AbbVie Submits Marketing Authorization Application to EMA for Atogepant for the Preventive Treatment of Migraine

AbbVie (NYSE: ABBV) today announced it has submitted a marketing authorization application (MAA) to the European Medicines Agency (EMA) for atogepant for the prophylaxis of migraine in adult patients who have at least four migraine days per month. The application is supported by the pivotal Phase 3 ADVANCE and PROGRESS studies evaluating the safety, efficacy, and tolerability of atogepant in adult patients with episodic migraine and chronic migraine, respectively.[i],[ii]  

Migraine is a complex neurological disease and one of the leading causes of disability worldwide.[iii] It is highly prevalent, affecting more than 1 billion people worldwide,3 including an estimated 11.4 percent of the population in Europe.[iv] If approved, atogepant would be the first daily oral CGRP receptor antagonist for the prophylaxis of migraine for adult patients in Europe.

Far too many people around the world are impacted from the debilitating challenges of migraine, which places a significant social and work-life burden for patients and care partners,” said Michael Gold, M.D., therapeutic area head, neuroscience development, AbbVie. “At AbbVie, we are committed to advancing science to provide patients impacted by migraine with effective treatment options. If approved, atogepant will provide a prophylactic treatment option for adult migraine patients suffering for more than four days a month.”

The pivotal, Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group ADVANCE trial evaluated the efficacy, safety, and tolerability of once daily (QD) oral atogepant for the prophylaxis of episodic migraine. The study met its primary endpoint of a statistically significant reduction in mean monthly migraine days across the 12-week treatment period compared to placebo. This was found across all active treatment arms of atogepant – 10 mg, 30 mg, and 60 mg QD doses. The adult patients enrolled met the International Classification of Headache Disorders (ICHD) criteria for a diagnosis of migraine with or without aura. The study also found that a greater proportion of atogepant-treated participants achieved at least a 50% reduction in mean monthly migraine days for all doses compared to placebo and met other key secondary endpoints.

The pivotal, Phase 3, global, randomized, double-blind, placebo-controlled, parallel-group PROGRESS study, evaluating the safety, efficacy, and tolerability of oral atogepant in adult patients for the prophylaxis of chronic migraine, met its primary endpoint of statistically significant reduction from baseline in mean monthly migraine days compared to placebo across the 12-week treatment period. The trial also demonstrated that treatment with atogepant 60 mg once daily (QD) and 30 mg daily (BID), resulted in statistically significant improvements in all secondary endpoints. This includes a key secondary endpoint that measured the proportion of patients that achieved at least a 50 percent reduction in mean monthly migraine days across the 12-week treatment period.

In both, the Phase 3 PROGRESS and Phase 3 ADVANCE studies, all doses were well tolerated, and the overall safety profiles were consistent with safety findings observed in previous studies for the prophylaxis of episodic migraine and chronic migraine populations. The most common adverse events were constipation and nausea.

The atogepant MAA will be reviewed by the Committee for Medicinal Products for Human Use, which will issue an opinion that will be valid for all member states of the European Union, as well as Iceland, Lichtenstein, Northern Ireland and Norway.

About Atogepant

Atogepant is an orally administered, CGRP receptor antagonist (gepant) specifically developed for the prophylaxis treatment of migraine. CGRP and its receptors are expressed in regions of the nervous system associated with migraine pathophysiology. Studies have shown that CGRP levels are elevated during migraine attacks and selective CGRP receptor antagonists confer clinical benefit in migraine.

About the Phase 3 ADVANCE Clinical Trial1

The pivotal Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was designed to evaluate the efficacy, safety, and tolerability of oral atogepant for the prevention of migraine in those with 4 to 14 migraine days per month. A total of 910 patients were randomized to one of four treatment groups evaluating 10 mg, 30 mg, or 60 mg of atogepant once daily, or placebo. Efficacy analyses were based on the modified intent-to-treat (mITT) population of 873 patients. 

The primary endpoint was change from baseline in mean monthly migraine days across the 12-week treatment period. All atogepant dose groups met the primary endpoint and demonstrated statistically significantly greater decreases in mean monthly migraine days compared to placebo. Patients treated in the 10 mg/30 mg/60 mg atogepant arms experienced a decrease of 3.69/3.86/4.2 days, respectively, all compared to patients in the placebo arm, who experienced a decrease of 2.48 days (all dose groups vs. placebo, p=<.0001).

A key secondary endpoint measured the proportion of patients that achieved at least a 50% reduction in mean monthly migraine days across the 12-week treatment period. The trial demonstrated that 55.6%/58.7%/60.8% of patients in the 10 mg/30 mg/60 mg atogepant arms, respectively, achieved at least a 50% reduction, compared to 29.0% of patients in the placebo arm (all dose groups vs. placebo, p=<.0001).

Additional secondary endpoints measured across the 12-week treatment period included change from baseline in mean monthly headache days, mean monthly acute-medication use days, and mean monthly performance of daily activities and physical impairment domain scores of the Activity Impairment in Migraine-Diary (AIM-D), and change from baseline in the Migraine-Specific Quality of Life Questionnaire (MSQ) Role Function-Restrictive domain score at week 12. The trial demonstrated that treatment with 30 mg and 60 mg doses resulted in statistically significant improvements in all secondary endpoints, while treatment with the 10 mg dose resulted in statistically significant improvements in four out of the six secondary endpoints.

No new safety risks were observed compared to the safety profile observed in the previous trial evaluating atogepant. Serious adverse events occurred in 0.9% of patients treated in the atogepant 10 mg arm and 0.9% of patients in the placebo arm. No patients in the atogepant 30 mg or 60 mg treatment arms experienced a serious adverse event. The most common adverse events reported with a frequency ≥ 5% in at least one atogepant treatment arm, and greater than placebo, were constipation (7.7%, 7.0% and 6.9% in the 10 mg/30 mg/60 mg atogepant arms, respectively vs. 0.5% for placebo), nausea (5.0%, 4.4% and 6.1% in the 10 mg/30 mg/60 mg atogepant arms, respectively vs. 1.8% for placebo), and upper respiratory tract infection (4.1%, 5.7% and 3.9% in the 10 mg/30 mg/60 mg atogepant arms, respectively vs. 4.5% for placebo). The majority of cases of constipation, nausea and upper respiratory tract infection were mild or moderate in severity and did not lead to discontinuation. There were no hepatic safety issues identified in this trial.

About the Phase 3 PROGRESS Clinical Trial2

The Phase 3 PROGRESS clinical trial evaluated the safety, tolerability and efficacy of oral atogepant for the prophylaxis treatment of chronic migraine. The patient population for the study included patients with a diagnosis of chronic migraine for at least one year, and ≥ to 15 headache days with eight migraine days in the 28 days prior to randomization. The primary endpoint measured the reduction from baseline in mean monthly migraine days compared to placebo, for both doses, including 60 mg once daily (QD) and 30 mg twice daily (BID), across a 12-week treatment period. The overall safety profile of the Phase 3 PROGRESS study was consistent with safety findings observed in previous studies in an episodic migraine population.

Key secondary endpoints for all regions included: Change from baseline in mean monthly headache days across the 12-week of treatment period​ (baseline is defined as the number of migraine days during the last 28 days prior to the randomization date); Change from baseline in mean monthly acute medication use days across the 12-week treatment period​ (baseline is defined as the number of migraine days during the last 28 days prior to the randomization date); Proportion of participants with at least a 50% reduction in mean monthly migraine days across the 12-week treatment period​; and change from baseline in MSQ v2.1 Role Function-Restrictive domain score at Week 12. The MSQ v2.1 is a questionnaire designed to measure health-related quality of life impairments attributed to migraine in the past four weeks. It is divided into three domains, assessing how a patient’s daily, social, and work activities are limited by migraine; how migraine prevents these activities; and assesses the emotional function related with migraine.

For a full listing of secondary endpoints across all regions, please go to www.clinicaltrials.gov (NCT03855137).

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