Once a controversial European depression treatment that never made it to the U.S. market, reboxetine may soon see new life under Axsome Therapeutics' stewardship.
Since collecting the exclusive U.S. rights and data on the drug from Pfizer in 2020, Asxome has been busy building on its two earlier studies of AXS-12 in narcolepsy. Now, with fresh phase 3 data in hand, the company plans to head to the FDA to see if the drug can make a comeback.
“The results of the ENCORE trial confirm the efficacy of AXS-12 in patients with narcolepsy with cataplexy, which has now been demonstrated in three positive controlled trials, and indicate that the potential benefits of AXS-12 are substantial and sustained with long-term treatment,” CEO Herriot Tabuteau, M.D., said a Tuesday press release.
Axsome’s phase 3 ENCORE trial measured the drug’s effect on the frequency of cataplexy attacks in narcolepsy patients with the condition, which is defined as sudden bouts of muscle weakness typically triggered by strong emotions. The study consisted of a six-month treatment period, followed by three weeks of withdrawal. After that, patients were randomized to either continue treatment with AXS-12 or switch to placebo.
The final period of the trial showed that those who switched to placebo experienced a statistically significant worsening in average weekly frequency of cataplexy attacks compared to those who continued on AXS-12, Axsome explained. The placebo group experienced an increase of 10.29 attacks per week during this period, compared to 1.32 for the AXS-12 group.
Long-term treatment also led to improvements in various narcolepsy symptoms including excessive daytime sleepiness, cognition and work productivity, Axsome said.
“Importantly, these improvements were accompanied by a favorable long-term safety and tolerability profile,” Tabuteau said.
Axsome now plans to move “expeditiously” toward an FDA filing, but it will first request a pre-new drug application meeting with the agency, the executive added.
If approved, Axsome’s offering would compete with Jazz Pharmaceuticals' top-selling Xyrem and Avadel Pharmaceuticals’ newer entrant Lumryz. Both products are comprised of sodium oxybate, which is a sodium salt of central nervous system depressant gamma-hydroxybutyric acid.
Due to the risk of abuse, Xyrem and its generics are only available through a Risk Evaluation and Mitigation Strategy program. Analysts at William Blair see AXS-12’s safety profile as a “key differentiator” from the competition, but they pointed to tachycardia (elevated heart rate while resting) as a potential side effect for further monitoring.
In all, the analysts described the treatment as an “approvable and effective” therapy that is “undervalued” by investors, the team wrote in a recent note to clients, modeling peak sales at $440 million.
Conversely, Mizuho analyst Graig Suvannavejh, Ph.D., said in a separate note that his team views AXS-12 as a "minor" opportunity with potential peak sales of $120 million.
When the FDA first reviewed the norepinephrine reuptake inhibitor as an antidepressant in 1999, the agency granted Pfizer a preliminary approval letter, only to snatch it back after further studies in 2001. In 2010, the British Medical Journal came out with an analysis based on published and unpublished data that called the antidepressant “ineffective and potentially harmful.” The medicine was previously marketed as Edronax in some European countries.
Axsome took over the rights from Pfizer in 2020 a deal that also included Pfizer’s discarded fibromyalgia candidate esreboxetine. The company is looking to file that drug for potential approval as well, it said in its recent third-quarter earnings report.