Better late than never? Axsome depression drug is approved a year after FDA delay

An Axsome Therapeutics depression drug designed to start working quickly now has its long-awaited approval one year after the target date for an FDA decision. The regulatory nod announced Friday makes the product the first new oral drug in decades that addresses a novel target for depression.

The drug, which was known in development by the code name AXS-05, will be marketed under the brand name Auvelity. New York-based Axsome plans to launch the twice-daily pill in the fourth quarter.

With the regulatory approval, Auvelity is set to join a depression drug market full of older products, many of which take a long time to start working and come with serious side effects. Many of these drugs work by targeting monamine oxidase (MAO), blocking that enzyme’s ability to remove key neurotransmitters from the brain. MAO inhibitor drugs are widely prescribed, but a large contingent of patients don’t respond to them and for those who do, the effect can take six weeks or more to begin.

Auvelity may be a new drug, but its two main components are older medicines. The product pairs buproprion, the active ingredient in the old GSK anti-depressant and smoking cessation drug Wellbutrin, with dextromethorphan, an ingredient in many cough medicines. Dextromethorphan crosses the blood brain barrier to target the part of the brain that causes coughing. Auvelity uses dextromethorphan to block the NMDA receptor, which the company says makes it the first new oral depression drug in more than 60 years that works by addressing a target other than MAO. The bupropion part of the drug increases the levels of dextromethorphan in the blood. Axsome combines both active ingredients with proprietary technology that modulates the delivery of each compound.

During a Friday conference call to discuss the approval, one financial analyst asked whether physicians might try to get around Auvelity by prescribing its two generic components together. CEO Herriot Tabuteau responded that Auvelity is a proprietary formulation designed to provide a distinct pharmacokinetic effect. He added that the drug’s efficacy, safety and tolerability were demonstrated in clinical trials. In a placebo-controlled Phase 3 study enrolling 327 participants, Axsome reported that its drug met the main goal of showing a statistically significant reduction in depression symptoms at week six as measured according to rating scale for depressive episodes.

Axsome also noted that statistically significant results were observed at week one—four days after receiving the target dose. With data showing rapid onset of effect and durability of that effect throughout the treatment period, Axsome submitted a new drug application in early 2021; the FDA set an August 22, 2021 target date for a regulatory decision. Just prior to that date, the agency told the company it needed more time.

Tabuteau said Friday that the main holdup was a manufacturing issue. He also said that the submission was made in the midst of the pandemic’s disruptive effects to many companies and government agencies, including the FDA.

Though Auvelity is the first pill that works by blocking NMDA, it’s not the first FDA-approved depression drug that works this way. Johnson & Johnson’s Spravato also blocks this target and its 2019 approval covers the treatment adults whose depression has not responded to earlier lines of therapy. That product is a version of ketamine, an old anesthetic that has been abused for its ability to produce hallucinations. Though Spravato’s nasal spray formulation offers a fast-acting effect, the drug is a Schedule III controlled substance that must be taken while under the observation of a healthcare professional in a treatment center.

The drug label for Auvelity covers the treatment of major depressive disorder broadly in adults. Tabuteau said that the clinical trials enrolled patients who had varying levels of prior experience with other depression therapies. Whether Auvelity should be prescribed as a first treatment or as a second- or third-line therapy is up to the clinician, he said.

In clinical testing, Axsome said there were no indications of psychotic symptoms or weight gain, which are common side effects of other depression drugs. The drug’s label carries a black box warning that notes an increase in suicidal thoughts and behaviors are a risk posed by anti-depressants in children and young adults. Tabuteau noted that this warning is standard for depression drugs and Auvelity is not approved for children, though a pediatric study is planned. Axsome is also developing the drug as a potential treatment of agitation in Alzheimer’s patients.

Axsome is still finalizing Auvelity’s price, which will be announced in coming weeks, Lori Englebert, the company’s executive vice president of commercial and business development, said. She added that Axsome aims to set a price that ensures broad patient access while also taking into account the drug’s innovation. Auvelity’s ability to start working at week one and show remission of depression symptoms at week two, “is incredibly differentiating in the marketplace right now,” Englebert said.

In a research note sent to investors Friday afternoon, William Blair analyst Myles Minter wrote that his firm believes the rapid onset of effect combined with a differentiated mechanism of action will position Auvelity well against standard-of-care drugs that can take six weeks to start working.

“With 21 million U.S. patients experiencing [a major depressive disorder] episode in the prior year and 78% of patients unsatisfied with current treatment, we believe that the market is poised for disruption by an agent like Auvelity,” Minter said.