AbbVie's Oral CGRP Receptor Antagonist Atogepant Under FDA Review for Once-Daily Preventive Treatment of Migraine

March 30, 2021 News /BioValleyBIOON/ -- AbbVie recently announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for atogepant for the preventive treatment of migraine in adult patients meeting the criteria for episodic migraine (EM). AbbVie expects that,FDAA regulatory decision is expected by the end of the third quarter of 2021. If approved, atogepant will be the first and only oral calcitonin gene-related peptide (CGRP) receptor antagonist (gepant) developed specifically for the preventive treatment of migraine, providing patientsTo provide a simple, safe, and effective prophylactic treatment administered orally once daily.

Migraine is a complex chronic disorder, and its attacks often impair patients’ ability to carry out normal daily activities or work, manifesting as severe head pain along with neurological and autonomic symptoms. The symptoms and severity of migraine vary widely among individuals.Migraine attacks can be debilitating, but migraine is a treatable condition.

Atogepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist (gepant) specifically developed for the preventive treatment of migraine. CGRP and its receptors are expressed in regions of the nervous system associated with the pathophysiology of migraine. Studies have shown that CGRP levels increase during migraine attacks, and selective CGRP receptor antagonists demonstrate clinical efficacy in the treatment of migraine.

The atogepant NDA is supported by robust data from a clinical program conducted in nearly 2,500 patients experiencing 4–14 migraine days per month. This program evaluated the efficacy, safety, and tolerability of oral atogepant for the preventive treatment of migraine, and included the pivotal Phase 3 ADVANCE study, the pivotal Phase 2b/3 study (CGP-MD-01), and a Phase 3 long-term safety study.

Data from the Phase 3 ADVANCE study showed that during the 12-week treatment period, all doses of atogepant (10 mg, 30 mg, and 60 mg) significantly reduced the mean number of migraine days per month from baseline compared with placebo. Furthermore, the two higher doses (30 mg and 60 mg) demonstrated statistically significant improvements across all six secondary endpoints.

In the field of migraine, AbbVie is marketing BOTOX® (onabotulinumtoxinA) and Ubrelvy (ubrogepant). Among these, BOTOX is the first preventive medication approved by the U.S. FDA for chronic migraine in adults, while Ubrelvy isFDAThe first approved oral CGRP receptor antagonist (gepant) for the acute treatment of migraine (with or without aura) in adults.

Michael Gold, Vice President of Neuroscience Development at AbbVie, stated, “With the integration of Allergan, AbbVie is now a committed leader in the migraine field, with nearly 25 years of history in migraine research. We look forward to adding a new treatment option to our portfolio, which will help more migraine patients. We believe that as a safe and effective oral preventive treatment option, atogepant represents an advancement in migraine therapy, with the potential to provide meaningful therapeutic benefits. Despite other migraine treatment options available, the medical community and migraine patients recognize that there are unmet medical needs for those suffering from this unpredictable and debilitating disease.”

Chemical Structure of Atogepant (Image source: genome.jp)

Regarding the Pivotal Phase III ADVANCE Trial:ADVANCE was a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase III trial designed to evaluate the efficacy, safety, and tolerability of oral atogepant for the preventive treatment of migraine. A total of 910 patients were randomized into four treatment groups receiving once-daily oral administration of atogepant at three doses (10 mg, 30 mg, or 60 mg) or placebo. Efficacy analyses were based on the modified intent-to-treat (mITT) population comprising 873 patients.

The primary endpoint was the change from baseline in the mean number of migraine days per month during the 12-week treatment period. The data showed that all atogepant dose groups met the primary endpoint, with a statistically significant reduction in the mean number of migraine days per month compared with placebo. The reductions were 3.69, 3.86, and 4.2 days for the 10 mg, 30 mg, and 60 mg atogepant groups, respectively, versus 2.48 days for the placebo group (p≤0.0001 for all dose groups vs. placebo).

A key secondary endpoint measured the proportion of patients who achieved at least a 50% reduction in monthly migraine days during the 12-week treatment period. The data showed that 55.6%, 58.7%, and 60.8% of patients in the 10 mg, 30 mg, and 60 mg atogepant groups, respectively, achieved at least a 50% reduction, compared with 29.0% in the placebo group (p ≤ 0.0001 for all dose groups versus placebo).

Other secondary endpoints measured during the 12-week treatment period included: mean monthly headache days, mean monthly days of acute medication use, changes from baseline in the mean monthly scores for the Activity Impairment and Physical Impairment domains of the Migraine Diary Activity Impairment (AIM-D), and changes from baseline in the Role Function-Restrictive domain score of the Migraine-Specific Quality of Life Questionnaire (MSQ) at Week 12. The trial demonstrated statistically significant improvements across all secondary endpoints in the 30 mg and 60 mg dose groups, whereas the 10 mg dose group showed statistically significant improvements in 4 out of the 6 secondary endpoints.

In terms of safety, no new safety risks were observed compared with those reported in previous trials evaluating atogepant. Serious adverse events occurred in 0.9% of patients in the 10 mg dose group and 0.9% of patients in the placebo group; no serious adverse events occurred in either the 30 mg or 60 mg dose groups. The most common adverse events occurring at a frequency ≥5% and higher than placebo in at least one atogepant treatment group were constipation (6.9–7.7% across all dose groups vs. 0.5% with placebo), nausea (4.4–6.1% across all dose groups vs. 1.8% with placebo), and upper respiratory tract infection (3.9–5.7% across all dose groups vs. 4.5% with placebo). Most cases of constipation, nausea, and upper respiratory tract infection were mild or moderate in severity and did not result in discontinuation. No hepatic safety concerns were identified in this trial.

Regarding the Phase 2/3 CGP-MD-01 Study:This study evaluated the efficacy, safety, and tolerability of oral atogepant. The data showed that all atogepant treatment groups met the primary endpoint, with a significant reduction from baseline in the mean number of monthly migraine days during the 12-week treatment period compared with placebo (10 mg QD vs. placebo, p=0.0236; 30 mg QD vs. placebo, p=0.0390; 60 mg QD vs. placebo, p=0.0390; 30 mg BID vs. placebo, p=0.0034; 60 mg BID vs. placebo, p=0.0031). The study results were released in June 2018. (Bioon.com)

Original source: U.S.FDA Accepts AbbVie's New Drug application for Atogepant for the Preventive Treatment of Migraine