The company also announced a CEO transition to sharpen its focus on its orexin pipeline as phase 2a data shows ORX750 improved key measures of wakefulness and cataplexy.
Key takeaways:
- Phase 2a data shows ORX750 achieved statistically significant improvements across NT1, NT2, and IH on measures like the Maintenance of Wakefulness Test and Epworth Sleepiness Scale.
- In NT1 patients, ORX750 reduced the weekly cataplexy rate by 87% compared to placebo and improved mean sleep latency on the MWT by over 20 minutes at the 1.5 mg dose.
- The drug was generally well-tolerated; the most common treatment-emergent adverse events were pollakiuria (51%), insomnia (22%), dizziness (13%), and headache (11%).
- Mario Alberto Accardi, PhD, will become CEO on Jan 1, 2026, succeeding Saurabh Saha, MD, PhD, as Centessa concentrates on its orexin program.
- The company plans to initiate a registrational program for ORX750 in the first quarter of 2026.
Centessa Pharmaceuticals announced positive phase 2a data from initial cohorts for its orexin receptor 2 (OX2R) agonist, ORX750, showing statistically significant and clinically meaningful improvements in patients with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH).
On the heels of the clinical update, the company announced a leadership transition intended to sharpen its focus on its orexin pipeline. Mario Alberto Accardi, PhD, president and founder of Centessa’s orexin program, will be appointed chief executive officer (CEO), effective Jan 1, 2026. He will succeed Saurabh Saha, MD, PhD, who will become an advisor to the CEO.
According to the company, the phase 2a data on 55 participants marks the first robust demonstration of an oral OX2R agonist addressing wakefulness in NT1, NT2, and IH patient populations.
For NT1, the 1.5 mg once-daily dose of ORX750 achieved a greater than 20-minute change from baseline in mean sleep latency on the MWT compared with placebo (p=0.0026). It also reduced the mean ESS total score to 5.1 from a baseline of 19.6 (p=0.0001) and produced an 87% relative reduction in the weekly cataplexy rate compared with placebo (p=0.0025).
For NT2, the 4.0 mg dose achieved a greater than 10-minute change from baseline in mean sleep latency on the MWT versus placebo (p=0.0193). For IH, the 2.0 mg dose also showed statistically significant and clinically meaningful improvements on the MWT (p=0.0213).
“In these early cohorts, ORX750 has already achieved notable improvements on MWT, ESS, and WCR—key measures of symptom normalization in NT1—translating clinical efficacy into meaningful, real-world gains in wakefulness and daily functioning,” says Mario Alberto Accardi, PhD, incoming CEO and president of Centessa’s Orexin Program, in a release. “And, for IH, ORX750 is the first OX2R agonist to demonstrate statistically significant and clinically meaningful improvements on multiple efficacy measures including on the MWT.”
ORX750 was observed to be generally well-tolerated. All treatment-emergent adverse events were transient and mild to moderate in severity. The most common were pollakiuria (51%), insomnia (22%), dizziness (13%), and headache (11%). One participant in the NT2 cohort discontinued treatment due to urinary urgency.
The leadership change reflects the company’s strategic shift to a “pure-play orexin portfolio,” according to Francesco De Rubertis, PhD, chair of Centessa’s Board.
With its ongoing phase 2a CRYSTAL-1 study, Centessa expects to initiate a registrational program for ORX750 in the first quarter of 2026. The company is also advancing two other OX2R agonists, ORX142 and ORX489, with plans to initiate clinical studies for both in the first quarter of 2026, subject to IND clearance for ORX489.
