Rimegepant orally disintegrating tablets in the acute treatment of migraine: a profile of their use

DOI: https://doi.org/10.1007/s40267-020-00790-2

Abstract-Summary A single sublingual dose of rimegepant ODT 75 mg provided freedom from pain, freedom from the most bothersome migraine symptoms (e.g., nausea, phonophobia, photophobia), and freedom from functional disability at 2-h post dose relative to placebo in adults with a migraine attack with pain of moderate or severe intensity ± aura.

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Beneficial effects on migraine were provided as early as 1-h post dose, and were sustained for 2–48 h. Rimegepant ODT was well tolerated, with a tolerability profile similar to that of placebo, with no reports of serious, cardiovascular, or hepatic adverse events in patients with migraine.

What is the Rationale for Developing Rimegepant ODT to Treat Migraine? Although a number of migraine-specific medications (triptans and dihydroergota- mine) and non-specific medications (e.g. NSAIDs, non-opioid and opioid analge- sics, and antiemetics) are available for the acute treatment of migraine [52], many of these options are limited by inadequate efficacy, poor tolerability, and a lack of patient adherence to their recommended use [35].

In the case of triptans, which have been the mainstay of acute treatment of migraine since the early 1990s [35], around one-third of migraine patients do not respond adequately to treatment [53].

The recent approval of calcitonin gene-related peptide (CGRP)-related monoclo- nal antibodies (mAbs) for the preventive treatment of migraine has rekindled inter- est in small-molecule CGRP receptor antagonists (also known as gepants) for the acute and preventive treatment of migraine [54].

First-generation gepants have shown effectiveness in aborting migraine attacks, with no CV or hemodynamic symptoms, but concerns of liver toxicity with their long-term use had led to a loss of momentum in their development [35].

For Whom is Rimegepant ODT Indicated? Rimegepant ODT is approved in the USA for the acute treatment of migraine ± aura in adults, and is not indicated for the preventive treatment of migraine [55].

The safety of treating ≥15 migraine attacks with rimegepant ODT in a 30-day

period has not been established [55].

What Are the Pharmacodynamic Properties of Rimegepant? Rimegepant is a CGRP receptor antagonist [55].

In phase 1 studies, rimegepant displayed durable efficacy against a strong CGRP stimulus, and antagonized CGRP-induced increases in facial blood flow (a surro- gate marker for intracranial artery dilation) [56, 57].

In a primate study, exposure to high concentrations of rimegepant (>10 × higher than that in humans at the recommended dose of 75 mg) had no effect on hemody- namic or electrocardiographic parameters [58]; in addition, there were no changes in CV parameters after 9 months of rimegepant 50 mg/kg daily (≈20 × the human therapeutic dose) [58].

In healthy volunteers, rimegepant + sumatriptan (two 6-mg subcutaneous injec- tions taken 1 h apart) did not cause clinically relevant differences in resting blood pressure relative to sumatriptan alone [55, 59].

What Is the Pharmacokinetic Profile of Rimegant ODT? Rimegepant ODT had a time to peak concentration (tmax) of 1.5 h and a bioavail- ability of ≈64% in healthy fasting adults [55].

Although a high-fat meal can delay the tmax of rimegepant ODT by 1 h, reduce the maximum rimegepant concentration) by 42–52%, and reduce the area under the

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concentration-time curve by 32–38%, the clinical impact of reduced rimegepant exposure from food administration is unknown.

Rimegepant has a steady state volume of distribution of 120 L and a plasma pro-

tein binding rate of ≈96% [55].

Rimegepant has an elimination half life of ≈11 h [55].

What Is the Efficacy of Rimegepant ODT in Treating Migraine? The efficacy of rimegepant in the acute treatment of migraine was initially shown in a phase 2 dose-finding trial, in which single doses of rimegepant 75 mg, as well as higher doses of 150 mg and 300 mg, were superior to placebo with regard to the proportion of pain-free patients at 2-h post dose [60].

After receiving appropriate training, patients were sent home with instructions to treat a single migraine attack of moderate or severe pain intensity with a single dose of study medication (rimegepant ODT 75  mg or matching placebo) sublingually after answering electronic diary (eDiary) questions regarding pain and symptoms (including MBS, from among the migraine-associated symptoms of nausea, phono- phobia and photophobia) [44].

In a pooled subgroup analysis of the three phase 3 trials (n = 3507), rimegepant was significantly (p < 0.0001) more effective than placebo with regard to freedom from pain, freedom from MBS, and pain relief at 2-h post dose in patients who had discontinued at least one triptan, a well as those who were current triptan users [61].

What is the Tolerability Profile of Rimegepant ODT? The most common AEs (reported by ≥1% of patients in either treatment group) were nausea (2% of rimegepant ODT recipients vs <1% of placebo recipients), urinary tract infection (1% vs 1%), and dizziness (1% vs 1%).

In rimegepant recipients, nausea and urinary tract infection were the most com- mon AEs (≤1.5% of patients), and there were no serious treatment-related AEs, liver safety concerns [62], or treatment-emergent CV-related AEs [58].

There were no signs of hepatotoxicity, even in a subgroup of 279 patients who received rimegepant 75 mg every other day supplemented with as-needed adminis- tration on nonscheduled administration days; there were no reports of AST or ALT levels > 3 × the ULN or bilirubin levels > 2 × the ULN during treatment [63].

In a subgroup of 13 patients taking a stable dose of an anti-CGRP mAb for the preventive treatment of migraine, there were no reports of serious AEs, or ALT or AST levels > 3 × the ULN [64].

What Is the Current Clinical Position of Rimegepant ODT? According to the American Headache Society (AHS), patients who have contraindi- cations to the use of triptans or who have failed to respond to or tolerate at least two oral triptans, are eligible for emerging acute treatments, such as rimegepant ODT [52].

Rimegepant is effective for the acute treatment of migraine irrespective of past or current triptan use [61], possibly owing to their different mechanisms of action [65]. Rimegepant ODT is one of two gepants [55, 66] available for the acute treatment

of migraine ± aura in adults in the USA.

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Larger studies of the concomitant use of an oral small-molecular CGRP receptor antagonist, such as rimegepant, in patients receiving an injectable anti-CGRP mAb would also be of interest [64].

Acknowledgement A machine generated summary based on the work of Kim, Esther S.; Lyseng- Williamson, Katherine A. 2020 in Drugs & Therapy Perspectives.

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