Rimegepant significantly reduced pain and the most bothersome symptom while showing an "excellent" safety profile for patients with acute migraine attacks.
Richard B. Lipton, MD
The CGRP antagonist rimegepant significantly reduced pain and the most bothersome symptom (MBS) while showing an "excellent" safety profile for patients with acute migraine attacks, according to findings from a phase III study presented at the 2018 American Headache Society annual meeting.
At 2 hours’ post-dose, 19.6% of patients were free of pain in the rimegepant arm compared with 12% in the placebo group, representing a superior reduction in pain (P = .0006). Additionally, 37.6% of patients treated with rimegepant were free of their MBS, which was usually photophobia, compared with 25.2% with placebo (P <.0001). The rates of liver toxicity were similar between arms (2.4% with rimegepant vs 2.2% for placebo).
"There was a broad and clinically important drug benefit with a single-dose of rimegepant. A majority of patients achieved pain relief, and the benefit was durable with lower use of rescue meds," said lead investigator Richard B. Lipton, MD, Department of Neurology, Albert Einstein College of Medicine. "Rimegepant had an excellent safety profile, similar to placebo, including liver function tests. Tolerability profile was similar to placebo and favorable compared to historical triptan experience."
Rimegepant is an oral antagonist of the CGRP receptor, which is thought to play a role in migraine pathophysiology. The recent approval of monoclonal antibodies against CGRP along with research in small molecule inhibitors, like rimegepant, represents an advance over the triptans, widely used agonists for the 5-HT1B/1D serotonin receptor. Although effective, triptans do not work for a third of patients and there are often recurrences. Moreover, they are contraindicated in some individuals, said Lipton.
"Perhaps a third of people with migraine don't respond to triptans, 30% to 40% have recurrent attacks, and according to our estimate 3.5 million people have absolute or relative contraindications for triptans among the 40 million people who get migraines," Lipton said. "Clearly there are unmet needs, and the hope is that 'gepants' will address some of those needs."
The phase III study randomized 1072 patients to receive rimegepant at 75 mg (n = 537) or matched placebo (n = 535) taken at the time of attack. Patient characteristics were matched across arms, with an average age of 40.6 years. A majority of participants were female (88.7%) and the mean number of attacks per month was 4.6. Those with chronic migraines (>15) were excluded from the study. The most common MBS was photophobia (57.7%).
At 2 hours 37.4% of patients were photophobia-free with rimegepant compared with 22.3% with placebo (P <.0001). A similar portion of patients were phonophobia-free (36.7% vs 26.8%; P = .0039). Pain relief at 2 hours was achieved for 58.1% of patients with rimegepant compared with 26.8% for placebo (P <.0001). Nearly half of patients were nausea-free with rimegepant (48.1%) compared with 43.3% with placebo (P = .2084).
Rescue medication was required for 21% of patients in the rimegepant arm compared with 37% for placebo, representing a significant difference (P <.0001). The duration of pain relief was sustained for 2 to 48 hours for 36.3% of patients in the rimegepant group and for 22.6% in the placebo group (P <.0001). Pain relapsed between hour 2 and 48 for nearly half of patients in both groups (49.6% vs 50%; P = .9648).
There was an increasing benefit seen with rimegepant over placebo between hours 2 and 8 post treatment. At 2 hours, there was an 8% difference between the two arms. By hour 8, this improvement had doubled to 16% (48% vs 32%). "A greater proportion of subjects achieving pain relief and normal function without additional dosing or rescue medications," Lipton added.
An adverse event (AE) of any cause or severity was experienced by 17.1% of patients in the rimegepant arm compared with 14.2% with placebo. The most common events reported by 1% or more of patients for rimegepant and placebo, respectively, were nausea (1.8% vs 1.1%) and urinary tract infection (1.5% vs 1.1%). Of these AEs, 1.8% were deemed related to treatment in the rimegepant arm compared with 0.6% in the placebo group.
One patient had serious back pain in the rimegepant arm, which was deemed unrelated to treatment. Two patients had serious AEs in the placebo group. No patients discontinued treatment due to AEs.
Serum levels of the liver enzymes AST and ALT were above the upper limit of normal (ULN) for 2.4% of patients in the rimegepant group and for 2.2% in the placebo arm. No patients had an increase in these enzymes of over 3 times the ULN and no patients had an increase in bilirubin was elevated by more than 2 times the ULN.
"Most of the patients I see with migraine are actively working and raising children, and relieving pain and restoring function means they can once again take care of their families and return to work," Lipton said. "The new data reviewed today encourages me that rimegepant, if approved, can meet their needs for an acute treatment with lasting clinical benefit.”
Biohaven Pharmaceuticals, the developer of rimegepant, announced that it planned to submit a new drug application to the FDA in early 2019.
Lipton RB, Coric V, Stock EG, et al. Efficacy, Safety, and Tolerability of Rimegepant 75 mg, an Oral CGRP Receptor Antagonist, for the Acute Treatment of Migraine: Results from a Double-Blind, Randomized, Placebo-Controlled Trial, Study 302. Presented at: 2018 American Headache Society annual meeting; June 27 - July 1, 2018. San Francisco, CA. Abstract IOR-02LB.