2.5 mg dose restored normative wakefulness with mean sleep latency of 32 minutes as measured by the Maintenance of Wakefulness Test (MWT)
Favorable safety and tolerability profile with no observations of frequently reported on-target adverse events (AEs) associated with other OX2R agonists, visual disturbances or hepatotoxicity as of the data cutoff date 1
PK profile supports once-daily dosing
Company plans to rapidly initiate Phase 2 studies of ORX750 in patients with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH)
Sept. 10, 2024 -- Centessa Pharmaceuticals plc (Nasdaq: CNTA), a clinical-stage pharmaceutical company that aims to discover and develop medicines that are transformational for patients, today announced positive interim data from an ongoing Phase 1 trial of its highly potent and selective 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 (1.0 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 wakefulness2 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 (AEs) associated with other OX2R agonists, and no cases of hepatotoxicity or visual disturbances across all three dose levels tested (1.0 mg, 2.0 mg, and 2.5 mg), as of the data cutoff date.1 Based on the interim data, the Company plans to rapidly 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,” said Saurabh Saha MD PhD, Chief Executive Officer of Centessa. “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. 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.”
The Phase 1 clinical study is an ongoing first-in-human, randomized, placebo-controlled study designed to evaluate the safety, tolerability and pharmacokinetics (PK) of single-ascending doses (SAD) and multiple-ascending doses (MAD) of ORX750 in healthy adult subjects. In parallel to the SAD, a placebo-controlled cross-over pharmacodynamic (PD) assessment is being performed utilizing the MWT and Karolinska Sleepiness Scale (KSS) in acutely sleep-deprived healthy adult subjects with the goal of rapidly generating early efficacy data to inform dosing for planned studies in patients. As of September 10, 2024, the study has completed three SAD cohorts of healthy volunteers (27 active, 9 placebo) with doses of 1.0 mg, 2.0 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 1.0 mg (n=8) and 2.5 mg (n=8), administered as a single oral dose. Dosing in the MAD portion of the study is also ongoing.
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 (p<0.05) and clinically meaningful increased sleep latency on the MWT (time to sleep onset over the four sessions performed at ~2, 4, 6, and 8 hours after dosing at 11 p.m., maximum 40 minutes per session) compared to placebo across all doses. Mean sleep latencies, as measured by the MWT, for 1.0 mg dose of ORX750 and placebo were 18 minutes and 10 minutes, respectively (p-value = 0.04) (least squares mean). Mean sleep latencies, as measured by the MWT, for 2.5 mg dose of ORX750 and placebo were 32 minutes and 17 minutes, respectively (p-value = 0.01) (least squares mean). 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.1All observed treatment related AEs were mild and transient with none leading to treatment discontinuation.
No observations of frequently reported on-target AEs 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 (ECG) 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 (p-value = 0.03).
Encouraging linear PK profile supports the use of ORX750 as a once-daily oral dosing regimen with rapid absorption (plasma concentrations of ORX750 peaked at 2h 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,” said Mario Alberto-Accardi PhD, President, Centessa Orexin Program. “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 (EDS) across multiple conditions.”
Data cutoff date of August 26, 2024.
Doghramji K, et al., A normative study of the maintenance of wakefulness test (MWT). Electroencephalogr Clin Neurophysiol 1997; 103:554-62.
Centessa Pharmaceuticals plc is a clinical-stage pharmaceutical company that aims to discover and develop medicines that are transformational for patients. Our most advanced programs include a hemophilia program, an orexin agonist program for the treatment of narcolepsy and other sleep-wake disorders, and an immuno-oncology program focused on our LockBody® technology platform. We operate with the conviction that each of our programs has the potential to change the current treatment paradigm and establish a new standard of care. For more information, visit www.centessa.com, which does not form part of this release.
Orexin is a neuropeptide that regulates the sleep-wake cycle, leading to arousal and promoting wakefulness. Low levels of orexin result in excessive daytime sleepiness (EDS) and poor regulation of rapid eye movement (REM) sleep and, in narcolepsy type 1 (NT1), cataplexy and other symptoms. Centessa is developing a pipeline of potential best-in-class orexin receptor 2 (OX2R) agonists, including ORX750 for the treatment of sleep-wake disorders, including NT1, narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH), and ORX142 for the treatment of EDS in select neurological, neurodegenerative, and psychiatric disorders. The Company’s lead asset, ORX750, is in a Phase 1 clinical study. ORX750 and ORX142 have not been approved by the FDA or any other regulatory authority.
The content above comes from the network. if any infringement, please contact us to modify.
