The U.S. Food and Drug Administration (FDA) approved combination dextromethorphan and bupropion extended-release tablets for the treatment of major depressive disorder (MDD) in adults. The newly approved agent (AUVELITY, Axsome Therapeutics, Inc) is a proprietary formulation and dose of dextromethorphan (DXM) and bupropion. It is the first and only rapid-acting oral medicine approved for the treatment of MDD.
The approved combination dextromethorphan-bupropion is a glutamate receptor modulator, which is a novel mechanism of action, meaning it works differently than currently approved oral therapies for major depressive disorder. Dextromethorphan (figure) is a weak N-methyl-d-aspartate (NMDA) receptor antagonist, with stronger binding affinity for the serotonin transporter (SERT) and sigma 1 receptors. It is rapidly metabolized by CYP450 2D6, making it difficult to achieve therapeutic blood levels without concomitant administration of a CYP450 2D6 inhibitor. Bupropion (figure) is a norepinephrine and dopamine reuptake inhibitor (NDRA) and serves to increase plasma dextromethorphan concentrations by inhibiting its CYP2D6 metabolism.
The approval is based on a comprehensive clinical program that included more than 1,100 participants with depression. Efficacy for the dextromethorphan-bupropion combination was demonstrated in the GEMINI placebo-controlled study, and the ASCEND double-blind, controlled trial. In the GEMENI study, Auvelity was statistically and significantly superior to placebo in improvement of depressive symptoms as measured by the change in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at the study’s primary endpoint, week 6. The difference between AUVELITY and placebo in change from baseline in MADRS total score was statistically significant at week 1 and week 2.
The ASCEND trial assessed the efficacy and safety of AXS-05 versus the active comparator bupropion in patients with MDD. In the ASCEND study, Auvelity was statistically and significantly superior to bupropion sustained-release tablets 105 mg twice daily on the primary outcome measure. The most common adverse reactions were dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis.
>> Axsome Therapeutics, Inc. Press Release
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