An analysis of ACHIEVE II suggests that the oral CGRP antagonist from Allergan provides significant pain freedom and relief of the most bothersome symptoms for adults with migraine for at least one dose assessed.
Richard B. Lipton, MD
Analysis of the ACHIEVE II clinical trial suggests that ubrogepant, an investigational therapy developed by Allergan for acute migraine treatment, may be able to provide pain freedom and freedom of the most bothersome symptoms for adults with migraine.
Compared to placebo, treatment with the oral calcitonin gene-related peptide (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).
In March, the FDA accepted a new drug application for the Allergan agent, with supporting data coming from this study as well as its predecessor, ACHIEVE I, and 2 additional safety studies. The review period was set at 10 months, with a Prescription Drug User Fee Act (PDUFA) action date in the fourth quarter of this year.
Led by Richard B. Lipton, MD, Edwin S. Lowe Professor and vice-chair of neurology, professor of epidemiology and population health, and professor of psychiatry and behavioral sciences, Albert Einstein College of Medicine, and director, Montefiore Headache Center, the phase 3 study included 1465 patients randomized to either ubrogepant 50 mg (n = 562), 25 mg (n = 561), or placebo (n = 563). The participants were 90% of women with a mean age of 41.5 years.
“The current results indicate that 50 mg of ubrogepant has the potential to address key treatment goals in the acute treatment of migraine,” Lipton and colleagues noted, pointing out that the widely used medications all carry their own challenges—triptans and ergotamine derivatives have cardiovascular contraindications, NSAIDs can cause serious gastrointestinal and cardiovascular effects, and opioids are currently not recommended for migraine treatment. “Ubrogepant’s mechanism of action may make it an option for people who do not respond to currently available medications.”
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).
Lipton and colleagues noted that the results of the sensitivity analysis, which imputed those who missed the 2-hour post-dose symptom assessment as nonresponders, confirmed the robustness of the primary analysis.
The secondary outcome of pain relief from 2 to 24 hours revealed responder rates that were significantly greater for the 50-mg group compared to the placebo group (OR, 2.16 [95% CI, 1.59—2.92]; adjusted P = .01), as well as for sustained pain freedom in that same time frame (OR, 1.85 [95% CI, 1.20—2.83]; adjusted P = .01). And while this tendency was held at 2 hours for the absence of photophobia (OR, 1.52 [95% CI, 1.14—2.02]; adjusted P = .02) and phonophobia (OR, 1.39 [95%CI, 1.05—1.84]; adjusted P = .04), this did not hold for the absence of nausea (OR, 1.12 [95% CI, 0.83–1.51]).
The safety population 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%]).
“The changes in neural function initiated by CGRP receptor antagonism in the setting of a migraine attack remain to be determined,” Lipton and colleagues detailed. “According to the results of this study, the full benefits of ubrogepant are not captured by the rates of pain freedom at the 2-hour time point, and similar effects have been reported for other acute treatments of migraine. Other measures of efficacy outcome measures, such as the rates of pain relief (63%) and normal function (41%%) at 2 hours, and the rate of rescue medication use (26%), should be considered when assessing the clinical benefit of 50 mg of ubrogepant.”
Lipton and colleagues also reported 3 limitations. First, that since ACHIEVE II was designed to assess adults with migraine of moderate to severe headache pain, these findings may not represent what would be seen in those who have mild pain intensity. Second, that the safety data is based on outcomes after a single attack and thus do not reflect what may occur after repeated use (though a long-term extension will assess this), and third that in a single-attack trial such as this, the consistency of ubrogepant’s ability to provide relief for recurrent attacks cannot be determined.
At the American Headache Society Annual Meeting, NeurologyLive spoke with study coauthor Jessica Ailani, MD, director, MedStar Georgetown Headache Center, and associate professor, neurology, MedStar Georgetown University Hospital, about ubrogepant’s long-term safety and efficacy. Watch her share her insight below.
Lipton RB, Dodick DW, Ailani J, et al. Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine The ACHIEVE II Randomized Clinical Trial. JAMA. 2019;322(19):1887-1898. doi:10.1001/jama.2019.16711.