Alkermes’ oral, selective orexin 2 receptor (OX2R) agonist has shown continued benefit nine months after the start of treatment in patients with narcolepsy types 1 (NT1) and 2 (NT2).
In an interim analysis of an ongoing long-term extension (LTE) study evaluating alixorexton in adults with narcolepsy, patients who received the study drug sustained clinically meaningful improvement from baseline on the maintenance of wakefulness Test (MWT) and Epworth sleepiness scale (ESS) at week 24.
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Including the run-in from the randomised double-blind period of the Vibrance-1 and Vibrance-2 Phase II studies, this equates to approximately nine months of treatment.
Alixorexton also demonstrated sustained and clinically meaningful improvement from baseline across patient-reported outcomes (PROs) evaluating cognition and fatigue at week 24. Alixorexton was generally safe and well tolerated at all doses tested.
Dr Yves Dauvilliers, director of the Sleep-Wake Disorders Center at the University of Montpellier, France, and who has also previously presented Vibrance data alongside Alkermes, said: “For people living with narcolepsy, symptom burden extends beyond excessive daytime sleepiness and can affect cognitive function and fatigue. It is exciting to see clinically meaningful improvements sustained across these important measures in this analysis of the long-term extension study of alixorexton in patients with narcolepsy type 1 and type 2. The consistency of the data in up to nine months of treatment provides further evidence that alixorexton, across a range of doses, has the potential to address important aspects of the disease burden of narcolepsy regardless of narcolepsy type 1 or type 2 diagnosis.”
The LTE remains ongoing and is open for enrolment for participants who complete ongoing Phase II and Phase III studies of alixorexton.
NT1 patients achieved “normative” levels
All alixorexton dose groups for those who completed Vibrance-1 achieved normative wakefulness on the MWT (mean sleep latency (MSL) ≥20 minutes) at week 24 of the LTE, with a mean observed MSL of approximately 29 minutes across LTE participants.
MSL on MWT was 1.7, 2.2 and 3.4 at baseline in the 4mg, 6mg an 8mg cohorts, respectively. After 24 weeks of the LTE, this reached 35.3, 30.7 and 28.1 in the same doses, respectively.
At week 24, most NT1 patients across all doses had cognitive functioning scores within the normal range, as measured by the British Columbia – Cognitive Complaints Inventory (BC-CCI), and mean fatigue scores were within the normal range, as measured by PROMIS-Fatigue, across all doses
Improvements seen in NT2 cohort
In the NT2 cohort – those who completed Vibrance-2, MSL on MWT was 2, 4.8 and 5.2 at baseline in the 10mg, 14mg and 18mg cohorts, respectively. After the LTE cutoff, the same cohorts reported scores of 21.1, 18 and 17.3.
At week 24, most NT2 patients across all doses had cognitive functioning scores within the normal or mild range, as measured by the BC-CCI, and mean fatigue scores were within the normal range, as measured by PROMIS-Fatigue, across all doses.
While the dual primary endpoints in the high doses in a Phase II narcolepsy type 2 (NT2) trial were met, they were only achieved in the 14mg and 18mg cohorts and were “adjusted for multiplicity”, meaning statistical methods were used to correct for the increased chance of a false positive, or Type I error.
Alkermes plans to present these results at an upcoming medical meeting. Alixorexton is currently being evaluated in the Phase III Brilliance Studies in adults with NT1 and NT2, and in the Phase II Vibrance-3 study in adults with idiopathic hypersomnia (IH).
OX2R race heating up
Alkermes is not the only company coming to late-stage development with an OX2R agonist, with Centessa hot on its heels. In November 2025, Centessa announced positive data from the Phase IIa CRYSTAL-1 trial (NCT06752668) of ORX750, an OX2R agonist, in NT1, NT2 and IH.
Furthest ahead in the race is Takeda with its candidate oveporexton, which has shown success in Phase III trials, with the US Food and Drug Administration (FDA) having set a Prescription Drug User Fee Act (PDUFA) date of 10 August 2026.
Even if this class of drugs make it to market, they will face competition from already approved therapies for sleep disorders, according to a GlobalData report. This includes Jazz Pharmaceuticals’ Xywav (calcium oxybate, magnesium oxybate, potassium oxybate, and sodium oxybate) and Biogen’s Wakix (pitolisant hydrochloride), both of which are expected to exceed $1bn in sales in 2030. There are no approved OX2R agonists for NT1, NT2 or IH.
