Plante, David T.

Abstract Study Objectives Narcolepsy is a chronic condition affecting the sleep/wake cycle that is challenging to diagnose. Epidemiological data from large US-focused studies remain limited, with no validated claims-based case selection definitions for narcolepsy. We estimated the prevalence/incidence of diagnosed narcolepsy (type 1 [NT1], type 2 [NT2], overall) in an insured US population using validated, claims-based narcolepsy case definitions. Materials and Methods This observational study used HealthVerity administrative claims-linked electronic medical records to develop case definitions identifying individuals with NT1, NT2, and overall narcolepsy from diagnosis, medication, and procedure codes. Claims-based case definition performance (NT1, NT2, overall narcolepsy) was assessed using positive predictive values (PPVs). Prevalence (per 100 000 persons, on December 31, 2023) and annual incidence (per 100 000 person-years [PY], 2020 − 2023) were calculated/adjusted using PPVs for each case definition. Results Unadjusted point prevalence among individuals with ≥12 months of continuous enrollment were 15.5/100 000 (NT1), 51.1/100 000 (NT2), and 67.0/100 000 (overall narcolepsy). Unadjusted incidence rates were stable from 2020 − 2023 for NT1 (range, 2.0 − 2.3/100 000 PY) but declined across years for NT2 (9.1 − 7.6/100 000 PY) and overall narcolepsy (11.3 − 9.6/100 000 PY). PPVs (95% confidence interval) of NT1, NT2, and overall narcolepsy were 0.81 (0.72 − 0.88), 0.84 (0.75 − 0.91), and 0.80 (0.71 − 0.87), contributing to epidemiologic estimates being reduced by ~20% after PPV adjustment. Prevalence and incidence were higher in females than males. Individuals with NT1 were ~ 4 years younger versus NT2. Conclusions Validated definitions for narcolepsy can reduce potential misclassification. Our findings highlight a relatively low NT1 prevalence in the US. In contrast, NT2 prevalence estimates were > 3 times higher than NT1.

Abstract Introduction Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment) is a phase 4, prospective, multicenter, single-arm, multiple-cohort, open-label study (NCT05875974) assessing the effectiveness of low-sodium oxybate (LXB; Xywav®) treatment on daytime and nighttime symptoms in participants with narcolepsy (type 1 [NT1] or 2 [NT2]) or idiopathic hypersomnia. Data presented are from the narcolepsy cohort. Methods DUET included a screening period (with 2-week washout for current oxybate users), 8-day baseline (BL) period, 2- to 8-week LXB titration period, 2-week stable-dose period, 8-day end-of treatment (EOT) period, and 2-week safety follow-up. The primary endpoint was change in Epworth Sleepiness Scale (ESS) score from BL to EOT. Key secondary endpoints for the narcolepsy cohort included change in polysomnography parameters: total shifts from deeper to lighter sleep stages, stage N3 sleep duration (minutes), and number of awakenings. Additional endpoints included Patient Global Impression of Change (PGIc)–overall narcolepsy disease. Primary and key secondary endpoints were controlled for multiplicity with sequential testing; other P-values are considered nominal. Results Fifty-five narcolepsy participants enrolled and were dosed with LXB (NT1, n=26; NT2, n=29); 13 transferred to another cohort and 34 were completers (NT1, n=16; NT2, n=18). Enrolled participants were mostly female (72.7%) and White (80.0%); mean (SD) age was 33.4 (12.9) years (NT1=34.6 [12.6]; NT2=32.4 [13.2]). For completers, least-squares mean (LSM) (SE) changes in ESS score were −7.7 (0.9), P<.0001, overall; NT1=−6.5 (1.4), P<.0001; NT2=−8.8 (1.3), P<.0001. Compared with BL, sleep architecture at EOT showed fewer deeper to lighter sleep stage shifts (LSM [SE]: −13.1 [2.9], P<.0001, overall; NT1=−13.9 [4.3], P=0.0029; NT2=−12.3 [4.1], P=0.0050); increased stage N3 sleep (minutes) (45.0 [8.8], P<.0001, overall; NT1=49.8 [13.0], P=0.0006; NT2=40.8 [12.3], P=0.0023); and fewer awakenings (−3.2 [0.9], P=0.0015, overall; NT1=−4.1 [1.4], P=0.0056; NT2=−2.3 [1.3], P=0.0771). Most participants (93.3%, n=30; NT1, 86.7%, n=15; NT2, 100%, n=15) reported improvement (very much, much, minimally) in overall narcolepsy disease on PGIc. Treatment-emergent adverse events were consistent with the known safety profile of LXB. Conclusion Participants with NT1 and NT2 taking open-label LXB showed improvements in daytime sleepiness (decreased ESS scores) and reduced symptom burden (improved PGIc), which paralleled improvements in sleep architecture and disruption. Support (if any) Jazz Pharmaceuticals

Abstract Introduction Introduction: Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment) is a phase 4, prospective, multicenter, single-arm, multiple-cohort, open-label study (NCT05875974) evaluating the effectiveness of low-sodium oxybate (LXB, Xywav®) treatment on daytime and nighttime symptoms, including excessive daytime sleepiness (EDS) and polysomnography in participants with idiopathic hypersomnia (IH) or narcolepsy. Data presented are from the IH cohort. Methods DUET included screening (with 2-week washout for oxybate users), 8-day baseline (BL), 2- to 8-week LXB titration, 2-week stable-dose, 8-day end-of-treatment (EOT), and 2-week safety follow-up periods. The primary endpoint was change in Epworth Sleepiness Scale (ESS) score from BL to EOT. Secondary endpoints for the IH cohort included change in Idiopathic Hypersomnia Severity Scale (IHSS) total score, Patient Global Impression of Change (PGIc)−overall IH disease, PGIc−sleep inertia, and Patient Global Impression of Severity (PGIs)−sleep inertia. Exploratory endpoints included IHSS component scores (daytime functioning, sleep inertia). Primary and key secondary (IHSS total score) endpoints were controlled for multiplicity with sequential testing; all other P-values are considered nominal. Results Forty-six people with IH enrolled and were dosed with LXB; 40 were completers. Enrolled participants were mostly female (80.4%) and White (84.8%), with a mean (SD) age of 38.1 (11.8) years. For completers, BL mean (SD) ESS score and IHSS total score were 16.5 (2.7) and 32.9 (7.1), respectively; least-squares mean (LSM) (SE) changes from BL to EOT were −8.4 (0.7), P<.0001 and −15.5 (1.5), P<.0001. BL mean (SD) IHSS component scores for daytime functioning and sleep inertia were 17.7 (4.2) and 10.7 (3.1), respectively; LSM (SE) changes from BL to EOT were −8.8 (1.0), P<.0001 and −4.8 (0.4), P<.0001. At EOT, most participants reported improvement (very much, much, minimally) on PGIc−overall IH disease (94.6%) and PGIc−sleep inertia (81.1%). At BL, 25.0% of participants reported sleep inertia severity as very mild/mild/not present on PGIs–sleep inertia vs 59.0% at EOT. Treatment-emergent adverse events were consistent with the known safety profile of LXB. Conclusion People with IH taking open-label LXB showed improvements in EDS and sleep inertia (decreased ESS and IHSS component scores) and reported reduced multi-symptom burden (decreased IHSS total scores and improved PGIc/PGIs ratings). Support (if any) Jazz Pharmaceuticals