TIDMPRTC
PureTech Health PLC
14 November 2023
14 November 2023
PureTech Health plc
PureTech's LYT-300 (Oral Allopregnanolone) Achieved Primary
Endpoint in a Phase 2a Acute Anxiety Trial in Healthy
Volunteers
Orally administered LYT-300 achieved a statistically significant
(p=0.0001) reduction in the stress hormone response, as measured by
salivary cortisol, compared to placebo
This proof-of-concept trial demonstrating a reduction in the
physiological stress response supports the further development of
LYT-300 as a potential treatment for a range of anxiety
disorders
Anxiety disorders affect nearly 30 percent of U.S. adults(1) ,
yet current standard-of-care treatments can have drawbacks
including mixed efficacy, abuse potential, delayed onset of action
and/or poor tolerability; LYT-300 has potential to overcome these
challenges as a novel therapeutic in an area of serious patient
need
LYT-300 was well-tolerated across the trial with only transient
mild or moderate adverse events
PureTech Health plc (Nasdaq: PRTC, LSE: PRTC) ("PureTech" or the
"Company"), a clinical-stage biotherapeutics company dedicated to
changing the lives of patients with devastating diseases, today
announced topline results from its Phase 2a, randomized,
placebo-controlled, proof-of-concept trial of LYT-300 (oral
allopregnanolone). The trial was designed to evaluate the salivary
cortisol response in the Trier Social Stress Test (TSST), a
validated clinical model of anxiety in healthy volunteers.
Oral administration of LYT-300 achieved the trial's primary
endpoint of a statistically significant reduction versus placebo in
the increase from baseline to peak levels of the stress hormone
salivary cortisol (p=0.0001 ). The LYT-300 treatment effect size
versus placebo was 0.72, as measured by Cohen's d, which is one of
the most common ways to measure effect size. LYT-300 showed a
similar effect size to previously observed results for alprazolam,
a benzodiazepine drug indicated for treatment of anxiety disorders,
when assessed following the TSST procedure(2) . A n increase in c
ortisol levels after the TSST is a physiological response and an
objective biomarker of acute stress. E ighty healthy volunteers
were randomized and treated with either LYT-300 or placebo in a 1:1
ratio. LYT-300 was well tolerated, with all treatment-related
adverse events transient, mild or moderate and consistent with the
known pharmacology profile of allopregnanolone. Additional data
from the study will be presented in a scientific forum.
"Anxiety disorders are an area of significant unmet medical need
and current standard-of-care treatments leave much room for
improvement due to inconsistent efficacy and adverse events. We
know that benzodiazepines, like alprazolam, can reduce the salivary
cortisol response to stress in the TSST. Cortisol is an important
marker of the physiological response to stress, and reduction of
stress overreactivity may be an important mechanism for treating
anxiety and stress-related disorders," said Murray Stein, MD, MPH,
FRCPC, Distinguished Professor of Psychiatry and Public Health at
the University of California San Diego and an advisor to PureTech.
"LYT-300, a non-benzodiazepine neurosteroid, blunts this stress
response, highlighting its novel pharmacology and potential for
helping patients in serious need of new treatment options."
"These data validate that LYT-300 has potential to make a
difference for people living with anxiety, where there's been a
dearth of innovation and existing treatments have drawbacks," said
Daphne Zohar, Founder and Chief Executive Officer of PureTech
Health. "The successful outcome of this trial builds on our
strategy of identifying drugs with proven clinical efficacy but
with historical limitations that have held back their therapeutic
use, and then applying an innovative solution to enhance their
potential for patients. In the CNS arena, we previously applied
this strategy to invent KarXT for the treatment of schizophrenia.
Building on this approach, we now have seven wholly owned CNS
programs powered by our Glyph(TM) platform, which is designed to
enable the oral bioavailability of drugs with high first-pass
metabolism and resolve hepatotoxicity."
LYT-300 is an oral prodrug of allopregnanolone, an endogenous
neurosteroid. Allopregnanolone has been recognized for its
potential to treat a range of neurological and neuropsychiatric
indications with a well-established rapid onset of action in mood
disorders. The major hurdles associated with endogenous
neurosteroids in the past have been their lack of oral
bioavailability and inability to chronically administer them to
patients, which means they otherwise can only be administered via a
long, cumbersome intravenous infusion. To overcome the challenges
with this method of administration, medicinal chemistry approaches
have been applied to synthesize orally bioavailable chemical
analogs of allopregnanolone. These oral analogs may have different
pharmacological effects than endogenous allopregnanolone and
therefore may not capture its full therapeutic potential . LYT-300
is designed to achieve oral administration of an endogenous
allopregnanolone that has the potential to capture the breadth of
the natural biological response.
"The data generated with PureTech's LYT-300 suggest this may be
a promising treatment for anxiety disorders, as well as a range of
related neurological and neuropsychiatric conditions," said
Maurizio Fava, MD, Psychiatrist-in-Chief at Massachusetts General
Hospital and an advisor to PureTech. "The Glyph platform and the
therapeutic candidates being developed at PureTech have the
potential to treat a range of central nervous system
disorders."
These results further validate PureTech's Glyph platform, which
is designed to employ the lymphatic system's natural lipid
absorption and transport process to enable the oral administration
of certain therapeutics that otherwise cannot be administered
orally. PureTech has generated seven CNS programs based on its
Glyph platform, including LYT-300 and LYT-310 ( oral cannabidiol),
which is currently in development for the treatment of epilepsies
and other neurological indications.
As part of an overall development strategy in anxiety-related
indications, PureTech will be conducting additional studies in
2024. Further guidance will be provided regarding 2024 catalysts
associated with the planned studies.
About LYT-300
LYT-300 is a clinical-stage therapeutic candidate that is in
development as a potential treatment for neurological and
neuropsychiatric conditions, including anxiety disorders, mood
disorders and Fragile X-associated Tremor/Ataxia Syndrome .
Developed using PureTech's Glyph (TM) technology platform, LYT-300
is an oral prodrug of endogenous allopregnanolone that is designed
to overcome its poor oral bioavailability. PureTech completed a
randomized, placebo-controlled, Phase 2a, proof-of-concept trial of
LYT-300 using a validated clinical model of anxiety in healthy
volunteers in 2023 , which demonstrated a statistically significant
reduction in stress response, as measured by salivary cortisol.
PureTech also completed a Phase 1 clinical trial of LYT-300 in
2022, which demonstrated oral bioavailability, tolerability and
<GAMMA>-aminobutyric-acid type A (GABA(A) ) receptor target
engagement in healthy volunteers.
About the Glyph(TM) Platform
Glyph is PureTech's lymphatic-targeting platform which is
designed to employ the lymphatic system's natural lipid absorption
and transport process to enable the oral administration of certain
therapeutics. Glyph reversibly links a drug to a dietary fat
molecule, creating a novel prodrug. The linked fat molecule
re-routes the drug's normal path to the systemic circulation,
bypassing the liver and instead moving from the gut into the
lymphatic vessels that normally process dietary fats. PureTech
believes this technology has the potential to provide a broadly
applicable means of enhancing the bioavailability of certain orally
administered drugs that would otherwise be limited by first-pass
liver metabolism. PureTech is accelerating development of a Glyph
portfolio that leverages validated efficacy, prioritizing highly
characterized drugs to evaluate the ability of the Glyph technology
to improve oral bioavailability or lymphatic targeting. PureTech's
lead Glyph therapeutic candidate, LYT-300 (oral allopregnanolone),
completed a randomized placebo-controlled, Phase 2a,
proof-of-concept trial using a validated clinical model of anxiety
in healthy volunteers in 2023 . A Phase 2 clinical trial of LYT-300
in FXTAS in collaboration with the University of California, Davis,
is expected to initiate in 2024. PureTech has now generated seven
CNS programs based on the Glyph platform. PureTech has a robust
intellectual property (IP) portfolio that includes licensed patents
as well as wholly owned IP, covering the Glyph technology platform,
which is based on the pioneering research of Christopher Porter,
PhD, and his research group at the Monash Institute of
Pharmaceutical Sciences at Monash University. The Porter Research
Group and collaborators have published research in Nature
Metabolism , Angewandte Chemie and the Journal of Controlled
Release supporting the Glyph platform's ability to directly target
the lymphatic system with a variety of therapies.
About the Trier Social Stress Test
The Trier Social Stress Test ( TSST; Kirschbaum, Pirke, &
Hellhammer, 1993 ) is a validated clinical model of anxiety.
It is a widely used and well-established psychological and
physiological laboratory test designed to induce acute psychosocial
stress in human participants. It is considered the gold standard in
human experimental stress research and is used by researchers to
investigate how individuals respond to acute stressors, how stress
affects cognitive and emotional processes, and how stress might
contribute to various psychological and physiological conditions.
The TSST puts the participant in situations designed to elicit
unpredictable, novel, anticipatory, and social stress such as
preparing and giving a speech, performing arithmetic, and being
observed by judges. It models stress reactivity, which is an
important component in many mood, stress and anxiety disorders, and
the TSST robustly increases physiological markers of stress
including salivary cortisol. Benzodiazepines, a clinically
effective drug class indicated for the treatment of anxiety,
reliably blunt the increased salivary cortisol in the TSST.
Juliane Hellhammer, PhD, founder and CEO of daacro (a contract
research organization specialized on psychotropic drug effects) and
recognized expert on the Trier Social Stress Test, is an advisor to
PureTech.
About PureTech Health
PureTech is a clinical-stage biotherapeutics company dedicated
to giving life to new classes of medicine to change the lives of
patients with devastating diseases. The Company has created a broad
and deep pipeline through its experienced research and development
team and its extensive network of scientists, clinicians and
industry leaders that is being advanced both internally and through
its Founded Entities. PureTech's R&D engine has resulted in the
development of 27 therapeutics and therapeutic candidates,
including two (Plenity(R) and EndeavorRx(R)) that have received
both US FDA clearance and European marketing authorization and a
third (KarXT) that has been filed for FDA approval. A number of
these programs are being advanced by PureTech or its Founded
Entities in various indications and stages of clinical development,
including registration enabling studies. All of the underlying
programs and platforms that resulted in this pipeline of
therapeutic candidates were initially identified or discovered and
then advanced by the PureTech team through key validation
points.
For more information, visit www.puretechhealth.com or connect
with us on X (formerly Twitter) @puretechh.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of
1995. All statements contained in this press release that do not
relate to matters of historical fact should be considered
forward-looking statements, including without limitation those
statements that relate to our expectations around the design of and
the timelines and key milestones associated with clinical trials
for LYT-300 and other programs from the Glyph(TM) platform,
including in anxiety-related indications, the therapeutic potential
of LYT-300, our expectations regarding the Glyph platform including
the potential for new treatment applications, our therapeutic
candidates and approach towards addressing major diseases, and our
future prospects, developments, and strategies. The forward-looking
statements are based on current expectations and are subject to
known and unknown risks, uncertainties and other important factors
that could cause actual results, performance and achievements to
differ materially from current expectations, including, but not
limited to, those risks, uncertainties and other important factors
described under the caption "Risk Factors" in our Annual Report on
Form 20-F for the year ended December 31, 2022 filed with the SEC
and in our other regulatory filings. These forward-looking
statements are based on assumptions regarding the present and
future business strategies of the Company and the environment in
which it will operate in the future. Each forward-looking statement
speaks only as at the date of this press release. Except as
required by law and regulatory requirements, we disclaim any
obligation to update or revise these forward-looking statements,
whether as a result of new information, future events or
otherwise.
Contact:
PureTech
Public Relations
publicrelations@puretechhealth.com
Investor Relations
IR@puretechhealth.com
EU Media
Ben Atwell, Rob Winder
+44 (0) 20 3727 1000
ben.atwell@FTIconsulting.com
U.S. Media
Nichole Sarkis
+1 774 278 8273
nichole@tenbridgecommunications.com
(1]) Any Anxiety Disorder. (n.d.). National Institute of Mental Health (NIMH). https://www.nimh.nih.gov/health/statistics/any-anxiety-disorder
(2]) Psychoneuroendocrinology, 31(10), 1278-1288.
https://doi.org/10.1016/j.psyneuen.2006.09.009 .
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