Bogan, Richard

Abstract Introduction Narcolepsy type 2 (NT2) is characterized by excessive daytime sleepiness, heterogeneous symptom severity, and typically normal endogenous orexin levels. The Vibrance-2 phase 2 study evaluated alixorexton, a selective orexin 2 receptor agonist, in patients with NT2. Methods Vibrance-2 was a placebo-controlled, dose-ranging phase 2 study. After a 2-week washout from current narcolepsy medications, adults with NT2 meeting ICSD-3-TR diagnostic criteria were randomized 1:1:1:1 to receive placebo or alixorexton once daily at doses of 10, 14, or 18mg for 8 weeks, followed by an optional 5-week open-label extension. Dual primary endpoints were the change from baseline to week 8 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT) and on the Epworth Sleepiness Scale (ESS). Safety evaluation included treatment-emergent adverse events (TEAEs). P-values were adjusted for multiplicity. Results Ninety-three patients were randomized to placebo (n=24) or alixorexton (10mg, n=23; 14mg, n=22; 18mg, n=24); 90 completed double-blind treatment. At baseline, patients had severe symptoms (MWT: 5.6 minutes; ESS: 17.4). The study met its dual primary endpoints. At week 8, MSL on MWT increased 9.3, 6.7, and 6.7 minutes at 10, 14, and 18mg, respectively, from baseline versus placebo, with statistically significant differences observed for the 14 and 18mg doses (adjusted p< 0.05). ESS improved by -2.1, -3.2, and -3.6 points from baseline versus placebo at week 8 for the 10, 14, and 18mg groups, respectively, with statistical significance observed for the 18mg dose (adjusted p< 0.05), where more than 70% of patients achieved normalization. TEAEs in 10% of all alixorexton-treated patients through week 8 were pollakiuria, insomnia, micturition urgency, dizziness, and headache. Most TEAEs were mild-to-moderate with no serious TEAEs. Conclusion Vibrance-2 was the first large clinical trial in patients with NT2 to demonstrate positive results with an orexin 2 receptor agonist. Alixorexton resulted in statistically significant and clinically meaningful improvements in wakefulness and daytime sleepiness at Week 8 and was generally well tolerated. These results support phase 3 clinical development of alixorexton as a treatment for NT2. Support (if any) Alkermes, Inc.

Abstract Introduction Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment; NCT05875974) was the first study to evaluate effectiveness/safety of low-sodium oxybate (LXB; Xywav®) >9 g/night (outside the recommended range: 6–9 g/night). This analysis evaluated changes in patient-reported hypersomnolence measures in participants with narcolepsy taking LXB >9 g/night compared with LXB 9 g/night. Methods DUET was a phase 4, prospective, open-label study with screening, 8-day LXB 9 g/night (9g-baseline), titration/optimization, stable-dose, and 8-day end-of-treatment (EOT) optimized LXB >9 g/night (up to 12g; >9g-EOT) periods. Patient-reported measures included Epworth Sleepiness Scale (ESS), electronic sleep diaries (completed daily during 9g-baseline and >9g-EOT; subjective total sleep time [TST], number of awakenings, sleep efficiency [TST divided by time in bed], sleep quality [5-point scale; “very good” to “very poor”], and how rested/refreshed the participant felt upon awakening [5-point scale; “very well” to “not at all”]), Karolinska Sleepiness Scale (KSS; administered 90 minutes post-polysomnography awakening at 9g-baseline and >9g-EOT), and Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10). LSM differences (95% CI) from 9g-baseline to >9g-EOT (nominal P-values) were 9g-baseline-adjusted. Results Forty-eight participants took LXB >9g (mean±SD age: 39.2±10.9 years; 62.5% female). Total stable-dose LXB (mean±SD) was 11.1±1.0 g/night (n=45). From 9g-baseline to >9g-EOT, ESS scores improved (LSM [95% CI]: –3.1 [–4.2, –1.9]; P< 0.0001; n=44), nocturnal TST increased (0.3h [0.1, 0.4]; P=0.0163; n=26), sleep efficiency increased (3.8% [1.7, 5.9]; P=0.0011; n=26), and number of awakenings remained stable (–0.2 [–0.7, 0.3]; P=0.3959; n=26). Percentage of participants rating sleep quality as “very good”/”good” increased from 26.9% (9g-baseline) to 61.5% (>9g-EOT), as did rested sleep (“very well”/”well”/”somewhat” rested) from 57.7% to 69.2%, respectively. From 9g-baseline to >9g-EOT, KSS scores decreased (–0.9 [–1.4, –0.4]; P=0.0004; n=39); FOSQ-10 scores also increased (1.3 [0.5, 2.0]; P=0.0014; n=40). Of 48 participants, 36 (75.0%) experienced ≥1 TEAE (mostly mild/moderate and 1 serious [syncope, unrelated to treatment]). No changes in respiratory polysomnography measures were observed. Conclusion Participants with narcolepsy who optimized to LXB >9 g/night, relative to 9 g/night, reported increased sleep quality and restfulness that paralleled improvements in daytime sleepiness and daytime functioning. TEAEs were consistent with those at lower dosages. Support (if any) Jazz Pharmaceuticals

Abstract Introduction AXS-12 (reboxetine) is a highly selective norepinephrine reuptake inhibitor and cortical dopamine modulator under development for the treatment of narcolepsy. Long-term efficacy and safety of AXS-12 in participants with narcolepsy with cataplexy (NT1) were previously reported from the Phase 3 ENCORE trial. To better understand the impact of AXS-12 on overall functional burden in NT1, we evaluated changes in cognition and functional outcomes during the ENCORE trial. Methods ENCORE included a 24-week open-label extension (OLE) period, followed by a 3-week double-blind randomized-withdrawal (DBRW) period. During the OLE, participants received AXS-12 (5 mg once-daily for 1 week, twice-daily for 23 weeks). Following this, participants were randomized 1:1 to continue twice-daily AXS-12 for 3 weeks or switch to once-daily AXS-12 plus placebo for 1 week, then placebo twice-daily for 2 weeks. P-values reported are nominal. Results ENCORE enrolled 68 participants; 42 completed the OLE and entered the DBRW (AXS-12, n=22; placebo, n=20). In the OLE, participants treated with AXS-12 reported improvement in the NSAQ Ability to Concentrate item at 1 (54.8%) and 6 (58.5%) months. Participants reported improvement in concentration, assessed by PGI-C, at 1 (66.7%) and 6 (70.0%) months. Narcolepsy overall, assessed by the CGI-C, improved at 1 (90.3%) and 6 (90.2%) months; and improved at 1 (77.8%) and 6 (80.0%) months, assessed by the PGI-C. Functional impairment, assessed by the WPAI, was reduced from 53.0% at baseline to 34.0% at 1 month and 24.3% at 6 months. In the DBRW, a greater proportion of participants switched to placebo experienced worsening on the NSAQ Ability to Concentrate item (52.6% vs 14.3%; P=0.011), and PGI-C for ability to concentrate (57.9% vs 22.2%; P=0.029) at 3 weeks compared with those continuing AXS-12. A greater proportion switched to placebo also reported worsening of their narcolepsy overall (PGI-C) at 3 weeks compared with those continuing AXS-12 (52.6% vs 16.7%; P=0.024). Treatment with AXS-12 was generally well tolerated. Conclusion Long-term, open-label treatment with AXS-12 was associated with improvements in cognitive/functional domains and productivity. Randomized withdrawal to placebo led to worsening cognition and narcolepsy overall. These results further support the long-term therapeutic benefit of AXS-12 for narcolepsy. Support (if any) Axsome Therapeutics Inc.

Abstract Introduction AXS-12 (reboxetine) is a highly selective norepinephrine reuptake inhibitor and cortical dopamine modulator under development for narcolepsy. In the Phase 3 SYMPHONY trial, AXS-12 significantly reduced weekly cataplexy attacks from baseline to Week 5 versus placebo in patients with narcolepsy. Here we report the Phase 3 ENCORE trial, assessing long-term efficacy and safety of AXS-12 in participants who completed SYMPHONY. Methods ENCORE included a 24-week open-label extension (OLE) period, followed by a 3-week double-blind randomized-withdrawal (DBRW) period. During the OLE, participants received AXS-12 (5 mg once-daily for 1 week, twice-daily for 23 weeks). Following this, remaining participants were randomized 1:1 to continue twice-daily AXS-12 or switch to once-daily AXS-12 plus placebo for 1 week, then placebo twice-daily for 2 weeks. The primary endpoint was change in frequency of cataplexy attacks from randomization to DBRW Week 3. OLE efficacy outcomes included change in weekly frequency of cataplexy attacks, cataplexy response (≥50% reduction), and change in cataplexy-free days. Additional analyses are ongoing. Results ENCORE enrolled 68 participants; 42 completed the OLE and entered the DBRW (AXS-12, n=22; placebo, n=20). In SYMPHONY, baseline mean weekly frequency of cataplexy attacks was 31.5. At DBRW randomization, mean weekly frequency of cataplexy attacks was 4.2 (AXS-12) and 6.9 (placebo). Participants randomized to placebo experienced a mean increase of 10.29 weekly cataplexy attacks versus 1.32 for AXS-12, at end of DBRW (p=0.017). In the OLE, weekly frequency of cataplexy attacks decreased by 22.3 (71%) and 24.1 (77%) at 1 and 6 months, respectively. Cataplexy response was achieved by 72% and 82% at 1 and 6 months, respectively. Cataplexy-free days increased from 14.3% to 61% and 70% at 1 and 6 months, respectively. Common adverse events (AEs; ≥5%) during the OLE were nausea and tachycardia (both 5.9%); no new safety signals were detected. Discontinuations due to AEs occurred in 17.6% of participants in the OLE. Conclusion AXS-12 significantly reduced the frequency of cataplexy attacks during the DBRW. AXS-12 was well-tolerated and demonstrated maintenance of efficacy with long-term open-label use. These results align with SYMPHONY, supporting the positive therapeutic impact of AXS-12 for narcolepsy. Support (if any) Axsome Therapeutics, Inc.

Abstract Introduction Narcolepsy is a chronic neurologic condition associated with severe symptom burden, impaired functioning and reduced quality of life. Patients commonly report comorbid mood disorders. AXS-12 (reboxetine) is a selective norepinephrine reuptake inhibitor and cortical dopamine modulator under investigation for the treatment of narcolepsy. In the Phase 3 SYMPHONY trial, AXS-12 met the primary endpoint, a statistically significant reduction in weekly cataplexy attacks from baseline to Week 5 versus placebo. Here, we report secondary endpoints assessing symptom severity, daily functioning, and mood. Methods SYMPHONY was a randomized, double-blind, placebo-controlled trial in patients with narcolepsy type 1 (NT1). Participants (15-75 years) were randomized 1:1 to AXS-12 or placebo for 5 weeks. Stable, concurrent modafinil/armodafinil use was allowed. Secondary endpoints included: the Clinical Global Impression of Severity (CGI-S) for narcolepsy, the Functional Outcomes of Sleep Questionnaire short version (FOSQ-10), and the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire anxiety/depression domain. Results Ninety participants were enrolled. At baseline, mean (SD) CGI-S for narcolepsy score was 5.2 (1.0) in the AXS-12 arm and 4.9 (1.0) in the placebo arm. AXS-12 led to a significant reduction versus placebo in CGI-S for narcolepsy at Week 5 (LS mean difference [95% CI]=0.72 [0.29, 1.16]; p=0.001). At baseline, mean FOSQ-10 total score was 11.1 (3.1) in the AXS-12 arm and 11.6 (3.2) in the placebo arm. AXS-12 led to a statistically significant improvement from baseline to Week 5 in FOSQ-10 total scores compared to placebo (1.66 [0.51, 2.82], p=0.005). At baseline, 47.8% of participants in the AXS-12 arm and 45.5% in the placebo arm reported anxiety/depression (EQ-5D-5L). A numerically greater proportion of participants achieved improvements on this domain with AXS-12 (55.0%) versus placebo (31.6%) at Week 5 (p=0.146). Conclusion AXS-12 demonstrated significant reductions in clinical impressions of narcolepsy symptom severity. Functional impairment due to EDS was also significantly reduced, in-line with previously reported improvement in clinician-rated assessments. Anxiety and depression-related symptoms showed trends favoring AXS-12. Combined with prior findings on cataplexy and cognitive improvements, these results highlight the potential of AXS-12 as a therapeutic option addressing multiple symptoms of narcolepsy which affect QoL and functioning. Support (if any) Axsome Therapeutics, Inc.