The clinical trial will evaluate the safety, tolerability, and pharmacokinetics of Centessa Pharmaceuticals’ orexin receptor 2 agonist.

Summary: Centessa Pharmaceuticals has received FDA authorization to start a phase 1 trial of ORX750, an investigational oral treatment aimed at narcolepsy and other sleep-wake disorders. ORX750, a selective orexin receptor 2 agonist, addresses the loss of orexin neurons associated with narcolepsy type 1 and may also benefit type 2 and idiopathic hypersomnia. The trial will assess the drug’s safety, tolerability, and pharmacokinetics through single and multiple-ascending doses in healthy volunteers. Additionally, a cross-over pharmacodynamic study using the Maintenance of Wakefulness Test and Karolinska Sleepiness Scale will help in dose selection. Dosing is expected to begin soon, with proof-of-concept results anticipated in the second half of 2024.

Key Takeaways:

Centessa Pharmaceuticals has received authorization from the FDA for the Investigational New Drug application, allowing the company to begin a phase 1 clinical trial of ORX750, a drug candidate designed to treat narcolepsy and potentially other sleep-wake disorders.
ORX750 is a highly potent, orally administered selective orexin receptor 2 (OX2R) agonist that targets the underlying pathophysiology of orexin neuron loss in narcolepsy type 1 and may also be applicable to narcolepsy type 2 and idiopathic hypersomnia.
The study will evaluate the safety, tolerability, and pharmacokinetics of ORX750 using single-ascending and multiple-ascending doses in sleep-deprived healthy subjects.

Clinical-stage pharmaceutical company Centessa Pharmaceuticals announced that the US Food and Drug Administration (FDA) has cleared the Investigational New Drug application to initiate a phase 1 first-in-human clinical trial of ORX750 for the treatment of narcolepsy.

ORX750 is an investigational, orally administered, highly potent, and selective orexin receptor 2 (OX2R) agonist designed to directly target the underlying pathophysiology of orexin neuron loss in narcolepsy type 1, with potential applicability to narcolepsy type 2, idiopathic hypersomnia, and other sleep-wake disorders with normal orexin levels.

Evaluating ORX750

The phase 1 study will evaluate the safety, tolerability, and pharmacokinetics of single-ascending doses and multiple-ascending doses of ORX750 in healthy adult subjects.

In parallel to the single-ascending doses, a cross-over pharmacodynamic assessment will be performed utilizing the Maintenance of Wakefulness Test and Karolinska Sleepiness Scale in acutely sleep-deprived healthy adult subjects which is intended to provide proof-of-concept data to enable dose selection for narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia indications.

The study has a maximum exposure limit specified by the FDA which the company believes significantly exceeds the predicted efficacious doses of ORX750 in indications associated with or without orexin loss; therefore, the company does not expect this limit to affect any of the planned clinical development activities for ORX750.

Dosing of ORX750 to Begin Soon

The company expects to commence dosing of the phase 1 study in healthy volunteers imminently, and proof-of-concept data are anticipated in the second half of 2024.

“This is a significant milestone for the development of our potential best-in-class OX2R agonist, ORX750, for the treatment of narcolepsy and other sleep-wake disorders,” says Saurabh Saha, MD, PhD, chief executive officer of Centessa, in a release. “We are excited to begin executing what we believe is an elegant, adaptive phase 1 study aimed at generating early proof-of-concept data for ORX750 in acutely sleep-deprived healthy volunteers in the second half of this year. We expect this study to enable dose selection for planned studies evaluating ORX750 in patients with [narcolepsy type 1] and in patient populations with normal orexin levels, including [narcolepsy type 2] and [idiopathic hypersomnia].”