Centessa Prioritizes Orexin Program Following Positive Data

Summary: Centessa Pharmaceuticals announced its third-quarter financial results and updates to its development pipeline, including positive interim data from its phase 1 study of ORX750, an orexin receptor 2 agonist aimed at treating narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH). Following promising results, Centessa has initiated a phase 2a clinical trial for ORX750 in these sleep disorders, with data expected in 2025. The company also made a strategic decision to discontinue the clinical development of SerpinPC, a hemophilia B treatment, reallocating approximately $200 million to focus on its orexin agonist program.

Key Takeaways:

ORX750 Advances to Phase 2 Trials: Centessa has initiated a phase 2a trial for ORX750 in patients with NT1, NT2, and IH, following positive interim data that demonstrated increased wakefulness in acutely sleep-deprived volunteers.
Strategic Shift to Focus on Orexin Agonists: The company has discontinued the development of SerpinPC for hemophilia B to prioritize its orexin receptor program, reallocating $200 million to advance treatments for sleep-related and neurological disorders.
Expanding Orexin Agonist Pipeline: In addition to ORX750, Centessa is progressing with ORX142 and ORX489, aiming to address excessive daytime sleepiness and other symptoms associated with neurological, neurodegenerative, and psychiatric conditions.

Centessa Pharmaceuticals has reported third-quarter 2024 financial results and unveiled new interim data supporting the potential of its orexin receptor 2 agonist, ORX750, in treating narcolepsy and idiopathic hypersomnia, while also discontinuing development of SerpinPC to focus resources on its expanding sleep disorder pipeline.

“The totality of data across our OX2R agonist program continues to reinforce the strength of our discovery engine and the therapeutic potential of these assets across a broad spectrum of disorders,” says Saurabh Saha, MD, PhD, chief executive officer of Centessa, in a release. “The phase 1 interim data for ORX750, now updated to include over 70 subjects dosed with ORX750, continue to support its best-in-class potential in NT1 (narcolepsy type 1), NT2 (narcolepsy type 2), and IH (idiopathic hypersomnia).

“Based on the strength of these interim data, we recently initiated a phase 2a clinical study of ORX750 in patients with NT1, NT2 and IH. Similar to our phase 1 study, which enabled a move from IND clearance to clinical data in the course of a few months, we expect our phase 2a study design to generate clinical data for all three indications in 2025 and enable dose selection for future pivotal studies with the potential to be first-in-class in NT2 and IH.”

Saha continues in a release, “In addition to ORX750, we are advancing a growing pipeline of OX2R agonists targeting excessive daytime sleepiness (EDS) in neurological, neurodegenerative, and psychiatric disorders, as well as other potential symptoms including impaired attention, cognitive deficits, and fatigue. ORX142 is currently in IND-enabling studies, and subject to IND clearance, we expect to initiate clinical development and share clinical data in acutely sleep-deprived healthy volunteers in 2025. We’re also pleased to be kicking off our next wave of candidates with ORX489, our most potent OX2R agonist to date based on preclinical data, which is entering IND-enabling studies.”

Interim Data from Ongoing Phase 1 Clinical Study of ORX750

The additional interim data from the ongoing phase 1 clinical trial of ORX750 in healthy volunteers includes results from two single-ascending dose cohorts at 3.5 mg (n=12: 9 active, 3 placebo) and 5.0 mg (n=12: 9 active, 3 placebo), a cohort of acutely sleep-deprived healthy volunteers within the cross-over assessment at 3.5 mg (n=10) administered as a single oral dose, and two multiple-ascending dose (MAD) cohorts at 2.0 mg (n=10: 8 active, 2 placebo) and 3.0 mg (n=10: 8 active, 2 placebo).

The interim data showed:

Significantly increased wakefulness in acutely sleep-deprived healthy volunteers compared to placebo at all doses tested, with a clear dose-dependent response.
Treatment with ORX750 resulted in statistically significant (p<0.05) and clinically meaningful increased sleep latency in the Maintenance of Wakefulness Test (MWT) (time to sleep onset over the four sessions performed at ~two, four, six, and eight hours after dosing at 11 pm, maximum 40 minutes per session) compared to placebo at all doses tested.
The 3.5 mg dose was shown to restore normative wakefulness with a mean sleep latency of 34 minutes and a placebo-adjusted mean sleep latency of 20 minutes, as measured by the MWT.
A favorable safety and tolerability profile with all observed treatment-emergent adverse events being mild and transient with none leading to treatment discontinuation. No cases of hepatotoxicity or visual disturbances were observed. Additionally, there were no clinically significant treatment-emergent changes in hepatic and renal parameters, vital signs, or electrocardiogram parameters.

Interim Safety Data from Ongoing Phase 1 Clinical Study of ORX750

	SAD Cohorts						MAD Cohorts
	Placebo(n=15)	ORX7501.0 mg(n=9)	ORX7502.0 mg(n=9)	ORX7502.5 mg(n=9)	ORX7503.5 mg(n=9)	ORX7505.0 mg(n=9)	Placebo(n=4)	ORX7502.0 mg(n=8)	ORX7503.0 mg(n=8)
Any TEAE, n (%)	4 (27)	3 (33)	3 (33)	1 (11)	0	3 (33)	2 (50)	4 (50)	3 (38)
Related	4 (27)	0	2 (22)	1 (11)	0	2 (22)	1 (25)	4 (50)	2 (25)
Nonrelated	1 (7)	3 (33)	2 (22)	0	0	2 (22)	2 (50)	2 (25)	1 (12)
Mild	4 (27)	3 (33)	3 (33)	1(11)	0	3 (33)	2 (50)	4 (50)	3 (38)
Moderate	0	0	0	0	0	0	0	0	0
Severe	0	0	0	0	0	0	0	0	0
TEAEs leading to discontinuation, n (%)	0	0	0	0	0	0	0	0	0
Serious TEAEs, n (%)	0	0	0	0	0	0	0	0	0
Frequently reported AEs associated with other OX2R agonists
Insomnia	0	0	0	0	0	0	1 (25)	2 (25)	0
Urinary frequency/urgency	1 (7)	0	0	0	0	1 (11)	0	1 (12)	1 (12)
Visual disturbances	0	0	0	0	0	0	0	0	0
Hepatotoxicity	0	0	0	0	0	0	0	0	0
Blood pressure increased	0	0	0	0	0	0	0	0	0

An encouraging linear pharmacokinetic (PK) profile that supports the use of ORX750 as a once-daily oral dosing regimen with rapid absorption (plasma concentrations of ORX750 peaked 2h after the first dose). The systemic exposure of ORX750 increased in a dose-proportional manner.

Phase 2a Clinical Study of ORX750

The phase 2a study is a randomized, double-blind, placebo-controlled, cross-over basket study to evaluate the safety, tolerability, and PK of ORX750 in patients with NT1, NT2, and IH. There will be separate cohorts for each indication. Initial dosing for NT1 will be 1.0 mg and for NT2 and IH will be 2.0 mg with sequential dose escalation/de-escalation between cohorts. Each dosing cohort consists of a six-week treatment duration with crossover study design.

During the six weeks of treatment, each participant will be randomized to one of two blinded treatment sequences and receive a total of four weeks of treatment with ORX750 and two weeks of treatment with placebo.

Efficacy assessments will evaluate the effect of ORX750 on excessive daytime sleepiness (using the MWT and Epworth Sleepiness Scale (ESS)), cataplexy (NT1 patients only), and overall symptom improvement (measured by Narcolepsy Severity Scale (NSS) and Idiopathic Hypersomnia Severity Scale (IHSS)). Other exploratory assessments include measures of sleep, cognition, attention, memory, and general health.

“The phase 2a study of ORX750 is intended to accelerate overall timelines and inform future registrational studies,” says Mario Alberto Accardi, PhD, president of Centessa’s orexin program, in a release. “This well-powered study leverages highly innovative design elements which we believe have the potential to enable efficient data generation with an optimal number of patients in each indication. With this design, all participating patients will receive ORX750 for at least 4 weeks. We aim to generate data across all three indications in 2025, which could enable ORX750 to be first-in-class in NT2 and IH.”

SerpinPC Clinical Program Update

The company has decided to discontinue the global clinical development of SerpinPC, a novel inhibitor of activated protein C that was being evaluated for the treatment of hemophilia B. This action was driven by the company’s decision to prioritize capital toward the development of its OX2R agonist program and the outcome of a planned interim analysis of part 1 of the PRESent-2 study of SerpinPC.

Within the interim analysis, SerpinPC was observed to have a favorable safety and tolerability profile; however, the Company determined that additional time and investment would be required to further develop SerpinPC with a more competitive profile for the treatment of hemophilia B in light of the evolving treatment and market landscape for hemophilia B, including the recent FDA approval of a competing product.

The company says in a news release that it would like to thank the hemophilia community and all the patients, caregivers, and physicians who participated in the SerpinPC clinical trials. Centessa is now exploring potential strategic alternatives for SerpinPC.

“Moving forward, we intend to prioritize our resources and reallocate net savings of approximately $200 million associated with the planned commercial launch of SerpinPC towards expanding our potential best-in-class OX2R agonist franchise, where we see significant opportunities to both address unmet patient needs and create shareholder value,” says John Crowley, chief financial officer, in a relese “With a cash runway that extends into mid-2027, we believe Centessa is well positioned to support our OX2R agonist franchise through multiple, potential value-creating milestones.”

Recent Highlights

In September, Centessa presented preclinical data from non-human primate studies of ORX142 at the 27th Congress of the European Sleep Research Society (Sleep Europe 2024).
In September, the company announced positive interim data from the ongoing phase 1 clinical trial of ORX750 in acutely sleep-deprived healthy volunteers as of an Aug 26, 2024, data cutoff date.

Anticipated Upcoming Program Milestones

OX2R Agonist Program –
- ORX750: Subject to acceptance, a presentation of phase 1 clinical data is planned at a medical conference in the second quarter of 2025. Centessa expects to share phase 2a data for NT1, NT2, and IH in 2025.
- ORX142: Advancing through IND-enabling studies. The company is focused on obtaining IND clearance and initiating clinical development with the goal of sharing clinical data in acutely sleep-deprived healthy volunteers in 2025.
- ORX489: Entering IND-enabling studies.
- OX2R Agonist Pipeline: Progressing additional OX2R agonists as well as research efforts on differentiated pharmacology associated with the activation of the orexin system.
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