Clinical data builds upon body of evidence
suggesting EXS-21546 is a highly potent and selective A2AR
antagonist with low CNS exposure
Exscientia anticipates initiating Phase 1b/2 in
patients with high adenosine signature cancers in second half of
2022
Ongoing translational work to establish
predictive biomarker to enable targeting of patients most likely to
benefit from EXS-21546
Exscientia plc (Nasdaq: EXAI) today announced data from its
Phase 1 healthy volunteer study of EXS-21546, its highly selective
A2A receptor antagonist co-invented and developed through a
collaboration between Exscientia and Evotec SE (Frankfurt Stock
Exchange: EVT, MDAX/TecDAX, ISIN: DE0005664809; Nasdaq: EVO).
Topline data from this healthy volunteer study confirmed
Exscientia’s target product profile design, including potency, high
receptor selectivity and expected low brain exposure with no CNS
adverse events reported, supporting advancement of EXS-21546 to a
Phase 1b/2 study in patients with solid tumours exhibiting high
adenosine signatures.
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“Topline data from our phase 1a study of EXS-21546 demonstrate
the ability of our AI-based platform to create novel molecules
based upon defined design objectives and with a high level of
translatability to human biology. EXS-21546 is a pilot programme
from the early days of our platform, and we are proud that it
achieved our targeted objectives of potency, selectivity and
pharmacokinetics,” said David Hallett, Ph.D., Chief Operating
Officer and head of drug discovery for Exscientia. “Moving forward,
a primary challenge in clinical development of an A2AR antagonist
is identifying patients who will benefit the most from this type of
immunomodulatory therapy. We believe that utilising our unique
precision medicine platform to analyse patient tumour
microenvironments ex vivo, including immune function, will help us
identify the right patients for our drug.”
The EXS-21546 phase 1a study was a three-part dose-finding trial
evaluating the safety, tolerability, pharmacokinetics (PK), and
pharmacodynamics (PD) of single ascending doses (SAD) and multiple
ascending doses (MAD) of EXS-21546. The study randomised 60 healthy
male subjects across all three parts. One of the study’s primary
goals was to inform the optimal starting dose for EXS-21546 for the
Phase 1b/2 study in cancer patients.
The study showed that observed human PK for EXS-21546 was in
line with what had been designed for and predicted in preclinical
modeling, supporting a twice-daily (BID) dose for continuous A2A
receptor inhibition over a dosing interval.
EXS-21546 showed dose-dependent inhibition of CREB
phosphorylation in CD8-positive cells, with the PD profile
mirroring plasma exposure. Inhibition of A2A receptor signaling was
sustained over the BID dosing period, demonstrating a level of
lasting target engagement.
EXS-21546 was well-tolerated with no CNS adverse events reported
in the SAD portion at all doses (30mg, 90mg, 250mg, 400mg) and in
the MAD portion at 150mg BID. In the MAD phase, a lab abnormality
of elevated ALT and AST was observed in one subject that was
classified as a Grade 3 Serious Adverse Event. This event was
observed in one subject three days after completion of 14 days of
treatment and resolved without medical intervention. The subject
was asymptomatic during the treatment period and reported no
adverse events while on drug.
Based on these results, Exscientia expects to initiate a Phase
1b/2 study of EXS-21546 in patients with high adenosine signature
solid tumours in the second half of 2022. The Phase 1b/2 study is
being designed to evaluate higher doses of EXS-21546.
The Company expects to share additional data from this Phase 1a
study at future medical meetings.
About EXS-21546
EXS-21546, an AI-designed A2A receptor antagonist, was
co-invented and developed by Exscientia and Evotec. Exscientia
designed the compound leveraging its AI-driven platform and Evotec
provided biology and chemistry capabilities.
Some tumours produce high levels of adenosine, which binds and
activates A2A receptors on immune cells, resulting in the
suppression of the anti-tumour activity of the immune system.
EXS-21546 is being investigated for its ability to prevent high
concentrations of adenosine from activating the A2A receptor, and
thereby its potential to promote the anti-tumour activity of the
immune cells.
About the EXS-21546 Phase 1a Trial
The Phase 1 study was a three-part study in male healthy
volunteers to assess the safety, tolerability, pharmacokinetics and
pharmacodynamics (PK/PD) of EXS-21546. Part 1 was a randomised,
double-blind, placebo-controlled, SAD study with a food effect
assessment where 41 healthy volunteers were randomised 3:1 (in a
ratio of 6 active to 2 placebo per cohort). Part 2 was a
randomised, double-blind, placebo controlled, MAD study over 14
days. Part 2 was completed after the enrolment of 1 cohort (8
subjects) who received 150mg EXS-21546 BID. Part 3 was a 3-way
crossover, open label, randomised study, where 11 subjects were
enrolled to evaluate a capsule formulation (fed and fasted) as
compared to an oral suspension (fasted) formulation.
About Exscientia
Exscientia is an AI-driven pharmatech company committed to
discovering, designing and developing the best possible drugs in
the fastest and most effective manner. Exscientia developed the
first-ever functional precision oncology platform to successfully
guide treatment selection and improve patient outcomes in a
prospective interventional clinical study, as well as to progress
AI-designed small molecules into the clinical setting. Our pipeline
demonstrates our ability to rapidly translate scientific concepts
into precision-designed therapeutic candidates, with more than 30
projects underway. By designing better drugs, faster, we believe
the best ideas of science can rapidly become the best medicines for
patients.
Exscientia is headquartered in Oxford (England, U.K.), with
offices in Vienna (Austria), Dundee (Scotland, U.K.), Boston
(Mass., U.S.), Miami (Fla., U.S.), Cambridge (England, U.K.), and
Osaka (Japan).
Visit us at https://www.exscientia.ai or follow us on Twitter
@exscientiaAI.
Forward-Looking Statements
This press release contains certain forward-looking statements
within the meaning of the “safe harbor” provisions of the Private
Securities Litigation Reform Act of 1995, including statements with
regard to Exscientia’s expectations with respect to the progress of
development of candidate molecules, timing and progress of, and
data reported from, preclinical studies and clinical trials of
Exscientia’s product candidates, and Exscientia’s expectations
regarding its precision medicine platform and AI-driven drug
discovery platform. Words such as “anticipates,” "believes,"
“expects,” "intends," "projects," "anticipates," and "future" or
similar expressions are intended to identify forward-looking
statements. These forward-looking statements are subject to the
uncertainties inherent in predicting future results and conditions,
including the scope, progress and expansion of Exscientia’s product
development efforts; the initiation, scope and progress of
Exscientia’s and its partners’ clinical trials and ramifications
for the cost thereof; clinical, scientific, regulatory and
technical developments; and those inherent in the process of
discovering, developing and commercialising product candidates that
are safe and effective for use as human therapeutics, and in the
endeavor of building a business around such product candidates.
Exscientia undertakes no obligation to publicly update or revise
any forward-looking statements, whether as a result of new
information, future events or otherwise, except as may be required
by law.
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version on businesswire.com: https://www.businesswire.com/news/home/20220614005457/en/
Investors: Sara Sherman investors@exscientia.ai
Media: Amanda Galgay media@exscientia.ai
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