Centessa Pharmaceuticals plc announced new preclinical data from in vivo and in vitro studies of its investigational novel orexin receptor 2 (OX2R) agonist, ORX750, that support its potential profile for the treatment of narcolepsy and other sleep-wake disorders.

The preclinical data will be featured in an oral presentation by Sarah Wurts Black, PhD, head of biology for Centessa’s orexin agonist program at the World Sleep Congress in Rio De Janeiro, Brazil.

“We are very excited to share this robust preclinical dataset, which we believe shows the significant activity of low doses of ORX750 in highly predictive, translational models of narcolepsy type 1,” says Mario Alberto Accardi, PhD, president of Centessa’s orexin agonist program, in a release. 

The preclinical data showed ORX750 achieved maximal wake times and suppressed cataplexy at 0.1 mg/kg, the lowest oral dose tested in a DTA mouse model. Notably, this activity was observed in both the DTA and Atax mouse models that recapitulate narcolepsy type 1 symptoms in humans. 

The data also showed ORX750 significantly increased wake time in healthy wild-type mice at 1 mg/kg, the lowest oral dose tested, supporting the potential for expansion into broader sleep-wake disorders with normal orexin tone, including narcolepsy type 2 and idiopathic hypersomnia.

“ORX750 is a highly potent and selective novel orexin agonist that closely mimics the function of the endogenous peptide,” says Saurabh Saha, MD, PhD, chief executive officer of Centessa, in a release. “These preclinical data showed that ORX750 has the potential to address the underlying pathophysiology of orexin neuron loss in [narcolepsy type 1] and promote wakefulness during the day and suppress cataplexy, including at levels that correspond to very low predicted human doses.”

In addition, notes Saha, the preclinical pharmacokinetic profile of ORX750, informed by pharmacokinetic testing in multiple species, including non-human primates, suggests the potential for ORX750 to have high, early, and sustained brain exposure. 

“We believe these data provide a strong translational foundation for clinical development. We are focused on rapidly moving ORX750 through IND-enabling studies, obtaining IND clearance, and initiating clinical development of ORX750 with the goal of sharing clinical proof of concept data in 2024,” says Saha in the release. “We look forward to providing further updates in the coming months.”

Overview of ORX750 preclinical results:

  • ORX750 is a full OX2R agonist that potently activated the OX2R with an in vitro EC50 of 0.11 nM and 9,800-fold selectivity over the human orexin receptor.
  • In highly predictive, translational Atax and DTA mouse models, oral administration of ORX750 showed significant activity at the lowest dose tested, which was 0.1 mg/kg in a DTA mouse model, 0.3 mg/kg in an Atax mouse model, and 1 mg/kg in healthy wild type mice. ORX750:
    • Achieved maximal (100%) wake time for at least three hours post-dose
    • Suppressed cataplexy for at least six hours post-dose
    • Increased latency to sleep and cataplexy, which was maintained for >14 days of dosing
    • Increased consolidation of wakefulness

ORX750 is Centessa’s first orexin product candidate being developed for the treatment of narcolepsy with potential expansion into other sleep-wake disorders. ORX750 is currently undergoing IND-enabling activities and has not been administered as an investigational drug to humans in any jurisdiction.

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