FDA “Tentative Approval” of Once-Nightly Sodium Oxybate: Not a “Product” Issue, but a “Patent” Issue on the Cusp

Narcolepsy is classified as a chronic disease characterized by excessive daytime sleepiness (EDS), cataplexy, disrupted nighttime sleep (DNS), sleep paralysis, and hypnagogic/hypnopompic hallucinations.¹ In 2016, the estimated prevalence of narcolepsy was around 44 per 100,000 people, and it appears to be increasing over time, although this may be due to better diagnostic recognition.² Narcolepsy can have an impact on quality of life because patients may experience EDS, which can lead to fatigue, a decline in work performance, difficulty staying awake while driving, and impairments in the ability to focus and maintain personal relationships.³

Symptom management for narcolepsy is typically achieved through both behavioral and pharmacological therapy.⁴ Pharmacological treatments for excessive somnolence in narcolepsy include stimulants such as methylphenidate, modafinil, amphetamines, solriamfetol, and codeine. Sodium oxybate is commonly used to treat cataplexy, EDS, and DNS.⁴ Currently, the only approved version of sodium oxybate in the United States has a short half-life and immediate-release formulation, which requires twice-nightly dosing with a second dose taken 2.5 to 4 hours after the first dose.^5,6 A once-nightly formulation of the drug has been developed and showed good safety and efficacy in a phase 3 clinical trial. On July 18, 2022, once-nightly sodium oxybate for the treatment of narcolepsy received tentative approval from the US Food and Drug Administration (FDA).⁷ The agency had no issue with the formulation’s safety or efficacy; rather, full approval was delayed because of patent issues.

Background on FDA Tentative Approval

The FDA issues a tentative approval when a product meets the approval requirements of safety, efficacy, and quality under the Federal Food, Drug, and Cosmetic Act, but there are legal reasons that the product is not yet approvable.⁸ The FDA can issue a tentative approval if a new drug application (NDA) otherwise meets their requirements but there are patent or exclusivity issues.⁸ Final approval is only granted once any blocking patents or exclusivity have been extinguished or otherwise resolved.⁸

Tentative approval is more commonly issued in the context of generic drugs.⁹ These generics are often new versions of previously approved drugs such as fixed-dose combinations or new strengths or formulations that are designed for ease of use or for children. The situation may also arise in the context of an NDA in a hybrid application known as a 505(b)(2) NDA that builds off of the FDA’s findings of safety and effectiveness for other drug products called the reference listed drug. Whenever there is a reliance on a reference listed drug, patent and exclusivity protections govern approval, regardless of the safety and efficacy profile of the drug product.⁸ The drug cannot be sold in the United States until the barriers have been addressed.⁸

Phase 3 REST-ON Trial

The once-nightly sodium oxybate formulation currently pending full FDA approval was evaluated in the phase 3 REST-ON trial (NCT02720744).¹⁰ The double-blind, placebo-controlled, 2-arm, multicenter, randomized study enrolled 222 patients with narcolepsy, with or without cataplexy. Participants included patients with type 1 or type 2 narcolepsy, the majority of whom were diagnosed with type 1 with cataplexy. The 3 main endpoints were:

• Change from baseline in mean sleep latency on the Maintenance of Wakefulness Test
• Clinical Global Impression-Improvement rating
• Mean number of cataplectic episodes per week

REST-ON’s design included a 3-week screening period, a 13-week treatment period, and a 1-week follow-up period.¹⁰ The study drug was titrated so that all participants received all dosages.¹⁰ The initial dose was 4.5 g for 1 week and increased to 6 g for weeks 2 to 3, 7.5 g for weeks 4 to 8, and 9 g for weeks 9 to 13.¹⁰

All 3 main endpoints demonstrated statistically significant improvements compared with placebo. At 9 g of once-nightly sodium oxybate, sleep latency was increased to 10.8 minutes versus 4.7 minutes with placebo (least squares mean difference [LSMD, 95% CI], 6.13 [3.52 to 8.75]); 72.0% versus 31.6% were rated much/very much improved on Clinical Global Impression-Improvement (odds ratio [95% CI], 5.56 [2.76 to 11.23]); decrease in mean weekly number of cataplexy attacks was –11.5 versus –4.9 (LSMD [95% CI], –6.65 [–9.32 to –3.98]), and change in Epworth Sleepiness Scale was –6.5 and –2.7, respectively (LSMD [95% CI], –6.52 [–5.47 to –2.26]). See Figure 1 for changes at all doses of sodium oxybate. The Epworth Sleepiness Scale also showed significant improvement for patients treated with once-daily sodium oxybate compared with placebo.¹⁰

Figure 1. Change from baseline for the 3 primary endpoints.¹⁰

 CGI-I, Clinical Global Impression of Improvement; LSM, least squares mean; LSMD, least squares mean difference; mITT, modified intent to treat; MWT, Maintenance of Wakefulness Test; ON-SXB, once-nightly sodium oxybate; OR, odds ratio; SD, standard deviation.

The safety profile for once-daily sodium oxybate was similar to what is already known for this medication, with no new safety signals emerging in this trial.^6,10,11 Common adverse reactions included nausea, vomiting, headache, dizziness, and enuresis.

Why Is There No FDA Approval for Marketing of Once-Nightly Sodium Oxybate?

The FDA application for once-nightly sodium oxybate hinges on the safety and efficacy of a modified version of a previously approved moiety, which is the twice-nightly version. The once-nightly version, Lumryz, is a modified version of twice-nightly Xyrem.⁶ Because Xyrem was the reference listed drug in the application, its sponsor can litigate certain listed patents, which are listed by the FDA in a resource called the Orange Book, prior to product launch. Jazz Pharmaceuticals (Jazz) had a listed patent covering risk evaluation and mitigation strategies (REMS) in the Orange Book; this required that the FDA be informed that the REMS would be infringed by the launch of the proposed drug product. The FDA plays a ministerial role and only evaluates what the reference listed drug sponsor states that the patent covers. Jazz sued Avadel Pharmaceuticals (Avadel; sponsor of Lumryz), arguing patent infringement on the REMS patent. Avadel countersued, claiming that the REMS patent should never have been listed in the Orange Book because the patent covers a method of distribution, not the drug or a method of using it.

On November 18, 2022, the US District Court ordered Jazz Pharmaceuticals’ sodium oxybate REMS patent delisted from the Orange Book. Jazz has appealed this decision and was granted a stay until the appeal has been resolved. That means that if the REMS patent is delisted from the Orange Book, then it should not have been litigated before the launch of the Avadel product. Avadel is unable to request that the FDA convert its tentative approval to final approval until the litigation has been resolved, and the Federal Circuit may take a few months (early 2023) to decide. The patent in question expires in June 2023, so final approval is expected by then.

Impact on Clinical Practice and Patient Care

Narcolepsy can be difficult to treat, and clinicians need effective therapies. A once-nightly medication is beneficial for patients because they do not need to wake up in the middle of the night to take a second dose. Only 55% of patients with narcolepsy have good adherence (80% or better) to wakefulness-promoting medication, and overall medication adherence in this population is considered suboptimal.¹² The ability to take only one nightly dose is expected to improve patient adherence to the medication.^12,13 Forced awakening is disruptive to some patients, particularly individuals who already experience sleep fragmentation and poor sleep quality.¹⁴

Conclusion

Sodium oxybate has been available for over 2 decades with accompanying data showing efficacy and safety. A phase 3 clinical trial demonstrated that once-nightly sodium oxybate has safety and efficacy similar to twice-nightly sodium oxybate, but it is not available to patients in the United States due to a patent issue, not any issues of efficacy, safety, or manufacturing. Once-nightly dosing has the potential to make a real difference for patients and positively impact their quality of life. However, the FDA approval process is complicated and goes beyond considerations of safety, efficacy, and quality. For once-nightly sodium oxybate, the delay in approval is not due to product efficacy and safety, but to a REMS patent.

References

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14. Center for Drug Evaluation and Research (CDER). The Voice of the Patient: Narcolepsy. US Food and Drug Administration; 2014.