Summary: Centessa Pharmaceuticals announced positive interim data from its ongoing phase 1 trial of ORX750, an orexin receptor 2 agonist, in acutely sleep-deprived healthy volunteers. The trial demonstrated that ORX750 significantly increased wakefulness, with the 2.5 mg dose restoring normative wakefulness in participants. ORX750 showed a favorable safety and tolerability profile, with no adverse events typically associated with other OX2R agonists. Based on these findings, Centessa is planning to advance ORX750 into phase 2 trials in patients with narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia in the fourth quarter of 2024.
Key Takeaways:
- Improved Wakefulness: ORX750 significantly increased sleep latency in sleep-deprived individuals, with the 2.5 mg dose restoring normative wakefulness, as measured by the Maintenance of Wakefulness Test.
- Favorable Safety Profile: ORX750 demonstrated a favorable safety and tolerability profile, with no observations of common adverse events like hepatotoxicity or visual disturbances.
- Phase 2 Trial Plans: Centessa plans to initiate phase 2 trials for ORX750 in the fourth quarter of 2024, targeting patients with narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia.
Centessa Pharmaceuticals plc, a clinical-stage pharmaceutical company, announced positive interim data from an ongoing phase 1 trial of its orexin receptor 2 (OX2R) agonist, ORX750, in acutely sleep-deprived healthy volunteers.
ORX750 showed clinically meaningful and statistically significant improvements in mean sleep latency at the first two doses evaluated (1 mg and 2.5 mg) in the Maintenance of Wakefulness Test (MWT) compared to placebo. More specifically, the 2.5 mg dose was shown to restore normative wakefulness with a mean sleep latency of 32 minutes as measured by the MWT.
ORX750 was also shown to have a favorable safety and tolerability profile with no observations of frequently reported on-target adverse events associated with other OX2R agonists and no cases of hepatotoxicity or visual disturbances across all three dose levels tested (1 mg, 2 mg, and 2.5 mg), as of the data cutoff date. Based on the interim data, the company plans to advance ORX750 into phase 2 studies in patients with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH) beginning in the fourth quarter of 2024.
“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,” says Saurabh Saha, MD, PhD, chief executive officer of Centessa, in a release. “We are very pleased that the data support the potential for ORX750 to restore normative wakefulness in patients with NT1, NT2, and IH at very low, once-daily oral doses.
Saha adds in a release, “Underpinning these data is a favorable initial safety and tolerability profile for ORX750, which provides us with the flexibility to explore the therapeutic potential of OX2R agonists. Given the strength of the data generated to date and the exciting potential opportunities we see with ORX750, we are aggressively pursuing our clinical development plans and expect to initiate phase 2 studies of ORX750 in patients with NT1, NT2, and IH beginning in the fourth quarter of 2024.”
Phase 1 Clinical Study
The phase 1 clinical study is an ongoing first-in-human, randomized, placebo-controlled study designed to evaluate the safety, tolerability, and pharmacokinetics of single-ascending doses (SAD) and multiple-ascending doses of ORX750 in healthy adult subjects.
In parallel to the SAD, a placebo-controlled cross-over pharmacodynamic assessment is being performed utilizing the MWT and Karolinska Sleepiness Scale in acutely sleep-deprived healthy adult subjects with the goal of generating early efficacy data to inform dosing for planned studies in patients.
As of Sept 10, the study has completed three SAD cohorts of healthy volunteers (27 active, nine placebo) with doses of 1 mg, 2 mg, and 2.5 mg and has advanced through two cohorts within the cross-over assessment of acutely sleep-deprived healthy volunteers with doses of 1 mg (n=8) and 2.5 mg (n=8), administered as a single oral dose. Dosing in the multiple-ascending doses portion of the study is also ongoing.
Summary of Data
The interim phase 1 clinical data for ORX750 demonstrated:
- Significantly increased wakefulness in acutely sleep-deprived healthy volunteers compared to placebo at both doses tested. Treatment with ORX750 resulted in statistically significant and clinically meaningful increased sleep latency on the MWT (time to sleep onset over the four sessions performed at approximately two, four, six, and eight hours after dosing at 11 pm, maximum 40 minutes per session) compared to placebo across all doses.
- Mean sleep latencies, as measured by the MWT, for 1 mg dose of ORX750 and placebo were 18 minutes and 10 minutes, respectively. Mean sleep latencies, as measured by the MWT, for 2.5 mg dose of ORX750 and placebo were 32 minutes and 17 minutes, respectively. The 2.5 mg dose was shown to restore normative wakefulness with a mean sleep latency of 32 minutes as measured by the MWT.
- Favorable safety and tolerability observed as of the data cutoff date. All observed treatment-related adverse events were mild and transient with none leading to treatment discontinuation.
- No observations of frequently reported on-target adverse events associated with other OX2R agonists, including urinary frequency, urinary urgency, insomnia, blood pressure increases, and salivary hypersecretion.
- No cases of hepatotoxicity, visual disturbances or hallucinations were observed. Additionally, there were no clinically meaningful treatment-emergent changes in hepatic and renal parameters, vital signs, or electrocardiogram parameters.
- Acutely sleep-deprived healthy volunteers who received a 2.5 mg dose of ORX750 showed a significant 1.6 point improvement versus placebo in mean KSS score compared to baseline.
- Encouraging linear pharmacokinetics profile supports the use of ORX750 as a once-daily oral dosing regimen with rapid absorption (plasma concentrations of ORX750 peaked at two hours after the first dose). The systemic exposure of ORX750 increased in an approximately dose-proportional manner.
“With these interim data, we believe we have successfully demonstrated a potential best-in-class profile for ORX750 having achieved normative wakefulness at once-daily low doses in subjects with normal orexin tone, coupled with a favorable safety and tolerability profile,” says Mario Alberto-Accardi, PhD, president of Centessa’s orexin program, in a release.
Alberto-Accardi continues, “Consistent with what we’ve seen preclinically, we believe these data validate our unique structural biology driven orexin research platform and accelerate translation of our growing pipeline of orexin agonists, including the future development of ORX142, our second orexin agonist development candidate. We are excited to leverage these data to expedite the progression of our multi-asset orexin franchise to potentially treat sleep-wake disorders and excessive daytime sleepiness across multiple conditions.”
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