Centessa Pharmaceuticals Presents Preclinical Data for ORX142 at Sleep Europe 2024

Centessa Pharmaceuticals Plc, a clinical-stage company listed on Nasdaq under the ticker CNTA, has disclosed new preclinical findings for ORX142, an innovative orexin receptor 2 (OX2R) agonist. The announcement was made during a late-breaking poster session at the 27th Congress of the European Sleep Research Society (Sleep Europe 2024) in Seville, Spain. ORX142 is currently undergoing Investigational New Drug (IND)-enabling studies and is being developed to address excessive daytime sleepiness (EDS) associated with specific neurological, neurodegenerative, and psychiatric disorders.

Dr. Sarah Wurts Black, Head of Biology for Centessa’s Orexin Agonist Program, presented the findings under the title, “ORX142, an Oral, Highly Potent and Selective Orexin Receptor 2 Agonist, Promotes Wakefulness in Non-Human Primates.” The preclinical data underscore the efficacy of ORX142 in promoting wakefulness at minimal doses in non-human primate (NHP) models, which are considered highly predictive and translational.

Dr. Saurabh Saha, Centessa’s Chief Executive Officer, highlighted the significance of the findings, stating that ORX142 demonstrated notable increases in wake times at the lowest tested dose of 0.03 mg/kg. This revelation points to the drug's potential as a groundbreaking treatment for EDS in various neurological and psychiatric conditions. Dr. Saha emphasized the company’s commitment to expediting ORX142 through further IND-enabling studies based on the promising preclinical data and its prospective market value.

The poster presented at Sleep Europe 2024 detailed several key aspects of ORX142's preclinical performance:
- ORX142 is a full OX2R agonist, developed by leveraging advanced high-resolution crystallography and cryo-EM structural chemistry techniques.
- It showed potent activation of the human OX2R with an EC50 of 0.069 nM, displaying more than 13,000-fold selectivity over the human orexin receptor 1 (hOX1R).
- In NHP models, oral administration of ORX142 at the lowest dose of 0.03 mg/kg resulted in significant wakefulness, reducing both NREM and REM sleep phases.
- The wakefulness induced by ORX142 was linked with normal physiological arousal and EEG power spectra indicative of increased alertness and attention.
- No significant pharmacological activity was observed in GPCR selectivity and in vitro safety panels.

ORX142's development is part of Centessa’s broader Orexin Agonist Program, which includes another candidate, ORX750, currently in Phase 1 clinical trials. These agonists target the orexin system, a critical regulator of the sleep-wake cycle. Dysregulation of orexin levels can lead to conditions such as EDS and narcolepsy. The company aims to position ORX142 and ORX750 as potential best-in-class treatments for sleep-wake disorders, including narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH).

Centessa Pharmaceuticals focuses on developing transformative medicines across various therapeutic areas. Its pipeline includes programs targeting hemophilia, sleep-wake disorders, and cancer, utilizing innovative platforms like LockBody® technology. The company remains dedicated to advancing its clinical programs with the ambition to redefine treatment paradigms and significantly improve patient outcomes.