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

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.

Bioequivalence of rimegepant, a small molecule CGRP receptor antagonist, administered as an oral tablet, a sublingual orally disintegrating tablet, and a supralingual orally disintegrating tablet: two phase 1 randomized studies in healthy adults.

BACKGROUND: Rimegepant is an orally administered small molecule calcitonin gene-related peptide receptor antagonist indicated for the acute and preventive treatment of migraine. METHODS: Two single-center, phase 1, open-label, randomized bioequivalence studies were conducted in healthy adult non-smokers, aged 18-55 years. One study compared the rate and extent of absorption of the marketed formulation of rimegepant 75 mg orally disintegrating tablet (ODT) administered sublingually with rimegepant 75 mg oral tablet, an earlier development formulation; the second compared the rate and extent of absorption of 75 mg rimegepant ODT administered supralingually with rimegepant oral tablet. RESULTS: The ln-transformed geometric mean ratios for the area under the curve (AUC) from time 0 to the last available concentration time point (time t) (AUC0-t), AUC from time 0 to infinity (AUC0-inf), and maximum observed concentration (Cmax) of sublingual rimegepant ODT vs. rimegepant tablet were 97, 97, and 105%, respectively, and the 90% confidence intervals (CIs) were all within the predefined range (80-125%) for bioequivalence. The ln-transformed geometric mean ratios for the AUC0-t and AUC0-inf of supralingual rimegepant ODT vs. rimegepant tablet were 98%, the 90% CIs were within the predefined range (80-125%), and the geometric mean ratio for Cmax was 103% with the 95% upper confidence bound for the scaled average bioequivalence criterion of -0.0575 (within-participant coefficient of variation for the reference for Cmax > 30%) for bioequivalence. CONCLUSIONS: Rimegepant 75 mg ODT, administered sublingually or supralingually, and rimegepant 75 mg oral tablet were bioequivalent.

Rimegepant orally disintegrating tablet 75 mg for acute treatment of migraine in adults from China: a subgroup analysis of a double-blind, randomized, placebo-controlled, phase 3 clinical trial.

BACKGROUND: Rimegepant orally disintegrating tablet (ODT), an oral small-molecule calcitonin gene-related peptide receptor antagonist, is indicated for acute and preventive treatment of migraine in the United States and other countries. Previously, a large clinical trial assessed the efficacy and safety of rimegepant ODT 75 mg for the acute treatment of migraine in adults living in China or South Korea. A post hoc subgroup analysis of this trial was performed to evaluate the efficacy and safety of rimegepant for acute treatment of migraine in adults living in China. METHODS: Eligible participants were ≥ 18 years of age and had a ≥ 1-year history of migraine, with 2 to 8 attacks of moderate or severe pain intensity per month and < 15 headache days per month during the 3 months before screening. Participants self-administered rimegepant ODT 75 mg or matching placebo to treat a single migraine attack of moderate or severe pain intensity. The co-primary endpoints were pain freedom and freedom from the most bothersome symptom (MBS) at 2 h post-dose. Key secondary endpoints included pain relief at 2 h post-dose, ability to function normally at 2 h post-dose, use of rescue medication within 24 h post-dose, and sustained pain freedom from 2 to 24 h and 2 to 48 h post-dose. All p values were nominal. Safety was assessed via treatment-emergent adverse events (TEAEs), electrocardiograms, vital signs, and routine laboratory tests. RESULTS: Overall, 1075 participants (rimegepant, n = 538; placebo, n = 537) were included in the subgroup analysis. Rimegepant was more effective than placebo for the co-primary endpoints of pain freedom (18.2% vs. 10.6%, p = 0.0004) and freedom from the MBS (48.0% vs. 31.8%, p <  0.0001), as well as all key secondary endpoints. The incidence of TEAEs was comparable between the rimegepant (15.2%) and placebo (16.4%) groups. No signal of drug-induced liver injury was observed, and no study drug-related serious TEAEs were reported in the rimegepant group. CONCLUSIONS: A single dose of rimegepant 75 mg rimegepant was effective for the acute treatment of migraine in adults living in China, with safety and tolerability similar to placebo. TRIAL REGISTRATION: Clinicaltrials.gov NCT04574362 Date registered: 2020-10-05.

A placebo-controlled, randomized, single and multiple dose study to evaluate the safety, tolerability, and pharmacokinetics of rimegepant in healthy participants.

BACKGROUND: Rimegepant is an oral, small molecule calcitonin gene-related peptide receptor antagonist for acute treatment of migraine and migraine prevention. METHODS: This was a single-site, placebo-controlled, sequential, single and multiple ascending dose study in healthy males and females, aged 18-55 years, with no clinically significant medical history. The objectives were to assess the safety, tolerability, and pharmacokinetics of the oral capsule free-base formulation. Single oral doses of rimegepant from 25-1500 mg were evaluated in the single ascending dose phase, and 75-600 mg/day doses administered for 14 days were evaluated in the multiple ascending dose phase. RESULTS: No dose-related trends were observed in orthostatic systolic and diastolic blood pressure or heart rate after rimegepant administration. Rimegepant was rapidly absorbed with the median time of maximum observed plasma concentration from 1-3.5 hours. Rimegepant showed a more than dose-proportional increase in exposure from 25-1500 mg following a single dose and from 75-600 mg/day following multiple doses. CONCLUSIONS: Rimegepant was safe and generally well tolerated at single oral doses up to 1500 mg and multiple doses up to 600 mg/day for 14 days in healthy participants in this study. Median terminal half-life ranged from 8-12 hours across the wide range of single doses studied.

Efficacy of rimegepant for the acute treatment of migraine based on triptan treatment experience: Pooled results from three phase 3 randomized clinical trials.

BACKGROUND: This post-hoc analysis from three phase 3 treatment trials of rimegepant 75 mg - an oral small molecule calcitonin gene-related peptide receptor antagonist for acute and preventive treatment of migraine - assessed efficacy in adults with migraine based on triptan treatment experience. METHODS: Participants were assigned to one of four groups based on triptan treatment experience: insufficient response (e.g. lack of efficacy and/or poor tolerability) to 1 triptan, insufficient response to ≥2 triptans, current triptan users, and triptan-naïve participants. The co-primary efficacy endpoints were pain freedom and most bothersome symptom freedom at two hours postdose. RESULTS: In the three trials (N = 3507; rimegepant n = 1749, placebo n = 1758), 1235 (35.2%) participants had a history of insufficient response to 1 triptan (n = 910 [25.9%]) or ≥2 triptans (n = 325 [9.3%]), and 2272 (64.8%) had no history of insufficient response to triptans (current use = 595 [17.0%], naïve = 1677 [47.8%]). Rimegepant was effective on the co-primary endpoints in all subgroups (p ≤ 0.013), except for freedom from the most bothersome symptom in the triptan-naïve group (p = 0.06). No differences on co-primary endpoints were found in pairwise comparisons of rimegepant-treated participants. CONCLUSIONS: Rimegepant was effective for the acute treatment of migraine in adults with a history of insufficient response to 1 or ≥2 triptans and in current triptan users. Efficacy on co-primary endpoints did not differ based on the number of insufficient triptan responses.Trial registration: Clinicaltrials.gov: NCT03235479, NCT03237845, NCT03461757.

Effects of rimegepant 75 mg daily on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate in healthy female participants.

OBJECTIVE: To assess the effect of single and multiple doses of rimegepant 75 mg dose on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol (EE)/norgestimate (NGM) in healthy females of childbearing potential or non-menopausal females with tubal ligation. BACKGROUND: Females of childbearing age experience the highest prevalence of migraine and frequently inquire about the concomitant use of anti-migraine medications and contraceptives. Rimegepant, a calcitonin gene-related peptide receptor antagonist, demonstrated efficacy and safety for treating an acute migraine attack and preventing migraine. METHODS: This open-label, single-center, phase 1, drug-drug interaction study explored the effects of rimegepant 75 mg daily dose on the pharmacokinetics of an oral contraceptive containing EE/NGM 0.035 mg/0.25 mg in healthy females of childbearing potential or non-menopausal females with tubal ligation. During cycles 1 and 2, participants received EE/NGM once daily for 21 days followed by placebo tablets with inactive ingredients for 7 days. Rimegepant was administered during only cycle 2 for 8 days, from days 12 through 19. The primary endpoint was the effect of single and multiple doses of rimegepant on the pharmacokinetics of EE and norelgestromin (NGMN), an active metabolite of NGM, at steady state, including area under the concentration-time curve for 1 dosing interval (AUC0-τ,ss ) and maximum observed concentration (Css[max] ). RESULTS: The study enrolled 25 participants, with pharmacokinetic data assessed for 20 participants. A single 75 mg dose of rimegepant co-administered with EE/NGM increased exposures of EE and NGMN by ≤16% (geometric mean ratio [GMR], 1.03; 90% confidence interval [CI], 1.01-1.06; and GMR, 1.16; 90% CI, 1.13-1.20, respectively). After 8 days of co-administering EE/NGM with rimegepant, EE pharmacokinetic parameters, AUC0-τ,ss and Css(max) , increased by 20% (GMR, 1.20; 90% CI, 1.16-1.25) and 34% (GMR, 1.34; 90% CI, 1.23-1.46), respectively, and NGMN pharmacokinetic parameters increased by 46% (GMR, 1.46; 90% CI, 1.39-1.52) and 40% (GMR, 1.40; 90% CI, 1.30-1.51), respectively. CONCLUSIONS: The study identified modest elevations in overall EE and NGMN exposures after multiple doses of rimegepant, but these elevations are unlikely to be clinically relevant in healthy females with migraine.

Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Rimegepant is a calcitonin gene-related peptide receptor antagonist that has shown efficacy and safety in the acute treatment of migraine. We aimed to compare the efficacy of rimegepant with placebo for preventive treatment of migraine. METHODS: We did a multicentre, phase 2/3, randomised, double-blind, placebo-controlled trial at 92 sites in the USA. Adults with at least a 1-year history of migraine were recruited. After a 4-week observation period, eligible participants were randomised using an interactive web response system to oral rimegepant 75 mg or matching placebo every other day for 12 weeks (double-blind treatment phase). The primary efficacy endpoint was change from the 4-week observation period in the mean number of migraine days per month in the last 4 weeks of the double-blind treatment phase (weeks 9-12). Participants who received at least one dose of their assigned study medication and who had 14 days or more of data in the observation period and 14 days or more of data for at least one 4-week interval during the double-blind treatment phase were analysed for efficacy. Those who received at least one dose of study medication were analysed for safety. This study is registered with ClinicalTrials.gov, NCT03732638. FINDINGS: Between Nov 14, 2018, and Aug 30, 2019, 1591 participants were recruited and assessed for eligibility, of whom 747 were randomly allocated either rimegepant (n=373) or placebo (n=374). 695 participants were included in the analysis for efficacy, of whom 348 were assigned rimegepant and 347 were allocated placebo. Rimegepant was superior to placebo on the primary endpoint of change in the mean number of migraine days per month during weeks 9-12. The change from the observation period in mean number of migraine days per month during weeks 9-12 was -4·3 days (95% CI -4·8 to -3·9) with rimegepant and -3·5 days (-4·0 to -3·0) with placebo (least squares mean difference -0·8 days, 95% CI -1·46 to -0·20; p=0·0099). 741 participants received study medication and were included in the safety analysis. 133 (36%) of 370 patients who received rimegepant reported an adverse event, compared with 133 (36%) of 371 who received placebo. Seven (2%) participants who received rimegepant and four (1%) who received placebo discontinued the study due to an adverse event; no patients died. INTERPRETATION: Taken every other day, rimegepant was effective for preventive treatment of migraine. Tolerability was similar to that of placebo, and no unexpected or serious safety issues were noted. FUNDING: Biohaven Pharmaceuticals.

Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine.

BACKGROUND: Calcitonin gene-related peptide receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin gene-related peptide receptor antagonist that may be effective in acute migraine treatment. METHODS: In a multicenter, double-blind, phase 3 trial, we randomly assigned adults with at least a 1-year history of migraine and two to eight migraine attacks of moderate or severe intensity per month to receive rimegepant orally at a dose of 75 mg or matching placebo for the treatment of a single migraine attack. The primary end points were freedom from pain and freedom from the most bothersome symptom (other than pain) identified by the patient, both of which were assessed 2 hours after the dose of rimegepant or placebo was administered. RESULTS: A total of 1186 patients were randomly assigned to receive rimegepant (594 patients) or placebo (592 patients); of these, 537 patients in the rimegepant group and 535 patients in the placebo group could be evaluated for efficacy. The overall mean age of the patients evaluated for efficacy was 40.6 years, and 88.7% were women. In a modified intention-to-treat analysis, the percentage of patients who were pain-free 2 hours after receiving the dose was 19.6% in the rimegepant group and 12.0% in the placebo group (absolute difference, 7.6 percentage points; 95% confidence interval [CI], 3.3 to 11.9; P<0.001). The percentage of patients who were free from their most bothersome symptom 2 hours after the dose was 37.6% in the rimegepant group and 25.2% in the placebo group (absolute difference, 12.4 percentage points; 95% CI, 6.9 to 17.9; P<0.001). The most common adverse events were nausea and urinary tract infection. CONCLUSIONS: Treatment of a migraine attack with the oral calcitonin gene-related peptide receptor antagonist rimegepant resulted in a higher percentage of patients who were free of pain and free from their most bothersome symptom than placebo. (Funded by Biohaven Pharmaceuticals; ClinicalTrials.gov number, NCT03237845.).

Zavegepant nasal spray for the acute treatment of migraine: A Phase 2/3 double-blind, randomized, placebo-controlled, dose-ranging trial.

OBJECTIVE: Evaluate the efficacy, safety, and tolerability of zavegepant nasal spray in the acute treatment of migraine. BACKGROUND: Calcitonin gene-related peptide-targeting agents are a novel class of therapeutics for migraine, but none are currently available as a nonoral option for acute treatment. Zavegepant, a high-affinity, selective, and structurally unique calcitonin gene-related peptide-receptor antagonist in late-stage development, is formulated as a nasal spray for the acute treatment of migraine. METHODS: This randomized, dose-ranging, placebo-controlled, Phase 2/3 trial in adults aged ≥18 years with migraine (NCT03872453) was conducted at US study sites. Participants were randomized by an interactive web response system and treated a single attack of moderate to severe pain intensity with zavegepant nasal spray 5, 10, 20 mg, or placebo. Coprimary efficacy endpoints were pain freedom and freedom from the most bothersome symptom at 2 h postdose. RESULTS: Of the 1673 participants aged 18 to 79 years who were randomized, 1588 were treated with study medication, and 1581 (mean age 40.8 years, 85.5% female) were analyzed for efficacy: zavegepant 5 mg (n = 387), 10 mg (n = 391), 20 mg (n = 402), and placebo (n = 401). Zavegepant 10 and 20 mg were more effective than placebo on the coprimary endpoints of pain freedom at 2 h postdose (placebo: 15.5% [98.3% confidence interval (CI), 11.1, 19.8]; 10 mg: 22.5% [98.3% CI, 17.5, 27.6; p = 0.0113]; 20 mg: 23.1% [98.3% CI, 18.1, 28.2; p = 0.0055]) and freedom from the most bothersome symptom at 2 h postdose (placebo: 33.7% [98.3% CI, 28.0, 39.3]; 10 mg: 41.9% [98.3% CI, 36.0, 47.9; p = 0.0155]; 20 mg: 42.5% [98.3% CI, 36.6, 48.4; p = 0.0094]). Findings for the 5 mg dose were not significant. The most common treatment-emergent adverse events with zavegepant 10 and 20 mg and placebo were dysgeusia (13.5% to 16.1% vs. 3.5%), nausea (2.7% to 4.1% vs. 0.5%), and nasal discomfort (1.3% to 5.2% vs. 0.2%). Most adverse events were mild or moderate and resolved without treatment. There was no signal of hepatotoxicity. CONCLUSION: Zavegepant nasal spray, in single doses of 10 or 20 mg, was effective for the acute treatment of migraine, with a favorable safety profile. Additional research is needed to confirm its potential as a nonoral medication for the acute treatment of migraine.

Matching-adjusted indirect comparisons of oral rimegepant versus placebo, erenumab, and galcanezumab examining monthly migraine days and health-related quality of life in the treatment of migraine.

OBJECTIVE: Rimegepant is an orally administered small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, with demonstrated efficacy in the acute treatment of migraine. Recent estimates from a single-arm trial (BHV3000-201) have also shown evidence of long-term preventive effects in monthly migraine days (MMDs) and health-related quality of life (HRQoL). This study aimed to compare MMDs and HRQoL data for oral rimegepant to those obtained in placebo-controlled trials for injectable anti-CGRP monoclonal antibodies (mAbs) galcanezumab and erenumab. METHODS: Matching-adjusted indirect comparisons (MAICs) were conducted using rimegepant subject-level data and published aggregate-level results from mAb trials. Rimegepant baseline characteristics were matched to the pooled subject characteristics from EVOLVE-I/II (galcanezumab vs. placebo; n = 1773) and STRIVE (ereumab vs. placebo; n = 955) by reweighting the rimegepant subjects to more closely match the distributions observed in these trials. To align with inclusion criteria of the mAb trials, only the subset of rimegepant subjects with a history of 4-14 MMDs were included (n = 257). Weighted mean differences were used to calculate adjusted change in MMDs, Migraine Disability Assessment Test (MIDAS) score, and Migraine-Specific Quality of Life Questionnaire version 2 (MSQv2) scores from baseline to week 12. RESULTS: When matched to the EVOLVE trials, rimegepant was superior to placebo with a mean difference in MMD change from baseline [95% confidence interval] of -1.16 [-1.80, -0.52] and was not statistically significantly different from galcanezumab 0.59 [-0.13, 1.32]. When matched to the STRIVE trial, rimegepant was superior to placebo -1.59 [-2.15, -1.03] and was not statistically significantly different from erenumab -0.06 [-0.61, 0.50]. Rimegepant showed superior MIDAS and MSQv2 results compared with placebo in both EVOLVE trials and in the STRIVE trial, no statistically significant differences from galcanezumab and erenumab regarding MIDAS, and favorable results compared with erenumab across all MSQv2 domains, while being generally similar to galcanezumab across all MSQv2 domains. CONCLUSIONS: When adjustments were made to reflect baseline characteristics in published literature, supporting data from BHV3000-201 suggest that rimegepant every other day is an effective therapy in reducing disability and MMDs and enhancing migraine-specific HRQoL. These data support the preventive benefit observed in randomized trials of rimegepant and further validate its efficacy for both acute and preventive treatment of migraine.

Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial.

BACKGROUND: Rimegepant, a small molecule calcitonin gene-related peptide receptor antagonist, has shown efficacy in the acute treatment of migraine using a standard tablet formulation. The objective of this trial was to compare the efficacy, safety, and tolerability of a novel orally disintegrating tablet formulation of rimegepant at 75 mg with placebo in the acute treatment of migraine. METHODS: In this double-blind, randomised, placebo-controlled, multicentre phase 3 trial, adults aged 18 years or older with history of migraine of at least 1 year were recruited to 69 study centres in the USA. Participants were randomly assigned to receive rimegepant (75 mg orally disintegrating tablet) or placebo and instructed to treat a single migraine attack of moderate or severe pain intensity. The randomisation was stratified by the use of prophylactic medication (yes or no), and was carried out using an interactive web response system that was accessed by each clinical site. All participants, investigators, and the sponsor were masked to treatment group assignment. The coprimary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 h postdose. The efficacy analyses used the modified intention-to-treat population, which included all patients who were randomly assigned, had a migraine attack with pain of moderate or severe intensity, took a dose of rimegepant or placebo, and had at least one efficacy assessment after administration of the dose. The safety analyses included all randomly assigned participants who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT03461757, and is closed to accrual. FINDINGS: Between Feb 27 and Aug 28, 2018, 1811 participants were recruited and assessed for eligibility. 1466 participants were randomly assigned to the rimegepant (n=732) or placebo (n=734) groups, of whom 1375 received treatment with rimegepant (n=682) or placebo (n=693), and 1351 were evaluated for efficacy (rimegepant n=669, placebo n=682). At 2 h postdose, rimegepant orally disintegrating tablet was superior to placebo for freedom from pain (21% vs 11%, p<0·0001; risk difference 10, 95% CI 6-14) and freedom from the most bothersome symptom (35% vs 27%, p=0·0009; risk difference 8, 95% CI 3-13). The most common adverse events were nausea (rimegepant n=11 [2%]; placebo n=3 [<1%]) and urinary tract infection (rimegepant n=10 [1%]; placebo n=4 [1%]). One participant in each treatment group had a transaminase concentration of more than 3â€ˆ× the upper limit of normal; neither was related to study medication, and no elevations in bilirubin greater than 2â€ˆ× the upper limit of normal were reported. Treated participants reported no serious adverse events. INTERPRETATION: In the acute treatment of migraine, a single 75 mg dose of rimegepant in an orally disintegrating tablet formulation was more effective than placebo. Tolerability was similar to placebo, with no safety concerns. FUNDING: Biohaven Pharmaceuticals.

Safety of Rimegepant, an Oral CGRP Receptor Antagonist, Plus CGRP Monoclonal Antibodies for Migraine.

OBJECTIVE: Evaluate the safety and tolerability of oral rimegepant when used for acute treatment concomitantly with a monoclonal antibody (mAb) targeting the calcitonin gene-related peptide (CGRP) ligand or receptor (CGRP mAb) for the preventive treatment of migraine. BACKGROUND: The efficacy of CGRP mAbs for the preventive treatment of migraine and the small molecule CGRP receptor antagonist rimegepant for acute treatment has been demonstrated in randomized controlled clinical trials. Over the past few years, the US Food and Drug Administration has approved 4 CGRP mAbs for the preventive treatment of migraine and 2 small molecule CGRP receptor antagonists for the acute treatment of migraine. A previous case report of 2 patients receiving concomitant treatment with rimegepant and erenumab suggested that rimegepant may be safely used as acute treatment in patients who are also receiving a preventive regimen involving CGRP mAbs. We report here 13 additional patients with migraine who simultaneously used rimegepant and either erenumab, fremanezumab, or galcanezumab and assess the rate of on-treatment adverse events (AEs). METHODS: This was a substudy nested within a multicenter, open-label, long-term safety study in adults with 2-14 monthly migraine attacks of moderate to severe pain intensity. A subgroup experiencing 2-8 monthly attacks and taking a stable dose of a CGRP mAb also took rimegepant 75 mg as needed up to once daily for acute treatment for 12 weeks. RESULTS: The 13 patients (11 women [85%]; mean age 49.9 years) enrolled in the substudy were being treated with CGRP mAbs (erenumab [n = 7], fremanezumab [n = 4], or galcanezumab [n = 2]). Mean (SD) time in the rimegepant treatment period was 9.6 (4.6) weeks. Mean (SD) 4-week rimegepant exposure was 7.8 (5.5) doses; a total of 224 doses were taken. Five (38%) patients reported ≥1 on-treatment AE. Of these, 2 (15%) patients had mild or moderate nasopharyngitis; no other AEs occurred in ≥2 patients. Three patients had AEs of mild or moderate severity that were considered potentially treatment-related. No patients had serious AEs, AEs leading to discontinuation, or aminotransferase levels >3× the upper limit of normal. CONCLUSION: Rimegepant, when used as an oral acute treatment in patients receiving CGRP mAbs as preventive treatment, was well tolerated; no safety issues were identified. Studies involving larger patient populations are needed to confirm these findings.

Safety of Rimegepant in Patients Using Preventive Migraine Medications: A Subgroup Analysis of a Long-Term, Open-Label Study Conducted in the United States.

Purpose: To evaluate the safety and tolerability of rimegepant 75 mg for the acute treatment of migraine in participants concurrently using a preventive migraine medication. Patients and Methods: This long-term, open-label safety study (NCT03266588) enrolled adults with a history of 2-14 moderate or severe migraine attacks per month. Participants self-administered rimegepant 75 mg (1) up to once daily as needed for 52 weeks to treat attacks of any pain intensity or (2) every other day plus as needed for 12 weeks. Preventive migraine medications were allowed if dosing was stable for ≥2 months prior to the baseline visit. Results: Of 1800 rimegepant-treated participants, 243 (13.5%) took a concomitant preventive medication. The most common preventive medication was topiramate (26.3%). Rimegepant exposure was comparable in both groups (mean [SD] number of doses per 4 weeks was 7.8 [4.5] in those taking preventives and 7.7 [4.7] in those not taking preventives). The proportion of participants experiencing ≥1 on-treatment adverse event (AE) was 68.7% among those using preventive medication and 59.2% among those not using preventives. Serious AEs occurred in 4.5% of those using preventive medication and 2.3% of those who were not using preventives. AEs leading to study drug discontinuation occurred in 4.5% of those taking preventive medication and 2.4% of those not taking preventives. AEs occurring in ≥5% of participants in either cohort (with preventives vs without preventives) were upper respiratory tract infection (7.4% vs 9.0%), nasopharyngitis (7.8% vs 6.6%), sinusitis (7.0% vs 4.8%), urinary tract infection (5.3% vs 3.6%), and back pain (5.3% vs 2.8%). Conclusion: Acute treatment of migraine with rimegepant 75 mg for up to 52 weeks was well tolerated and had a favorable safety profile in adults who were concomitantly using preventive migraine medication.

The Pharmacokinetics, Safety, and Tolerability of Rimegepant 75 mg Are Similar in Elderly and Nonelderly Adults: A Phase 1, Open-Label, Parallel-Group, Single-Dose Study.

Rimegepant is a small-molecule calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine ± aura and preventive treatment of migraine in adults. The pharmacokinetics of rimegepant in elderly and nonelderly subjects were evaluated. In an open-label Phase 1 study, 14 elderly (aged 65 years or older) and 14 nonelderly (aged 18 to less than 45 years) subjects each received a single oral dose of rimegepant 75 mg. Blood samples were collected before dosing and through 96 hours after dosing. The pharmacokinetic parameters of rimegepant after a single dose were similar in both age groups. Geometric least-squares mean ratios (elderly/nonelderly) of the natural log-transformed maximum observed plasma concentration and natural log-transformed area under the plasma concentration-time curve from time 0 extrapolated to infinity were 96.6 and 104.6, respectively. Eight (28.6%) subjects (4 elderly, 4 nonelderly) experienced 1 or more adverse events (AEs); all AEs were mild in intensity, and no serious AEs or AEs leading to discontinuation were reported. Following a single 75-mg dose of oral rimegepant, pharmacokinetic parameters were similar in elderly and nonelderly adults; no dose adjustment is warranted in elderly subjects.

A Drug-Drug Interaction Study to Evaluate the Impact of Rimegepant on OCT2- and MATE1-Mediated Transport of Metformin in Healthy Participants.

Rimegepant is a calcitonin gene-related peptide receptor antagonist approved for migraine treatment. This phase 1, open-label, single-center, fixed-sequence study evaluated the effect of rimegepant on the pharmacokinetics (PK) of metformin. Twenty-eight healthy participants received metformin 500 mg twice daily from Days 1 to 4 and Days 7 to 10, and once daily on Days 5 and 11. Rimegepant, 75 mg tablet, was administered once daily from Days 9 to 12. At pre-specified time points, plasma metformin concentration, serum glucose levels, and safety and tolerability were evaluated. A 16% increase in the area under the plasma metformin concentration-time curve (AUC) for 1 dosing interval (AUC0-τ,ss), a statistically insignificant increase in maximum and minimum steady-state metformin concentration (Cmax,ss and Cmin,ss), and a decrease in metformin renal clearance were observed on Day 11 following metformin-rimegepant coadministration compared with metformin alone; however, the changes were not clinically relevant. Additionally, coadministration of rimegepant with metformin did not induce clinically meaningful change in the maximum observed glucose concentration (Gmax) or AUCgluc compared with metformin alone. Overall, rimegepant and metformin coadministration did not result in clinically relevant changes in metformin PK, renal clearance, or the antihyperglycemic effects of metformin. Rimegepant is considered safe for use with metformin.

Concentration-QTc and cardiac safety analysis of single and multiple zavegepant nasal spray doses in healthy participants to support approval.

Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in adults. The cardiovascular safety of zavegepant nasal spray was assessed in both single-ascending dose (SAD) and multiple-ascending dose (MAD) studies in healthy participants. The SAD study included 72 participants (54 active/18 placebo) who received 0.1-40 mg zavegepant or placebo. The MAD study included 72 participants (56 active/16 placebo) who received 5-40 mg zavegepant or placebo for 1-14 days. Plasma zavegepant pharmacokinetics and electrocardiographic (ECG) parameters (Fridericia-corrected QT interval [QTcF], heart rate, PR interval, ventricular depolarization [QRS], T-wave morphology, and U-wave presence) were analyzed pre- and post-zavegepant administration. Using pooled data from the SAD and MAD studies, the relationship between time-matched plasma zavegepant concentrations and QTc interval was assessed using a linear mixed-effects model to evaluate the potential for QTc interval prolongation. Results showed that single and multiple doses of zavegepant had no significant impact on ECG parameters versus placebo, and there was no concentration-dependent effect on QTcF interval. The estimated slope of the plasma zavegepant concentration-QTcF model was -0.053 ms per ng/mL with a 90% confidence interval of -0.0955 to -0.0110 (p = 0.0415), which is not considered clinically meaningful. At doses up to four times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.

No clinically relevant electrocardiogram effects in a randomized TQT study of single therapeutic/supratherapeutic rimegepant doses in healthy adults.

A single-center, phase I, partially double-blind (double-blind regarding doses of rimegepant and placebo, and open label with respect to moxifloxacin), randomized, 12-sequence, four-period crossover study of therapeutic (75 mg) and supratherapeutic (300 mg) doses of rimegepant with placebo and moxifloxacin (400 mg) controls was designed to evaluate drug effect on the Fridericia corrected QT (QTcF) interval in healthy fasted adults. A total of 38 participants were randomized and dosed in the study. Electrocardiogram (ECG) data were available from 37 participants in the rimegepant 75-mg group, 38 participants in the rimegepant 300-mg group, and 36 participants in the moxifloxacin and placebo groups. Both the 75- and 300-mg doses of rimegepant had no clinically relevant effect on ECG parameters, including QTcF, heart rate, PR and QRS interval, T-wave morphology, and U-wave presence. All upper 90% confidence intervals for the QTcF effect with rimegepant were less than or equal to 4.69 ms, well below the 10-ms threshold for potential clinical significance. Assay sensitivity was demonstrated by the QT effect of moxifloxacin. Using both by-timepoint and concentration-QTc analysis, a placebo-corrected change-from-baseline QTcF greater than 10 ms could be excluded for rimegepant plasma concentrations up to ~10,000 ng/mL, representing concentrations at least 10.8-fold the maximum observed concentration of the 75-mg therapeutic dose of rimegepant.

A contrast in safety, pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the γ-secretase inhibitor avagacestat.

AIM: To evaluate the single dose pharmacokinetics, pharmacodynamics, and preliminary tolerability of the γ-secretase inhibitor BMS-708163 (avagacestat) in young and elderly men and women. METHODS: All subjects received double-blinded administration of a single 50 mg dose of avagacestat in capsule form or matching placebo. Main evaluations included pharmacokinetics, safety, plasma amyloid-ß (Aß)(1-40) concentratios and exploration of Notch biomarkers. RESULTS: Avagacestat 50 mg capsule was well tolerated and rapidly absorbed among young and elderly subjects, with a median t(max) between 1 and 2 h post dose and an average half-life between 41 and 71 h. In general, subjects aged 75 years or more had higher AUC(0,∞) values than those aged less than 75 years. An exploratory analysis of Aß(1-40) serum concentrations showed a pattern of decreasing concentrations over the first 4-6 h followed by a rise above baseline that was maintained until the end of the assessment period. Adverse events were generally mild, occurring more frequently in elderly subjects, with no observed difference between subjects receiving avagacestat and placebo. No dose limiting gastrointestinal effects of avagacestat were observed and exploratory biomarkers of Notch inhibition did not change significantly. CONCLUSIONS: The favourable safety profile and pharmacokinetic effects of avagacestat in this study support its continued development, especially in the target population of elderly subjects with mild cognitive impairment or Alzheimer's disease.