Sleep Pharmaceutical Update Nov/Dec 2024
Eight abstracts presenting data from across the sleep portfolio of Jazz Pharmaceuticals plc were featured at the 37th annual Psych Congress, held Oct. 29–Nov. 2, 2024 in Boston. That data included topline results of the Phase 4 DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment) trial, which evaluated the effectiveness of low-sodium oxybate on key sleep outcomes in adults with narcolepsy or idiopathic hypersomnia (IH).
These DUET data are the first to show prospective improvements on excessive daytime sleepiness (EDS), as well as key polysomnography (PSG) outcomes of sleep disruption, among adults with narcolepsy treated with Xywav® (calcium, magnesium, potassium, and sodium oxybates) oral solution. Further, new DUET data evaluating nighttime Xywav treatment in adults with IH demonstrate clinical improvements on daytime symptoms, including sleep inertia.
“The new DUET data presented today demonstrate the impact of low-sodium Xywav treatment on key narcolepsy and idiopathic hypersomnia symptoms,” said Logan Schneider, MD, adjunct clinical associate professor of sleep medicine at Stanford Sleep Center and consultant neurologist at Stanford/VA Alzheimer’s Center. “These data build on our confidence that appropriate treatment can meaningfully impact the outcomes that matter to patients and their functioning.”
The DUET trial is a Phase 4, prospective, single-arm, open-label study to assess the effect of Xywav treatment on EDS, PSG parameters, and functional outcomes in adults with narcolepsy or IH. Observed adverse events were consistent with the known safety profile of Xywav, with the most common including nausea, dizziness, and headache.
AXS-12 Achieves Primary Endpoint in ENCORE Long-Term Phase 3 Trial in Narcolepsy
Axsome Therapeutics, Inc. announced that AXS-12 (reboxetine) achieved the primary endpoint in the ENCORE Phase 3 trial, demonstrating a statistically significant improvement in the frequency of cataplexy attacks compared to placebo. A highly selective and potent norepinephrine reuptake inhibitor and cortical dopamine modulator, AXS-12 was also well-tolerated with long-term dosing with a safety profile consistent with previously completed trials.
“Narcolepsy is a complex and heterogeneous condition defined by distinct symptom clusters and there remains great need for options that can address this variety in disease presentation,” commented 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 New York. “The results from the ENCORE study support AXS-12 as a potentially important new option for physicians and patients.”
ENCORE was a multi-center, two-period Phase 3 trial evaluating the long-term efficacy and safety of AXS-12 in patients with narcolepsy with cataplexy. It consisted of a six-month open-label AXS-12 treatment period, followed by a three-week double-blind, placebo-controlled, randomized withdrawal period. The trial enrolled 68 patients in the six-month AXS-12 treatment period. Patients (n=42) were then randomized in a 1:1 ratio to continue treatment with AXS-12 or to discontinue AXS-12 and switch to placebo for three weeks.
AXS-12 met the primary endpoint of the change from randomization in the frequency of cataplexy attacks as compared to placebo at week three of the double-blind period. Patients randomized to switch to placebo experienced a statistically significant worsening in the average weekly number of cataplexy attacks compared with patients randomized to continue AXS-12 treatment, with an increase of 10.29 attacks per week with placebo vs.1.32 with AXS-12, at three weeks (p=0.017).
“Clinical evidence continues to support AXS-12 as a novel treatment option for narcolepsy that has the potential to rapidly and durably ameliorate one of the most debilitating symptoms for patients, cataplexy, while also reducing the severity of excessive daytime sleepiness, and improving cognition and overall function,” Dr. Thorpy said.
According to CEO Herriot Tabuteau, MD, Axsome Therapeutics plans to move expeditiously towards an NDA filing for AXS-12 and intends to request a pre-NDA meeting with the FDA.
U.S. District Court Upholds FDA Approval and Orphan Drug Exclusivity of LUMRYZ
With its original approval on May 1, 2023, the U.S. Food and Drug Administration granted seven years of orphan drug exclusivity to LUMRYZ for the treatment of cataplexy or EDS in adults with narcolepsy due to a finding of clinical superiority of LUMRYZ relative to currently available oxybate treatments. Jazz Pharmaceuticals then filed a complaint against the FDA to challenge the drug’s orphan status and clinical superiority.
Avadel CNS Pharmaceuticals LLC intervened to defend the FDA’s actions and successfully argued to uphold approval of LUMRYZ, the first and only once-at-bedtime oxybate treatment for cataplexy or excessive daytime sleepiness in adults with narcolepsy.
On Oct. 30, 2024, the U.S. District Court for the District of Columbia ruled in favor of the FDA and denied Jazz’s challenge of the drug. With this ruling, the approval of LUMRYZ is upheld based on the FDA’s determination that LUMRYZ is clinically superior to Jazz’s twice-nightly oxybate products.
“Yesterday’s ruling further solidifies LUMRYZ’s unique once-at-bedtime dosing schedule as a major contribution to patient care and enables us to continue executing on our commercial launch and expanding LUMRYZ’s reach within the narcolepsy community,” said Greg Divis, chief executive officer at Avadel Pharmaceuticals.
The FDA approval of LUMRYZ was supported by results from REST-ON, a randomized, double-blind, placebo-controlled, pivotal Phase 3 trial in adults with narcolepsy that showed LUMRYZ demonstrated statistically significant and clinically meaningful improvements in EDS, clinicians’ overall assessment of patients’ functioning, and cataplexy attacks. On Oct. 16, 2024, Lumryz was additionally approved as a once-at-bedtime treatment for cataplexy or excessive daytime sleepiness in pediatric patients aged 7 and older with narcolepsy.
Source: Sleepworld Magazine November/December 2024 Issue
