Centessa to Advance Orexin Agent ORX750 to Phase 2 Studies Following Positive Interim Data

Saurabh Saha, MD, PhD

Centessa Pharmaceutical recently announced positive interim results from a phase 1 trial of ORX750, an orexin receptor 2 (OX2R) agonist, aimed at treating sleep disorders. In a cohort of healthy volunteers, treatment with the agent resulted in significant improvements in wakefulness at doses of 1.0 mg and 2.5 mg, as measured by the Maintenance of Wakefulness Test (MWT).¹

All told, the data revealed that the 2.5 mg dose of ORX750 was particularly effective, restoring normal wakefulness with a sleep latency of 32 minutes. In addition, ORX750 was considered safe and well tolerated, with no common adverse events (AEs), liver toxicity, or visual issues. Encouraged by these findings, the company plans to advance the investigational agent to phase 2 trials targeting narcolepsy types 1 and 2, and idiopathic hypersomnia, starting in late 2024.

"The Phase 1 acutely sleep-deprived healthy volunteer sleep study set a high bar for ORX750, and the early data generated has exceeded our expectations, giving us the confidence to accelerate the program into the next stage of clinical development earlier than anticipated," Saurabh Saha, MD, PhD, chief executive officer at Centessa, said in a statement. "We are very pleased that the data support the potential for ORX750 to restore normative wakefulness in patients with NT1, NT2, and IH at very low, once-daily oral doses. Underpinning these data is a favorable initial safety and tolerability profile for ORX750, which provides us with the flexibility to explore the therapeutic potential of OX2R agonists."

As of September 10, 2024, the placebo-controlled study 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. Thus far, single doses of 1.0 mg (n = 8) and 2.5 (n = 8) have been administered to this group, which will serve as additional efficacy data to inform dosing for planned studies in patients. The company stated that the multiple ascending dose (MAD) portion of the trial remains ongoing.

Interim results revealed that in comparison with placebo, ORX750-treated patients across all doses had statistically significant and meaningful increased sleep latency on the MWT over the 4 sessions performed at 2, 4, 6, and 8 hours after dosing at 11:00 PM. Mean sleep latencies measured by the MWT were 18 minutes for the 1.0 mg dose of ORX750 and 10 minutes for placebo (p = 0.04). For the 2.5 mg dose, latencies were 32 minutes for ORX750 and 17 minutes for placebo (p = 0.01). The 2.5 mg dose restored normal wakefulness with a mean latency of 32 minutes.

"Given the strength of the data generated to date and the exciting potential opportunities we see with ORX750, we are aggressively pursuing our clinical development plans and expect to initiate Phase 2 studies of ORX750 in patients with NT1, NT2 and IH beginning in the fourth quarter of 2024," Saha added.

Compared with baseline, acutely sleep-derived healthy volunteers on the 2.5 mg dose of ORX750 exhibited a 1.6-point improvement on mean KSS score relative to placebo (P = .03). Above all, the pharmacokinetic profile supported the use of ORX750 as a once-daily oral dosing regimen with rapid absorption, with plasma concentrations that peaked at 2 hours after the first dose.

As of the August 26, 2024, the cutoff date, the agent demonstrated a favorable safety profile, with treatment-related AEs being mild and transient in nature. Notably, the study did not show any frequently reported on-target AEs associated with other OX2R agonists, including urinary frequency, urinary urgency, insomnia, blood pressure increases, and salivary hypersecretion. There were no AEs that led to treatment discontinuation as well as no clinically meaningful treatment-emergent changes in hepatic and renal parameters, vital signs, or electrocardiogram parameters.

READ MORE: Alkermes Initiates Phase 2 Study of Orexin Receptor Agent ALKS 2680 in Narcolepsy Type 2

"With these interim data, we believe we have successfully demonstrated a potential best-in-class profile for ORX750 having achieved normative wakefulness at once-daily low doses in subjects with normal orexin tone, coupled with a favorable safety and tolerability profile," Mario Alberto-Accardi, PhD, president of Centessa Orexin Program, said in a statement.¹ "Consistent with what we’ve seen preclinically, we believe these data validate our unique structural biology driven orexin research platform and accelerate translation of our growing pipeline of orexin agonists, including the future development of ORX142, our second orexin agonist development candidate."

ORX750, designed by Centessa using structure-based drug design capabilities, high-resolution protein crystallography, and cyro-EM, is built to activate orexin signaling in the brain and treat the underlying cause of narcolepsy type 1. In previous preclinical models, ORX750 has been shown to potently activate the OX2R with an in vitro EC50 of 0.11 nM and 9,800-fold selectivity over the human orexin receptor.

Alberto-Accardi added, "We are excited to leverage these data to expedite the progression of our multi-asset orexin franchise to potentially treat sleep-wake disorders and excessive daytime sleepiness (EDS) across multiple conditions."

Over the years, there has been significant industry interest in the development of OXR2 agonists to treat narcolepsy and other sleep disorders. Recently, in August, Eisai announced enrollment for a phase 1 study assessing its investigational agent E2086 in patients with narcolepsy.² Weeks later, Alkermes initiated its phase 2 study, dubbed Vibrance-2 (NCT06555783) that assesses the therapeutic potential of ALKS 2680, an OX2R agonist, in patients with narcolepsy type 2. This was the second phase 2 study in its development program, behind Vibrance-1, which includes those with narcolepsy type 1.³

REFERENCES
1. Centessa Announces Positive Interim Phase 1 Clinical Data with its Novel Orexin Receptor 2 (OX2R) Agonist, ORX750, in Acutely Sleep-Deprived Healthy Volunteers. News release. Centessa Pharmaceuticals. September 10, 2024. Accessed September 11, 2024. https://www.globenewswire.com/news-release/2024/09/10/2943494/0/en/Centessa-Announces-Positive-Interim-Phase-1-Clinical-Data-with-its-Novel-Orexin-Receptor-2-OX2R-Agonist-ORX750-in-Acutely-Sleep-Deprived-Healthy-Volunteers.html
2. Eisai to begin enrolling study in patients with narcolepsy. News release. Eisai. July 8, 2024. Accessed September 11, 2024. https://www.prnewswire.com/news-releases/eisai-to-begin-enrolling-study-in-patients-with-narcolepsy-302190859.html
3. Alkermes announces initiation of Vibrance-2 phase 2 study evaluating ALKS 2680 for the treatment of narcolepsy type 2. News release. August 22, 2024. Accessed September 11, 2024. https://www.prnewswire.com/news-releases/alkermes-announces-initiation-of-vibrance-2-phase-2-study-evaluating-alks-2680-for-the-treatment-of-narcolepsy-type-2-302227858.html