorable tolerability and sustained and increasing treatment benefits with rimegepant 75 mg (EOD and as‐needed dosing) over 52 weeks for the preventive treatment of migraine. NCT03732638.

Plain Language Summary

Rimegepant is a tablet approved to treat and/or prevent migraine, but few studies have looked at its long‐term use to prevent migraine. This trial found that participants who took rimegepant every other day and as needed (up to one 75 mg tablet a day) experienced a reduction in migraine days and experienced few side effects. Moreover, the treatment benefits of rimegepant increased over a 1‐year period without losing effectiveness.

Abbreviations

AE

adverse event

ALT

alanine aminotransferase

AST

aspartate aminotransferase

CGRP

calcitonin gene–related peptide

CI

confidence interval

CTCAE

Common Terminology Criteria for Adverse Events

DAIDS

Division of Acquired Immunodeficiency Syndrome

DB

double blind

eDiary

electronic diary

EOD

every other day

LFT

liver function test

MedDRA

Medical Dictionary for Regulatory Activities

MMD

monthly migraine day

OLE

open‐label extension

PRN

pro re nata (as needed)

SAE

serious adverse event

SD

standard deviation

S‐STS

Sheehan Suicidality Tracking Scale

TBIL

total bilirubin

ULN

upper limit of normal

INTRODUCTION

Migraine is a chronic, debilitating neurologic disorder estimated to affect more than one billion individuals worldwide, with an age‐standardized point global prevalence of ~14%. ¹ Migraine is characterized by recurrent attacks of headache that are typically unilateral, pulsatile, and may be accompanied by various combinations of the accompanying symptoms of nausea, vomiting, photophobia, and phonophobia. ² Almost all patients with migraine require acute therapy and more than one third of patients may be suitable for preventive therapy. ³ , ⁴ The majority of available oral preventive migraine therapies were initially developed for other therapeutic indications and may be associated with low adherence and persistence due to limited efficacy and tolerability concerns. ⁵

Several lines of evidence support the crucial role of calcitonin gene–related peptide (CGRP) in the pathophysiology of migraine, which led to the development of multiple CGRP‐targeted treatments. These include monoclonal antibodies for the preventive treatment of migraine ⁶ , ⁷ , ⁸ , ⁹ and small‐molecule CGRP receptor antagonists for the acute ¹⁰ , ¹¹ , ¹² and preventive ¹³ , ¹⁴ treatment of migraine. Rimegepant is an oral, small‐molecule CGRP receptor antagonist approved in the United States, Europe, and United Kingdom for the acute treatment of migraine and preventive treatment of episodic migraine in adults. Multiple clinical studies have demonstrated that a single 75 mg dose of rimegepant is effective and safe for the acute treatment of migraine, with sustained analgesic effects through 48 h after dosing accompanied by improvements in other migraine symptoms and patient function. ¹² , ¹⁵ , ¹⁶ , ¹⁷

In a multicenter, phase 2/3, randomized, double‐blind (DB), placebo‐controlled trial (NCT03732638), rimegepant 75 mg taken every other calendar day (EOD), was effective for preventive treatment of migraine. ¹⁴ During the 12‐week DB period of the trial, rimegepant was demonstrated to be superior to placebo in reducing the mean number of monthly migraine days (MMDs) during weeks 9–12 as well as overall (weeks 1–12) during the DB period, and the safety profile of rimegepant was similar to placebo with no unexpected or major safety issues. ¹⁴ However, the safety and efficacy of long‐term rimegepant use for the prevention of migraine has not been assessed to date. Here, therefore, we report results for the 52‐week open‐label extension (OLE) period of study NCT03732638, focusing on long‐term safety, tolerability, and therapeutic effects of open‐label rimegepant.

METHODS

Study design

This was a multicenter, randomized, DB, placebo‐controlled trial to assess the safety, tolerability, and efficacy of rimegepant 75 mg for preventive treatment of migraine. The study was conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Harmonised Tripartite Guideline and the Declaration of Helsinki. Participants provided written informed consent before screening. The protocol was approved by a central institutional review board (Advarra IRB, Columbia, MD, USA) and an institutional review board at one study site (MedStar Georgetown Headache–Georgetown University, McLean, VA, USA).

The study consisted of four periods: (1) a screening period that included a 28‐day observation period; (2) a 12‐week DB period; (3) a 52‐week OLE period; and (4) an 8‐week follow‐up safety period. The study (DB and OLE) was conducted from November 2018 to February 2021. A full description of study design and results from the first two periods of this study (observation and 12‐week DB) have been reported. ¹⁴ All participants enrolled in the OLE period completed the DB period of the study.

Participants

Full inclusion/exclusion criteria have been previously described. ¹⁴ Briefly, participants eligible for the DB period were aged ≥ 18 years with at least 4, but not more than 18, migraine attacks of moderate or severe pain intensity per month (4 weeks) during the 3 months before the screening visit and at least 6 migraine days during the observation period. Preventive migraine medication was permitted if the dose was stable for ≥ 3 months. Participants were allowed to use acute headache treatments (i.e., triptans, nonsteroidal anti‐inflammatory drugs, acetaminophen, antiemetics, muscle relaxants, and aspirin) as needed. The use of CGRP antagonists (biologic or small molecule) other than rimegepant was prohibited during the entire study period. Triptan medications, allowed as rescue medication during the DB period, were prohibited during the OLE period.

Key exclusion criteria included > 18 headache days (migraine or non‐migraine) during the observation period, a history of nonresponse to > 2 drug categories for preventive treatment of migraine, a history or current evidence of any medical condition that would expose them to undue risk of a significant adverse event (AE) or interfere with assessments of safety or efficacy, evidence of alcohol or drug abuse within the past 48 weeks, history of drug or other allergy that made them unsuitable for participation, or if they had an electrocardiogram or laboratory test finding that raised safety or tolerability concerns. Participants were eligible to participate in the OLE if they continued to meet the study entry criteria, including acceptable laboratory test results, at the end of the DB period.

Treatment

During the 12‐week DB treatment phase (weeks 1–12), participants were randomized using an interactive web response system to oral rimegepant 75 mg tablet or matching placebo EOD. During the 52‐week OLE period (weeks 13–64), all participants were instructed to take one tablet of rimegepant 75 mg EOD. If needed for the acute treatment of migraine, participants could take one tablet of rimegepant 75 mg on non‐scheduled dosing days (pro re nata [PRN] dosing). Therefore, during the OLE period, participants could take a maximum of one rimegepant 75 mg tablet per calendar day for this 52‐week period (EOD + PRN dosing). Treatment compliance was reviewed at each study visit by review of electronic diary (eDiary) entries and returned study medication.

Endpoints

The primary study endpoint evaluated efficacy during the 12‐week DB treatment period, which has been published previously. ¹⁴ The objective of the OLE period was to evaluate the safety and tolerability of rimegepant based on medical review of AE reports and the results of vital sign and physical measurements, electrocardiograms, physical examinations, clinical laboratory tests, and pregnancy testing. Secondary safety endpoints included the frequencies of the following events or findings during the OLE period: AEs, serious AEs (SAEs), AEs leading to rimegepant discontinuation, clinically relevant (i.e., grade 3–4) laboratory test abnormalities, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3× upper limit of normal (ULN) concurrent with total bilirubin (TBIL) > 2× ULN, hepatic‐related AEs, and hepatic‐related AEs leading to rimegepant discontinuation. The frequency of liver function test (LFTs), AST, ALT, or TBIL elevations was an exploratory safety endpoint. In addition to hepatic‐related AEs, prespecified AEs of special interest included potential drug abuse AEs, cardiovascular AEs, and suicidality AEs. Suicidality was also assessed using the Sheehan Suicidality Tracking Scale (S‐STS).

AEs were assessed throughout the OLE and follow‐up period. In addition to baseline assessments, the following were assessed during the OLE: vital signs (every 4 weeks from weeks 16–64/end of treatment and at 2‐week follow‐up), electrocardiograms (weeks 16, 24, 48, 64/end of treatment and at 2‐week follow‐up), physical examinations (weeks 16, 24, and 64/end of treatment), clinical laboratory tests (weeks 16, 24, 48, and 64/end of treatment), LFTs (week 14, every 4 weeks from weeks 16–64/end of treatment, and 2‐ and 8‐week follow‐up), and the S‐STS (week 14, every 4 weeks from weeks 16–64/end of treatment, and 2‐week follow‐up).

Exploratory efficacy endpoints included the mean change from the observation period in the number of MMDs by pain severity (any; moderate or severe) at each month and over the entire course of the OLE period, and percentages of participants achieving ≥ 50% and 100% reductions in MMDs from the observation period by pain severity at each month and over the entire course of the OLE period. Mean monthly non‐scheduled medication days and rescue medication days over time during the OLE data were reported post hoc. Migraine occurrence and severity and use of rimegepant on non‐scheduled dosing days was captured daily by participants in an eDiary. Use of rescue medication was captured daily in a paper diary.

Statistical analysis

Safety endpoints were assessed for OLE rimegepant‐treated participants, defined as enrolled participants who received at least one dose of open‐label rimegepant. Safety endpoints were summarized descriptively based on observed data in the overall OLE rimegepant‐treated population and in cohorts grouped according to whether they received rimegepant (DB rimegepant/OLE rimegepant) or placebo (DB placebo/OLE rimegepant) during the 12‐week DB period prior to receiving open‐label rimegepant in the 52‐week OLE. Categorical variables were tabulated with counts and percentages. Continuous variables were summarized with univariate statistics (e.g., n, mean, standard deviation [SD]).

AEs were coded in Medical Dictionary for Regulatory Activities (MedDRA) version 24.0. Laboratory test values were graded according to numeric laboratory test criteria using the Common Terminology Criteria for Adverse Events (CTCAE), if available; otherwise, according to Division of Acquired Immunodeficiency Syndrome (DAIDS) 2017 Table for Grading the Intensity of Adult and Pediatric Adverse Events. Concurrent LFT elevations were defined as those on the same laboratory test collection date. Efficacy endpoints were assessed for OLE evaluable efficacy participants, defined as randomized participants who received at least one dose of open‐label rimegepant, and had ≥ 14 days of eDiary efficacy data (not necessarily consecutive) in both the observation period and ≥ 1 month (4‐week interval) of the OLE period. MMDs were based on 4‐week (28‐day) intervals and were prorated to account for missing eDiary efficacy data. In efficacy analyses, participants had to have ≥ 14 days of eDiary efficacy data (not necessarily consecutive) in a particular month (4‐week interval) to be evaluated at that month. Mean change in MMDs from the observation period at each study month (months 1–16) and for the overall OLE period was presented along with 95% confidence intervals (CIs). The proportions of participants experiencing ≥ 50%, ≥ 75%, and 100% reduction in MMDs, relative to the observation period, at study months 1, 3, 6, 9, and 12 of the OLE period were also reported along with 95% CIs. All statistics were generated using SAS statistical software version 9.4 or higher (SAS Institute Inc., Cary, NC, USA). Sample size was not based on the OLE period but rather was based on having approximately 370 participants in each of the two groups (placebo and rimegepant) in the DB period prior to the OLE.

RESULTS

Participants

Of the 741 participants who were treated with DB rimegepant or placebo, 603 were treated with rimegepant in the OLE. Participant disposition in the OLE period is displayed in Figure 1. Of the 603 OLE rimegepant‐treated participants, 428 (71.0%) completed the OLE period. The most common reasons for not completing the OLE period were withdrawal by participant (n = 57), lost to follow‐up (n = 32), non‐compliance (n = 29), AEs (n = 19), and physician decision (n = 18).

FIGURE 1.

Disposition of participants during the 52‐week OLE period. This figure summarizes the disposition of all participants treated with rimegepant during the OLE period. Participants are grouped according to whether they received rimegepant (DB rimegepant/OLE rimegepant) or placebo (DB placebo/OLE rimegepant) during the 12‐week DB period before receiving open‐label rimegepant during the 52‐week OLE period. AE, adverse event; DB, double‐blind; OLE, open‐label extension.

Table 1 shows demographics and clinical characteristics at baseline (prior to the start of the DB period) for all participants who were treated with rimegepant during the OLE. Demographics and clinical characteristics of those who were treated with rimegepant in the OLE were similar regardless of their DB treatment assignment (placebo or rimegepant).

TABLE 1.

Baseline demographics and clinical characteristics of participants treated with rimegepant during the 52‐week OLE period.

	DB rimegepant, OLE rimegepant (n = 302)	DB placebo, OLE rimegepant (n = 301)	Total (N = 603)
Age, years	42.6 (12.9)	41.9 (13.4)	42.3 (13.1)
Sex
Female	241 (79.8)	255 (84.7)	496 (82.3)
Male	61 (20.2)	46 (15.3)	107 (17.7)
Race
White	241 (79.8)	254 (84.4)	495 (82.1)
Black or African American	50 (16.6)	36 (12.0)	86 (14.3)
American Indian or Alaskan native	5 (1.7)	1 (0.3)	6 (1.0)
Asian	1 (0.3)	5 (1.7)	6 (1.0)
Multiple	5 (1.7)	2 (0.7)	7 (1.2)
Native Hawaiian or other Pacific Islander	0	3 (1.0)	3 (0.5)
Height, cm	166.0 (9.0)	165.5 (8.4)	165.7 (8.7)
Weight, kg	73.5 (13.3)	72.0 (12.8)	72.7 (13.1)
BMI, kg/m2	26.6 (3.7)	26.2 (3.9)	26.4 (3.8)
Age at migraine onset, years a	22.0 (11.3)	21.0 (11.2)	21.5 (11.3)
Duration of untreated migraine attacks, h a	29.8 (21.5)	27.9 (20.5)	28.9 (21.0)
Number of moderate to severe migraine attacks per month a	7.9 (2.8)	7.9 (2.7)	7.9 (2.7)
History of chronic migraine present a	59 (19.5)	77 (25.6)	136 (22.6)
Primary migraine type a
Without aura	186 (61.6)	187 (62.1)	373 (61.9)
With aura	116 (38.4)	114 (37.9)	230 (38.1)
Number of MMDs in the OP b
Any pain severity	10.1 (3.04)	9.6 (3.03)	9.9 (3.05)
Moderate or severe pain severity	8.7 (3.28)	8.4 (3.22)	8.5 (3.25)

Note: Unless noted otherwise, all participants treated with rimegepant during the OLE are included in the table. Participants are grouped according to whether they received rimegepant (DB rimegepant/OLE rimegepant) or placebo (DB placebo/OLE rimegepant) during the 12‐week DB period before receiving open‐label rimegepant during the 52‐week OLE. Data are mean (SD) or n (%).

Abbreviations: BMI, body mass index; DB, double‐blind; eDiary, electronic diary; OLE, open‐label extension; OP, observation period; MMDs, monthly migraine days; SD, standard deviation.

^a Denotes historical data.

^b Based on the OLE evaluable efficacy population, which consisted of participants with ≥ 14 days of eDiary efficacy data (not necessarily consecutive) in both the observation period and ≥ 1 month (4‐week interval) in the OLE (n = 288 DB rimegepant/OLE rimegepant; n = 292 DB placebo/OLE rimegepant; n = 580 total).

Overall, the mean (SD) time on OLE rimegepant was 42.5 (16.14) weeks; 508 (84.2%) participants received OLE rimegepant for ≥ 6 months and 372 (61.7%) participants received OLE rimegepant for ≥ 12 months. The mean (SD) OLE rimegepant exposure was 14.6 (2.45) tablets per month; 202 (33.5%), 289 (47.9%), and 112 (18.6%) participants took an average of ≤ 14, >14 to ≤16, and > 16 tablets per month, respectively.

Safety

AEs reported among rimegepant‐treated participants during the OLE period are summarized in Table 2. The number of participants reporting at least one AE was 312 (51.7%). Most AEs were mild in severity. SAEs were infrequent, occurring in 13 (2.2%) participants. Only one SAE (diverticulitis, 2 participants) occurred in more than one participant. All SAEs were considered by the investigator to be not related to study drug. Severe AEs were reported in 14 (2.3%) participants, and migraine (n = 2) was the only severe AE occurring in more than one participant. Overall, three severe AEs were considered related to rimegepant: hepatic enzyme increased, sunburn, and migraine (n = 1 each). No AEs of medication‐overuse headache were reported (based on AEs coded to the MedDRA Preferred Term of “medication overuse headache”).

TABLE 2.

Summary of AEs reported among rimegepant‐treated participants during the 52‐week OLE period.

	DB rimegepant, OLE rimegepant (n = 302)	DB placebo, OLE rimegepant (n = 301)	Total (N = 603)
Any AE	150 (49.7)	162 (53.8)	312 (51.7)
AE occurring in ≥ 2% of participants
Upper respiratory tract infection	21 (7.0)	22 (7.3)	43 (7.1)
Nasopharyngitis	23 (7.6)	15 (5.0)	38 (6.3)
Influenza	9 (3.0)	14 (4.7)	23 (3.8)
Urinary tract infection	10 (3.3)	9 (3.0)	19 (3.2)
Sinusitis	8 (2.6)	10 (3.3)	18 (3.0)
Back pain	13 (4.3)	13 (4.3)	26 (4.3)
Arthralgia	5 (1.7)	10 (3.3)	15 (2.5)
Intensity
Mild AE	114 (37.7)	115 (38.2)	229 (38.0)
Moderate AE	76 (25.2)	79 (26.2)	155 (25.7)
Severe AE	7 (2.3)	7 (2.3)	14 (2.3)
AE related to rimegepant	49 (16.2)	42 (14.0)	91 (15.1)
SAE	7 (2.3)	6 (2.0)	13 (2.2)
SAE related to rimegepant	0	0	0
Death	1 (0.3)	1 (0.3)	2 (0.3)
Death related to rimegepant	0	0	0
AE leading to rimegepant discontinuation	9 (3.0)	8 (2.7)	17 (2.8)
Hepatic‐related AE	2 (0.7)	9 (3.0)	11 (1.8)
Severe hepatic‐related AE	0	1 (0.3)	1 (0.2)
Hepatic‐related SAE	0	0	0
Hepatic‐related AE leading to rimegepant discontinuation	1 (0.3)	1 (0.3)	2 (0.3)
Potential drug abuse AE	14 (4.6)	10 (3.3)	24 (4.0)
Cardiovascular AE	0	1 (0.3)	1 (0.2)
Suicidal ideation AE	1 (0.3)	0	1 (0.2)

Note: All participants treated with rimegepant during the OLE are included in the table. Participants are grouped according to whether they received rimegepant (DB rimegepant/OLE rimegepant) or placebo (DB placebo/OLE rimegepant) during the 12‐week DB period before receiving open‐label rimegepant during the 52‐week OLE. Data are n (%).

Abbreviations: AE, adverse event; DB, double‐blind; OLE, open‐label extension; SAE, serious adverse event.

AEs related to rimegepant were reported in 91 (15.1%) participants. The most frequently reported (> 0.5%) AEs considered to be treatment related were constipation (n = 6, 1.0%), upper respiratory tract infection (n = 5, 0.8%), nausea, migraine, ALT increased, AST increased, and weight increased (n = 4, 0.7% each).

Tolerability

Overall, 17 (2.8%) participants reported AEs leading to rimegepant discontinuation during the OLE period (Table 2), including 2 (0.3%) participants who discontinued rimegepant due to hepatic‐related AEs (both due to increased liver enzymes). There were no clinically meaningful signals or trends for worst abnormalities, toxicity grade shifts, or changes from baseline for hematology, serum chemistry, or urinalysis parameters, and no clinically meaningful changes from baseline for vital signs, physical measurements, or electrocardiograms during the entire OLE period. The rates of clinically relevant (i.e., grade 3–4) laboratory test abnormalities were low (all < 2%, Table S1 in supporting information), with only eight incidences of grade 4 abnormalities (creatine kinase, n = 7; high potassium, n = 1).

Liver safety

Hepatic‐related AEs occurred with low frequency (all treated participants, n = 11, 1.8%; DB placebo/OLE rimegepant, n = 9, 3.0%; DB/OLE rimegepant, n = 2, 0.7%) and comprised primarily LFT abnormalities detected at scheduled visits and one AE of hepatic steatosis. Overall, low frequencies of LFT elevations were observed during the OLE period and there were no elevations of ALT or AST > 3× ULN concurrent with TBIL > 2× ULN (Table 3). One participant (31‐year‐old female) had an SAE of acute hepatitis B and Epstein–Barr virus infection with multiple reports of follow‐up LFT elevations (ALT > 20× ULN, AST > 10× ULN, TBIL elevations > 2× ULN, and alkaline phosphatase > 2× ULN). Rimegepant treatment was discontinued due to asymptomatic elevated LFTs at this week 16 study visit and the participant was subsequently hospitalized 17 days later because of the acute hepatitis B. Treatment with tenofovir was started with resolution of the SAE and she was discharged to home. The results of LFTs obtained at the 8‐week follow‐up visit were all within reference ranges except for alkaline phosphatase, which was 108 U/L (reference range: 35–104 U/L). The investigator and sponsor assessed the SAE of acute hepatitis B as not related to rimegepant. The case was assessed by an independent panel of hepatologists, while the DB treatment assignment was blinded, which concluded that the likelihood of drug‐induced liver injury due to rimegepant was unlikely.

TABLE 3.

Summary of liver function test elevations among rimegepant‐treated participants during the 52‐week OLE period.

	DB rimegepant, OLE rimegepant (n = 297)	DB placebo, OLE rimegepant (n = 296)	Total (N = 593)
ALT or AST
>ULN	60 (20.2)	69 (23.3)	129 (21.8)
>3× ULN	8 (2.7)	12 (4.1)	20 (3.4)
>5× ULN	2 (0.7)	6 (2.0)	8 (1.3)
>10× ULN	0	1 (0.3)	1 (0.2)
>20× ULN	0	0	0
TBIL
>ULN	9 (3.0)	8 (2.7)	17 (2.9)
>1.5× ULN	0	0	0
>2× ULN	0	0	0
ALT or AST >3× ULN concurrent a with TBIL >2× ULN	0	0	0
ALT or AST >3× ULN concurrent a with TBIL >2× ULN and ALP ≤2× ULN	0	0	0

Note: All participants treated with rimegepant during the OLE and having liver function test data during the OLE are included in the table. Participants are grouped according to whether they received rimegepant (DB rimegepant/OLE rimegepant) or placebo (DB placebo/OLE rimegepant) during the 12‐week DB period before receiving open‐label rimegepant during the 52‐week OLE. Data are n (%).

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DB, double‐blind; OLE, open‐label extension; TBIL, total bilirubin; ULN, upper limit of normal.

^a Same laboratory test collection date.

The only other participant to discontinue rimegepant due to elevated LFTs was a 53‐year‐old female with ALT and AST > 3× ULN during an AE of influenza of moderate intensity in the course of which the participant took acetaminophen and ibuprofen. The elevations were noted in the routine safety lab tests obtained at the week 20 visit. All LFTs were within normal range at an 8‐week follow‐up visit 23 days later. The investigator assessed the AE of hepatic enzyme increase as possibly related to rimegepant. An external liver panel assessed the case, while the DB treatment assignment was blinded, and concluded that the likelihood of drug‐induced liver injury due to rimegepant was possible.

AEs of special interest

Potential drug abuse AEs were reported in 24 (4.0%) participants. Most (n = 17, 2.8%) were mild in severity compared with moderate (n = 8, 1.3%) or severe (n = 1, 0.2%; drug abuse/verbatim term “cocaine use disorder” considered unrelated to rimegepant). The most common potential drug abuse AEs were depression (n = 5, 0.8%) and insomnia (n = 4, 0.7%).

One cardiovascular event was reported (myocardial infarction as an SAE) during the OLE, which led to rimegepant discontinuation. This participant, a 66‐year‐old female, was a former smoker with a history of hyperlipidemia and a family history (brother) of myocardial infarction and coronary artery disease. The participant was diagnosed with non‐ST elevation myocardial infarction (mild) and was discharged the day after admission. She received placebo during the DB period of the study and the SAE was considered by the investigator not related to rimegepant.

One suicide‐related AE was reported—suicidal ideation coincident with depressive delusion, which were classified as SAEs of moderate intensity—and led to rimegepant discontinuation. This participant, a 26‐year‐old female, was hospitalized for a week and responded well to treatment. Her S‐STS total scores were 0 at baseline and at all time points except her week 44 visit—the next assessment following hospitalization—at which her S‐STS total score was 2, before returning to 0 at her follow‐up visit. The participant had a history of alcoholism, cocaine abuse, and major depressive and bipolar II disorders that were not disclosed at screening.

Treatment effects

Efficacy

In the observation period (prior to starting DB treatment), the population of participants meeting criteria for inclusion in the exploratory efficacy analyses during the OLE (see Methods section for details) had a mean (SD) of 9.9 (3.05) days of MMDs of any pain severity, and 8.5 (3.25) days of moderate or severe MMDs (Table 1). In the OLE period, the overall mean (SD) decrease from the observation period in the number of MMDs of any pain severity was 6.2 (3.81) days per month, which supports that the treatment benefit of rimegepant is sustained and increases beyond the first 12 weeks of DB treatment (Figure S1A in supporting information). A similar effect was seen for moderate or severe MMDs, with an overall mean (SD) decrease of 5.7 (3.71) days per month from the observation period (Figure S1B). The percentages of participants who achieved ≥ 50%, ≥ 75%, and 100% reductions in MMDs over time during the OLE period are displayed by pain severity (any; moderate or severe) in Figure S2A,B, respectively.

In addition, there was a low use of rescue medication (including migraine‐specific rescue medication) on non‐scheduled dosing days during the OLE period (Tables S2 and S3 in supporting information).

It should be noted that these results include data from an uncontrolled open‐label period and caution should be applied when drawing conclusions about the therapeutic effects.

DISCUSSION

This OLE of a phase 2/3, randomized, DB, placebo‐controlled trial demonstrates a favorable safety profile for rimegepant 75 mg EOD for the preventive treatment of migraine, over the 52‐week treatment period. An additional rimegepant dose was allowed to treat breakthrough attacks occurring on non‐dosing days; therefore, these data also support the safety of PRN rimegepant in addition to the EOD preventive dosing regimen. Rimegepant safety was favorable and consistent with that seen in previous migraine studies with rimegepant 75 mg, including the DB period of this study. ¹² , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ The majority of AEs that occurred were of mild or moderate severity and no SAEs were considered related to rimegepant treatment. The dosing approach used in this study (EOD + PRN) is consistent with the expected clinical use. There were no signals suggestive of hepatotoxicity, cardiovascular risk, drug abuse potential, or suicidality during this extended treatment period. Furthermore, hepatic‐related AEs occurred with low frequency and fewer than 1% of participants discontinued rimegepant due to hepatic‐related AEs. No instances of medication‐overuse headache were reported during the OLE period. This is reassuring as participants could use rimegepant ad libitum, up to once daily during the OLE period. Laboratory parameter assessments during the OLE period indicated no clinically significant trends or signals. Importantly, this OLE had a high retention rate of participants either continuing or starting rimegepant, which adds support for the long‐term use of rimegepant for the preventive and acute treatment of migraine.

The emergence of CGRP‐targeted therapy for the treatment of migraine represents a notable advancement. Several monoclonal antibodies that target the CGRP pathway have been approved in the United States and Europe for the preventive treatment of migraine. ²⁰ , ²¹ , ²² , ²³ In addition, other small‐molecule CGRP receptor‐targeting therapies have been developed, including ubrogepant and zavegepant for acute treatment and atogepant for preventive treatment. ¹³ , ²⁴ , ²⁵ , ²⁶ Rimegepant is the only agent approved for both preventive and acute treatment of migraine. The dosing approach of EOD (preventive) and PRN (for acute treatment) using one agent offers a simple approach to migraine treatment with several potential advantages. Individuals with migraine may gain a tangible sense of control over their condition, being able to adjust their use of medication to meet their needs, considering the fluctuating nature of migraine attacks. This has potential implications for avoiding excess use of medications and reducing the use of additional health‐care resources. In the OLE period, approximately two thirds of participants took more than 14 tablets per month, with median exposure, at 14.4 tablets/month, close to a value consistent with EOD dosing. Participants were able to effectively manage their migraine through use of rimegepant EOD and PRN as demonstrated by the low use of rescue medications (including migraine‐specific rescue medication) during the OLE period (Tables S2 and S3).

Reported adherence and persistence to migraine medication is often variable and low, ²⁷ and may worsen over the course of 12 months. ²⁸ Even with newer agents, such as the injected CGRP receptor‐targeting monoclonal antibody erenumab, adherence is less than optimal (approximately 31%–42% at 6 months). ²⁹ In the DB period of this study, approximately 95% of participants were at least 80% compliant with rimegepant EOD dosing. Suboptimal adherence to treatment is also observed for preventive treatments, ⁵ and the current trial data suggest that adherence with preventive rimegepant may be higher.

The current phase 2/3 trial demonstrated high participation and retention rates. More than 80% of participants from the DB treatment period continued in the trial and either continued or initiated rimegepant treatment. Of these participants, > 70% completed the OLE and > 60% took rimegepant for at least 12 months.

This OLE study has several strengths, including a relatively large population, an extended period of treatment, and a demographically similar population to the DB study, which indicates limited participation bias. Limitations that should be considered when interpreting these data include the exclusion of participants with > 18 headache days during the observation period and the lack of an active comparator. While headache and migraine frequencies vary over time, this exclusion likely limited participation by people with daily or extremely frequent headaches. In addition, the cumulative proportion of participants who achieved and maintained a ≥ 50% reduction in MMDs may underestimate the sustained effectiveness of rimegepant treatment, as requiring an absolutely consistent response each month likely attenuated the proportions. These data are also based, in part, on an analysis set in which participants dropped out post randomization for a variety of reasons, potentially skewing the sample who entered the OLE period. Moreover, as the OLE lacked a comparator, differentiating between treatment and external events is challenging, and as the extension was open label, all participants were aware they were on active drug, potentially introducing bias into how they experienced and reported the frequency and severity of attacks. As described, efficacy endpoints were exploratory as the primary objective of the study was to assess long‐term safety. These limitations preclude making definitive conclusions regarding efficacy. Further studies are warranted to compare the safety and effectiveness of available treatments and define predictors of response to help guide clinical decision making.

CONCLUSIONS

The safety profile of EOD + PRN dosing of rimegepant 75 mg was favorable during long‐term treatment. The trial is also suggestive of sustained efficacy with rimegepant treatment. Rimegepant for the preventive treatment of migraine, as demonstrated in the DB period, does not indicate any evidence of a diminution of effect over 64 weeks of treatment. Overall, this OLE period supports a positive benefit/risk assessment for the use of rimegepant 75 mg up to once daily over a sustained period of treatment for the preventive and acute treatment of migraine.

AUTHOR CONTRIBUTIONS

David Kudrow: Investigation; writing – review and editing. Robert S. Croop: Conceptualization; investigation; methodology; project administration; supervision; writing – original draft; writing – review and editing. Alexandra Thiry: Data curation; formal analysis; methodology; writing – review and editing. Richard B. Lipton: Investigation; writing – review and editing.

CLINICAL TRIALS REGISTRATION NUMBER

NCT03732638.

FUNDING INFORMATION

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

CONFLICT OF INTEREST STATEMENT

David Kudrow declares advisory board fees from AbbVie; speaker's bureau fees from AbbVie; and has been an investigator on studies sponsored by Aeon, AbbVie, Biohaven Pharmaceuticals, Eli Lilly, Ipsen, and Pfizer. Robert S. Croop was an employee of Biohaven Pharmaceuticals and Pfizer; has received research payments from Pfizer; owns stock/options in Actio Biosciences, Inc. and Biohaven Ltd.; and provides services to Collima LLC, which has had consulting agreements with Actio Biosciences, Inc., Aptose Biosciences Inc., Biohaven Pharmaceuticals, Manistee Therapeutics, NVP Associates, LLC, Pfizer, Soleil Labs, LLC, and Vida Ventures Management Co., LLC. Alexandra Thiry was an employee of Biohaven Pharmaceuticals, owns stock in Biohaven Ltd., is an employee of Pfizer, and owns stock/options in Pfizer. Richard B. Lipton is on the editorial boards of: Neurology and Cephalalgia (not paid); is a senior advisor for: Headache (not paid); reports research support from: NIH, FDA, National Headache Foundation, Marx Foundation; research grants from: Allergan/AbbVie, Amgen, Novartis; Reviewer: NIA, NINDS; consultant/advisory board/honoraria from: Aeon, Allergan/AbbVie, Amgen, Biodelivery Sciences International, Biohaven Pharmaceuticals, CoolTech LLC, Dr. Reddy's Laboratories, electroCore, Eli Lilly, GlaxoSmithKline, Impel Neuropharma, Lundbeck Manistee, Merck, Novartis, Satsuma, Teva, Vedanta; royalties from Wolff's Headache (8th ed), Informa; and stock/stock options from: Axon, Biohaven Ltd., CoolTech, and Manistee.

Supporting information

Figure S1.

Figure S2.

Table S1.

Table S2.

Table S3.

DATA AVAILABILITY STATEMENT

All authors had access to the study data. 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. See https://www.pfizer.com/science/clinical‐trials/trial‐data‐and‐results for more information.