In August 2022, the FDA approved the Axsome Therapeutics drug Auvelity (dextromethorphan Hbr-bupropion HCl) for major depressive disorder (MDD). Auvelity is a rapid-acting, extended-release oral tablet, which in clinical trials offered statistically significant and sustained antidepressant efficacy within just a week of starting treatment, along with a relatively favorable safety profile. While most existing anti-depressant drugs work via the same neurotransmitters, primarily dopamine and serotonin, Auvelity works on NMDA, a glutamate receptor. Thus, Auvelity offers a new mechanism of action in the treatment of MDD and could potentially be the very first in a new class of antidepressants.
Major depressive disorder or MDD is a serious and widespread health problem, ranked by the World Health Organization (WHO) as the leading cause of disability worldwide. Even before the COVID-19 pandemic, more than 20 million Americans were estimated to be affected by MDD. The social isolation and other conditions resulting from the pandemic have only added to these numbers, increasing them to as many as 80 million affected people. MDD is a complex, frequently recurring condition, whose cause is multifactorial. Biological, genetic, environmental and psychosocial factors can all influence the complex neuroregulatory systems and circuits in the brain, causing disturbances in various neurotransmitter systems.
This complexity has made MDD a particularly difficult condition to effectively treat. There can be immense variability between individual patients in their response to a particular drug, both in terms of its effectiveness as well as its safety and tolerability. Selecting the right drug for an individual depends on the physician’s ability to accurately assess the patient’s symptoms, co-morbidities, ability to tolerate specific side-effects, and other patient-specific factors. About two-thirds of those receiving existing antidepressant drugs do not adequately respond to therapy, and those that do respond may not achieve a clinical benefit for as long as 6-8 weeks after starting treatment. Drugs to treat MDD have become increasingly safe over the years since the introduction in the 1950s of the classical antidepressants, monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). However, significant adverse reactions can still impact the safety and tolerability of many modern drug therapies, including the multiple selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and atypical antidepressants such as bupropion. Thus, considerable medical unmet need has existed for improved therapeutics for MDD.
Auvelity was approved by the FDA based on the results of two Phase 3 clinical trials that together included over 1,100 participants. In the ‘GEMINI’ trial, Auvelity was shown superior to placebo as measured by changes in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at week 6, the trial’s primary endpoint. The difference between Auvelity and placebo in change from baseline in MADRS total score was statistically significant even at week 1 and 2 timepoints, showing the drug’s rapid onset. Moreover, the early benefit observed with Auvelity was maintained and increased with continued treatment. The only other approved treatment for MDD that was shown to act as quickly as Auvelity is Johnson & Johnson’s Spravato (esketamine), which unlike Auvelity must be administered in a doctor’s office.
In the ‘ASCEND’ trial, Auvelity was shown to be statistically superior to the twice-daily, 105 mg bupropion sustained-release tablets. Adverse reactions to Auvelity (dizziness, headache, diarrhea, sleepiness, dry mouth, sexual dysfunction, and excessive sweating) were at par with other oral antidepressants. Also, like other antidepressants, the Auvelity prescribing label warns of a possible link to suicidal thoughts and behaviors in pediatric patients and young adults.
Axsome expects to commercially launch Auvelity in the United States during Q4 of this year, although pricing has not yet been finalized. The new drug’s approval may pave the way for other similar therapies targeting NMDA, creating a distinct new class of therapeutics. However, it remains to be seen how Auvelity and other potential NMDA inhibitors will stack up against other drugs for MDD, given the multiple pathways that can lead to depression and the high variability of patient response and tolerability.