Centessa Pharmaceuticals (CNTA) Announces Open IND for ORX750; Proof-of-Concept data in sleep-deprived healthy volunteers planned for the second half of 2024

Centessa Pharmaceuticals plc (Nasdaq: CNTA), a clinical-stage pharmaceutical company focused on discovering and developing medicines that are transformative for patients, today announced that the U.S. Food and Drug Administration (FDA) has cleared the Investigational New Drug application (IND) 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 address the underlying pathophysiology of orexin neuron loss in narcolepsy type 1 (NT1), with potential applicability to narcolepsy type 2 ( NT2), idiopathic hypersomnia (IH) and other sleep-wake disorders with normal orexin levels.

The Phase 1 study will evaluate the safety, tolerability and pharmacokinetics of single ascending doses (SAD) and multiple ascending doses (MAD) of ORX750 in healthy adult subjects. In parallel with the SAD, a crossover pharmacodynamic (PD) assessment will be performed using the Maintenance of Wakefulness Test (MWT) and the Karolinska Sleepiness Scale (KSS) in healthy adult subjects with acute sleep deprivation, which aims to provide evidence of draft data to enable dose selection for NT1, NT2 and IH indications. The study has an FDA-specified maximum exposure limit that the company believes significantly exceeds predicted effective doses of ORX750 in indications related to or without orexin loss; therefore, the company does not expect this limit to impact the planned clinical development activities for ORX750. The company expects to begin dosing the Phase 1 study in healthy volunteers soon, with proof-of-concept data expected in the second half of 2024.

The ORX750 Phase 1 study design includes SAD paired with PoC cohorts to assess PD effects of ORX750 by measuring sleep latency with the MWT and subjective sleepiness with the KSS in healthy subjects with acute sleep deprivation.

“This is an important milestone for the development of our potential best-in-class OX2R agonist, ORX750, for the treatment of narcolepsy and other sleep-wake disorders,” said Saurabh Saha MD PhD, Chief Executive Officer of Centessa. “We are excited to begin conducting what we believe is an elegant, adaptive Phase 1 study aimed at generating early proof-of-concept data for ORX750 in healthy volunteers with acute sleep deprivation in the second half of this year. We expect this study will enable dose selection for planned studies evaluating ORX750 in patients with NT1 and in patient populations with normal orexin levels, including NT2 and IH.”

About ORX750
ORX750 is an experimental, orally administered, highly potent and selective orexin receptor 2 (OX2R) agonist designed to directly address the underlying pathophysiology of orexin neuron loss in narcolepsy type 1 (NT1). ORX750 has been shown to potently activate the OX2R with an in vitro EC50 of 0.11 nM and 9,800-fold selectivity over the human orexin receptor (hOX1R). ORX750 is Centessa’s first orexin product candidate being developed for the treatment of narcolepsy with potential expansion to narcolepsy type 2 (NT2), idiopathic hypersomnia (IH) and other sleep-wake disorders.