Orally disintegrating rimegepant increased freedom from pain and from most bothersome symptom at 2 h in acute migraine

Abstract

Question In patients with acute migraine, what are the efficacy and safety of an orally disintegrating tablet (ODT) of rimegepant? Methods Design Randomized placebo-controlled trial. ClinicalTrials.gov NCT03461757. Allocation Concealed.* Blinding Blinded* {patients, clinicians, data collectors, data analysts, and sponsor}. Follow-up period Up to 7 days after treatment. Setting 69 clinical centers in the USA. Patients 1466 adults (mean age 40 y, 85% women) who had a history of migraine with or without aura for 1 year, with onset at <50 years of age, 2 to 8 moderate- or severe-intensity episodes per month, and <15 d/mo with migraine or nonmigraine headache in the past 3 months; could distinguish migraine attacks from tension-type and cluster headaches; and, if taking preventive migraine medication, were on a stable dose for 3 months. Exclusion criteria included alcohol or drug abuse in the past 12 months or medical conditions that might expose patients to undue risk for serious adverse events or interfere with study assessments. Intervention 1 sublingual ODT of rimegepant, 75 mg (n =732), or placebo (n =734) taken for a moderate to severe migraine within 45 days of randomization. Outcomes Primary outcomes were freedom from pain and freedom from the most bothersome symptom (phonophobia, photophobia, or nausea) at 2 hours. Secondary outcomes included ability to function normally at 2 hours, sustained freedom from pain and sustained freedom from the most bothersome migraine symptom between 2 and 48 hours, and adverse events and serious adverse events at up to 7 days. Patient follow-up 92% (intention-to-treat analysis). Main results Efficacy results are in the Table. Groups did not differ for adverse events; no serious adverse events were reported. Conclusion In patients with migraine, acute treatment with an orally disintegrating tablet of rimegepant increased the likelihood of freedom from pain and from the most bothersome symptom at 2 hours. Orally disintegrating tablet of rimegepant vs placebo in patients with acute migraine Outcomes Event rates RBI (95% CI) NNT (CI) Rimegepant Placebo At 2 h Freedom from pain 21% 11% 96% (51 to 154) 10 (7 to 16) Freedom from most bothersome symptom 35% 27% 31% (11 to 54) 13 (8 to 30) Ability to function normally 38% 26% 48% (26 to 73) 9 (6 to 14) At 2 to 48 h Sustained freedom from pain 14% 5.4% 148% (72 to 258) 13 (9 to 21) Sustained freedom from most bothersome symptom 23% 16% 41% (14 to 76) 15 (10 to 40) Abbreviations defined in Glossary. RBI, NNT, and CI calculated from event rates in article. Commentary Triptans are widely used as the prototypical acute migraine therapy because they are effective, generic forms are available, and they can be prescribed in different doses. However, >40% of patients using triptans for migraine do not have an adequate response and many develop recurrent or medication-overuse headache (1). Small-molecule calcitonin gene-related peptide (CGRP) inhibitors, known as gepants, have been studied for acute migraine treatment for more than a decade. A phase 2 dose-finding trial found that rimegepant, a small-molecule CGRP inhibitor, increased the likelihood of freedom from pain at 2 hours compared with placebo and did not differ from oral sumatriptan (2). The methodologically identical phase 3 trials by Croop and Lipton and their respective colleagues show modest improvements in pain relief with rimegepant, 75 mg, compared with placebo. The efficacy of rimegepant in the 2 trials was lower than expected, with absolute risk differences of 10.4% and 7.6% in freedom from pain at 2 hours compared with placebo. This is lower than the risk difference of 16% with rimegepant and 20% with sumatriptan in the phase 2 trial (2) and lower than the estimated 19% risk difference with sumatriptan in a meta-analysis of much earlier migraine trials (1). Rimegepant did not increase risk for adverse events in the phase 3 trials, whereas previous studies showed that sumatriptan did increase risk for adverse events (1). Nausea, although rare, was the only notable increased side effect in the trial by Croop and colleagues (2% vs <1%) but was not increased in the trial by Lipton and colleagues. Small-molecule CGRP inhibitors, such as rimegepant, may benefit patients for whom triptans are ineffective or intolerable, as well as those concerned about side effects. Patients who cannot take triptans due to concerns about cardiovascular safety may be able to use CGRP inhibitors. Although there is some concern about potential inhibition of vasodilation with CGRP inhibition, this was not shown in these trials or previous trials with the 3 CGRP-inhibiting monoclonal antibodies approved by the US Food and Drug Administration for migraine prevention (3). Further assessment with longer and more frequent use of rimegepant is warranted given the hepatotoxicity seen with other small-molecule CGRP inhibitors and the theoretical and vascular adverse effects seen in animal models (3). CGRP small-molecule inhibitors like rimegepant will probably add to the expanding migraine acute treatment landscape for selected migraine patients.