Axsome Therapeutics Announces New SYMPHONY, CRESCENDO Data in Narcolepsy

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Axsome Therapeutics announced on March 25 reboxetine (AXS-12) achieved the primary endpoint in the SYMPHONY phase 3 trial in narcolepsy, and the CRESCENDO trial revealed current narcolepsy treatments fall short.^1,2

The CRESCENDO trial surveyed 203 adult patients with narcolepsy type 1 who were undergoing current treatment options for narcolepsy: wake-promoting agents (53%), oxybates (47%), and stimulants (42%).² However, despite receiving treatment, many narcolepsy patients still experienced symptoms, such as cataplexy in 77% of the patients, excessive daytime sleepiness in 64% of patients, cognitive impairment in 74% of patients, and depression and anxiety experienced by approximately 45% and 57% of patients, respectively.

Although the CRESCENDO trial showed current narcolepsy treatments are not effective enough, the opposite was the case for the SYMPHONY trial assessing reboxetine in narcolepsy type 1.

In the SYMPHONY trial, reboxetine, compared to placebo, significantly reduced cataplexy attacks, achieved remission of cataplexy, reduced excessive daytime sleepiness, improved concentration and memory, reduced severity of narcolepsy, and improved function and quality of life.¹

SYMPHONY, a phase 3 multicenter, randomized, double-blind, placebo-controlled trial, evaluated reboxetine, a selective and potent norepinephrine reuptake inhibitor, and a cortical dopamine modulator, in 90 patients with narcolepsy and cataplexy. Participants were randomized to take reboxetine or placebo for 5 weeks.

“Despite the existence of multiple approved narcolepsy treatments, significant unmet need still exists given the high rates of persistent symptoms reported by patients,” said Michael Thorpy, MD, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center and Professor of Neurology at Albert Einstein College of Medicine, in the press release. “Based on the concurrent improvements observed on cataplexy, severity of excessive daytime sleepiness, cognition, and overall function, I believe AXS-12 represents a meaningful enhancement to the treatment armamentarium for narcolepsy patients and clinicians and will be a welcome treatment option in our fight against the devastating impact of narcolepsy on patients and their loved ones.”

The trial met its primary endpoint since participants had significantly fewer weekly cataplexy attacks after 5 weeks on reboxetine, with a reduction from baseline of 83% for the reboxetine group and 66% for placebo (P = .018). Reboxetine rapidly reduced weekly cataplexy attacks; already by week 1, participants on reboxetine had a 56% reduction compared to a 31% reduction for placebo (P = .007).

By week 5, 33% of participants on reboxetine had a remission of cataplexy, compared to only 9.5% of placebo participants (P = .008).

The study showed a rapid achievement of remission; by week 2, 24% of participants on reboxetine reached remission, compared to 4.5% of placebo patients (P = .008).

Overall, reboxetine increased the number of days with zero cataplexy attacks to 84.5% at week 5, compared to 22.6% for placebo (P = .014).

Other than reducing and reaching remission of cataplexy attacks, reboxetine also significantly decreased excessive daytime sleepiness. By week 5, participants on reboxetine had a mean reduction of excessive daytime sleepiness compared to placebo (1.8 points vs 0.9 points, respectively) (P = .027).

The team saw improved excessive daytime sleepiness for participants on reboxetine versus placebo by week 1 (P = .006).

Improvement in concurrent excessive daytime sleepiness and cataplexy response was achieved at week 5 by 57% of patients on reboxetine compared to 44% of patients on placebo (P = .029). Improvement was considered a ≥ 30% reduction in unintentional naps and a ≥ 50% reduction in cataplexy attacks.

At week 5, the team saw 54% of patients on reboxetine compared to 28% of patients on placebo had a reduction of inadvertent naps (P = .016). Patients on reboxetine had greater improvement on the Epworth Sleepiness Scale than placebo with a reduction difference from baseline of 4.7 points vs 3.4 points, respectively. In total, 60% of participants on reboxetine had a ≥ 3-point from improvement from baseline on the Epworth Sleepiness Scale.

Furthermore, reboxetine significantly improved concentration and memory from baseline to week 5 (P = .004). Participants achieved cognitive and cataplexy response by week 5 for 41% of patients with reboxetine and 17% with placebo (P = .016).

The study found reboxetine brought a rapid and significant reduction in narcolepsy severity compared to placebo by week 5 (P = .007). The team saw improvements in narcolepsy severity as early as week 1 (P < .001). Additionally, reboxetine significantly improved function and quality of life by week 5, compared to placebo (P = .005).

Of the 45% of participants who had anxiety and depression at baseline, reboxetine improved these psychiatric symptoms in 55% of patients, compared to the 32% of patients on placebo.

Overall, reboxetine was well-tolerated, with the most common adverse events—dry mouth, nausea, and constipation—being mild to moderate in severity.

Since reboxetine was granted an Orphan Drug Designation for the treatment of narcolepsy in October 2018, Axsome may exclusively market the drug in the US for 7 years upon the US Food and Drug Administration (FDA) application.

“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,” said Herriot Tabuteau, CEO of Axsome Therapeutics, in a press release.

^References

1. ^{Axsome Therapeutics Announces AXS-12 Achieves Primary Endpoint in the SYMPHONY Phase 3 Trial in Narcolepsy. GlobalNewsWire. March 25, 2024. https://www.globenewswire.com/news-release/2024/03/25/2851469/33090/en/Axsome-Therapeutics-Announces-AXS-12-Achieves-Primary-Endpoint-in-the-SYMPHONY-Phase-3-Trial-in-Narcolepsy.html. Accessed March 25, 2024.}
2. ^{Axsome Therapeutics Announces Results of CRESCENDO Narcolepsy Patient Survey Demonstrating Unmet Needs in Treated Narcolepsy Type 1 Patients. GlobalNewsWire. March 25, 2024. https://www.globenewswire.com/news-release/2024/03/25/2851482/33090/en/Axsome-Therapeutics-Announces-Results-of-CRESCENDO-Narcolepsy-Patient-Survey-Demonstrating-Unmet-Needs-in-Treated-Narcolepsy-Type-1-Patients.html. Accessed March 25, 2024.}