Centessa Advancing Pipeline of Orexin Receptor 2 Agonists

Summary: Centessa Pharmaceuticals has made progress in its orexin receptor 2 agonist program, focusing on the development of treatments for sleep-wake disorders such as narcolepsy and idiopathic hypersomnia. The company has initiated a phase 1 clinical trial for ORX750, with safety and efficacy data expected later this year. Additionally, Centessa has nominated ORX142 as a new development candidate, which is currently undergoing Investigational New Drug-enabling activities for potential use in treating neurological, neurodegenerative, and psychiatric disorders associated with excessive daytime sleepiness.

Key Takeaways:

Initiation of Phase 1 Trial for ORX750: Centessa has begun a phase 1 clinical trial for ORX750, targeting sleep-wake disorders like narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia, with proof-of-concept data expected in the second half of 2024.
Development of ORX142: The company has advanced ORX142 as a development candidate, aiming to expand its orexin agonist pipeline to address additional neurological, neurodegenerative, and psychiatric disorders associated with excessive daytime sleepiness.
Future Potential: The data from these studies may enable dose selection for further clinical trials and open new avenues for treating a range of disorders where excessive daytime sleepiness is a significant burden.

Centessa Pharmaceuticals plc, a clinical-stage pharmaceutical company, reported second-quarter highlights showcasing progress in its orexin agonist program.

During the second quarter, the company initiated a phase 1 clinical study with ORX750, a potential best-in-class orexin receptor 2 (OX2R) agonist being developed for sleep-wake disorders, including narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia.

“Today, we are fast approaching a potentially transformative milestone with safety and efficacy data in acutely sleep-deprived healthy volunteers assessed using the MWT (maintenance of wakefulness test), an established registrational and objective endpoint for EDS (excessive daytime sleepiness) in sleep-wake disorders, on track for the second half of this year,” says Saurabh Saha, MD, PhD, chief executive officer of Centessa, in a release.

Since healthy volunteers have normal orexin levels, data from the study could enable dose selection for future clinical trials of ORX750 in patients with narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia, according to Saha.

“The data also has the potential to open the door to evaluation of our growing pipeline of orexin agonists in clinical studies for a range of disorders where EDS is a significant burden,” says Saha in a release.

Additionally, Centessa nominated ORX142, an orally administered, highly potent, and selective OX2R agonist, as its development candidate for potential indication expansion into select neurological, neurodegenerative, and psychiatric disorders with EDS.

ORX142 is currently in Investigational New Drug-enabling activities, and preclinical data is expected to be shared in the near term.

Recent Sleep Portfolio Highlights

In May, Centessa announced that it had initiated a phase 1 first-in-human clinical trial 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 cross-over efficacy assessment is being performed utilizing the MWT and Karolinska Sleepiness Scale in acutely sleep-deprived healthy adult subjects which is intended to provide data to enable dose selection for planned clinical studies in subjects with narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia.
In April, the company announced that the US Food and Drug Administration (FDA) cleared the Investigational New Drug application to initiate a phase 1 first-in-human clinical trial of ORX750.

Anticipated Upcoming Orexin Agonist Program Milestones

The phase 1 first-in-human clinical study of ORX750 is ongoing. The company expects to share phase 1 proof-of-concept safety and efficacy data in acutely sleep-deprived healthy volunteers assessed using the MWT, an established registrational and objective endpoint for EDS in sleep-wake disorders, in the second half of the year.

ORX750 and ORX142 have not been approved by the FDA or any other regulatory authority.