Treatment Of Excessive Daytime Sleepiness Research Articles

492 Efficacy of FT218, a Once-Nightly Sodium Oxybate Formulation, by Stimulant Use: A Post Hoc Analysis From the REST-ON Study

Abstract Introduction FT218 is an investigational, once-nightly, controlled-release formulation of sodium oxybate for the treatment of narcolepsy. The purpose of this post hoc analysis of the REST-ON study was to evaluate the effect of FT218 on measures of excessive daytime sleepiness (EDS) in patients with narcolepsy with or without stimulant use. Methods This was a randomized, double-blind, placebo-controlled, multicenter study in patients with narcolepsy ≥16 years old. Patients were stratified by stimulant use and randomized 1:1 to receive FT218 or matching placebo: 4.5 g/night for 1 week, 6.0 g/night for 2 weeks, 7.5 g/night for 5 weeks, and 9.0 g/night for 5 weeks (maximum treatment duration, 13 weeks). Assessments of EDS included mean sleep latency (minutes) on maintenance of wakefulness test (MWT) and Clinical Global Impression-Improvement (CGI-I) in sleepiness. Results A total of 190 patients were included in the modified intent-to-treat population (stimulants: FT218, n=66; placebo, n=53; no stimulants: FT218, n=31, placebo, n=40). Overall, 63% of patients were on concomitant stimulants. Patients receiving FT218 had significant improvement vs placebo in MWT regardless of stimulant use. LS mean difference in mean sleep latency vs placebo for stimulant use was 5.99 for 9.0 g (week 13), 5.51 for 7.5 g (week 8), and 5.35 for 6.0 g (week 3; all P<0.001). For no stimulant use, LS mean difference was 6.28 for 9.0 g (P=0.001), 7.14 for 7.5 g (P<0.001), and 4.19 for 6.0 g (P=0.007). More patients receiving FT218 rated sleepiness as much/very much improved on CGI-I vs placebo (stimulant use: 9.0 g, 80.5% vs 35.3%, odds ratio [OR] 7.55; 7.5 g, 66.3% vs 26.5%, OR 5.44; 6.0 g, 39.8% vs 4.4%, OR 14.27 [all P<0.001]; no stimulant use: 9.0 g, 55.1% vs 27.2%, OR 3.29 [P=0.047]; 7.5 g, 54.5% vs 17.5%, OR 5.64 [P=0.006]; 6.0 g, 40.0% vs 7.7%, OR 8.04 [P=0.003]). FT218 was generally well tolerated. Conclusion FT218 had similar efficacy on EDS at all evaluated doses in narcolepsy patients with or without stimulant use, with improvement over placebo on MWT and CGI-I. FT218 may provide effective treatment for EDS in patients with narcolepsy regardless of stimulant use. Support (if any) Avadel Pharmaceuticals.

491 Efficacy of FT218, a Once-Nightly Sodium Oxybate Formulation, by Narcolepsy Subtype: A Post Hoc Analysis From the REST-ON Study

Abstract Introduction FT218 is an investigational, once-nightly, controlled-release formulation of sodium oxybate for the treatment of narcolepsy. The purpose of this post hoc analysis of the REST-ON study was to evaluate the effect of FT218 on measures of excessive daytime sleepiness (EDS) in patients with narcolepsy subtypes 1 (NT1) and 2 (NT2). Methods This was a randomized, double-blind, placebo-controlled, multicenter study in patients with narcolepsy ≥16 years old. Patients were stratified by narcolepsy subtypes and randomized 1:1 to receive FT218 or matching placebo: 4.5 g/night for 1 week, 6.0 g/night for 2 weeks, 7.5 g/night for 5 weeks, and 9.0 g/night for 5 weeks (maximum treatment duration, 13 weeks). Assessments of EDS included mean sleep latency (minutes) on maintenance of wakefulness test (MWT) and Clinical Global Impression-Improvement (CGI-I) in sleepiness. Results A total of 190 patients were included in the modified intent-to-treat population (NT1: FT218, n=72; placebo, n=73; NT2: FT218, n=21, placebo, n=24). Patients with NT1 or NT2 receiving FT218 had significant improvement in MWT. LS mean difference in mean sleep latency (minutes) vs placebo for NT1 was 5.97 for 9.0 g (week 13), 7.02 for 7.5 g (week 8), and 4.89 for 6.0 g (week 3; all P<0.001), and for NT2, 6.27 for 9.0 g (P=0.020), 4.01 for 7.5 g (P=0.162), and 5.33 for 6.0 g (P=0.020). A higher proportion of NT1 patients receiving FT218 had significant improvement on CGI-I vs placebo (9.0 g: 75.5% vs 35.9%; 7.5 g: 66.9% vs 27.9%; 6.0 g: 39.9% vs 7.8%; all P<0.001). A higher number of NT2 patients receiving FT218 were consistently rated as much/very much improved vs placebo, based on descriptive statistics. FT218 was generally well tolerated. Conclusion FT218 had similar efficacy on EDS at evaluated doses in NT1 and NT2, with improvement in MWT and CGI-I greater than placebo. FT218 may provide effective treatment for EDS in patients with narcolepsy, with or without cataplexy. Support (if any) Avadel Pharmaceuticals.

Efficacy and safety of modafinil in patients with idiopathic hypersomnia without long sleep time: a multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison study

BackgroundFew treatments are available for patients with idiopathic hypersomnia (IH). Modafinil, an established treatment for narcolepsy, was tested for efficacy and safety in Japanese patients with IH without long sleep time. MethodsThis multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison study was conducted at 20 institutions in Japan. Patients who met the diagnostic criteria of IH in the International Classification of Sleep Disorders (second edition) were included. The study comprised a ≥17-day observation period and a 3-week treatment period during which modafinil (200 mg) or placebo was administered orally once daily (in the morning). The primary efficacy endpoint was change in mean sleep latency on the Maintenance of Wakefulness Test (MWT). Adverse events (AEs) were also recorded to evaluate safety. ResultsIn total, 123 patients were screened and 71 were randomized to receive modafinil (N = 34) or placebo (N = 37). Patients treated with modafinil experienced a significantly prolonged mean sleep latency on the MWT at the end of the study compared with placebo (5.02 min, 95% confidence interval: 3.26–6.77 min; p < 0.001). AEs occurred in 58.8% (20/34) and 27.0% (10/37) of patients in the modafinil and placebo groups, respectively. Frequent AEs in the modafinil group were headache (n = 6), dry mouth (n = 3), and nausea (n = 3); no clinically significant AEs occurred. ConclusionModafinil was shown to be an effective and safe treatment for excessive daytime sleepiness in patients with IH without long sleep time. Clinical trial registrationJapicCTI; 142539.

New pharmacologic agents for insomnia and hypersomnia.

Insomnia and hypersomnia are conditions with multifactorial causes that can be difficult to treat. There have been recent developments and changes in the treatment of both conditions, including the addition of some agents that have a novel mechanism of action. This review summarizes recent changes and highlights pertinent updates. Benzodiazepine receptor agonists received a warning in 2019 regarding the possibility of complex sleep behaviors, such as sleepwalking. Zolpidem has been marketed in new dosage forms that include sublingual tablets and oral spray formulations. Orexin receptor antagonists appear to be well tolerated with a good safety profile. Suvorexant received an approval for the treatment of patients with comorbid insomnia and dementia. Lemborexant was demonstrated to be effective for maintenance insomnia. Trazodone was shown to affect the oligomerization of tau proteins thus suggesting potential implications in attenuating dementia pathology. Pitolisant, a novel histamine-3 receptor antagonist/inverse agonist, gained approval for the treatment of excessive daytime sleepiness in adults with narcolepsy as well as obstructive sleep apnea. Solriamfetol, a new norepinephrine and dopamine reuptake inhibitor, was approved for hypersomnolence based on good efficacy, but with cardiovascular warnings. Recent advancements in the treatment of insomnia includes agents with novel mechanisms, new indications, and new dosage forms. Risk of complex sleep behaviors, and possible next-day driving impairment, should be discussed for all agents used for insomnia, including orexin receptor antagonists. Novel agents also are available for hypersomnia and there are options beyond traditional stimulants that may have great utility.

Solriamfetol for the Treatment of Excessive Daytime Sleepiness in Participants with Narcolepsy with and without Cataplexy: Subgroup Analysis of Efficacy and Safety Data by Cataplexy Status in a Randomized Controlled Trial

Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, improved wakefulness and reduced excessive daytime sleepiness (EDS) in studies of participants with narcolepsy with and without cataplexy. Prespecified subgroup analyses of data from a 12-week randomized, double-blind, placebo-controlled, phase III trial of solriamfetol for EDS in narcolepsy evaluated the efficacy and safety of solriamfetol by cataplexy status. Participants with narcolepsy received solriamfetol (75, 150, or 300mg/day) or placebo and were stratified by cataplexy status. Coprimary endpoints were change from baseline on Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS); Patient Global Impression of Change (PGI-C) was the key secondary endpoint. Change in frequency of cataplexy attacks was evaluated in participants reporting cataplexy at baseline. Safety was evaluated. No adjustments were made for multiple comparisons; therefore p values are nominal. There were 117 participants in the cataplexy subgroup and 114 in the non-cataplexy subgroup. At week 12, least-squares (LS) mean (95% confidence interval [CI]) differences from placebo on change from baseline in MWT for solriamfetol 75, 150, and 300mg in the cataplexy subgroup were 1.6 (-3.6 to 6.9), 6.1 (0.7-11.4), and 8.9 (3.5-14.2) minutes, respectively (p < 0.05; 150 and 300mg), and in the non-cataplexy subgroup were 3.4 (-1.9 to 8.7), 9.1 (3.8-14.3), and 11.2 (5.8-16.6) minutes, respectively (p < 0.001; 150 and 300mg). At week 12, LS mean (95% CI) differences from placebo on ESS change from baseline for solriamfetol 75, 150, and 300mg in the cataplexy subgroup were -1.3 (-3.9 to 1.3), -3.7 (-6.4 to -1.1), and -4.5 (-7.1 to -1.9), respectively (p < 0.01; 150 and 300mg), and in the non-cataplexy subgroup were -3.0 (-5.6 to -0.4), -3.7 (-6.3 to -1.2), and -4.9 (-7.6 to -2.2), respectively (p < 0.05; all doses). For PGI-C at week 12, the mean percentage difference from placebo (95% CI) for solriamfetol 75, 150, and 300mg in the cataplexy subgroup was 10% (-15 to 35), 33% (9-57), and 39% (16-61), respectively (p < 0.05; 150 and 300mg), and in the non-cataplexy subgroup was 48% (25-70), 44% (21-67), and 52% (30-73), respectively (p < 0.001; all doses), with somewhat differential treatment effects for 75mg by cataplexy status. No changes in the number of cataplexy attacks were observed for solriamfetol compared with placebo (mean ± standard deviation changes: -3.6 ± 13.3 [combined solriamfetol] and -3.5 ± 9.8 [placebo]). Common adverse events (headache, nausea, decreased appetite, and nasopharyngitis) were similar between cataplexy subgroups. These data strongly indicate that solriamfetol was effective in treating EDS in participants with narcolepsy with or without cataplexy, as indicated by robust effects on MWT, ESS, and PGI-C. The safety profile was similar regardless of cataplexy status. ClinicalTrials.gov NCT02348593. 28 January 2015.

0745 The Pharmacokinetics of FT218, Once Nightly Sodium Oxybate: Food Effect and Bioavailability Compared to Twice Nightly Sodium Oxybate

Abstract Introduction Sodium oxybate is an effective treatment for excessive daytime sleepiness and cataplexy in patients with narcolepsy. The FDA approved formulation requires twice-nightly dosing; at bedtime and 2.5 - 4 hours later. FT218 is a controlled-release formulation of sodium oxybate intended for once-nightly dosing, using Avadel’s proprietary Micropump™ technology. The objective of this study was to evaluate the relative bioavailability of investigational once-nightly sodium oxybate, FT218, 6 g, compared to commercially available twice-nightly sodium oxybate and the food effect of FT218. Methods Two crossover, single-dose pharmacokinetic studies were conducted in healthy volunteers. The first, a relative bioavailability study (n=28) was completed comparing FT218 6 g to twice-nightly sodium oxybate 6 g (in two divided doses of 3 g). The second, evaluated the food effect (n=16) of FT218 6g in the Fed vs. Fasted state. Results FT218 had a lower overall Cmax than twice-nightly sodium oxybate, while AUC was equivalent. C8h level and variability was comparable between FT218 and twice-nightly sodium oxybate. In the Fed, compared to the Fasted state, FT218 had a longer Tmax, lower Cmax and decreased AUC (Cmax 67%, AUC 86%, Tmax 1-hour slower than Fasted values). Adverse Events with FT218 were mostly mild or moderate in severity, non-serious and known AEs associated with sodium oxybate. The safety profiles of FT218 and twice-nightly sodium oxybate at 6 g appeared similar. Conclusion Once-nightly FT218 at 6 g demonstrated a lower overall Cmax and similar exposure to twice-nightly sodium oxybate, with similar C8h plasma levels and C8h variability. In the Fed state, AUC and Cmax of FT218 was lower than in the Fasted State. FT218 was generally safe and well tolerated and the safety profile appeared comparable to twice-nightly sodium oxybate. Support This work was supported by Avadel Pharmaceuticals.

0743 The Pharmacokinetic Adverse Event Relationship for FT218, a Once-Nightly Sodium Oxybate Formulation

Abstract Introduction Sodium oxybate is an effective treatment for excessive daytime sleepiness and cataplexy in patients with narcolepsy. The approved formulation requires twice-nightly dosing: at bedtime and 2.5 - 4 hours later, which results in two distinct Cmax’s. FT218 is a controlled-release formulation of sodium oxybate intended for once-nightly dosing, using Avadel’s proprietary Micropump™ technology. The objective of this study was to evaluate the pharmacokinetic-adverse event (AE) relationship for FT218, an investigational once-nightly sodium oxybate formulation. Methods Six single-dose, randomized, crossover studies that assessed the pharmacokinetics of FT218 at 4.5, 6, 7.5 and 9 g in healthy voluntters were used in this analysis. Lattice plots, “spaghetti” plots, and scatter plots of individual gamma hydroxybutyrate concentrations and indicators when AEs by system, organ, or class (SOC) were created to determine any PK-AE relationship. Results A total of 129 healthy volunteers received single doses of FT218 between 4.5 - 9 g. Most AEs, specifically for the neurological and gastrointestinal SOC, occurred close to Tmax, during the Cmax period, which for FT218 was around 1.5-2 hours after dosing. These AEs were known AEs associated with sodium oxbyate. There appeared to be no clear correlation between individual plasma GHB concentrations levels and AEs between subjects. Individual AEs were equally distributed above and below the mean population Cmax and AUCinf for the dataset. Conclusion In general, adverse events for FT218 occurred around Tmax. There was no clear population toxicokinetic range for when AEs occur with FT218, but mostly individual thresholds. Since it appears AEs are related to Cmax, and FT218 only has one Cmax compared to two with the currently available product, it is hypothesized that FT218 will have a favorable safety profile compared to twice-nightly dosing. Support This work was supported by Avadel Pharmaceuticals

0767 Analysis Of The Effect On Blood Pressure And Heart Rate When Adding Solriamfetol (Sunosi) To Stimulant Therapy

Abstract Introduction Solriamfetol is a non-stimulant wakefulness-promoting agent (WPA) indicated for the treatment of excessive daytime sleepiness in adult patients with obstructive sleep apnea or narcolepsy. It acts by inhibiting reuptake of dopamine and norepinephrine. Since many patients with excessive daytime sleepiness take stimulants, clinicians commonly ponder the safety of adding solriamfetol in this population due to concern of increased blood pressure and/or heart rate (HR). Methods We conducted a retrospective chart review and identified 18 patients who had solriamfetol added to their stimulant therapy. Of those, 7 to date have had a follow-up appointment after the addition of solriamfetol (6 on 150mg, 1 on 75mg). We collected the blood pressure and HR readings at the appointment immediately prior to and following the addition of solriamfetol and conducted a paired t-test. Results The systolic blood pressure (SBP) had a mean difference of -0.57 (95% CI -9.6 to 8.5, p=0.88), diastolic blood pressure (DBP) 1.7 (95% CI -4.4 to 7.9, p=0.52), mean arterial pressure (MAP) 0.95 (95% CI -5.6 to 7.5, p=0.73), and HR 6.6 (95% CI -0.07 to 13.2, p=0.052). Conclusion The addition of solriamfetol to stimulant therapy did not lead to a significant increase in SBP, DBP, MAP, or HR. Support none

0747 Study Design of an Open-Label Extension and Switch Study for Once Nightly Sodium Oxybate, FT218, in NT1 and NT2 Patients

Abstract Introduction Avadel Pharmaceuticals has developed FT218, a once nightly sodium oxybate (SO) formulation for the treatment of excessive daytime sleepiness (EDS) and cataplexy in narcoleptic patients. REST-ON, a pivotal efficacy/safety study is expected to be completed in the first half of 2020. Previous Phase 1 studies have demonstrated FT218 delivers a pharmacokinetic profile needed for once-nightly dosing. The purpose of this study is to evaluate long-term safety of FT218 in REST-ON completers and dosing strategy when switching from twice-nightly SO to FT218. Methods The study will enroll NT1/NT2 patients who completed REST-ON or patients switching from stable dose of twice-nightly SO to FT218. REST-ON completers will initiate FT218 at 4.5 g and increase by 1.5 g to the highest tolerated dose or the dose deemed effective (up to 9 g). Switch patients will initiate FT218 at the equivalent/closest dose to their current twice-nightly SO and titrate in accord with safety/efficacy. The study will enroll approximately 250 patients for a duration of two years. Results The primary endpoint for REST-ON completers will be safety and tolerability. Secondary endpoints for REST-ON completers will include changes in ESS, reported cataplexy and other REM associated phenomena as well as changes in clinician and patient global impression. For switch patients, endpoints will include percentage of subjects that stay on the same, higher or lower dose of FT218 compared to twice-nightly SO, as well as the percentage of subjects who report a preference for the once-nightly dosing regimen. Conclusion The results of this open label extension/switch study will further elucidate the potential benefits of once-nightly FT218 regarding long term safety/tolerability, nocturnal safety/tolerability and efficacy, and importantly provide dosing and preference data for patients switching from twice-nightly SO to once-nightly FT218. Support This work was supported by Avadel Pharmaceuticals.

0766 Safety And Tolerability Of Pitolisant In The Treatment Of Adult Patients With Narcolepsy: Final Analysis Of An Open-label, Expanded Access Program In The United States

Abstract Introduction Pitolisant Expanded Access Clinical Evaluation (PEACE) provided adult patients with narcolepsy access to treatment with pitolisant while it was an investigational medication in the United States. Methods Pitolisant was titrated to 35.6 mg/day (or the highest tolerable dose) over a 3-week period. Dose adjustments were permitted at the discretion of the treating physician based on patient response. Treating physicians followed their standard of care and were required to report adverse events (AEs). Demographic and baseline information for all enrolled patients, and safety results available through October 30, 2019, are reported here (presentation will include final data from the PEACE program). Results In all, 623 patients (67.9% female; 84.6% white; mean age, 40.0 years; narcolepsy type 1, 51.5%) were treated with pitolisant in the PEACE program. Nearly all patients (98.4%) had been previously treated with other narcolepsy medications (88.1% with ≥2 narcolepsy medications). Overall, 35.2% of patients discontinued from the program; 16.7% due to an AE and 12.2% for lack of effect. At Month 1, 97.3% of patients remained in the study, 88.2% at Month 3, 76.5% at Month 6, 66.9% at Month 9, and 55.0% at Month 12. In all, 256 (41.1%) patients experienced ≥1 AE; majority (52.5%) of these AEs occurred early in treatment (by Week 3). The most commonly reported AEs were headache (9.8% of AEs), nausea (6.6%), anxiety (5.6%), and insomnia (4.7%). Conclusion In the PEACE program, patient characteristics were generally reflective of the US narcolepsy patient population. The safety and tolerability profile of pitolisant was similar to that seen in the clinical development program, with no new safety signals identified. The program ceased enrollment in August 2019 after the US approval of pitolisant for the treatment of excessive daytime sleepiness in adult patients with narcolepsy. Support Harmony Biosciences, LLC.

0755 Pitolisant (Wakix) is an Effective Anti-Cataplexy Agent in Narcolepsy Type 1

Abstract Introduction Harmony Biosciences initiated the Pitolisant Expanded Access Clinical Evaluation (PEACE) program to allow treatment with pitolisant in adult patients with narcolepsy while pitolisant was an investigational medication in the United States. Starting in March 2019, Comprehensive Sleep Medicine Associates (CSMA) offered enrollment to patients who met the inclusion/exclusion criteria and who were deemed appropriate based on clinical judgment. All patients who enrolled were taking at least one standard-of-care agent for narcolepsy at enrollment. Many of the enrolled patients had refractory/challenging cases of narcolepsy. On August 14, 2019, Wakix received FDA approval for the treatment of excessive daytime sleepiness in adult patients with narcolepsy, which contrasts with the European label that states that Wakix is indicated for the treatment of narcolepsy in adults with or without cataplexy. Methods CSMA enrolled 21 patients in the PEACE program. The charts for all 10 narcolepsy type 1 (NT1) patients were reviewed. The 2 patients who did not have follow up after starting pitolisant were excluded. Results Of the 8 NT1 patients who had at least one follow up visit after initiating pitolisant, 6 reported substantial improvement or complete resolution of cataplexy compared to baseline. For example, one patient’s wife stated, “I forgot my husband was funny because he would avoid telling jokes until he started pitolisant.” Another stated, “I have not had an episode of cataplexy since starting pitolisant.” 5 of these patients were taking an anti-cataplectic agent at the time of starting pitolisant (sodium oxybate 3, venlafaxine 2). Conclusion While a relatively small sample size, these results demonstrate that in a “real world” uncontrolled population of refractory/challenging NT1 patients, pitolisant is an effective anti-cataplectic agent. As there are relatively few treatment options for NT1, clinicians should consider use of pitolisant for patients with cataplexy, and further consideration for adding an indication for pitolisant to treat cataplexy is warranted. Support Harmony Biosciences (PEACE trial)

Pitolisant: A Review in Narcolepsy with or without Cataplexy.

Pitolisant (Wakix®), an orally available, first-in-class antagonist/inverse agonist of the histamine 3 receptor, is approved in the EU (as of March 2016) for the treatment of narcolepsy with or without cataplexy in adults and in the USA (as of August 2019) for the treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy. Pitolisant was demonstrated to have minimal risk of abuse in preclinical and clinical studies, and is the only anti-narcoleptic drug not scheduled as a controlled substance in the USA. The totality of evidence from pivotal and supportive phase III trials suggests that pitolisant administered at up to the recommended maximum dose of 36mg once daily reduces EDS and cataplexy in adults with narcolepsy relative to placebo. Noninferiority of pitolisant to modafinil in the management of EDS was not demonstrated. Pitolisant was generally well tolerated in clinical trials. Consistent with its mechanism of action, the most common treatment-emergent adverse events included headache, insomnia and anxiety. With minimal abuse potential and offering the convenience of oral, once-daily administration, pitolisant extends the range of approved treatment options available to adult patients with narcolepsy with or without cataplexy.

Incidence and duration of common adverse events in 2 solriamfetol phase 3 studies for treatment of excessive daytime sleepiness in obstructive sleep apnoea and narcolepsy

Incidence and duration of common adverse events in 2 solriamfetol phase 3 studies for treatment of excessive daytime sleepiness in obstructive sleep apnoea and narcolepsy

The safety and tolerability of pitolisant in the treatment of excessive daytime sleepiness and cataplexy in adult patients with narcolepsy: an open-label, expanded access program in The United States

The safety and tolerability of pitolisant in the treatment of excessive daytime sleepiness and cataplexy in adult patients with narcolepsy: an open-label, expanded access program in The United States

Indirect treatment comparison of the efficacy and safety of solriamfetol, modafinil, and armodafinil for the treatment of excessive daytime sleepiness in obstructive sleep apnoea

Indirect treatment comparison of the efficacy and safety of solriamfetol, modafinil, and armodafinil for the treatment of excessive daytime sleepiness in obstructive sleep apnoea

Pooled analyses from 12-week randomised, controlled studies of solriamfetol in the treatment of excessive daytime sleepiness in participants with OSA or narcolepsy

Pooled analyses from 12-week randomised, controlled studies of solriamfetol in the treatment of excessive daytime sleepiness in participants with OSA or narcolepsy

Long-term study of the safety and maintenance of efficacy of solriamfetol (JZP-110) in the treatment of excessive sleepiness in participants with narcolepsy or obstructive sleep apnea.

Study ObjectivesTo evaluate long-term safety and maintenance of efficacy of solriamfetol treatment for excessive daytime sleepiness in narcolepsy and obstructive sleep apnea (OSA).MethodsParticipants with narcolepsy or OSA who completed a prior solriamfetol study were eligible. A 2-week titration period was followed by a maintenance phase (up to 50 weeks). Efficacy was assessed by Epworth Sleepiness Scale (ESS) and Patient and Clinical Global Impression of Change (PGI-C and CGI-C, respectively). After approximately 6 months of treatment, a subgroup entered a 2-week placebo-controlled randomized withdrawal (RW) phase. Change in ESS from beginning to end of the RW phase was the primary endpoint; PGI-C and CGI-C were secondary endpoints. Safety was assessed throughout the study.ResultsIn the maintenance phase, solriamfetol-treated participants demonstrated clinically meaningful improvements on ESS, PGI-C, and CGI-C. In the RW phase, least squares mean change on ESS was 1.6 in participants continuing solriamfetol versus 5.3 in participants switched to placebo (p < .0001). For both secondary endpoints, higher percentages of participants receiving placebo were reported as worse at the end of the RW phase versus solriamfetol (p < .0001). Common treatment-emergent adverse events (TEAEs) with solriamfetol were headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, and upper respiratory tract infection; 27 (4.2%) participants experienced at least one serious TEAE, and 61 (9.5%) withdrew because of TEAEs.ConclusionsThis study demonstrated long-term maintenance of efficacy of solriamfetol under open-label and double-blind, placebo-controlled conditions. Safety profile of solriamfetol was consistent with previous 12-week studies; no new safety concerns were identified.Trial RegistrationNCT02348632

First noncontrolled substance approved to treat narcolepsy in adults

In August, FDA approved pitolisant (Wakix—Harmony Biosciences) for treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy. The selective histamine-3 receptor antagonist/inverse agonist is the first and only treatment for narcolepsy that is not scheduled as a controlled substance. “The approval of Wakix provides health care professionals managing people living with narcolepsy a new and important treatment option for their patients,” said Jeffrey Dayno, MD, Harmony Bioscience’s chief medical officer, in a statement. “Wakix … offers an important benefit/risk profile to address the unmet medical need that exists in people living with narcolepsy.” Pitolisant is available as both a 4.45-mg and 17.8-mg tablet and should be stored at 20°C to 25°C (68°F to 77°F). FDA’s approval was based on Harmony 1 and Harmony 1bis—two multicenter, double-blind, placebo-controlled studies. The studies randomized 261 patients to receive pitolisant, placebo, or active control. Participants were treated for 8 weeks, including a 3-week dose-titration phase followed by a 5-week stable-dose phase. In both studies, patients treated with pitolisant showed statistically significant improvement in EDS, as measured by the Epworth Sleepiness Scale. Common adverse effects of pitolisant include insomnia, nausea, and anxiety. The drug may also cause QT interval prolongation. Pitolisant may interact with a number of drugs. Its use with strong CYP2D6 inhibitors, for instance, increases the amount of pitolisant that patients are exposed to by 2.2-fold. The dose of pitolisant should be reduced by one-half, with a maximum dosage of 17.8 mg once daily, for patients who are concurrently using strong CYP2D6 inhibitors. Use of pitolisant with strong CYP3A4 inducers decreases the amount of pitolisant exposure in the blood by 50%. In patients taking CYP3A4 inducers, a dose adjustment should be considered, as detailed in pitolisant’s prescribing information. Pitolisant works by increasing the synthesis and release of histamine, so use of the drug with histamine-1 (H1) receptor antagonists that cross the blood–brain barrier may reduce its effectiveness. Patients taking pitolisant should avoid using centrally acting H1 receptor antagonists. Because pitolisant can prolong the QT interval, the drug should not be used in combination with other drugs that cause QT prolongation, as this can increase the risk of cardiac arrhythmia. Pitolisant may also reduce the effectiveness of sensitive CYP3A4 substrates, including hormonal contraceptives. Before they begin treatment with pitolisant, advise patients to inform their physician if they are taking, or planning to take, any prescription or OTC drugs. Counsel patients to consult their physician immediately if they feel faint, lose consciousness, or have heart palpitations, as these could be signs of prolongation of the QT interval. Pitolisant (Wakix)Manufacturer: Harmony BiosciencesDrug class: Histamine-3 (H3) receptor antagonist/inverse agonistIndication: Treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsyDosage: 17.8 mg to 35.6 mg once daily, taken orally in the morning upon awakening. Week 1: Start with 8.9 mg. Week 2: Increase dosage to 17.8 mg. Week 3: May increase to the maximum-recommended dosage of 35.6 mg. See prescribing information for more details.Of note: Pitolisant is contraindicated in patients with severe hepatic impairment (Child-Pugh C). The drug may increase the QT interval and could reduce the efficacy of hormonal contraceptives. Manufacturer: Harmony Biosciences Drug class: Histamine-3 (H3) receptor antagonist/inverse agonist Indication: Treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy Dosage: 17.8 mg to 35.6 mg once daily, taken orally in the morning upon awakening. Week 1: Start with 8.9 mg. Week 2: Increase dosage to 17.8 mg. Week 3: May increase to the maximum-recommended dosage of 35.6 mg. See prescribing information for more details. Of note: Pitolisant is contraindicated in patients with severe hepatic impairment (Child-Pugh C). The drug may increase the QT interval and could reduce the efficacy of hormonal contraceptives. Pitolisant is metabolized extensively by the liver and is contraindicated in patients with severe hepatic impairment because the drug has not been studied in this population. Health care providers should monitor patients with moderate hepatic impairment, as these patients have shown increased amounts of the drug in their blood. Patients with mild hepatic impairment who are taking pitolisant should also be closely monitored. Emphasize to patients of reproductive potential that pitolisant may reduce the efficacy of hormonal contraceptives. Counsel these patients to use an alternative nonhormonal contraceptive method during treatment with pitolisant and for at least 21 days after discontinuing treatment. If a patient becomes pregnant during treatment with pitolisant, inform them that a pregnancy exposure registry is available to monitor pregnancy outcomes of the drug; patients can call 1-800-833-7460 to enroll or obtain information.

Treatment of Excessive Daytime Sleepiness in Patients with Narcolepsy.

The aim of this review is to discuss and summarize the main therapeutic strategies for the management of excessive daytime sleepiness (EDS) in patients with narcolepsy. An overview of novel therapies and potential future options are covered as well. First line treatments for EDS in narcolepsy patients include modafinil/armodafinil and sodium oxybate. Other options with a stimulant effect, such as methylphenidate and amphetamines are considered if the former do not control the symptoms. More recently, pitolisant (H3 receptor inverse agonist) was approved by the European Medicines Agency, and solriamfetol (dopamine and norepinephrine reuptake inhibitor) by the Food and Drug Administration, for the treatment of EDS in adult narcolepsy patients. Sodium oxybate was recently approved for EDS management in paediatric patients from the age of seven. Further studies involving the paediatric population are warranted to have solid evidence in the management of children with narcolepsy. Ongoing research of new molecules is based on several mechanisms of action (histamine antagonists/inverse agonists, GABA receptor modulators), and potential future strategies involve immunologic treatment and hypocretin-based therapies. Additionally to the wakefulness-promoting agents and stimulants classically used, other pharmacologic options have been recently approved for the treatment of EDS in Europe (pitolisant) and the US (solriamfetol). Emerging treatments are under development; newly developed wakefulness-promoting agents act via different mechanisms of action, whereas other forms of therapy are focused in the underlying hypocretin deficiency that characterizes narcolepsy type 1.

Evaluation of the abuse potential of pitolisant, a selective H3-receptor antagonist/inverse agonist, for the treatment of adult patients with narcolepsy with or without cataplexy.

ObjectivesTo evaluate the human abuse potential of pitolisant, a selective histamine 3 (H3)-receptor antagonist/inverse agonist recently approved by the US Food and Drug Administration for the treatment of excessive daytime sleepiness in adult patients with narcolepsy.MethodsNondependent, recreational stimulant users able to distinguish phentermine HCl 60 mg from placebo in a drug discrimination test were randomized in a four-period, double-blind, crossover design to receive single doses of pitolisant 35.6 mg (therapeutic dose), pitolisant 213.6 mg (supratherapeutic dose), phentermine HCl 60 mg, and placebo. The primary endpoint was maximum effect (Emax) on the 100-point Drug Liking (“at this moment”) visual analog scale.ResultsIn 38 study completers (73.7% male; 65.8% white; mean age, 33.3 years), mean Drug Liking Emax was significantly greater for phentermine versus pitolisant 35.6 mg (mean difference, 21.4; p < 0.0001) and pitolisant 213.6 mg (mean difference, 19.7; p < 0.0001). Drug Liking Emax was similar for pitolisant (both doses) and placebo. Similarly, for key secondary measures of Overall Drug Liking and willingness to Take Drug Again, mean Emax scores were significantly greater for phentermine versus pitolisant (both doses) and similar for pitolisant (both doses) versus placebo. The incidence of adverse events was 82.1% after phentermine HCl 60 mg, 72.5% after pitolisant 213.6 mg, 47.5% after pitolisant 35.6 mg, and 48.8% after placebo administration.ConclusionsIn this study, pitolisant demonstrated significantly lower potential for abuse compared with phentermine and an overall profile similar to placebo; this suggests a low risk of abuse for pitolisant.Clinical Trial RegistrationClinicalTrials.gov NCT03152123. Determination of the abuse potential of pitolisant in healthy, nondependent recreational stimulant users. https://clinicaltrials.gov/ct2/show/NCT03152123.