ORX750 for narcolepsy
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What is ORX750 for narcolepsy?
ORX750 is an experimental oral treatment currently being developed for the two main types of narcolepsy, a neurological condition characterized by excessive daytime sleepiness and other symptoms.
Narcolepsy type 1 (NT1) is driven by the loss of nerve cells that produce hypocretin (also known as orexin), a signaling molecule that helps control wakefulness and sleep. People with NT1 usually also experience cataplexy, or sudden episodes of muscle tone loss while they are awake. Scientists don’t entirely understand the causes of narcolepsy type 2 (NT2). Unlike NT1, hypocretin levels in people with NT2 are typically normal, and cataplexy is usually absent.
ORX750 is designed to bind and activate the orexin receptor 2, eliciting the same processes triggered by hypocretin binding to that receptor protein. This is expected to increase wakefulness and ease other narcolepsy symptoms.
Centessa Pharmaceuticals is developing ORX750 as a treatment for NT1, NT2, and idiopathic hypersomnia (IH), another sleep disorder. Phase 2 clinical trials are underway, and the company plans to initiate larger, later-stage studies in 2026, which could support regulatory applications for ORX750.
Therapy snapshot
| Treatment name | ORX750 |
| Administration | Oral capsules |
| Clinical testing | Currently in Phase 2 testing |
How will ORX750Â be administered in narcolepsy?
In a Phase 2 clinical trial involving people with narcolepsy, ORX750 is being administered in the form of oral capsules at various doses. It isn’t yet known what the recommended dosage for narcolepsy will be, or whether the therapy will be taken once daily or more frequently.
ORX750 in narcolepsy clinical trials
A Phase 2a clinical trial called CRYSTAL-1 (NCT06752668)Â is currently testing ORX750 in patients with narcolepsy. It includes participants with NT1, NT2, and IH, with three dosage groups for each disease. Within each dosage group, half of the participants will receive ORX750 for four weeks, then a placebo for two weeks, while the other half will receive a placebo followed by ORX750. Different dosage groups may receive different dose levels, with researchers using results from prior groups to adjust the dose as needed.
The study’s main goal is to assess ORX750’s safety, as well as its effects on metrics of wakefulness and sleepiness. For NT1 participants, investigators will also assess the number of cataplexy events per week.
Available results have shown that:
- When given at a dose of 1.5 mg, ORX750 significantly decreased daytime sleepiness for NT1 participants to levels similar to those seen for people without narcolepsy. Additionally, there was a significant 87% decrease in the weekly cataplexy rate.
- NT2 participants who received ORX750 at a dose of 4 mg experienced a significant decrease in daytime sleepiness to levels similar to those of the general population. The time ORX750-treated participants could stay awake during a wakefulness test also increased by more than 10 minutes by week two of treatment compared with a placebo.
Investigators plan to test larger doses in future groups.
After completing CRYSTAL-1, patients will be eligible to enter a Phase 2 extension trial (NCT07096674) and receive ORX750 for about nine more weeks.
ORX750 side effects
In CRYSTAL-1, the most commonly reported side effects in patients treated with ORX750 included:
- unusually frequent urination (pollakiuria)
- insomnia
- dizziness
- headache
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