World Narcolepsy Day 2023: Latest Literature of Therapeutic Progress

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On World Narcolepsy Day 2023, get a recap of the latest advances in narcolepsy that you might have missed over the last few months, compiled all into one place by the NeurologyLive team.

World Narcolepsy Day, held September 22, 2023, is a day dedicated towards raising awareness of narcolepsy on a global scale. Established by 28 patient advocacy organizations across 6 continents in 2019, World Narcolepsy Day unites the international narcolepsy community to inspire action, increase public knowledge, and elevate the voices of those dealing with narcolepsy worldwide.

It is estimated that anywhere from 135,000 to 200,000 people in the US have narcolepsy; however, since this condition often goes diagnosed, the number may be higher.1 Symptoms of narcolepsy include excessive daytime sleepiness, sleep attacks, cataplexy, sleep paralysis, hallucinations, and disrupted nighttime sleep.

In an effort to continue to raise awareness, NeurologyLive rounded up some of the most notable and recent coverage of news within the field of narcolepsy care. This includes advancements in drug development, the understanding of the disease, and new ways of monitoring its progression.

Click here for more coverage of the latest narcolepsy news from NeurologyLive®.

Latest Literature

Long-Term Safety and Tolerability of Sodium Oxybate Confirmed

Recently published in CNS Drugs, findings from a long-term analysis on a phase 3 trial (NCT03030599) investigating low-sodium oxybate (LXB; Xywav; Jazz Pharmaceuticals) showed a safety and tolerability profile that was consistent with previous studies of patients with narcolepsy with cataplexy.2

In the safety population of 201 patients, the most common LXB-emergent TEAE overall was headache (71 events; n = 42 [21%]; median duration, 1 day [range, 1-147]) from the open-label optimized treatment and titration period (OLOTTP) and the stable dose period (SDP). Following headache in this same population, the other most common TEAEs were nausea (31 events; n = 26 [13%]; median duration = 9 days [range, 1-54]) and dizziness (26 events; n = 21 [10%]; median duration = 7 days [1-117]).

In the analysis, researchers explored the time of onset and duration of common TEAEs for LXB throughout the 12-week OLOTTP and the SDP 2-week in the double-blind, placebo-controlled, randomized withdrawal trial, and the subsequent 24-week open-label extension (OLE). At study entry, participants aged 18-70 years with a diagnosis of narcolepsy with cataplexy received sodium oxybate (SXB) alone (n = 52), SXB with other anticataplectics (n = 23), other anticataplectics alone (n= 36), or were anticataplectic–treatment-naïve (n = 90). The authors noted that the other anticataplectics were tapered and discontinued during the OLOTTP.

Nocturnal Sodium Oxybate Treatment Functional Network Changes Associated With Anterior Cingulate GABA

Recently published in Cerebral Cortex, findings from a study demonstrated that anterior cingulate γ-aminobutyric acid (GABA) was associated with subacute changes in brain functional network connectivity following nocturnal sodium oxybate (GHB; Xyrem; Jazz Pharmaceuticals) treatment. These results provide evidence of the persisting internetwork connectivity changes in the morning following a nocturnal therapeutic dose of GHB, a therapeutic often used for patients with narcolespy.3

Among 16 healthy men, a significant effect was observed in the internetwork connectivity of the right central executive network (rCEN) with the salience network (SN) (one sample t-test: P = .038), which was not present in the placebo group (one sample t-test: P = .460). Also, rCEN-SN internetwork connectivity was significantly higher in the GHB group compared with placebo (paired t-test: P = 0.017, Cohen d = 0.49, respectively). Thus, this SN-rCEN coupling was significantly associated with changes in GABA levels in the anterior cingulate cortex (ACC) (all, P<.05).

Investigators conducted a placebo-controlled, double-blind, randomized, cross-over pharmacological magnetic resonance imaging study with a nocturnal administration of GHB, combined with magnetic resonance spectroscopy of GABA and glutamate in the ACC. There were 2 experimental nights investigating GHB versus placebo which were separated by a washout phase of 7 days. The participants wore an actimeter on the nondominant arm and kept a sleep–wake diary. At each experimental night, study participants were awoken at 2:30 AM to receive 50 mg/kg of GHB or placebo, representing the maximal therapeutic starting dose for narcolepsy. Following the treatment, researchers performed the fMRI resting state scans in the morning after both experimental nights.

Ulotaront Fails to Differentiate From Placebo in Phase 1b Crossover Trial for Narcolepsy-Cataplexy

Recently published in Sleep Medicine, findings from a phase 1b crossover trial (NCT05015673) assessing 2 doses of ulotaront (Sunovion) in adult patients with narcolepsy-cataplexy showed that the agent failed to demonstrate significant differences in efficacy from placebo despite increased latency or reduced duration in rapid eye movement (REM) sleep.4 These findings suggest that the effect of ulotaront on REM sleep parameters, not for symptomatic end points, represents a disconnect from efficacy observed with other medications used for narcolepsy-cataplexy.

Acute treatment with both 25 mg and 50 mg of ulotaront reduced minutes spent in nighttime REM compared with placebo (−29.9 min [SD, 16.7] vs. −38.0 min [SD, 46.7], respectively). Similarly, a sustained 2-week administration of both doses of ulotaront reduced the mean number of sleep-onset REM periods during daytime multiple sleep latency test (MSLT) compared with placebo (25 mg: 1.9 [SD, 2.0]; 50 mg: 2.0 [SD, 2.0]; placebo: 3.5 [SD, 1.8]). Despite a reduction in cataplexy events from baseline during the treatment period, neither dose statistically separated from placebo (25 mg: P = .76; 50 mg: P = .82).

In this multicenter, double-blind, placebo-controlled, randomized, 3-way crossover study, 16 adults with narcolepsy-cataplexy received treatment with either 2 oral doses of ulotaront (25 mg and 50 mg) or matching placebo for 2 weeks. Eligible patients were given diaries to document their sleep-wake patterns and consumption of alcohol, caffeine, and nicotine, as well as for assessment of cataplexy and excessive daytime sleepiness.

Opioids Improve Disturbed Nocturnal Sleep and Excessive Daytime Sleepiness in Narcolepsy Type 1

In a recent systematic literature review and questionnaire study published in Sleep Medicine, findings showed that opioids, specifically oxycodone and codeine, were associated with improvements in self-reported narcolepsy symptoms such as disturbed nocturnal sleep and excessive daytime sleepiness. Overall, these findings suggest that opioid use could provide symptom relief in patients with narcolepsy type 1.5

Among 7 studies selected for possible effects of opioids on narcolepsy symptom severity, 3 involved codeine, including 2 case reports and 1 report combining a case series, open label study and a randomized controlled trial. The analysis also yielded 1 conference presentation on methadone, 1 case series on tramadol, 1 case report on oxycodone and buprenorphine, and 1 postmortem study on the effects of morphine and heroin on hypocretin-producing neuron counts.

In a questionnaire of 100 respondents, recent opioid use was reported in 16% of patients comprising of 20 opioids (codeine, n = 7; tramadol, n = 6; oxycodone, n = 6; fentanyl, n = 1). Among these patients, narcolepsy symptom changes were reported in 11 individuals (95% CI, 32%-76%]) with 9 considered positive (95% CI, 24%-68%), 1 mixed (95% CI, 0%-27%]) and 1 negative report (95% CI, 0%-27%). Positive effects were observed on disturbed nocturnal sleep (9/20), excessive daytime sleepiness (4/20), hypnagogic hallucinations (3/17), cataplexy (2/18), and sleep paralysis (1/13), with effects most pronounced in patients who took oxycodone (4 of 6). Moderate positive effects were seen in patients who took codeine, with 4 of 7 individuals reporting a beneficial impact.

Longer Sleep Latency Time Observed With Recent Definition of Sleep Onset, Meta-Analysis Shows

In a recent systematic review and meta-analysis published in Sleep Medicine, findings showed a longer average of mean sleep latency among healthy adults using a more updated later definition of sleep onset compared. Investigators concluded that establishing updated ranges for mean sleep latency may guide decision-making surrounding sleep pathologies and better inform research in the future of the associations between patient variables, daytime sleepiness, and sleep pathologies.6

Among 110 cohorts involving 4058 healthy adults, the average mean sleep latency was 11.7 min (95% CI, 10.8–12.6; 95% PI, 5.2–18.2) for the studies assessed with the earlier definition of sleep onset and 11.8 min (95% CI, 10.7–12.8; 95% PI, 7.2–16.3) for those evaluated using the later definition. Despite no significant associations between mean sleep latency and demographic or methodological variables, a negative association of −0.29 per one unit increase (95% CI, −0.55 to −0.04) was observed between mean sleep latency and apnea-hypopnea index on prior night polysomnography.

Investigators provided an updated review of normative mean sleep latency values on the multiple sleep latency test (MSLT) in an analysis of healthy adult cohorts that ranged from 1968 to 2016. Researchers also investigated the impact of demographic variables including age, sex, body mass index, sleep architecture and sleep-disordered breathing as well as methodological variables like sleep onset definitions and multiple sleep latency test protocols.

The control cohorts were evaluated on 5 Likert (0–2) rating scales, rating how well the patients were screened for medical diseases, sleep-related illnesses, psychiatric illnesses, drug use, and representativeness of recruitment from the general population. The data from the studies, as well as the associated Likert scores of the control groups, were reviewed by 2 study authors. Estimates of the mean sleep latency from the studies were pooled using a random effects generic inverse meta-analysis with the means and standard errors used as input parameters. Authors then further reviewed reported MSL values from data in the pathological ranges seen in narcolepsy, since such values may reflect unmeasured prior sleep restriction or familiarity with sleep environment.

REFERENCES
1. Narcolepsy Fast Facts. Narcolepsy Network. Accessed September 20, 2023. https://narcolepsynetwork.org/about-narcolepsy/narcolepsy-fast-facts
2. Bogan RK, Foldvary-Schaefer N, Skowronski R, Chen A, Thorpy MJ. Long-Term Safety and Tolerability During a Clinical Trial and Open-Label Extension of Low-Sodium Oxybate in Participants with Narcolepsy with Cataplexy. CNS Drugs. 2023;37(4):323-335. doi:10.1007/s40263-023-00992-y
3. Bavato F, Esposito F, Dornbierer DA, et al. Subacute changes in brain functional network connectivity after nocturnal sodium oxybate intake are associated with anterior cingulate GABA. Cereb Cortex. 2023;33(12):8046-8055. doi:10.1093/cercor/bhad097
4. Szabo ST, Hopkins SC, Lew R, Loebel A, Roth T, Koblan KS. A multicenter, double-blind, placebo-controlled, randomized, Phase 1b crossover trial comparing two doses of ulotaront with placebo in the treatment of narcolepsy-cataplexy. Sleep Med. 2023;107:202-211. doi:10.1016/j.sleep.2023.04.019
5. Gool JK, van Heese EM, Schinkelshoek MS, et al. The therapeutic potential of opioids in narcolepsy type 1: A systematic literature review and questionnaire study. Sleep Med. 2023;109:118-127. doi:10.1016/j.sleep.2023.06.008
6. Iskander A, Jairam T, Wang C, Murray BJ, Boulos MI. Normal multiple sleep latency test values in adults: A systematic review and meta-analysis. Sleep Med. 2023;109:143-148. doi:10.1016/j.sleep.2023.06.019
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Sanjay R. Patel, MD, MS
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