Centessa Pharmaceuticals is set to advance its investigational orexin receptor 2 (OX2R) agonist, ORX750, into Phase 2 clinical trials for narcolepsy and idiopathic hypersomnia following positive interim results from a Phase 1 study. The data revealed significant improvements in wakefulness among sleep-deprived healthy volunteers treated with the agent.
The Phase 1 trial evaluated ORX750 in healthy volunteers experiencing acute sleep deprivation. Interim results, presented on September 10, 2024, showed that doses of 1.0 mg and 2.5 mg significantly increased sleep latency, as measured by the Maintenance of Wakefulness Test (MWT). Notably, the 2.5 mg dose restored what the company defined as normal wakefulness.
Phase 1 Trial Details and Results
The placebo-controlled study included single-ascending dose (SAD) cohorts of healthy volunteers receiving doses of 1.0 mg, 2.0 mg, and 2.5 mg. Additionally, sleep-deprived participants underwent a cross-over pharmacodynamic (PD) assessment with single doses of 1.0 mg and 2.5 mg. The primary endpoint was the change in sleep latency as measured by MWT.
Key findings from the interim analysis include:
- At the 1.0 mg dose, mean sleep latency on the MWT was 18 minutes for ORX750 compared to 10 minutes for placebo (p = 0.04).
- At the 2.5 mg dose, mean sleep latency was 32 minutes for ORX750 and 17 minutes for placebo (p = 0.01).
- The 2.5 mg dose was observed to restore normal wakefulness, defined as a mean latency of 32 minutes.
- Volunteers on the 2.5 mg dose of ORX750 exhibited a 1.6-point improvement on mean Karolinska Sleepiness Scale (KSS) score relative to placebo (P = .03).
"The Phase 1 acutely sleep-deprived healthy volunteer sleep study set a high bar for ORX750, and the early data generated has exceeded our expectations, giving us the confidence to accelerate the program into the next stage of clinical development earlier than anticipated," said Saurabh Saha, MD, PhD, chief executive officer at Centessa, in a statement.
Safety and Tolerability
ORX750 demonstrated a favorable safety profile in the Phase 1 trial. Treatment-related adverse events (AEs) were mild and transient. Importantly, the study did not reveal any frequently reported on-target AEs associated with other OX2R agonists, such as urinary frequency, urinary urgency, insomnia, blood pressure increases, and salivary hypersecretion. There were no AEs that led to treatment discontinuation, nor were there clinically meaningful treatment-emergent changes in hepatic and renal parameters, vital signs, or electrocardiogram parameters.
Planned Phase 2 Trials
Centessa plans to initiate Phase 2 studies of ORX750 in patients with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH) beginning in the fourth quarter of 2024. These trials will further evaluate the efficacy and safety of ORX750 in these patient populations.
Mechanism of Action
ORX750 is a selective orexin receptor 2 (OX2R) agonist designed using structure-based drug design capabilities. Preclinical models have demonstrated that ORX750 potently activates the OX2R with an in vitro EC50 of 0.11 nM and 9,800-fold selectivity over the human orexin receptor.
Competitive Landscape
Centessa is among several companies developing OX2R agonists for sleep disorders. Alkermes recently initiated a Phase 2 study of ALKS 2680 in narcolepsy type 2, and Eisai has begun enrollment for a Phase 1 study of E2086 in patients with narcolepsy. Takeda Pharmaceutical is also advancing an orexin drug in late-stage testing.
