Axsome Therapeutics Auvelity(dextromethorphan HBr -bupropion HCl) Becomes the First FDA-Approved Oral NMDA for Major Depression

Summary:

• The FDA has approved Axsome Therapeutics’ Auvelity for major depressive disorder (MDD) in adults, making it the first and only oral N-methyl D-aspartate (NMDA) receptor antagonist approved for this indication.
• AUVELITY is the first and only rapid-acting oral treatment approved with labeling of statistically significant improvement in depressive symptoms compared to placebo starting at one week1-4
• AUVELITY uses the first new oral mechanism of action approved for major depressive disorder in over 60 years1-4
• AUVELITY was developed with FDA Breakthrough Therapy designation and evaluated by the FDA under Priority Review

Auvelity (dextromethorphan HBr -bupropion HCl) is an extended-release tablet that uses the first new oral mechanism of action in over 60 years for MDD. Its dextromethorphan content works on the NMDA receptor, an ionotropic glutamate receptor, and the sigma-1 receptor in the brain, while the bupropion component helps increase dextromethorphan blood levels by inhibiting cytochrome P450 2D6.

The product is patented, extending at least to 2037-2040, and is expected to be commercially available by the fourth quarter in the U.S. It is not approved for use in children.

About Auvelity (dextromethorphan HBr -bupropion HCl)

• API– (dextromethorphan HBr -bupropion HCl)
• Description: AUVELITY is a novel, oral, NMDA receptor antagonist with multimodal activity approved for the treatment of MDD in adults. AUVELITY is a proprietary extended-release oral tablet containing dextromethorphan HBr (45 mg) and bupropion HCl (105 mg). The dextromethorphan component of AUVELITY is an antagonist of the NMDA receptor (an ionotropic glutamate receptor) and a sigma-1 receptor agonist. These actions are thought to modulate glutamatergic neurotransmission. The bupropion component of AUVELITY is an aminoketone and CYP2D6 inhibitor which serves to increase the increase and prolong the blood levels of dextromethorphan. The exact mechanism of action of Auvelity in the treatment of depression is unclear. AUVELITY received Breakthrough Therapy designation from the FDA for the treatment of MDD.
• Approval : The FDA granted Breakthrough Therapy designation for AUVELITY for the treatment of MDD in March 2019. This designation is granted to candidate drugs that show potential for benefit above that of available therapies based on preliminary clinical data, and it provides the sponsor with added focus from and greater interactions with FDA staff during the development of the candidate drug.  The AUVELITY New Drug Application (NDA) was evaluated by the FDA under Priority Review, which is granted by the FDA to applications for medicines that, if approved, would provide significant improvements in the effectiveness or safety of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.
• Mechanism of Action -AUVELITY uses the first new oral mechanism of action in more than 60 years for MDD. AUVELITY works on the NMDA receptor, an ionotropic glutamate receptor, and on the sigma-1 receptor in the brain via its dextromethorphan component. The bupropion component of AUVELITY is an aminoketone which increases blood levels of dextromethorphan by competitively inhibiting cytochrome P450 2D6 (CYP2D6), which catalyzes a major biotransformation pathway for dextromethorphan. The exact mechanism of action of AUVELITY in the treatment of MDD is unclear. The blood levels of AUVELITY are determined by the distinct pharmacokinetic interaction between its components which has been found to be non-linear at steady state. AUVELITY is protected by a robust patent estate extending out at least to 2037-2040.
• Indication – Major Depression Disorder

• Common Side Effects  –The most common side effects of Auvelity include dizziness, headache, diarrhea, feeling sleepy, dry mouth, sexual function problems, and excessive sweating.

Maurizio Fava, MD, Psychiatrist-In-Chief, Department of Psychiatry, Massachusetts General Hospital, Executive Director, Clinical Trials Network & Institute, Associate Dean for Clinical & Translational Research, and Slater Family Professor of Psychiatry, Harvard Medical School said, “The approval of Auvelity represents a milestone in depression treatment based on its novel oral NMDA antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile. Auvelity, which was granted Breakthrough Therapy designation by the FDA, represents the first new oral non-monoamine-based mechanism of action approved to treat major depressive disorder in over sixty years. Nearly two thirds of patients treated with currently available antidepressants do not adequately respond, and those that do may not achieve clinically meaningful responses for up to six to eight weeks. Given the debilitating nature of depression, the efficacy of Auvelity observed at one week and sustained thereafter may have a significant impact on the current treatment paradigm for this condition.”

Michael Pollock, Chief Executive Officer of the Depression and Bipolar Support Alliance (DBSA), a leading national patient advocacy organization focusing on depression and bipolar disorder said, “The mental health crisis in the United States is one of the most pressing health issues facing our country today. Over 20 million American adults experienced major depressive disorder each year prior to the COVID-19 pandemic. These numbers increased dramatically during the pandemic with approximately thirty percent of adults in the U.S. or more than 80 million Americans experiencing elevated symptoms of depression. The need for new treatment options, particularly those with new mechanisms of action, could not be clearer and more urgent for those living with, or impacted by, major depressive disorder.”

Dan V. Iosifescu, MD, Professor of Psychiatry at the New York University School of Medicine, and Director of the Clinical Research Division at the Nathan Kline Institute for Psychiatric Research said, “Major depressive disorder is disabling and potentially life-threatening, causes profound distress for patients and their families, and leads to substantial healthcare resource utilization. Auvelity’s oral NMDA receptor antagonist and sigma-1 receptor agonist activity, which targets glutamatergic neurotransmission, provides clinicians a long sought after new mechanistic approach which may benefit the millions of patients living with this serious condition. In clinical trials, Auvelity has demonstrated rapid and statistically significant improvement in depressive symptoms as early as Week 1, and increased rates of remission at Week 2 compared with placebo. This early benefit with Auvelity was maintained and increased with continued treatment, and was accompanied by a favorable safety and tolerability profile.”

Herriot Tabuteau, MD, Chief Executive Officer of Axsome said, “The approval of Auvelity is the culmination of the tremendous and focused research and development activities conducted by the Axsome team and our collaborators. We are extremely proud to deliver this Breakthrough Therapy-designated new treatment to the millions of patients living with depression at a time when it is most needed, given the recent sharp increase in depression prevalence. We are thrilled to contribute to potentially fundamental advances in neuropsychiatry by providing clinicians the first rapid-acting oral antidepressant demonstrated with FDA labeling, and the first oral glutamatergic medicine approved for depression. Auvelity and the rest of the Axsome neuroscience portfolio reflect our steadfast commitment to developing and delivering potentially life-changing medicines to people living with serious central nervous system disorders.”

About Major Depressive Disorder (MDD)

Major depressive disorder (MDD) is a debilitating, chronic, biologically-based disorder characterized by low mood, inability to feel pleasure, feelings of guilt and worthlessness, low energy, and other emotional and physical symptoms, and which impairs social, occupational, educational, or other important functioning. In severe cases, MDD can result in suicide. According to the U.S. Department of Health and Human Services, an estimated 21 million U.S. adults experienced MDD each year. According to the World Health Organization (WHO), depression is the leading cause of disability worldwide, and is a major contributor to the overall global burden of disease. Nearly two-thirds of diagnosed and treated patients do not experience adequate treatment response with available first-line treatment, highlighting the need for new therapies.

About Axsome Therapeutics, Inc.

Axsome Therapeutics, Inc. is a biopharmaceutical company developing and delivering novel therapies for central nervous system (CNS) conditions that have limited treatment options. Through development of therapeutic options with novel mechanisms of action, we are transforming the approach to treating CNS conditions. At Axsome, we are committed to developing products that meaningfully improve the lives of patients and provide new therapeutic options for physicians.

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