Symptom improvement with dosing above 9 g of low-sodium oxybate: effectiveness and safety in participants with narcolepsy in the DUET study

Abstract Purpose Evaluate effectiveness/safety of low-sodium oxybate (LXB; Xywav ® ) dosages > 9 g/night in participants with narcolepsy (type 1 [NT1] or 2 [NT2]). Methods Jazz DUET (prospective, multiple-cohort, open-label study [NCT05875974]) included screening, 9-day baseline (LXB 9 g/night [“LXB 9 g BL”]), 2–8-week titration, 2-week stable-dose, 9-day end-of-treatment (LXB > 9 g– ≤ 12 g [“optimized LXB > 9 g EOT”]; twice-nightly, first/second max doses = 7.5/4.5 g), and 2-week follow-up. Endpoints included Epworth Sleepiness Scale (ESS), Narcolepsy Severity Scale–clinical trials version (NSS-CT), Patient Global Impression of Severity (PGI-S) and Change (PGI-C), and polysomnography (PSG)-measured respiratory assessments. Results Forty-eight participants took LXB > 9 g/night (mean ± SD age: 39.2 ± 10.9 years; 62.5% female); 44 (NT1, n = 28; NT2, n = 16) completed the study. Mean ± SD stable-LXB dosage ( n = 45) was 11.1 ± 1.0 g/night (most common [43.8%], 12 g/night). From LXB 9 g BL to optimized LXB > 9 g EOT, mean ± SE ESS scores (11.4 ± 0.8 to 8.3 ± 0.9), NSS-CT (NT1) scores (17.3 ± 2.2 to 9.4 ± 2.1), and NSS-2-CT (NT2) scores (9.7 ± 1.7 to 4.3 ± 1.6) improved. Fewer participants rated their disease as severe (61.4% to 29.5%), and most (92.3%) reported their disease improved. AHI (1.8 ± 0.4 to 1.6 ± 0.3), CAI (0.01 ± 0.01 to 0.01 ± 0.00), and mean SpO 2 (95.8 ± 0.2 to 95.8 ± 0.1) remained stable. Common TEAEs included nausea (12.5%), vomiting (12.5%), and headache (10.4%). Conclusion Participants taking LXB > 9 g/night experienced further improvements in narcolepsy symptoms versus 9 g/night, suggesting some patients may require higher dosages for optimal benefit. No changes in mean respiratory PSG measures were observed. TEAEs align with the known safety profile. Findings support individualized clinical decision-making with higher LXB dosages. Clinical trial registration Trial name: A Study to Investigate the Effect of XYWAV on Sleepiness, Polysomnography, and Functional Outcomes in Participants With Idiopathic Hypersomnia or Narcolepsy; URL: https://clinicaltrials.gov/study/NCT05875974 ; ID number: NCT05875974. Brief summary Current knowledge/study rationale Narcolepsy is a heterogeneous disorder requiring individualized treatment strategies to optimize symptom management. This study fills a critical knowledge gap by evaluating effectiveness and safety of low-sodium oxybate (LXB) dosing regimens higher (> 9–12 g/night) than the recommended dosage (6–9 g/night). Study impact Participants with narcolepsy taking LXB > 9 g/night experienced further overall symptom benefit compared with 9 g/night at baseline, suggesting some patients may require higher dosages to achieve optimal therapeutic benefit. The safety profile, including respiratory safety parameters, was comparable to that observed at 9 g/night. Findings demonstrate that LXB can be utilized at dosages up to 12 g/night to optimize effectiveness, supporting individualized clinical decision-making. Plain language summary Low-sodium oxybate (LXB; Xywav ® ) is a medication used to treat narcolepsy symptoms. The recommended dosage range is 6 g to 9 g/night, but it has been reported that some people take higher dosages (greater than 9 g/night). This study was the first to evaluate higher dosages of LXB (greater than 9 g/night and up to 12 g/night). Before this study, these higher dosages had not been formally studied. This study was done to evaluate whether higher dosages improve narcolepsy symptoms and/or impact side effects. LXB is a central nervous system depressant, so there was a need to see if higher dosages could impact breathing during sleep. The study enrolled people who were already taking LXB at 9 g/night (the highest recommended dose) and who clinicians thought could benefit from higher dosages. While taking LXB 9 g/night, participants completed tests to measure their symptoms. Participants then worked with a clinician for 2 to 8 weeks to find a higher LXB dosage that worked best for them. The highest dosage allowed was 12 g/night. By the end of the study, the average dosage taken was 11.1 g/night, and almost half (44%) of participants were taking 12 g/night. Once participants found their ideal dosage, they stayed on this dosage for 2 weeks. Then, they repeated the same tests that they completed before. Forty-eight participants started the study. Forty-four completed the study. With higher LXB dosages (compared to 9 g/night), participants on average had less excessive daytime sleepiness, fewer cataplexy attacks, and less severe narcolepsy symptoms. At the beginning of the study when taking LXB 9 g/night, most participants (61.4%) said their disease was severe. After taking higher dosages, this dropped to 29.5%. At the end of the study, nearly all (92.3%) said their overall disease improved with higher dosages. Nobody said their disease worsened. In general, higher dosages did not worsen breathing during sleep. The most common side effects were nausea, vomiting, and headache. These side effects are similar to what is commonly experienced with lower dosages. This study shows that LXB treatment can be adjusted for each person. Higher dosages (>9–12 g/night) may help some patients find further improvement in their narcolepsy symptoms.