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GHB as a GABA Receptor Agonist for Narcolepsy Therapy

NeurologyLive, August 2021, Volume 4, Issue 4

γ-Hydroxybutyrate, known as GHB or oxybate, is a physiological compound present in the human body as both a precursor and degradation product of GABA.

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

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 efficiency1,3,18; specifically, GHB binds GABAB receptors to inhibit dopamine release3,9 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

Because narcolepsy has no known cure, current therapies focus on symptom management3,8,9; 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

REFERENCES
1. Kornum, B. R. et al. Narcolepsy. Nat Rev Dis. Primer 3, 16100 (2017).
2. Plazzi, G. et al. Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation. Lancet Child Adolesc. Health 2, 483–494 (2018).
3. Kothare, S. V. & Kaleyias, J. Pharmacotherapy of Narcolepsy: Focus on Sodium Oxybate. Clin. Med. Insights Ther. 2, CMT.S1087 (2010).
4. Dias Costa, F. et al. Narcolepsy in pediatric age – Experience of a tertiary pediatric hospital. Sleep Sci. 7, 53–58 (2014).
5. Bassetti, C. L. Narcolepsy: Selective hypocretin (orexin) neuronal loss and multiple signaling deficiencies. Neurology 65, 1152–1153 (2005).
6. Longstreth, W. T., Koepsell, T. D., Ton, T. G., Hendrickson, A. F. & van Belle, G. The Epidemiology of Narcolepsy. Sleep 30, 13–26 (2007).
7. Carter, L. P., Acebo, C. & Kim, A. Patients’ journeys to a narcolepsy diagnosis: a physician survey and retrospective chart review. Postgrad Med. 126, 216–224 (2014).
8. Narcolepsy Fact Sheet | National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Narcolepsy-Fact-Sheet.
9. Thorpy, M. J. & Bogan, R. K. Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications. Sleep Med. 68, 97–109 (2020).
10. Seiden, D., Tyler, C. & Dubow, J. Pharmacokinetics of FT218, a Once-Nightly Sodium Oxybate Formulation in Healthy Adults. Clin Ther. S0149-2918(21)00044–8 (2021) doi:10.1016/j.clinthera.2021.01.017.
11. Bogan, R. K. et al. Efficacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy. Sleep. 44, (2021).
12. Broughton, R. et al. Excessive Daytime Sleepiness and the Pathophysiology of Narcolepsy-Cataplexy: A Laboratory Perspective. Sleep 9, 205–215 (1986).
13. Sleep Neurobiology from a Clinical Perspective. Sleep (2011) doi:10.5665/SLEEP.1112.
14. Bowery, N. G. & Smart, T. G. GABA and glycine as neurotransmitters: a brief history. Br J Pharmacol. 147, S109–S119 (2006).
15. Developing New Treatments | Narcolepsy. https://healthysleep.med.harvard.edu/narcolepsy/treating-narcolepsy/developing-new-treatments.
16. Valencia Garcia, S. et al. Ventromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder. Nat Commun. 9, 504 (2018).
17. Szabadi, E. GHB for cataplexy: Possible mode of action. J Psychopharmacol. Oxf. Engl. 29, 744–749 (2015).
18. Kamal, R. M. et al. The Neurobiological Mechanisms of Gamma-Hydroxybutyrate Dependence and Withdrawal and Their Clinical Relevance: A Review. Neuropsychobiology 73, 65–80 (2016).
19.Maitre, M. THE γ-HYDROXYBUTYRATE SIGNALLING SYSTEM IN BRAIN: ORGANIZATION AND FUNCTIONAL IMPLICATIONS. Prog. Neurobiol. 51, 337–361 (1997).
20. Khatami, R. et al. Insufficient Non-REM Sleep Intensity in Narcolepsy-Cataplexy. Sleep. 30, 980–989 (2007).
21. A Multicenter Study of the Efficacy and Safety of Xyrem With an Open- Label Pharmacokinetic Evaluation and Safety Extension in Pediatric Subjects With Narcolepsy With Cataplexy - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02221869.
22. Jazz Pharmaceuticals Announces U.S. FDA Approval of XywavTM (calcium, magnesium, potassium, and sodium oxybates) Oral Solution for Cataplexy or Excessive Daytime Sleepiness Associated with Narcolepsy | Jazz Pharmaceuticals plc. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-xywavtm-calcium/.
23. Jazz Pharmaceuticals. A Double-Blind, Placebo-Controlled, Randomized-Withdrawal, Multicenter Study of the Efficacy and Safety of JZP-258 in Subjects With Narcolepsy With Cataplexy. https://clinicaltrials.gov/ct2/show/NCT03030599 (2020).
24. Resources to Help Manage XYWAV Patients | XYWAV for HCPs. Xywav HCP (Final) https://www.xywavhcp.com/resources/.
25. A Patient-Centric, Prospective, Observational, Non-Interventional Switch Study of XYWAV in Narcolepsy - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04803786.
26. Avadel Presents New Clinical Data from Pivotal Phase 3 REST-ON Trial Supporting Clinical Benefit of FT218 in Patients with Narcolepsy at SLEEP 2021. 3.
27. Avadel. A Double-blind, Randomized, Placebo Controlled, Two Arm Multi-center Study to Assess the Efficacy and Safety of a Once Nightly Formulation of Sodium Oxybate for Extended-Release Oral Suspension (FT218) for the Treatment of Excessive Daytime Sleepiness and Cataplexy in Subjects With Narcolepsy. https://clinicaltrials.gov/ct2/show/NCT02720744 (2020).
28. Avadel. Open Label Study of Safety/Tolerability of Once Nightly FT218 for the Treatment of Excessive Daytime Sleepiness and Cataplexy in Narcolepsy Patients That Have and Have Not Been Previously Maintained on Twice-nightly Sodium Oxybate IR. https://clinicaltrials.gov/ct2/show/NCT04451668 (2021).
29. Miyagawa, T. & Tokunaga, K. Genetics of narcolepsy. Hum. Genome Var. 6, 1–8 (2019).