GHB as a GABA Receptor Agonist for Narcolepsy Therapy

NARCOLEPSY IS A CHRONIC SLEEP DISORDER that can have debilitating consequences. The disorder typically begins in childhood or adolescence,^1-3 with mild initial symptoms that can worsen with time.^4,5 Narcolepsy is increasingly recognized as an autoimmune disorder,¹ whereby the immune system reacts to an external trigger (eg, viral) in such a way that it attacks the brain cells (ie, hypocretin neurons) that synthesize a neuropeptide (ie, hypocretin) that regulates wakefulness and sleep.⁴ However, the exact cause remains unknown; genetic risk factors or environmental triggers may precede the loss of hypocretin neurons and subsequent hormone imbalances characteristic of the disorder.^5,6 Because of heterogeneity in the development and severity of symptoms,^6,7 many individuals do not receive narcolepsy diagnosis until years after onset.^4,5,7,8

Jennifer S. Sun, PhD

Narcolepsy features excessive daytime sleepiness (EDS), sudden loss of muscle tone (cataplexy), disturbed nocturnal sleep, and hypnagogic and/or hypnopompic hallucinations.^1-3,9-11 EDS affects all patients with narcolepsy and is often a primary symptom,^1-3,11 accompanied by bouts of irresistible “sleep attacks” that occur without warning and can last up to several minutes.^3,12 Narcolepsy is categorized into 2 major types based on the presence/absence of cataplexy and the level of hypocretin: type 1, cataplexy present and hypocretin low; and type 2, cataplexy absent and hypocretin normal.^1,2,9,10 Cataplexy is a particularly disruptive symptom that is unique to narcolepsy that can leave patients fully immobile while they maintain conscious awareness.^1,3,11,12 Consequently, those with type 1 narcolepsy can experience more severe symptoms.⁸

Sleep and wakefulness are regulated by interconnected brain circuits that modulate systems of neurotransmitters such as norepinephrine, serotonin, dopamine, histamine, and hypocretin (FIGURE).^1,13 The most important inhibitory neurotransmitter of the mammalian central nervous system (CNS) is γ-aminobutyric acid (GABA),¹⁴ which can promote feelings of happiness and sedation.^9,15 GABA-containing neurons that originate in the ventrolateral and median preoptic areas of the hypothalamus inhibit wake-promoting neurons, which promotes non–rapid eye movement (REM) sleep.⁹ GABAergic neurons in the ventral medulla mediate the inhibition of motor neurons,¹⁶ whereas those in the amygdala can trigger cataplexy upon evoking positive emotions.⁹ Targeting GABA receptors may therefore enable regulation of sleep duration,⁹ mediate muscle tone,¹⁷ and prevent overstimulation.1⁴

γ-Hydroxybutyrate (GHB or oxybate), a physiological compound present in the human body as both a precursor and degradation product of GABA, acts as an agonist of dedicated GHB receptors (GABAA type¹⁷) and GABAB receptors.^1-3,18 GHB is present at the highest concentrations within the striatum of the developing brain,¹⁹ although it is also present at lower levels in other brain regions and tissues such as heart, liver, kidney, muscle, and brown fat.³ When sufficiently high levels of GHB are achieved through exogenous delivery, the neurotransmitter acts as a GABAB receptor agonist to increase sleep efficiency^1,3,18; specifically, GHB binds GABAB receptors to inhibit dopamine release^3,9 by modulating central cholinergic and serotonergic neurons.¹⁷ GHB has also been demonstrated to dampen the baseline activity of noradrenaline-releasing neurons to a low level that still permits maintenance of muscle tone.¹⁷ GHB at high concentrations is thus regarded as a depressant.¹⁸

SO, sodium oxybate.
(A) Wakefulness regulation by hypocretin neurons.¹
(B) FT218 (once-nightly SO) compared with Xyrem (twice-daily SO).¹⁰

Figure A reprinted with permission from Kornum BR, Knudsen S, et al. Narcolepsy. Nat Rev Dis Primers. 2017;3:16100. doi:10.1038/nrdp.2016.100.1

Figure B reprinted with permission from Seiden D, Tyler C, Dubow J. Pharmacokinetics of FT218, a once-nightly sodium oxybate formulation in healthy adults. Clin Ther. 2021:S0149-2918(21)00044-8. doi:10.1016/j.clinthera.2021.01.017.10

Because narcolepsy has no known cure, current therapies focus on symptom management^3,8,9; for example, GHB has been proven effective in reducing EDS and both the frequency and severity of cataplexy episodes.^2,3 Synthetic GHB is a highly hygroscopic compound that is amenable to oral administration.³ This exogenous GHB is absorbed and metabolized rapidly, reaching a peak plasma concentration 30 to 90 minutes after ingestion and decaying with a short half-life of approximately 60 minutes.^3,18 GHB has been shown to reduce the activity of patients’ thalamic, hippocampal, and neocortical neurons.³ Serotonin turnover in the brain is consequently increased, promoting slow-wave sleep.¹⁸ Dopamine release is also inhibited, improving sleep efficiency.3 GHB treatment is thus able to counteract sleep latency,¹⁸ promoting the deep, slow-wave, non-REM sleep that is severely lacking in individuals with narcolepsy.^19,20

Sodium oxybate (Xyrem; Jazz Pharmaceuticals), is the standard of care for the treatment of EDS and cataplexy in patients with narcolepsy and is FDA approved for those aged 7 years and older.^1-3 The pivotal phase 3 study (NCT02221869) recruited 106 participants aged 7 to 16 years who had received a diagnosis of narcolepsy with cataplexy.^2,21 Patients were excluded if they had significant comorbidities or had previously experienced lack of success with sodium oxybate therapy.² Enrolled patients were either sodium oxybate naive (70%) or already on a sodium oxybate regimen (30%).² Most patients were White (69%) and male (59%), with a median age of 12 years, and had received a diagnosis of narcolepsy a median of 1 to 2 years prior.² Treatment-naive patients first received dose titration to an effective and tolerable sodium oxybate dose (ranging from 3-9 g) over 3 to 10 weeks.² Following a stable-dose period of 2 to 3 weeks, participants were then randomly assigned to either continue sodium oxybate treatment or switch to placebo for a 2-week doubleblind treatment (randomized withdrawal) period.² During the subsequent 47-week open-label safety period, all patients received sodium oxybate.² The primary end point was change in the weekly number of cataplexy episodes from the end of the stable-dose period to the end of the treatment period.² Secondary end points included changes in the severity of cataplexy episodes (measured with the Clinical Global Impression-Improvement [CGI-I] scale) and in EDS (measured with the Epworth Sleepiness Scale [ESS]) over the same period.2 Patients on a median 7-g dose of sodium oxybate showed significant improvements in the number of weekly cataplexy episodes by week 2 (median of 21 weekly cataplexy attacks in weeks 1 and 2 of the double-blind treatment period for placebo vs 6 for treatment), in the severity of attacks (66% worse for placebo vs 17% worse for treatment), and in EDS (median change in ESS score of +3 for placebo vs 0 for treatment).^1-3 Adverse events (AEs), which were reported by 72% of patients, were mostly mild or moderate and were resolved without changing the sodium oxybate dose.² Taken together, results to date provide strong evidence of the effectiveness of sodium oxybate in managing EDS and cataplexy.

Xywav (JZP-258; Jazz Pharmaceuticals) is an oxybate formulation that contains the same active moiety as Xyrem but a different blend of cations (calcium, magnesium, potassium, and sodium) to reduce sodium intake by 92%.¹¹ Similar to Xyrem, Xywav is prescribed for the treatment of narcolepsy-associated EDS or cataplexy in patients as young as 7 years.¹¹ FDA approval was granted in 2020 after successful demonstration of efficacy and safety in a multicenter phase 3, placebo-controlled, doubleblind, randomized withdrawal study (NCT03030599).^21-23 Patient selection criteria included a history of at least 14 cataplexy attacks within a typical 2-week period in the absence of narcolepsy treatment.¹¹ Exclusion criteria included participants whose narcolepsy was secondary to another medical condition and individuals with major depression or a history of psychotic disorders, among others.¹¹ The study enrolled 201 patients aged 18 to 70 years, the majority of whom were White (88.1%) and female (60.7%).¹¹ Patients were categorized based on use of cataplexy treatments at study entry: sodium oxybate (Xyrem) only, sodium oxybate plus another anticataplectic, an anticataplectic other than sodium oxybate, or no anticataplectic medication.¹¹ Use of stimulants at study entry was allowed, with 39% of patients on stimulants at study entry maintaining a stable dose of stimulants throughout the trial.¹¹ Patients not on sodium oxybate therapy at entry immediately began Xywav at 4.5 g per night, whereas those already taking sodium oxybate were switched to Xywav at the same dosage as the sodium oxybate. After 2 weeks, the dose was titrated up at nightly steps of 1.5 g to a stable, tolerable, and effective level over the following 8 weeks (maximum 9 g per night).^11,24 Anticataplectics other than sodium oxybate were tapered down after 2 weeks and discontinued by week 10.11 After dose titration, all patients remained on the optimal dose of Xywav for a 2-week stable-dose period before being randomized to either continue Xywav treatment or switch to placebo for a 2-week double-blind randomized withdrawal period.¹¹ The primary end point was change in the weekly number of cataplexy attacks from during the stable-dose period to during the randomized withdrawal period.¹¹ The key secondary end point was change in EDS (measured with ESS) during the same interval.¹¹ Overall, Xywav was determined to have superior efficacy to placebo; patients randomized to the latter experienced significantly more weekly cataplexy attacks and worse EDS than those who remained on Xywav.¹¹ Although 76.1% of participants randomized to Xywav reported AEs, the symptoms were generally mild or moderate in severity.¹¹ A phase 4 clinical trial (NCT0479449113) and a noninterventional trial (NCT04803786)25 are currently underway to examine the real-world effects of transitioning from sodium oxybate to Xywav.

FT218 (Avadel Pharmaceuticals) is a new sodium oxybate drug that was granted orphan drug designation by the FDA in 2021 for use in adults with type 1 and 2 narcolepsy.²⁶ The advantage of FT218 lies in its once-nightly formulation10 compared with twice-nightly Xyrem or Xywav doses,² which is possible due to Avadel’s trademarked microparticle-based technology (MicroPump26) that delivers a blend of immediate and controlled-release pellets.^11,26 Four phase 1 crossover, single-dose studies (pilot, dose-proportionality, relative bioavailability, and food-effect studies) have demonstrated the effectiveness of a single 4.5- to 9-g dose of FT218 in improving nocturnal sleep consolidation.¹⁰ Results showed that peak plasma concentration was reached at a median of 2 hours post administration compared with the short tmax of 30 minutes for the first dose of twice-nightly sodium oxybate (FIGURE B).¹⁰ The half-life of FT218 was also longer compared with Xyrem (4 hours vs 1.5 hours).¹⁰ Although the maximum concentration of GHB was lower with FT218 than with the 2-dose Xyrem, exposure duration was maintained.¹⁰ Results further showed a predictable pharmacokinetic profile for FT218 that was less affected by coincident food intake compared with Xyrem.¹⁰ The phase 3, placebo-controlled, double-blind, randomized, multicenter REST-ON trial (NCT02720744) assessed the efficacy and safety of FT218 for treating EDS and cataplexy in adult patients with narcolepsy.²⁷ FT218 benefited patients with both type 1 and 2 narcolepsy, with CGI-I data revealing significantly more patients with improved EDS compared with placebo at all tested doses (type 1: 75.5% vs 35.9% at 9 g, 66.9% vs 27.9% at 7.5 g, and 39.9% vs 7.8% at 6 g; all P < .001).²⁶ Sleep latency was also improved compared with placebo, as measured with the Maintenance of Wakefulness Test; at the 9-g dose, the least squares mean difference was 6.0 minutes (P < .001) for patients with type 1 narcolepsy and 6.3 minutes (P < .05) for type 2.²⁶ Avadel is currently recruiting patients for RESTORE, a long-term safety and tolerability study (NCT04451668) of FT218 in patients who are oxybate therapy naive or are currently taking either FT218 or a twice-nightly oxybate therapy.²⁸

Therapeutic strategies that address the underlying cause of narcolepsy, rather than simply managing symptoms,^3,5,8 are desperately needed. Medically appropriate use of sodium oxybate is generally considered safe, with minimal risk of serious AEs; however, there have been reports of addiction, withdrawal syndrome, coma, and even death following abuse of illicit forms of GHB.^1,3,18,24 Systematic studies of the genetic landscape of narcolepsy could inform the development of innovative treatments based on gene therapy or stem cells.^15,29

For correspondence: jsun@nygenome.org
New York Genome Center, New York, NY

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