FDA Approves Once-Nightly Formulation of Sodium Oxybate to Treat Narcolepsy

Michael Thorpy, MD

After recently submitting an amendment to the FDA’s request for final approval, Avadel Pharmaceuticals announced the agency has officially approved its oral, extended-release formulation of sodium oxybate for the treatment of cataplexy or excessive daytime sleepiness in adults with narcolepsy. Marketed as Lumryz, it becomes the first and only FDA-approved once-nightly oxybate for patients with the condition.¹

Lumryz comes with a boxed warning as a central nervous system depressant, and for its potential abuse and misuse. It is currently only available through a restricted program under a Risk Evaluation and Mitigation Strategy called the Lumryz REMS. With the approval, the drug was granted 7 years of orphan drug exclusivity.

"This long-awaited therapy for people living with narcolepsy fills a critical unmet need by avoiding the burden of a second middle-of-the-night dose that immediate-release oxybate products require. The once-at-bedtime dosing regimen of LUMRYZ may help restore a more natural sleep-wake cycle," Michael Thorpy, MD, director, Sleep-Wake Disorders Center, Montefiore, and professor of neurology, Albert Einstein College of Medicine, said in a statement.¹

Thorpy was an investigator from the phase 3 REST-ON trial (NCT02720744), the pivotal study that led to the drug’s approval. Held under a special protocol assessment agreement with the FDA, the study featured 222 patients with narcolepsy type 1 or 2, all aged 16 years or older, who received uptitration doses of 4.5 g, 6 g, 7.5 g, and 9 g of Lumryz or placebo over the course of a 3-week screening period, 13-week treatment period, and 1-week follow-up period. All told, the study met all 3 of its primary end points of change from baseline in mean sleep latency on the Maintenance of Wakefulness test, Clinical Global Impression Improvement, and weekly cataplexy attacks within the 6-, 7.5-, and 9-g groups.²

The data from REST-ON showed a significantly greater increase in sleep latency with FT218 treatment at week 3 for the 6-g dose group (8.1 vs 3.1 min, respectively; least-squares mean difference [LSMD], 4.98; 95% CI, 2.90-7.05; P <.001); at week 8 for the 7.5-g dose group (9.6 vs 3.3 min, respectively; LSMD, 6.21; 95% CI, 3.84-8.58; P <.001); and at week 13 for the 9-g dose group compared with placebo (10.8 vs 4.7 min, respectively; LSMD, 6.13; 95% CI, 3.52-8.75; P <.001).

In December 2020, Avadel submitted a new drug application for Lumryz, otherwise known as FT218, along with amendments pursuant to §505(b)(2) and a proposed REMS. More than a year later, in July 2022, the FDA granted tentative approval to the extended-release formulation of sodium oxybate.³ At the time, the finalization of the approval was pending the disposition of the Jazz Pharmaceuticals’ REMS patent (US Patent No. 8,731,963) listed in the agency’s Orange Book, through the FDA noted that this formulation met all required safety, efficacy, and quality standards for approval.

Subsequently, Avadel filed a motion to the US District Court for the District of Delaware to delist the REMS patent from the FDA’s Orange Book, which was approved in a 3-0 unanimous panel decision in February 2023.⁴ The “963 patent” was related to Jazz’s single-distribution system, which controls access to Xyrem, its twice-nightly, previously approved, formulation of sodium oxybate. Xyrem’s active ingredient is sodium gamma-hydroxybutyrate, commonly known as sodium oxybate, which exerts a heavily sedating effect on patients. GHB is prone to heavy misuse and is infamously known as a date-rape drug.

"Today’s landmark approval and receipt of Orphan Drug Exclusivity represents a major milestone for both Avadel and people living with narcolepsy,” Greg Divis, chief executive officer, Avadel, said in a statement.¹ “As we have heard from key stakeholders, previously approved narcolepsy therapies have the potential to disrupt sleep by either causing insomnia or through forced awakening during the middle of the night for their crucial second dose. LUMRYZ can now offer people with narcolepsy the opportunity for an uninterrupted night sleep while receiving the full benefit of their prescribed treatment in one single bedtime dose that addresses their symptoms of narcolepsy."

REFERENCES
1. Avadel Pharmaceuticals announces final FDA approval of Lumryz (sodium oxybate) for extended-release oral suspension as the first and only once-at-bedtime oxybate for cataplexy or excessive daytime sleepiness in adults with narcolepsy. News release. Avadel Pharmaceuticals. May 1, 2023. Accessed May 1, 2023. https://www.globenewswire.com/news-release/2023/05/01/2658536/0/en/Avadel-Pharmaceuticals-Announces-Final-FDA-Approval-of-LUMRYZ-sodium-oxybate-for-Extended-Release-Oral-Suspension-as-the-First-and-Only-Once-at-Bedtime-Oxybate-for-Cataplexy-or-Exc.html
2. Kushida CA, Shapiro CM, Roth T, et al. Once-nightly sodium oxybate (FT218) demonstrated improvements of symptoms in a phase 3 randomized clinical trial in patients with narcolepsy. SLEEP. 2021; zsab200. doi:10.1093/sleep/zsab200
3. Avadel Pharmaceuticals Announces Tentative Approval of LUMRYZ™ (sodium oxybate) extended-release oral suspension. News release. Avadel. July 19, 2022. Accessed May 1, 2023. https://www.globenewswire.com/news-release/2022/07/19/2481626/0/en/Avadel-Pharmaceuticals-Announces-Tentative-Approval-of-LUMRYZ-sodium-oxybate-extended-release-oral-suspension.html

4. Avadel Pharmaceutical’s requests final FDA approval for Lumryz (sodium oxybate) extended-release oral suspension. News release. Avadel Pharmaceuticals. March 2, 2023. Accessed May 1, 2023. https://seekingalpha.com/pr/19154693-avadel-pharmaceuticals-requests-final-fda-approval-for-lumryz-sodium-oxybate-extended-release?hasComeFromMpArticle=false