Centessa Announces Positive Interim Phase 1 Clinical Data with its Novel Orexin Receptor 2 (OX2R) Agonist, ORX750, in Acutely Sleep-Deprived Healthy Volunteers
10 Setembro 2024 - 8:00AM
UK Regulatory
Centessa Announces Positive Interim Phase 1 Clinical Data with its
Novel Orexin Receptor 2 (OX2R) Agonist, ORX750, in Acutely
Sleep-Deprived Healthy Volunteers
- 2.5 mg dose restored normative wakefulness with mean sleep
latency of 32 minutes as measured by the Maintenance of Wakefulness
Test (MWT)
- Favorable safety and tolerability profile with no
observations of frequently reported on-target adverse events (AEs)
associated with other OX2R agonists, visual disturbances or
hepatotoxicity as of the data cutoff date
1
- PK profile supports once-daily dosing
- Company plans to rapidly initiate Phase 2 studies of ORX750
in patients with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2),
and idiopathic hypersomnia (IH)
BOSTON and LONDON, Sept. 10, 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 announced positive interim
data from an ongoing Phase 1 trial of its highly potent and
selective orexin receptor 2 (OX2R) agonist, ORX750, in acutely
sleep-deprived healthy volunteers. ORX750 showed clinically
meaningful and statistically significant improvements in mean sleep
latency at the first two doses evaluated (1.0 mg and 2.5 mg) in the
Maintenance of Wakefulness Test (MWT) compared to placebo. More
specifically, the 2.5 mg dose was shown to restore normative
wakefulness2 with a mean sleep latency of 32 minutes as
measured by the MWT. ORX750 was also shown to have a favorable
safety and tolerability profile with no observations of frequently
reported on-target adverse events (AEs) associated with other OX2R
agonists, and no cases of hepatotoxicity or visual disturbances
across all three dose levels tested (1.0 mg, 2.0 mg, and 2.5 mg),
as of the data cutoff date.1 Based on the interim data,
the Company plans to rapidly advance ORX750 into Phase 2 studies in
patients with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and
idiopathic hypersomnia (IH) beginning in the fourth quarter of
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,” said Saurabh Saha MD PhD, Chief Executive
Officer of Centessa. “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.
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.”
The Phase 1 clinical study is an ongoing first-in-human,
randomized, placebo-controlled study designed to evaluate the
safety, tolerability and pharmacokinetics (PK) of single-ascending
doses (SAD) and multiple-ascending doses (MAD) of ORX750 in healthy
adult subjects. In parallel to the SAD, a placebo-controlled
cross-over pharmacodynamic (PD) assessment is being performed
utilizing the MWT and Karolinska Sleepiness Scale (KSS) in acutely
sleep-deprived healthy adult subjects with the goal of rapidly
generating early efficacy data to inform dosing for planned studies
in patients. As of September 10, 2024, the study has completed
three SAD cohorts of healthy volunteers (27 active, 9 placebo) with
doses of 1.0 mg, 2.0 mg, and 2.5 mg, and has advanced through two
cohorts within the cross-over assessment of acutely sleep-deprived
healthy volunteers with doses of 1.0 mg (n=8) and 2.5 mg (n=8),
administered as a single oral dose. Dosing in the MAD portion of
the study is also ongoing.
Summary of Data:
The interim Phase 1 clinical data for ORX750 demonstrated:
- Significantly increased wakefulness in acutely sleep-deprived
healthy volunteers compared to placebo at both doses tested.
Treatment with ORX750 resulted in statistically significant
(p<0.05) and clinically meaningful increased sleep latency on
the MWT (time to sleep onset over the four sessions performed at
~2, 4, 6, and 8 hours after dosing at 11 p.m., maximum 40 minutes
per session) compared to placebo across all doses. Mean sleep
latencies, as measured by the MWT, for 1.0 mg dose of ORX750 and
placebo were 18 minutes and 10 minutes, respectively (p-value =
0.04) (least squares mean). Mean sleep latencies, as measured by
the MWT, for 2.5 mg dose of ORX750 and placebo were 32 minutes and
17 minutes, respectively (p-value = 0.01) (least squares mean). The
2.5 mg dose was shown to restore normative wakefulness with a mean
sleep latency of 32 minutes as measured by the MWT.
- Favorable safety and tolerability observed as of the data
cutoff date.1All observed treatment related AEs were
mild and transient with none leading to treatment
discontinuation.
- No observations of frequently reported on-target AEs associated
with other OX2R agonists, including urinary frequency, urinary
urgency, insomnia, blood pressure increases, and salivary
hypersecretion.
- No cases of hepatotoxicity, visual disturbances or
hallucinations were observed. Additionally, there were no
clinically meaningful treatment-emergent changes in hepatic and
renal parameters, vital signs, or electrocardiogram (ECG)
parameters.
- Acutely sleep-deprived healthy volunteers who received a 2.5 mg
dose of ORX750 showed a significant 1.6 point improvement versus
placebo in mean KSS score compared to baseline (p-value =
0.03).
- Encouraging linear PK profile supports the use of ORX750 as a
once-daily oral dosing regimen with rapid absorption (plasma
concentrations of ORX750 peaked at 2h after the first dose). The
systemic exposure of ORX750 increased in an approximately
dose-proportional manner.
“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,” said Mario Alberto-Accardi PhD, President,
Centessa Orexin Program. “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. 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.”
- Data cutoff date of August 26, 2024.
- Doghramji K, et al., A normative study of the maintenance of
wakefulness test (MWT). Electroencephalogr Clin Neurophysiol 1997;
103:554-62.
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.
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. The Company’s lead
asset, ORX750, is in a Phase 1 clinical study. ORX750 and ORX142
have not been approved by the FDA or any other regulatory
authority.
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;
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; its expectations
on executing its research and clinical development plans and the
timing thereof; its expectations as to the potential results and
impact of each of its clinical programs and trials; the Company’s
ability to differentiate ORX750 from other treatment options; the
development, design and therapeutic potential of ORX750; 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;
whether ORX750 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 or within anticipated timelines; our expectations
relating to the further clinical development of ORX750 including
initiation of phase 2 study and exploration of higher doses in the
phase 1 study, including the predicted timing of enrollment, the
predicted efficacious doses of ORX750 and our ability to
successfully conduct our clinical development of ORX750; whether
preclinical and initial clinical results for ORX750 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
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