Alkermes’ oral, selective orexin 2 receptor (OX2R) agonist has met its dual primary endpoints in the high doses in a Phase II narcolepsy type 2 (NT2) trial.
In the Vibrance-2 study (NCT06555783), there were statistically significant and clinically meaningful improvements from baseline compared to placebo on the Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) at week eight in patients dosed with alixorexton.
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Alkermes caveated, however, that these endpoints were 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.
This clarification seems to have spooked investors, with the company’s stock opening 17.27% lower on 12 November at $27.97 compared to a 11 November market close of $33.81. The company has a market cap of $4.87bn.
The company added that alixorexton was generally well tolerated at all doses tested, with most treatment-emergent adverse events (TEAEs) being mild to moderate in severity. No serious TEAEs were reported.
The trial enrolled 93 patients with NT2, a rare, chronic neurological sleep disorder that affects the brain’s ability to regulate the sleep-wake cycle, who were randomised into the 10mg, 14mg, or 18mg cohorts of alixorexton or placebo for eight weeks.
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By GlobalDataAlkermes did not divulge any of the data, but said it was strong enough to support the drug’s development into Phase III trials in narcolepsy type 1 (NT1) and NT2, which it anticipates will initiate in Q1 2026.
Previous Phase II data supports advancement
The Phase III advancement is also supported by the Vibrance-1 trial (NCT06358950) with the 4mg, 6mg and 8mg cohorts, leading to a 22.2 point, 24.1 point and 26.0 point improvement on the MWT. On the ESS, in the low, medium and high dose cohorts, there were reductions of 6.4, 8.7, and 8.3 points, respectively.
On the key secondary endpoint evaluating mean weekly cataplexy rates, alixorexton demonstrated numerical and clinically meaningful improvements across all doses compared to placebo at weeks five and six and, on the pre-specified analysis, achieved statistical significance at the 6mg dose.
Vibrance-3, a Phase II study (NCT06843590) evaluating the safety and efficacy of alixorexton in adults with idiopathic hypersomnia (IH), is currently enrolling patients.
GlobalData predicts a 2028 approval for Alkermes’ OX2R, with an annual sales and consensus forecast of $778m in 2031.
GlobalData is the parent company of Clinical Trials Arena.
OX2R race heating up
Alkermes is not the only company coming to late-stage development of an OX2R agonist, with Centessa hot on its heels. Earlier in November 2025, Centessa announced data from the Phase IIa CRYSTAL-1 trial (NCT06752668) of ORX750, an orexin receptor type 2 (OXR2) agonist, in NT1, NT2 and IH.
In both the NT1 and NT2 cohorts, there was statistically significant, clinically meaningful and dose-dependent improvements in the MWT and ESS seen in all doses.
In IH, ORX750 achieved statistically significant and clinically meaningful improvements on multiple efficacy measures including mean sleep latency on the MWT.
Centessa is also looking for a Q1 2026 initiation of Phase III registrational trials, with GlobalData also predicting a 2028 approval for the candidate.
GlobalData predicts Centessa’s drug to be slightly more successful, with a 2031 annual sales and consensus forecast of $875m.
Furthest ahead in the race is Takeda with its candidate oveporexton, which has shown success in Phase III trials, with GlobalData predicting a 2026 approval, with a 2031 sales forecast of $1.26bn. In the Phase III FirstLight (NCT06470828) and RadiantLight (NCT06505031) trials, twice-daily 2mg cohorts, MWT scores were 21.8 and 24.6, respectively, putting patients in the normative range. There was also a drop in the ESS from 19 points to 7 points and from 17.3 points to 6.4 points in FirstLight and RadiantLight, respectively.
Even if these drugs make it to market, they will face competition from already approved therapies, 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. Neither of these approved therapies are OX2R agonists.
