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The oral CGRP antagonist becomes the first in its class approved for the indication.
The US Food and Drug Administration (FDA) has approved ubrogepant (Ubrelvy) for the acute treatment of migraine with or without aura in adults, making it the first-in-class oral calcitonin gene-related peptide (CGRP) antagonist for this indication.
The new drug application (NDA) from Allergan was supported by data from a pair of pivotal studies—ACHIEVE I and II—as well as 2 additional safety studies showing that both doses were effective, with patients reporting significant rates of pain freedom and freedom from most bothersome symptoms at 2 hours post-dose.
It is contraindicated for co-administration with strong CYP3A4 inhibitors.
Billy Dunn, MD, acting director of the Office of Neuroscience at the FDA’s Center for Drug Evaluation and Research, said the organization is pleased to approve a novel migraine treatment.
“Migraine is an often-disabling condition that affects an estimated 37 million people in the US,” Dunn said in a statement. “Ubrelvy represents an important new option for the acute treatment of migraine in adults, as it is the first drug in its class approved for this indication.”
ACHIEVE I was a multicenter, double-blind, placebo-controlled study (NCT02828020) that included 1672 patients with migraine, randomly assigned 1:1:1 to either a 50 mg ubrogepant (n = 556), 100 mg ubrogepant (n = 557), or placebo (n = 559). Ultimately, the modified intention-to-treat population included 1436 participants.
Among the 3 dose groups, 19.2% of patients in the 50 mg ubrogepant group (P = .002, adjusted for multiplicity, for comparison with placebo), 21.2% of patients in the 100 mg ubrogepant group (P <.0001) and 11.8% of patients in the placebo group experienced freedom from pain at 2 hours after the initial dose.
At 2 hours, 38.6%, 37.7% and 27.8% of patients in the 50 mg, 100 mg, and placebo groups had freedom from the most bothersome symptom respectively.
At 48 hours post initial dose in ACHIEVE I, 12.9% of participants (n = 185) reported an AE. Within 30 days of any dose, the number of patients who reported an AE rose to 26.3% (n = 378). Among patients treated with 100 mg, 28.7% reported an AE, most of the 3 groups.
The most common adverse events during the trial were nausea (n = 44), somnolence (n = 20), and dry mouth (n = 16). In total, 5 patients across the 3 groups experienced a serious adverse event, though none were recorded within 48 hours after the first dose.
C. David Nicholson, PhD, Chief Research and Development Officer, Allergan, said in a statement that the oral administration at 2 doses "allows for treatment flexibility and relief when a migraine attack occurs. As we continue to drive innovation in migraine treatment, we are very proud to offer patients another option, and we are confident that it will make a difference for those in need. At Allergan, we believe that migraine patients deserve access to all new medications for this debilitating disease."4
ACHIEVE II showed that compared to placebo, treatment with the oral CGRP antagonist resulted in significant rates of pain freedom at 2 hours for both doses assessed (50 mg, P = .01; 25 mg, P = .03) as well as significant rates of freedom from the most bothersome symptom with the higher dose (50 mg, P = .01). the phase 3 study included 1465 patients randomized to either ubrogepant 50 mg (n = 562), 25 mg (n = 561), or placebo (n = 563).5
At 2 hours post-dose, pain-freedom was reported by 21.8% (101 of 464 patients; odds ratio [OR], 1.62 [95% CI, 1.14—2.29) of those in the 50-mg group, 20.7% (90 of 435; OR, 1.56 [95% CI, 1.09–2.22) in the 25-mg group, compared to only 14.3% (65 of 456) in the placebo group. The absolute difference between the 25-mg group and placebo was 6.4% (95% CI, 1.5–11.5) and between the 50-mg group and placebo was 7.5% (95% CI, 2.6–12.5).
Likewise, at 2 hours post-dose, the absence of the most bothersome symptoms—photophobia, phonophobia, and nausea—was reported by 38.9% (180 of 463; OR, 1.65 [95% CI, 1.25—2.20]) of the 50-mg group for an absolute difference from placebo of 11.5% (95% CI, 5.4–17.5). For the 25-mg group, absence of the symptom was reported by 34.1% (148 of 434; OR, 1.37 [95% CI, 1.02–1.83), for an absolute difference of 6.7% (95% CI, 0.6–12.7; P = .07).
The safety population of ACHIEVE II included 488 patients who took ≥1 dose of 50-mg ubrogepant, 478 who took ≥1 dose of 25-mg ubrogepant, and 499 who took ≥1 dose of placebo. In total, Treatment-emergent AEs were reported within 48 hours of the initial or optional second dose by 12.9% (63 of 488) of the 50-mg group, 9.2% (44 of 478) of the 25-mg group, and 10.2% (51 of 499) of the placebo group.
The most common adverse events within 2 days of any dose were nausea (50mg: 10 of 488 [2.0%]; 25mg: 12 of 478 [2.5%]; placebo: 10 of 499 [2.0%]) and dizziness (50mg: 7 of 488 [1.4%]; 25mg: 10 of 478 [2.1%]; placebo: 8 of 499 [1.6%]).