- Preclinical data demonstrated significant activity at low doses of ORX750 in

       highly predictive translational models of Narcolepsy Type 1 (NT1)
   - ORX750 advancing in IND-enabling studies; Clinical proof of concept data
                               planned for 2024

BOSTON and LONDON, Oct. 25, 2023 (GLOBE NEWSWIRE) -- Centessa Pharmaceuticals
plc (http://www.centessa.com/) (Nasdaq: CNTA), a clinical-stage pharmaceutical
company that aims to discover and develop medicines that are transformational
for patients, today announced a robust set of new preclinical data from in vivo
and in vitro studies of its investigational, novel orexin receptor 2 (OX2R)
agonist, ORX750, that support its potential best-in-class profile for the
treatment of narcolepsy and other sleep-wake disorders.
The preclinical data will be featured today in an oral presentation by Sarah
Wurts Black PhD, Head of Biology for Centessa's Orexin Agonist Program,
entitled, "ORX750, an Oral Selective Orexin Receptor 2 Agonist, Promotes
Wakefulness and Reduces Cataplexy in the Orexin/Ataxin-3 Mouse," at the World
Sleep Congress in Rio De Janeiro, Brazil.
"We are very excited to share this robust preclinical dataset, which we believe
shows the significant activity of low doses of ORX750 in highly predictive,
translational models of narcolepsy type 1 (NT1)," said Mario Alberto Accardi
PhD, President of Centessa's Orexin Agonist Program. "The preclinical data
showed ORX750 achieved maximal wake times and suppressed cataplexy at 0.1 mg/kg,
the lowest oral dose tested in the DTA mouse model. Notably, this activity was
observed in both the DTA and Atax mouse models that recapitulate NT1 symptoms in
humans. The data also showed ORX750 significantly increased wake time in healthy
wild type mice at 1 mg/kg, the lowest oral dose tested, supporting the potential
for expansion into broader sleep-wake disorders with normal orexin tone,
including narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH). We believe
these data highlight the breadth of ORX750's potential as a novel treatment for
individuals living with narcolepsy and other sleep-wake disorders."
"ORX750 is a highly potent and selective novel orexin agonist that closely
mimics the function of the endogenous peptide," said Saurabh Saha MD PhD, Chief
Executive Officer of Centessa. "These preclinical data showed that ORX750 has
the potential to address the underlying pathophysiology of orexin neuron loss in
NT1 and promote wakefulness during the day and suppress cataplexy, including at
levels that correspond to very low predicted human doses. In addition, the
preclinical pharmacokinetic (PK) profile of ORX750, informed by PK testing in
multiple species, including non-human primates, suggests the potential for
ORX750 to have high, early and sustained brain exposure. We believe these data
provide a strong translational foundation for clinical development. We are
focused on rapidly moving ORX750 through IND-enabling studies, obtaining IND
clearance and initiating clinical development of ORX750 with the goal of sharing
clinical proof of concept data in 2024. We look forward to providing further
updates in the coming months."
Overview of ORX750 Preclinical Results:

  * ORX750 is a full OX2R agonist that potently activated the OX2R with an in
    vitro EC50 of 0.11 nM and 9,800-fold selectivity over the human orexin
    receptor (hOX1R)(1).
  * In highly predictive, translational Atax and DTA mouse models, oral
    administration of ORX750 showed significant activity at the lowest dose

tested, which was 0.1 mg/kg in a DTA mouse model, 0.3 mg/kg in an Atax mouse

    model, and 1 mg/kg in healthy wild type mice. ORX750:
      * Achieved maximal (100%) wake time for at least 3 hours post-dose;(2)
      * Suppressed cataplexy for at least 6 hours post-dose;(2)
      * Increased latency to sleep and cataplexy, which was maintained for >14
        days of dosing;(3) and,
      * Increased consolidation of wakefulness.(4)

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. 2. As measured by electroencephalogram (EEG) and
electromyogram (EMG) with concurrent video in DTA and Atax mouse models. 3. As
measured by EEG and EMG with concurrent video in Atax mouse model. 4. PiezoSleep
assay as measured in DTA and Atax mouse models.
Centessa's preclinical data presentation for ORX750 will be available within a
recorded webcast on the Company's website at
https://investors.centessa.com/events-presentations immediately following the
World Sleep presentation taking place at 10:45 a.m. BRT / 9:45 a.m. ET.
About ORX750
ORX750 is an investigational, orally administered, highly potent and selective
orexin receptor 2 (OX2R) agonist designed to directly target the underlying
pathophysiology of orexin neuron loss in narcolepsy type 1 (NT1). ORX750 is
Centessa's first orexin product candidate being developed for the treatment of
narcolepsy with potential expansion into other sleep-wake disorders. ORX750 is
currently undergoing IND-enabling activities and has not been administered as an
investigational drug to humans in any jurisdiction.
About Centessa Pharmaceuticals
Centessa Pharmaceuticals plc (http://www.centessa.com/) is a clinical-stage
pharmaceutical company that aims to discover and develop medicines that are
transformational for patients. Our programs span discovery-stage to late-stage
development and cover a range of high-value indications. We operate with the
conviction that each one of our programs has the potential to change the current
treatment paradigm and establish a new standard of care. For more information,
visit http://www.centessa.com/, which does not form part of this release.
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statements related to: the Company's ability to deliver transformational
medicines to patients; the activity significance of low doses in highly
predictive, translational models of narcolepsy type 1 (NT1) including maximal
wake times and suppressed cataplexy at the lowest oral dose tested; the
Company's expectations on the timing of Ind-enabling studies of ORX750 in
narcolepsy and other sleep-wake disorders; the ability of our management team
and board to drive execution of the Company's portfolio of programs; our asset-
centric business model and the intended advantages and benefits thereof; the
scope, progress, results and costs of developing our product candidates or any
other future product candidates; our current expectations concerning, amongst
other things, the development and therapeutic potential and benefits of our
product candidates, including ORX750 and other OX2R agonists; strategy;
regulatory matters, including the timing and likelihood of initiating clinical
trials, reporting clinical trial results, ability to initiate or continue
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not limited to, risks related to the safety and tolerability profile of our
product candidates including ORX750; our ability to protect and maintain our
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Contact:
Kristen K. Sheppard, Esq.
SVP of Investor Relations
investors@centessa.com (mailto:investors@centessa.com)
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