VIBRANCE-1
Safety, tolerability, and efficacy of alixorexton, a selective orexin 2 receptor agonist for narcolepsy type 1 (Vibrance-1): a randomised, double-blind, placebo-controlled, phase 2 trial
Clinical Question
Can once-daily oral alixorexton, an orexin 2 receptor agonist, restore wakefulness and reduce cataplexy in adults with narcolepsy type 1?
Bottom Line
Once-daily oral alixorexton (4, 6, or 8 mg) produced large, clinically meaningful improvements in wakefulness, daytime sleepiness, and (at 6 mg) cataplexy over 6 weeks in narcolepsy type 1, with mean MWT sleep latency and ESS scores reaching normative ranges; it was generally well tolerated with on-target OX2R adverse events (pollakiuria, insomnia, salivary hypersecretion) and no serious treatment-emergent adverse events, supporting phase 3 development.
Major Points
- Primary endpoint met at all doses: placebo-corrected LSM change from baseline to week 6 in mean sleep latency on the MWT was 22.2 min (95% CI 17.2–27.2; adjusted p=0.0099) for 4 mg, 24.1 min (19.0–29.1; p<0.0001) for 6 mg, and 26.0 min (21.0–31.0; p<0.0001) for 8 mg
- Observed mean MWT sleep latency at week 6 reached the normative range (≥20 min) in all alixorexton groups (24.0–28.2 min) vs 2.3 min with placebo
- ESS improved vs placebo by −6.4 (4 mg), −8.7 (6 mg), and −8.3 (8 mg) points, with mean observed scores in the normal range (<10) at all post-baseline assessments
- Weekly cataplexy rate was significantly reduced only with 6 mg (IRR 0.31, 95% CI 0.14–0.70; adjusted p=0.0099); 16 of 37 (43%) participants on 6 or 8 mg were cataplexy-free during week 6
- Exploratory endpoints (NSS–CT, PROMIS–Fatigue, BC-CCI-E cognition, FOSQ-10, EQ-5D-5L, EQ VAS) all favored alixorexton; NSS–CT improvements exceeded the 8-point MCID and mean scores fell into the mild range for 6 and 8 mg
- Generally well tolerated: most common TEAEs were pollakiuria (55%), insomnia (28%), and salivary hypersecretion (25%); no serious TEAEs; 91 of 92 (99%) completed the double-blind period
- Findings support phase 3 evaluation of once-daily alixorexton in narcolepsy type 1
Design
Study Type: Randomised, double-blind, placebo-controlled, parallel-group, dose-ranging phase 2 trial with 6-week double-blind period and optional 7-week open-label extension
Randomization: 1
Blinding: Double-blind (sponsor, assessors, investigators, and participants masked) during the randomised treatment period; open-label extension unblinded
Allocation: Central 1:1:1:1 randomisation in blocks of four via interactive response technology, stratified by region (USA vs rest of world) and baseline weekly cataplexy rate (<8 vs ≥8)
Enrollment Period: May 24, 2024 to May 5, 2025
Follow-up Duration: 6 weeks double-blind; optional 7-week open-label extension (through week 13)
Centers: 46
Countries: USA, Europe, Australia
Sample Size: 92
Analyzed: 92
Analysis: All randomly assigned participants who received at least one dose (efficacy and safety); ANCOVA with multiple imputation for MSL and ESS; negative binomial regression for weekly cataplexy rate; graphical procedure to control multiplicity
Power Calculation: n=14 per group estimated to give 98% power for a 20-min MWT difference (SD 11.6) and 96% power for a 10-point ESS difference (SD 6.2); 80% power for an 80% WCR reduction (rate ratio 0.2); 80 participants planned assuming 30% dropout
Registration: ClinicalTrials.gov NCT06358950
Inclusion Criteria
- Age 18–70 years
- Narcolepsy type 1 diagnosed per ICSD-3, confirmed by overnight polysomnography and Multiple Sleep Latency Test or cerebrospinal hypocretin-1 concentrations
- Epworth Sleepiness Scale total score >12 at screening
- HLA-DQB1*06:02 genotype positive or documented CSF hypocretin-1 ≤110 pg/mL
- Mean of more than four cataplexy events per week during washout of ongoing narcolepsy medications
- Mean sleep latency ≤15 min on the Maintenance of Wakefulness Test
- Written informed consent
Exclusion Criteria
- Clinically significant comorbid sleep disorders or disturbed sleep
- Clinically significant cardiovascular disease
- Psychiatric or substance use disorder
- Other chronic conditions such as uncontrolled diabetes or clinically significant hepatic or renal disease
Arms
| Field | Control | Alixorexton 4 mg | Alixorexton 6 mg | Alixorexton 8 mg |
|---|---|---|---|---|
| N | 23 | 23 | 22 | 24 |
| Intervention | Matching placebo tablet once daily in the morning | Alixorexton (ALKS 2680) 4 mg oral tablet once daily in the morning | Alixorexton (ALKS 2680) 6 mg oral tablet once daily in the morning | Alixorexton (ALKS 2680) 8 mg oral tablet once daily in the morning |
| Duration | 6 weeks | 6 weeks | 6 weeks | 6 weeks |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Change from baseline to week 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT), using the first four post-dose MWT sessions (2, 4, 6, and 8 h post-dose) | Primary | Observed MSL 2.3 min (SD 2.7); LSM change from baseline −0.6 min (95% CI −4.5 to 3.3) | Observed MSL 24.0 min (4 mg), 25.9 min (6 mg), 28.2 min (8 mg); LSM change from baseline +21.6, +23.5, and +25.5 min respectively | LSM difference vs placebo: +22.2 min (4 mg), +24.1 min (6 mg), +26.0 min (8 mg) | Adjusted p=0.0099 (4 mg); adjusted p<0.0001 (6 mg and 8 mg) |
| Change from baseline to week 6 in Epworth Sleepiness Scale (ESS) score | Secondary | Results: Observed week-6 score: placebo 15.1 (SD 5.9), 4 mg 8.8 (5.5), 6 mg 6.6 (5.8), 8 mg 7.2 (5.8). LSM difference vs placebo: −6.4 (95% CI −9.6 to −3.3; adjusted p=0.0099) for 4 mg; −8.7 (−11.9 to −5.5; adjusted p<0.0001) for 6 mg; −8.3 (−11.4 to −5.2; adjusted p<0.0001) for 8 mg. Mean scores in normal range (<10) at all post-baseline assessments for all doses | |||
| Weekly cataplexy rate (WCR) over weeks 5 and 6 | Secondary | Results: Median observed episodes at week 6: placebo 7.6 (IQR 4.3–30.3), 4 mg 3.8 (1.4–11.3), 6 mg 1.0 (0.0–6.5), 8 mg 2.5 (0.0–9.2). Incidence rate ratio vs placebo: 0.49 (95% CI 0.23–1.05; adjusted p=0.17) for 4 mg; 0.31 (0.14–0.70; adjusted p=0.0099) for 6 mg; 0.64 (0.30–1.41; adjusted p=0.45) for 8 mg | |||
| Narcolepsy Severity Scale–Clinical Trials (NSS–CT) at week 6 (exploratory) | Secondary | Results: LSM difference vs placebo: −9.1 (95% CI −14.3 to −3.9; nominal p=0.0008) for 4 mg; −12.4 (−18.0 to −6.7; nominal p<0.0001) for 6 mg; −11.0 (−16.2 to −5.8; nominal p<0.0001) for 8 mg; all exceeding the 8-point MCID. Mild-range disease severity (<14) reached in 6 mg and 8 mg groups; disease rated mild at week 6 by 55% (4 mg), 67% (6 mg), and 78% (8 mg) vs 9% placebo | |||
| Cataplexy-free days during week 6 (exploratory) | Secondary | Results: Mean cataplexy-free days per week: placebo 2.9 (41%), 4 mg 3.8 (54%), 6 mg 5.0 (71%), 8 mg 4.8 (69%); 16 of 37 (43%) participants in the 6 mg and 8 mg groups had no cataplexy events during week 6 | |||
| PROMIS–Fatigue at week 6 (exploratory) | Secondary | Results: Reduced fatigue scores vs placebo across all doses (nominal p<0.01), evident from week 2 | |||
| BC-CCI-E cognitive complaints at week 6 (exploratory) | Secondary | Results: Reduced patient-reported cognitive impairment vs placebo across all doses (nominal p<0.0001), evident from week 2 | |||
| Quality of life: FOSQ-10, EQ-5D-5L index, EQ VAS at week 6 (exploratory) | Secondary | Results: Clinically meaningful improvements in all alixorexton groups | |||
| 91 of 92 (99%) completed the double-blind period; one participant (8 mg group) discontinued alixorexton due to TEAEs (tachycardia, blurred vision, and increased blood pressure) during the RDBT; during the OLE, 2 participants who transitioned from placebo to alixorexton 6 mg discontinued alixorexton due to TEAEs (depressed mood and depression), with 1 discontinuing from the study | Safety | ||||
| No serious treatment-emergent adverse events; most TEAEs mild to moderate | Safety | ||||
| Adverse events consistent with known on-target effects of OX2R agonism | Safety | ||||
| Safety monitored via clinical laboratory tests, vital signs, ECG, C-SSRS, and ophthalmological examinations reviewed by an independent data safety monitoring board including a neuro-ophthalmologist | Safety | ||||
| Pollakiuria | Adverse | 38 (55%) of alixorexton-treated participants | |||
| Insomnia | Adverse | 19 (28%) | |||
| Salivary hypersecretion | Adverse | 17 (25%) | |||
| Micturition urgency | Adverse | 10 (14%) | |||
| Blurred vision | Adverse | 10 (14%) | |||
| Hyperhidrosis | Adverse | 5 (7%) | |||
| Serious TEAEs | Adverse | None | |||
| Discontinuation due to adverse event (RDBT) | Adverse | 1 (8 mg group, due to tachycardia, blurred vision, and increased blood pressure); during the OLE, 2 participants who transitioned from placebo to alixorexton 6 mg discontinued alixorexton due to TEAEs (depressed mood and depression), with 1 discontinuing from the study | |||
Criticisms
- Small sample size (92 participants) typical of phase 2, limiting precision for dose comparisons
- Short 6-week double-blind duration for a chronic lifelong disease
- Cataplexy reduction reached significance only at the 6 mg dose, with a non-significant IRR at the highest (8 mg) dose
- Blinding integrity was not formally assessed by participant exit interviews or surveys
- Sponsor (Alkermes) had roles in study design, data collection, analysis, and interpretation
- 46% of participants had race not reported, limiting assessment of generalisability
Funding
Alkermes
Based on: VIBRANCE-1 (The Lancet Neurology, 2026)
Authors: Giuseppe Plazzi, Ronald R Grunstein, Emmanuel Mignot, ..., Yves Dauvilliers
Citation: The Lancet Neurology. 2026. doi:10.1016/s1474-4422(26)00278-4
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