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Presented at the 2023 World Sleep Congress, preclinical findings highlighted ORX750's potential as a novel treatment not only for narcolepsy type 1 but also for broader sleep-wake disorders, including narcolepsy type 2 and idiopathic hypersomnia.
Sarah Wurts Black, PhD,
New preclinical data from in vivo and in vitro studies assessing ORX750 (Centessa Pharmaceuticals), an investigational, novel orexin receptor 2 (OX2R) agonist, demonstrated significant activity in highly predictive translational models of narcolepsy type 1 (NT1) at low doses. These findings suggested that ORX750 has the potential to treat primary symptoms of NT1 as well as reduce excessive daytime sleepiness in patients presenting with normal orexin levels.1
Using electroencephalogram (EEG), electromyogram (EMG), and video recording assays, investigators observed that treatment with ORX750 increased time awake, consolidated wakefulness, and increased EEG gamma power during wakefulness in Atax mice. In the same mice population, the agonist reduced cataplexy occurrences, and increased latencies to sleep and cataplexy in a dose-related manner during the active phase. At the lowest dose of ORX750(0.3 mg/kg), the latency to sleep was 2.3 hours and the latency to cataplexy was 2.7 hours compared with vehicle (sleep, 0.69 hours; cataplexy, 1.3 hours).
“We believe this data set shows the significant activity of low doses of ORX750 in highly predictive, translational models of NT1. The data also showed ORX750 significantly increased wake time in healthy wild type mice supporting the potential for expansion into broader sleep-wake disorders with normal orexin tone, including narcolepsy type 2 and idiopathic hypersomnia. We believe these data highlight the breadth of ORX750’s potential as a novel treatment for individuals living with narcolepsy and other sleep-wake disorders- subject to review and approval,” Sarah Wurts Black, PhD, the head of biology in the orexin program at Centessa Pharmaceuticals, told NeurologyLive®. “Centessa is 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.”
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Presented at the 2023 World Sleep Congress, held October 20-25, in Rio De Janeiro, Brazil, lead author Sarah Wurts Black, PhD, the head of biology in the orexin program at Centessa Pharmaceuticals, and colleagues performed in vitro calcium mobilization (FLIPR), β-arrestin recruitment, and inositol-phosphate accumulation assays in Chinese hamster ovary cells that stably expressed human recombinant OX1R or OX2R. The investigators conducted electrophysiological recordings on slices of the ventral tuberomammillary nucleus (TMN) from the mouse hypothalamus. In addition, they measured the effects on membrane potential in the presence of 1 micromolar tetrodotoxin to block neuron firing. All told, in vivo efficacy for improving wakefulness was assessed in wild type and Atax mice during their rest phase using PiezoSleep. During the active phase in the mice, EEG, EMG, and video recordings were used to assess effects at 0.3-10 mg/kg on arousal states and cataplexy.
In the PiezoSleep assay, investigators observed that ORX750 increased time awake and the consolidation of wakefulness in wild type and Atax mice during the rest phase compared with vehicle in a dose-related manner. The authors also noted that Atax mice had increased sensitivity to these wake-promoting effects in comparison with wild type mice. It was noted that ORX750 acted as a potent full agonist at human OX2R relative to the native ligand orexin A (OXA)(EC50 = 0.11 nM; EC50 = 0.035 nM; respectively). At the same time, it showed 9800-fold selectivity over human OX1R in the FLIPR assay (EC50 = 1100 nM). The authors noted no detection of biased agonism by measurement of b-arrestin recruitment at OX2R in comparison with OXA. Additionally, in the TMN, ORX750 reduced the membrane potential in whole cell current-clamp recordings (EC50 = 5.0 nM; max DmV = 9.5).
“ORX750 is a highly potent and selective novel orexin agonist that closely mimics the function of the endogenous peptide,” Saurabh Saha, MD, PhD, chief executive officer at Centessa, said in a statement.2 “These preclinical data showed that ORX750 has the potential to address the underlying pathophysiology of orexin neuron loss in NT1 and promote wakefulness during the day and suppress cataplexy, including at levels that correspond to very low predicted human doses. In addition, the preclinical pharmacokinetic (PK) profile of ORX750, informed by PK 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. We look forward to providing further updates in the coming months.”
