Avadel Pharmaceuticals Urges FDA to Make Decision on Extended-Release Formulation of Sodium Oxybate
In a phase 3 study, extended-release sodium oxybate demonstrated statistically significant and clinically meaningful results in excessive daytime sleepiness, clinician’s assessment of patient’s functioning, and reduction in cataplexy attacks.
Greg Divis
Recently, Avadel Pharmaceuticals submitted an amendment to the FDA requesting final approval for its oral, extended-release formulation of sodium oxybate (Lumryz) for the treatment of cataplexy or excessive daytime sleepiness in adults with narcolepsy. The agent, previously known as FT218, received tentative approval from the agency in July 2022, but was blocked from final approval because of Jazz Pharmaceuticals’ REMS Patent in the FDA’s Orange Book.1
In late February 2023, a 3-0 unanimous panel decision by a US appeals court ordered Jazz to de-list the patent, for which they did days later. The “963 patent” is related to Jazz’s single-pharmacy distribution system, which controls access to Xyrem, its twice-nightly formulation of sodium oxybate. Both Lumryz and Xyrem use the same ingredient, though Lumryz is meant to be taken once per night.
"Today is an important day as we’ve taken what we believe is the last step in the NDA review process with the submission of our amendment to the LUMRYZ NDA seeking final approval. We look forward to working with FDA to bring LUMRYZ to all eligible patients as soon as possible," Greg Divis, chief executive officer, Avadel Pharmaceuticals.1 "The value proposition of LUMRYZ, demonstrated by its important benefit to people living with narcolepsy, has been our driving motivation throughout this process, and we stand ready to bring LUMRYZ to the narcolepsy community following an approval."
Xyrem’s active ingredient is sodium gamma-hydroxybutyrate (GHB), 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. Because of this, the FDA conditioned approval of Xyrem upon development of Risk Evaluation and Mitigation Strategies (REMS), which include protocols that must be followed prior to prescribing or dispending the therapy. Xyrem’s REMS originally restricted distribution to a single-pharmacy system, although the FDA waived that requirement in 2017.2
In December 2020, Avadel submitted a new drug application for FT218 along with amendments pursuant to §505(b)(2) and a proposed REMS. FT218’s REMS uses multiple pharmacies and databases for ensuring proper drug handling. Despite the differences between the 2 therapies, FDA required Avadel to file a certification regarding the ‘963 patent’s single-pharmacy system, for which Jazz subsequently sued Avadel for infringement. Avadel contemporaneously sued the FDA, alleging that it violated the Administrative Procedure Act by requiring certification over the ‘963 patent.
FT218’s new drug application was supported by data from the phase 3 REST-ON study (NCT02720744), which was 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 FT218 or placebo over the course of a 3-week screening period, 13-week treatment period, and 1-week follow-up period. The he 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.3
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).
