, 2025-04-16 09:12:00
SAN DIEGO — The investigational drug AXS-12 (reboxetine, Axsome Therapeutics) is safe and effective for the treatment of cataplexy (emotionally induced muscle weakness) and excessive daytime sleepiness (EDS) in patients with narcolepsy, a new study suggested.
Reboxetine was available previously in the United States as an antidepressant, but its preliminary approval was withdrawn in 2001 due to concerns over its efficacy in treating depressive symptoms. The current investigators repurposed the drug because of its noradrenergic- and dopaminergic-modulating traits.
In the phase 3 SYMPHONY trial, which included 90 patients with type 1 narcolepsy, those randomly assigned to receive AXS-12 had a significantly greater decrease in cataplexy attacks at week 5 compared with those who received a matching placebo.
Additionally, the frequency of cataplexy attacks went down at week 1 for the AXS-12 group — and at all other timepoints to the end of the study. They also had significantly greater cataplexy remission rates, improved EDS severity, and higher cognitive function scores.
The active drug was also well-tolerated with no associated serious adverse events (AEs).
“The results show that this drug, which is primarily an antidepressant drug that has norepinephrine activity, can be effective in treating patients with narcolepsy,” lead investigator Michael J. Thorpy, MD, director of the Sleep-Wake Disorder Center at the Montefiore Medical Center and professor of neurology at the Albert Einstein College of Medicine in Bronx, New York, told Medscape Medical News.
“We thought it would be effective for cataplexy, but we’ve never had any controlled studies of a similar drug. So it was surprising that it had its beneficial effect within a week. Very often, other medications used for cataplexy don’t have an effect so quickly,” said Thorpy.
He added that having another agent, especially one with a different mechanism of action, would give clinicians more flexibility in being able to treat these patients.
These findings were presented on April 8 at the American Academy of Neurology (AAN) 2025 Annual Meeting.
Orphan Drug Designation
Narcolepsy is a neurological disorder characterized by EDS and abnormal sleep phenomena such as cataplexy, disrupted night sleep, and/or sleep paralysis. It is also often accompanied by cognitive impairment. Type 1 narcolepsy is literally “narcolepsy with cataplexy.”
Thorpy noted that narcolepsy, especially the type 1 version, is thought to be caused by a loss of orexin, a neuropeptide found in the hypothalamus of the brain.
“Orexin neurons are important in stimulating weight-promoting neurons throughout the central nervous system. And these weight-promoting neurons have an effect on improving cataplexy by affecting neurotransmitters,” he explained.
Despite pharmacotherapy, which is the predominant treatment, most patients with narcolepsy continue to experience symptoms that can impair daily functioning and reduce productivity, Thorpy said.
He noted that in a survey study he presented earlier in the day, 77% of more than 200 participants with type 1 narcolepsy said, “Despite being on optimum treatment,” they continued having cataplexy, and more than 90% continued having EDS.
AXS-12 is a highly selective norepinephrine reuptake inhibitor and cortical dopamine modulator. It “regulates noradrenergic activity, which helps increase and maintain muscle tone during wakefulness. It may modulate noradrenergic and dopaminergic pathways to stabilize sleep-wake states and enhance alertness,” said Thorpy.
The drug was first approved in Europe in 1997 for the treatment of major depressive disorder and is still approved in multiple countries outside the United States. It was provisionally approved for this indication in the United States in 1999, but 2 years later that approval was withdrawn by the US Food and Drug Administration (FDA) due to efficacy concerns. It is currently not available in the country.
Because of its properties, the drug is now being studied as a potential treatment for narcolepsy — and has been granted Orphan Drug designation by the FDA for this purpose, according to its company.
The multicenter, double-blind SYMPHONY trial was created because of the positive results that came from the earlier phase 2 randomized CONCERT trial. Its findings showed a reduced number of cataplexy attacks and reduced EDS for patients with narcolepsy who received the drug compared with those who received a placebo.
Primary Endpoint Met
In SYMPHONY, 90 US patients with narcolepsy 1 and between the ages of 15 and 75 years were enrolled. Of these participants, 46 (mean age, 36 years; 54.3% women) were randomly assigned to receive 5 mg of AXS-12 once daily during week 1 and twice daily during weeks 2-5. The other 44 participants (mean age, 34 years; 65.9% women) received a placebo, with one tablet taken daily during week 1 and one tablet twice daily during weeks 2-5.
Key inclusion criteria included experiencing at least seven cataplexy attacks per week or at least 14 across a 2-week period. Investigators allowed stable concurrent use of modafinil/armodafinil, which was used by 32.6% of the AXS-12 group and 29.5% of the placebo group.
Change in weekly cataplexy attacks from baseline to week 5 was the primary endpoint. Key secondary outcomes included the percentage of participants with cataplexy remission and/or cataplexy-free days; change in EDS severity, as measured with Clinical Global Impression–Severity (CGI-S) scores; change in inadvertent nap frequency, as measured on the Narcolepsy Symptom Assessment Questionnaire; and change in score on cognitive function items of the Functional Outcomes of Sleep Questionnaire-10.
Mean weekly cataplexy attacks at baseline were 19.3 in the AXS-12 group and 21.6 in the placebo group. Week 5 results showed a greater rate of reduction in the attacks for the active treatment group (rate ratio, 0.5; P = .02).
Even at week 1, the reduction in attacks was significantly greater in the active treatment vs placebo groups (rate ratio, 0.7; P = .007) and it stayed significantly greater at week 2 (P = .006) and at weeks 3 and 4 (P = .03 for both).
Other significant differences at week 5 for the AXS-12 group vs the placebo group included higher rates of 100% cataplexy remission (33% vs 9.5%; P = .008), increased mean percentages of cataplexy-free days per week (84.5% vs 22.6%; P = .01), reduction in EDS severity as shown on the CGI-S (–1.8 vs –0.9; P = .03), and fewer inadvertent naps (54% vs 28%; P = .02).
The active treatment was also associated with greater improvements in concentration and memory scores compared with a placebo (1.6 vs 0.7 points; P = .004).
“AXS-12 was well-tolerated with no new safety signals or serious adverse events,” the investigators reported.
Common treatment-emergent AEs in this group included dry mouth (n = 6), nausea (n = 6), constipation (n = 4), and paresthesia (n = 4) — all of which were considered mild to moderate. There was one discontinuation due to AEs in each of the treatment groups, but no serious AEs were in either group.
Thorpy noted that AXS-12 not only met its primary endpoint, it also “reduced daytime sleepiness and improved subjective cognitive functioning, indicating that it has a potential to impact a number of symptoms that we see in narcolepsy.”
In November, topline results for the 6-month open-label ENCORE trial were announced, showing that AXS-12 again met its primary endpoint of reducing the number of cataplexy attacks vs placebo.
Based on results from both the SYMPHONY and ENCORE trials, Axsome Therapeutics is now moving “towards a new drug application filing” with the FDA, the company said in a release.
Promising Findings
Commenting for Medscape Medical News, Logan Schneider, MD, adjunct clinical associate professor of sleep medicine at Stanford University, Stanford, California, noted that SYMPHONY was an interesting study “that focused on the relevant symptoms we’re trying to manage” in patients with narcolepsy.
“Cataplexy as well as excessive daytime sleepiness are the more concerning symptoms. If you have bad dreams or sleep paralysis, those things are rather benign in comparison to things that can cause [real] harm. So I think the aims of demonstrating the benefit of this medication were certainly appropriate,” said Schneider, who was not involved with the study.
He noted that he would have liked to have seen more detailed information presented, such as how well various factors were controlled for and outcomes in subsets of the patients.
“But in general, in the data that were reported, the findings were positive for cataplexy control and patient-reported daytime sleepiness. And the other outcomes all went in the expected direction. So overall, I think the medication is promising,” Schneider said.
He added that he appreciates efforts to repurpose a treatment for new indications. Often, there are concerns about AEs from antidepressant use — but the AEs reported in this study appeared manageable, he said.
“It looks like they had a nice safety profile along with the strong benefit for the primary outcome,” Schneider said.
The study was funded by Axsome Therapeutics. Thorpy reported receiving personal compensation for serving as a consultant for Jazz Pharmaceuticals, Avadel Pharmaceuticals, Alkermes, Harmony Biosciences, and Centessa Pharmaceuticals and for serving on a Scientific Advisory or Data Safety Monitoring Board for Axsome Therapeutics. He had also received publishing royalties from a publication relating to healthcare. Schneider reported being on advisory boards and speaker’s bureaus for “most of the sleep medication companies,” including Axsome Therapeutics, Jazz Pharmaceuticals, Avadel Pharmaceuticals, and Harmony Biosciences.