Centessa provides update on OX2R agonist program

The Phase 2a data from initial dosing cohorts marks the first robust demonstration of an oral OX2R agonist addressing wakefulness needs across NT1 patients, who lack endogenous orexin, and the broader populations of NT2 and IH patients, who maintain normal to variable orexin levels. The Phase 2a study update includes a total of 55 participants with NT1, NT2 and IH who completed dosing with ORX750 in the 2-week crossover cohorts as of the September 23, 2025 data cut-off date. ORX750 was observed to be generally well-tolerated at all doses tested across each indication with all treatment-emergent adverse events being transient and mild to moderate in severity. One participant discontinued from treatment due to urinary urgency in the NT2 cohort. There were no clinically meaningful changes in cardiac, visual, liver or renal function. The most common TEAEs across all completed NT1, NT2 and IH cohorts were pollakiuria, insomnia, dizziness and headache. Initial NT1 dose cohorts included 1.0 mg and 1.5 mg doses administered once daily in the randomized 2-week crossover. For NT1, ORX750 achieved: Statistically significant, clinically meaningful and dose-dependent improvements from baseline compared with placebo in mean sleep latency on the MWT at both doses. In the 1.5 mg cohort, ORX750 achieved a greater than20 minute change from baseline in mean sleep latency compared with placebo on the MWT at Week 2, with half the participants achieving greater than30 minutes in mean sleep latency on the MWT. Dose escalation is progressing with both once-daily and split-dose regimens. Statistically significant, clinically meaningful and dose-dependent improvements from baseline in ESS total score compared with placebo at both doses. In the 1.5 mg cohort, participants had a mean ESS total score of 5.1 with ORX750 compared to a mean ESS total score of 18.7 with placebo at Week 2. Participants had a mean ESS total score of 19.6 at baseline. Statistically significant, clinically meaningful and dose-dependent reductions in Weekly Cataplexy Rate at both doses. In the 1.5 mg cohort, participants with ORX750 had an 87% relative reduction in WCR compared with placebo, with an estimated incidence rate ratio of 0.13 at Week 2. Initial NT2 dose cohorts included 2.0 mg and 4.0 mg doses administered once daily in the randomized 2-week crossover. For NT2, ORX750 achieved: Statistically significant, clinically meaningful and dose-dependent improvements from baseline compared with placebo in mean sleep latency on the MWT at both doses. In the 4.0 mg cohort, ORX750 achieved a greater than10 minute change from baseline in mean sleep latency compared with placebo on the MWT at Week 2. Dose escalation is progressing with both once-daily and split-dose regimens. Statistically significant, clinically meaningful and dose-dependent improvements from baseline in ESS total score compared with placebo at both doses. In the 4.0 mg cohort, participants had a mean ESS total score of 8.1 with ORX750 compared to a mean ESS total score of 15.9 with placebo at Week 2. Participants had a mean ESS total score of 17.3 at baseline. The initial IH dose cohort included a 2.0 mg dose administered once daily in the randomized 2-week crossover. At this dose, ORX750 achieved statistically significant and clinically meaningful improvements from baseline compared with placebo on multiple efficacy measures including mean sleep latency on the MWT. Dose escalation is progressing. ORX142 Phase 1 Study Update: The Phase 1 study update includes a total of 89 healthy adult volunteers who were dosed with ORX142 as of the October 3, 2025 data cut-off date. ORX142 demonstrated a rapid onset of action, differentiated pharmacokinetics and was observed to be generally well-tolerated at all doses tested. In addition, ORX142 achieved statistically significant and dose-dependent improvements from baseline compared to placebo in mean sleep latency on the MWT at all doses tested in acutely sleep-deprived healthy volunteers. Based on the totality of the Phase 1 data for ORX142, patient studies are planned for undisclosed indications.