FDA agrees to review new treatment for cataplexy attacks

The U.S. Food and Drug Administration (FDA) has agreed to review an application seeking approval of Axsome Therapeutics‘ experimental therapy AXS-12 (reboxetine) to treat cataplexy — a sudden drop in muscle tone — in people with narcolepsy.

The company said it expects the FDA to issue a decision by May 1, 2027.

When reviewing drug applications, the FDA sometimes holds advisory committee meetings in which outside experts weigh in on the available data for an experimental therapy. The FDA does not plan to hold an advisory committee meeting for AXS-12, Axsome said in a company press release.

Narcolepsy is a chronic disorder marked by abnormal daytime sleepiness. Many people with narcolepsy also experience cataplexy attacks, which can cause problems ranging from facial drooping to total collapse.

AXS-12 is designed to reduce the risk of cataplexy by boosting the activity of norepinephrine, a brain signaling molecule that normally helps promote wakefulness and increase muscle tone.

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Axsome sponsored a Phase 3 clinical trial, SYMPHONY (NCT05059223), that tested AXS-12 against a placebo in 90 people with narcolepsy. At the end of the five-week study, cataplexy attack frequency decreased by 83% in patients given AXS-12, compared with a reduction of 66% in patients given the placebo. Over the course of the trial, one-third (33%) of patients given AXS-12 were completely free from cataplexy, compared with fewer than one in 10 (9.5%) patients on the placebo.

Patients who completed SYMPHONY had the option to enroll in a long-term study called ENCORE (NCT05113745), in which all participants received AXS-12. After six months of therapy, the mean weekly rate of cataplexy attacks decreased by 77% relative to rates prior to starting AXS-12; more than 80% of trial participants experienced a reduction in cataplexy attack rates of at least 50%. Most patients also reported significant improvements in measures of daytime sleepiness and cognitive function.

In a second part of the ENCORE study, 42 patients who’d been on long-term AXS-12 were randomly assigned to keep taking the therapy or to switch to a placebo for a few weeks. Three weeks after the switch, average cataplexy rates increased by about 10 attacks per week in patients who switched to the placebo, whereas in patients who kept taking AXS-12, weekly attack rates increased by approximately one per week.

Results from SYMPHONY and ENCORE were broadly consistent with data from an earlier Phase 2 study, CONCERT (NCT03881852), which tested AXS-12 against a placebo in a smaller number of narcolepsy patients. Across the three clinical trials, the most commonly reported side effects of AXS-12 were anxiety, constipation, insomnia, dry mouth, nausea, and elevated heart rate (tachycardia).

The FDA has granted AXS-12 orphan drug designation as a potential narcolepsy treatment. The FDA gives this designation to experimental therapies designed to treat rare conditions, with the aim of offering extra incentives to drug developers. Among the perks, therapies given orphan drug designation get a guaranteed seven years of market exclusivity if they are approved.