On August 19, Axsome Therapeutics announced that the US FDA approved Auvelity (dextromethorphan 45mg + bupropion 105mg) compound sustained-release tablets for the treatment of adult major depressive disorder (MDD), which is the first and only drug Oral fast-acting N-methyl-D-aspartate (NMDA) receptor antagonist for the treatment of adult major depressive disorder, considered a new mechanism drug for the clinical treatment of depression for 60 years, is expected to be available in the United States in the fourth quarter of this year listed.
The two ingredients in Auvelity, dextromethorphan and bupropion, are not new molecules. Dextromethorphan is an antagonist of NMDA receptors (an ionotropic glutamate receptor) and a sigma-1 receptor agonist, acting on NMDA receptors and sigma-1 receptors in the brain, thereby regulating the Amino-nergic neurotransmission. Bupropion, a norepinephrine and dopamine reuptake inhibitor, also competitively inhibits CYP2D6, thereby increasing the bioavailability of dextromethorphan in vivo.
Axsome Therapeutics developed Auvelity (AXS-05) using a proprietary formulation and dosage and proprietary metabolic inhibition technology to modulate the delivery of pharmaceutical ingredients. Although the exact mechanism of action of AXS-05 in the treatment of depression has not been fully elucidated, it does not prevent it from becoming a major breakthrough in the clinical treatment of severe depression by virtue of its mechanism of action that is different from other drugs.
The phase II ASCEND study in patients with major depression included 80 patients with confirmed major depression and randomized them. The results showed that compared with the bupropion control group, AXS-05 could achieve rapid, durable and highly significant improvement in depressive symptoms, and the average change in the Montgomery Depression Rating Scale (MADRS) score during 6 weeks of treatment was significantly better than the baseline. In the control group (-13.7 vs -8.8, p less than 0.001), the degree of change from baseline in MADRS score at week 6 of treatment was significantly better than that in the control group (-17.2 vs -12.1, p=0.013), reaching the primary endpoint. The FDA granted breakthrough therapy designation for AXS-05 for the treatment of major depression in March 2019 based on the results of this study.
The Phase III GEMENI study of AXS-05 included 300 patients with moderate to severe depression, and compared the efficacy and safety of AXS-05 versus placebo, with the change from baseline in MADRS score at week 6 as the primary endpoint. The detailed results were published in the journal J Clin Psychiatry in May.
Results showed that AXS-05 demonstrated rapid, definitive, and statistically significant improvements over placebo in depressive symptoms and induction of remission, with more significant changes from baseline in MADRS scores at Week 6 (-15.9 vs -12.0, p= 0.002). Also, the change from baseline in MADRS scores was significantly greater in the AXS-05 group than in placebo at every stage after the start of Week 1. The remission rate was significantly higher in each phase starting at week 2, with a significant difference in remission rate at week 6 (39.5% vs 17.3%, p<0.001). The AXS-05-treated group outperformed placebo on other secondary endpoints across time periods.
In terms of safety, the most common adverse reactions of Auvelity were dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction and hyperhidrosis.
Major depressive disorder is a debilitating chronic disorder characterized by low mood, an inability to feel happy, feelings of guilt and worthlessness, low energy, and other emotional and physical symptoms that, in severe cases, can lead to suicide. According to statistics, about 21 million American adults experience major depression each year. Nearly two-thirds of diagnosed and treated patients have not achieved an adequate response to available first-line treatments, underscoring the need for new treatments.
The AXS-05 currently has more than 100 US and international patents valid through 2040. In addition, it has been granted Breakthrough Therapy Designation by the FDA for the treatment of Alzheimer’s disease agitation.
Dr. Herriot Tabuteau, Chief Executive Officer of Axsome, said: “The approval of Auvelity is the result of tremendous and dedicated research and development by the Axsome team and our collaborators. Given the recent sharp rise in depression prevalence, we are very proud to be able to make it at a time when it is most needed. This breakthrough therapy-designated new treatment is available to millions of people with depression. We are pleased to offer clinicians the first FDA-labeled fast-acting oral antidepressant and the first oral glutamine approved for depression acid medicines, thereby contributing to potentially fundamental advances in neuropsychiatry. Auvelity and other Axsome neuroscience portfolios reflect our strong commitment to developing and delivering potentially life-changing medicines to people with severe central nervous system disorders .”