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New Phase 2 Study to Test Orexin Receptor 2 Agent ORX750 in Various Sleep Disorders
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Key Takeaways
- ORX750 targets narcolepsy types 1 and 2, and idiopathic hypersomnia, with a phase 2 trial assessing safety, tolerability, and efficacy outcomes.
- The trial employs a randomized, double-blind, placebo-controlled, cross-over basket study design with separate cohorts for each condition.
In a previously completed phase 1 study, the treatment resulted in significant improvements in wakefulness at doses of 1.0 mg and 2.5 mg, prompting a follow-up study.
Matt Barnes
According to a new announcement from Nxera Pharma, the company has begun to initiate a phase 2 trial assessing an investigational selective orexin receptor 2 (OX2R) agonist, ORX750, as a treatment for narcolepsy type 1 (NT1) and type 2 (NT2), as well as idiopathic hypersomnia.1
The trial, a randomized, double-blind, placebo-controlled, cross-over basket study, will include separate cohorts for each condition studied. The initial dosing for NT1 will be 1.0 mg and for NT2 and idiopathic hypersomnia will be 2.0 mg with sequential dose escalation/de-escalation between cohorts. Each dosing cohort consists of a 6-week treatment duration in which patients receive active drug for 4 weeks and then crossover 2 weeks of treatment with placebo.
"This clinical development milestone with ORX750 is an important example of how our unique technology can be deployed to generate novel molecules with the potential to address unmet clinical needs," Matt Barnes, executive vice president, president of Nxera Pharma UK and head of research and development, said in a statement.1 "It also highlights the progress being made across the 12 clinical-stage programs in our extensive in-house and partnered portfolio. It is exciting to see this portfolio mature as it advances, and we look forward to reporting future milestones."
The study, intended to evaluate the safety, tolerability, and pharmacokinetics of ORX750, will also include other efficacy outcomes, such as testing the effect on excessive daytime sleepiness and cataplexy. In addition, investigators will also test overall symptom improvement, measured by Narcolepsy Severity Scale, and Idiopathic Hypersomnia Severity Scale. Other exploratory assessments include measures of sleep, cognition, attention, memory, and general health.
Nxera will receive a $3.5 million payment from Centessa for achieving a clinical milestone, recognized as revenue in Q4 FY2024. This milestone, part of their ORX750 collaboration with Medicxi since 2019, was reported in Centessa’s Q3 financial statement. Nxera, holding 929,353 Centessa shares (currently valued at around US$15 million), may gain further through potential milestone payments and royalties as ORX750 develops.
ORX750, or orally administered, highly potent agent, was designed by Centessa using structure-based drug design capabilities, high-resolution protein crystallography, and cryo-EM. This drug, which has shown promising results in a phase 1 study of healthy volunteers, is built to activate orexin signaling in the brain and treat the underlying cause of NT1. In previous preclinical models, the agent demonstrated an ability to activate the OX2R with an in vitro EC50 of 0.11 nM and 9800-fold selectivity over the human orexin receptor.
As of the latest update, given in September, the phase 1 trial had completed 3 single-ascending dose (SAD) cohorts of healthy volunteers (27 active, 9 placebo) with doses of 1.0 mg, 2.0 mg, and 2.5 mg. In parallel to the SAD, 2 cohorts of sleep-derived healthy adult participants have advanced through a cross-over pharmacodynamic (PD) assessment. Results showed that the 2.5 mg dose of ORX750 was particularly effective, restoring normal wakefulness with a sleep latency of 32 minutes.2
In the phase 1 study, the therapy was considered safe and well tolerated, with no common adverse events, liver toxicity, or visual issues. Compared with placebo, ORX750 significantly increased sleep latency on the Maintenance Wakefulness Test (MWT) across all doses in sessions conducted 2, 4, 6, and 8 hours after a 11:00 PM dose. The 1.0 mg ORX750 dose resulted in a mean sleep latency of 18 minutes versus 10 minutes with placebo (p = 0.04), while the 2.5 mg dose showed 32 minutes versus 17 minutes for placebo (p = 0.01). The 2.5 mg dose fully restored normal wakefulness, achieving a mean latency of 32 minutes.
In acutely sleep-deprived healthy volunteers, the 2.5 mg dose of ORX750 improved mean KSS scores by 1.6 points over placebo (P = .03). The pharmacokinetic profile supports ORX750 as a once-daily oral dose with rapid absorption, reaching peak plasma levels 2 hours after administration. Multiple ascending dose portions of the trial remain ongoing, according to the study’s announcement in September.
