Axsome Therapeutics’ Small Molecule Clears Phase III Trial in Narcolepsy

Narcolepsy_iStock, AndreyPopov

Pictured: Woman falling asleep at her workstation/iStock, AndreyPopov

Axsome Therapeutics on Monday announced that its drug candidate AXS-12 met the primary efficacy endpoint in the Phase III SYMPHONY trial, inducing significant cataplexy improvement in patients with narcolepsy.

At week 5, AXS-12 reduced cataplexy attacks—the sudden loss of muscle tone while a person is awake—by 83% from baseline, while placebo only elicited a 66% drop in cataplexy. This effect was statistically significant, with a p-value of 0.018, according to Axsome’s announcement. AXS-12 also took effect rapidly, cutting cataplexy attacks by 56% at week 1 compared to 31% in the placebo group.

SYMPHONY also showed that 33% of patients treated with AXS-12 achieved cataplexy remission at week 5—defined as a 100% reduction in attacks from baseline—versus only 9.5% in placebo comparators.

Axsome CEO Herriot Tabuteau said in a statement that SYMPHONY’s results “highlight AXS-12’s positive therapeutic impact” demonstrating a “rapid and substantial reduction of cataplexy events,” while also eliciting significant improvements in other efficacy metrics such as quality of life and functional performance.

“As a next step, we look forward to completing the ongoing open label safety extension trial of AXS-12 as we work to bring this treatment to individuals living with narcolepsy,” Tabuteau said.

SYMPHONY is a randomized, double-blinded and placebo-controlled trial with 90 narcolepsy patients enrolled. AXS-12 or placebo was given once-daily during the first week of treatment, followed twice-daily dosing during the second to fifth weeks. The study’s primary outcome was the frequency of cataplexy attacks.

In addition to cataplexy, SYMPHONY assessed the effects of AXS-12 on other narcolepsy symptoms and found that the candidate could likewise significantly improve excessive daytime sleepiness after five weeks versus placebo. AXS-12 treatment also resulted in rapid and significant improvements in cognitive function, quality of life, patient function and overall narcolepsy disease condition.

In terms of safety, SYMPHONY found AXS-12 to be well-tolerated, with most adverse events being mild to moderate in severity. Only one patient in the AXS-12 arm dropped out of the study due to side effects, and there were no serious adverse events reported.

AXS-12, also called reboxetine, is an investigational small molecule drug that works via two mechanisms of action. The drug blocks the reuptake of hormone noradrenaline, which helps regulate noradrenergic activity and maintains tone during wakefulness, while also modulating cortical dopamine levels to promote wakefulness and boost cognition.

The candidate has previously won the FDA’s Orphan Drug Designation, which may give it seven years of marketing exclusivity in the U.S. if approved by the regulator.

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

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