News|Articles|November 14, 2025

Orexin Agents ORX750 and ORX142 Show Promising Early Phase 1 and 2 Data

Listen

0:00 / 0:00

Key Takeaways

ORX750 demonstrated significant efficacy in NT1, NT2, and IH, with improvements in sleep latency and daytime sleepiness, and reduced cataplexy rates.
ORX142 showed rapid onset and favorable safety in phase 1 trials, with significant sleep latency improvements in sleep-deprived volunteers.
Centessa plans to advance ORX750 into a registrational program, highlighting its potential as a best-in-class OX2R agonist for sleep disorders.

Centessa Pharmaceuticals reveals promising early-stage results for its orexin receptor 2 agonists, ORX750 and ORX142, targeting neurologic sleep disorders.

In a recent company update, Centessa Pharmaceuticals shared positive early-stage data for its investigational orexin receptor 2 (OX2R) agonist agents, including ORX750 in various neurologic sleep disorders and ORX142 in healthy volunteers. ORX750, which showed treatment potential in both narcolepsy subtypes as well as idiopathic hypersomnia (IH), is expected to enter a registrational program early next year.

OXR750 is currently being tested in the CRYSTAL-1 trial (NCT06752668), a phase 2a, adaptive, double-blind, placebo-controlled study featuring independent cohorts of narcolepsy type 1 (NT1), type 2 (NT2), and IH. After the initial dose cohorts, the study transitioned to a 4-week parallel design enrolling at least 8 participants with NT1 and 12 with NT2 or IH per cohort, in which participants are randomized to one of two blinded sequences to receive 4 weeks of ORX750 or placebo followed by a 2-week crossover.

The latest update featured data from 55 patients in the phase 2 study, using September 23, 2025, as the cut-off date. CRYSTAL-1 evaluated once-daily ORX750 in a randomized 2-week crossover, using 1.0 mg and 1.5 mg doses for NT1, 2.0 mg and 4.0 for NT2, and a 2.0 mg dose for IH.

"We are thrilled to share significant progress marked by clinical data from our growing OX2R agonist program," Saurabh Saha, MD, PhD, chief executive officer at Centessa, said in a statement.¹ "Based on today’s update, ORX750 continues to stand out as a potential best-in-class OX2R agonist for the treatment of NT1, NT2 and IH, and potentially as the first OX2R agonist to treat NT2 and IH."

NT1 Results

Overall, ORX750 demonstrated statistically significant, clinically meaningful, and dose-dependent improvements across multiple efficacy measures. In the 1.5-mg cohort, patients showed more than a 20-minute increase in mean sleep latency on the MWT compared with placebo (P = 0.0026), with half achieving over 30 minutes, while dose escalation continues with both once-daily and split-dose regimens.

Participants also experienced marked reductions in daytime sleepiness, with mean ESS scores improving from 19.6 at baseline to 5.1 on ORX750 versus 18.7 on placebo (P = 0.0001). Additionally, ORX750 reduced the weekly cataplexy rate by 87% relative to placebo (incidence rate ratio = 0.13; P = 0.0025), confirming consistent benefit across endpoints.

NT2 Results

In patients with NT2, ORX750 produced statistically significant, clinically meaningful, and dose-dependent improvements across sleepiness and wakefulness measures at both doses. In the 4.0-mg cohort (n = 10), participants demonstrated over a 10-minute increase in mean sleep latency on the MWT compared with placebo at Week 2 (P = 0.0193), while dose escalation continues with both once-daily and split-dose regimens. Mean ESS scores improved from 17.3 at baseline to 8.1 with ORX750 versus 15.9 with placebo (P = 0.0023), reinforcing the agent’s consistent benefit in reducing excessive daytime sleepiness.

IH Results

While dose escalation continues on for this cohort, results revealed that those (n = 17) on a ORX750 at 2.0 mg doses achieved statistically significant and clinically meaningful improvements on multiple efficacy measures including mean sleep latency on the MWT (P = .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. In addition, ORX750’s distinct PK profile contributed to generally favorable safety and tolerability, along with a prolonged duration of action throughout the day,” Mario Alberto-Accardi, PhD, president of the Centessa Orexin Program, said in a statement.¹

He added, "ORX750 also achieved clinically meaningful wake promotion in NT2 with observed improvements to date that could potentially establish ORX750 as the new standard of care in NT2. 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. With more than 50 participants across ongoing cohorts, we expect to further enhance efficacy and dosing flexibility across all indications."

OXR142 Findings

OXR142, Centessa’s other OX2R agonist, was also evaluated in a phase 1, first-in-human, randomized, placebo-controlled trial. The study included a single-ascending dose (SAD) and multiple-ascending dose (MAD) portions in healthy adults, as well as a placebo-controlled crossover pharmacodynamic assessment in acutely sleep-deprived healthy adult participants.

The company update, which featured 89 adult volunteers who were dosed with the agent as of the October 3, 2025, cut-off, further supported the drug’s safety and efficacy profile. Here, ORX142 showed a rapid onset of action, differentiated pharmacokinetics, and was generally well tolerated across all tested doses. The agent produced statistically significant, dose-dependent improvements in mean sleep latency on the MWT compared with placebo in acutely sleep-deprived healthy volunteers. Based on these positive Phase 1 findings, patient studies are planned for undisclosed indications.

Previous Data

In a prior phase 1 study, ORX750 demonstrated a favorable safety and tolerability profile, with no reported common adverse events, liver toxicity, or visual disturbances. Compared with placebo, participants receiving ORX750 exhibited significant, dose-dependent increases in sleep latency on the MWT across sessions conducted 2, 4, 6, and 8 hours after an 11:00 PM dose. Specifically, the 1.0-mg dose produced a mean sleep latency of 18 minutes versus 10 minutes with placebo (P = 0.04), while the 2.5-mg dose achieved 32 minutes compared with 17 minutes for placebo (P = 0.01), fully restoring normal wakefulness.²