Centessa Pharmaceuticals Presents Preclinical Data for ORX142, a Novel Orexin Receptor 2 (OX2R) Agonist, at the 27th Congress of the European Sleep Research Society (Sleep Europe 2024)

Rhea-AI Summary

Centessa Pharmaceuticals (Nasdaq: CNTA) presented preclinical data for ORX142, a novel orexin receptor 2 (OX2R) agonist, at the 27th Congress of the European Sleep Research Society. The data from non-human primate (NHP) studies support ORX142 as a potential treatment for excessive daytime sleepiness (EDS) in select neurological, neurodegenerative, and psychiatric disorders.

Key findings include:

• ORX142 showed significant activity in promoting wakefulness at very low doses (0.03 mg/kg)
• It potently activated human OX2R with an EC50 of 0.069 nM and >13,000-fold selectivity over human OX1R
• Induced sustained increases in wakefulness, suppressing NREM and REM sleep
• Associated with normal physiological arousal and EEG power spectra signatures of enhanced alertness

ORX142 is currently in IND-enabling studies as Centessa's second OX2R agonist drug candidate.

Positive

• ORX142 showed significant wakefulness-promoting activity at very low doses (0.03 mg/kg) in NHP models
• High potency (EC50 of 0.069 nM) and selectivity (>13,000-fold) for human OX2R
• Induced sustained increases in wakefulness, suppressing NREM and REM sleep
• Associated with normal physiological arousal and enhanced alertness signatures
• No significant pharmacological activity observed in GPCR selectivity and in vitro safety panels

Negative

• None.

Insights

Neuroscience Researcher

The preclinical data on ORX142 shows promising potential for treating excessive daytime sleepiness (EDS) in various disorders. Key findings include:

• High potency and selectivity for OX2R (EC50 of 0.069 nM, 13,000% selectivity over OX1R)
• Significant wakefulness promotion at very low doses (0.03 mg/kg) in non-human primates
• Normal physiological arousal and EEG signatures of enhanced alertness
• No significant off-target effects observed

These results suggest ORX142 could be a powerful and targeted therapy for EDS. The low effective dose is particularly noteworthy, potentially indicating a favorable safety profile. However, it's important to remember that preclinical success doesn't guarantee clinical efficacy or safety in humans. The transition to IND-enabling studies marks an important step, but investors should remain cautious until human trial data becomes available.

Pharmaceutical Industry Analyst

Centessa's advancement of ORX142 represents a strategic move in the competitive orexin agonist space. Key points for investors:

• ORX142 is Centessa's second OX2R agonist candidate, demonstrating pipeline depth
• The company is leveraging structural biology capabilities for drug design
• Rapid progression to IND-enabling studies indicates confidence and urgency
• Targeting EDS in neurological, neurodegenerative and psychiatric disorders suggests a broad potential market

While promising, it's important to note that Centessa faces competition from larger pharma companies also developing orexin agonists. The $1.78 billion market cap suggests investors are pricing in some success, but significant value creation potential remains if ORX142 advances successfully. However, as an early-stage asset, it carries substantial development risk. Investors should monitor upcoming milestones, particularly the transition to human trials.

Late-breaking poster presentation of non-human primate (NHP) data support ORX142 as novel drug candidate for the treatment of excessive daytime sleepiness (EDS) in select neurological, neurodegenerative, and psychiatric disorders

BOSTON and LONDON, Sept. 26, 2024 (GLOBE NEWSWIRE) -- Centessa Pharmaceuticals plc (Nasdaq: CNTA), a clinical-stage pharmaceutical company that aims to discover and develop medicines that are transformational for patients, today shared new preclinical data from non-human primate (NHP) studies of ORX142, an investigational, novel, orexin receptor 2 (OX2R) agonist being advanced for the treatment of excessive daytime sleepiness (EDS) in select neurological, neurodegenerative and psychiatric disorders. ORX142 is the second drug candidate from the Company’s growing pipeline of OX2R agonists and is in IND-enabling studies.

The preclinical data were featured today in a late-breaking poster presentation entitled, “ORX142, an Oral, Highly Potent and Selective Orexin Receptor 2 Agonist, Promotes Wakefulness in Non-Human Primates,” by Sarah Wurts Black PhD, Head of Biology for Centessa’s Orexin Agonist Program, at the 27^th Congress of the European Sleep Research Society (Sleep Europe 2024) in Seville, Spain.

“ORX142 has shown significant activity in promoting wakefulness at very low doses in highly predictive and translational preclinical models,” said Saurabh Saha MD PhD, Chief Executive Officer of Centessa. “More specifically, the preclinical data showed ORX142 achieved significant increases in wake times at 0.03 mg/kg, the lowest oral dose tested in the NHP model. We’re excited to share these data at ESRS highlighting the breadth of ORX142’s potential as a novel treatment for individuals living with EDS in select neurodegenerative, neurological and psychiatric disorders. Based on the totality of data from our OX2R agonist program and the significant potential market opportunity for ORX142, we are focused on rapidly moving ORX142 through IND-enabling studies.”

Overview of ORX142 Preclinical Poster Presentation at Sleep Europe 2024:

• ORX142 is a full OX2R agonist designed by Centessa with the aid of high-resolution crystallography and cryo-EM structural chemistry capabilities.
• ORX142 potently activated the human OX2R with an EC₅₀ of 0.069 nM and > 13,000-fold selective over the human orexin receptor (hOX1R).¹
• In highly predictive, translational NHP models, oral administration of ORX142 showed significant activity at the lowest dose tested, which was 0.03 mg/kg.
• ORX142 induced sustained increases in wakefulness that suppressed NREM and REM sleep at the lowest dose tested, 0.03 mg/kg.
• Wakefulness induced by ORX142 was associated with normal physiological arousal and EEG power spectra signatures of enhanced alertness and attention.
• No significant pharmacological activity was observed in GPCR selectivity and in vitro safety panels.

References: 1. Fluorescent imaging plate reader (FLIPR) assay with Chinese hamster ovary (CHO) cells stably expressing recombinant human OX1R or OX2R; OXA EC50 at hOX2R = 0.035 nM; ORX142 EC50 at hOX1R = 930 nM.

Additional meeting information can be found on the Sleep Europe 2024 website at https://esrs.eu/sleep-congress/. The poster will also be available on the Centessa website at https://investors.centessa.com/events-presentations after the conference concludes. 

About Centessa’s Orexin Agonist Program
Orexin is a neuropeptide that regulates the sleep-wake cycle, leading to arousal and promoting wakefulness. Low levels of orexin result in excessive daytime sleepiness (EDS) and poor regulation of rapid eye movement (REM) sleep and, in narcolepsy type 1 (NT1), cataplexy and other symptoms. Centessa is developing a pipeline of potential best-in-class orexin receptor 2 (OX2R) agonists, including ORX750 for the treatment of sleep-wake disorders, including NT1, narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH), and ORX142 for the treatment of EDS in select neurological, neurodegenerative, and psychiatric disorders. ORX750 is in a Phase 1 clinical study. ORX750 and ORX142 have not been approved by the FDA or any other regulatory authority.

About Centessa Pharmaceuticals  
Centessa Pharmaceuticals plc is a clinical-stage pharmaceutical company that aims to discover and develop medicines that are transformational for patients. Our most advanced programs include a hemophilia program, an orexin agonist program for the treatment of narcolepsy and other sleep-wake disorders, and an immuno-oncology program focused on our LockBody® technology platform. We operate with the conviction that each of our programs has the potential to change the current treatment paradigm and establish a new standard of care. For more information, visit www.centessa.com, which does not form part of this release.

Forward Looking Statements
This press release contains forward-looking statements. These statements may be identified by words such as “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “intend,” “plan,” “objective,” “anticipate,” “believe,” “estimate,” “predict,” “potential,” “continue,” “ongoing,” “aim,” “seek,” and variations of these words or similar expressions that are intended to identify forward-looking statements. Any such statements in this press release that are not statements of historical fact may be deemed to be forward-looking statements, including statements related to the Company’s ability to discover and develop transformational medicines for patients; its expectations for executing on the Company's pipeline; the timing of commencement of new studies or clinical trials or clinical and preclinical data related to ORX750 and ORX142; its ability to identify, screen, recruit and maintain a sufficient number of or any subjects in its existing and anticipated studies or clinical trials including in respect of ORX750 and ORX142; its expectations on executing its research and clinical development plans and the timing thereof, including its ability to rapidly move ORX142 through IND-enabling studies; its expectations as to the potential results and impact of each of its clinical programs and trials; the Company’s ability to differentiate ORX750 and ORX142 from other treatment options; the development, design and therapeutic potential of ORX750 and ORX142; and regulatory matters, including the timing and likelihood of success of obtaining regulatory clearance, obtaining authorizations to initiate or continue clinical trials. Any forward-looking statements in this press release are based on our current expectations, estimates, assumptions and projections only as of the date of this release and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, risks related to the safety and tolerability profile of our product candidates, including ORX750 and ORX142; whether ORX750 and ORX142 could be shown to be ineffective; our ability to identify, screen and recruit a sufficient number of or any subjects in our existing and anticipated new studies or clinical trials including ORX750 and ORX142 or within anticipated timelines; our expectations relating to the further clinical development of ORX750 and ORX142 including initiation of phase 1 and/or phase 2 studies, including the predicted timing of enrollment, the predicted efficacious doses of ORX750 and ORX142 and our ability to successfully conduct our clinical development of ORX750 and ORX142; whether preclinical and initial clinical results for ORX750 and ORX142 will be predictive of results of further clinical trials; our ability to protect and maintain our intellectual property position; business (including commercial viability), regulatory, economic and competitive risks, uncertainties, contingencies and assumptions about the Company; risks inherent in developing product candidates and technologies; future results from our ongoing and planned clinical trials; our ability to obtain adequate financing, including through our financing facility with Oberland, to fund our planned clinical trials and other expenses; trends in the industry; the legal and regulatory framework for the industry, including the receipt and maintenance of clearances to conduct or continue clinical testing; our operating costs and use of cash, including cash runway, cost of development activities and conducting clinical trials, future expenditures risks; the risk that any one or more of our product candidates will not be successfully developed and/or commercialized; the risk that the historical results of preclinical studies or clinical studies will not be predictive of future results in ongoing or future studies; economic risks to the United States and United Kingdom banking systems; and geo-political risks such as the Russia-Ukraine war or the Middle East conflicts. These and other risks concerning our programs and operations are described in additional detail in our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and our other reports, which are on file with the U.S. Securities and Exchange Commission (SEC). We explicitly disclaim any obligation to update any forward-looking statements except to the extent required by law.

Contact:

Kristen K. Sheppard, Esq.
SVP of Investor Relations
investors@centessa.com

FAQ

What is ORX142 and what is its potential use according to Centessa Pharmaceuticals (CNTA)?

ORX142 is a novel orexin receptor 2 (OX2R) agonist being developed by Centessa Pharmaceuticals (CNTA) for the potential treatment of excessive daytime sleepiness (EDS) in select neurological, neurodegenerative, and psychiatric disorders.

What were the key findings from the ORX142 preclinical studies presented by Centessa (CNTA) at Sleep Europe 2024?

The preclinical studies showed that ORX142 promoted wakefulness at very low doses (0.03 mg/kg) in non-human primates, potently activated human OX2R with high selectivity, induced sustained increases in wakefulness suppressing NREM and REM sleep, and was associated with normal physiological arousal and enhanced alertness signatures.

What is the current development stage of ORX142 by Centessa Pharmaceuticals (CNTA)?

ORX142 is currently in IND-enabling studies, as stated in the press release by Centessa Pharmaceuticals (CNTA).

How does ORX142 compare to other orexin receptor agonists in Centessa's (CNTA) pipeline?

ORX142 is the second drug candidate from Centessa's (CNTA) growing pipeline of OX2R agonists, indicating it's part of a broader development strategy in this therapeutic area.