Planning underway for Phase 2 trial of LYT-300
in Fragile X-associated Tremor/Ataxia Syndrome
LYT-300 is also being evaluated in a Phase 2a
trial for anxiety disorders, and a Phase 2a in patients with
postpartum depression is planned to initiate in second half of
2023
LYT-300, LYT-310 and additional preclinical
programs for CNS indications have been produced from PureTech’s
Glyph™ technology platform for enhancing oral bioavailability
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 that the company has been awarded up to $11.4 million
from the U.S. Department of Defense (DoD) to advance its
therapeutic candidate, LYT-300 (oral allopregnanolone), for the
treatment of Fragile X-associated Tremor Ataxia Syndrome (FXTAS).
The funds will support a Phase 2 trial of LYT-300 in collaboration
with the University of California, Davis (UC Davis).
LYT-300, an oral prodrug of allopregnanolone, is PureTech’s
wholly-owned therapeutic candidate for the potential treatment of
anxiety disorders, postpartum depression, FXTAS and other
neurological and neuropsychiatric indications. LYT-300 was
developed using PureTech’s Glyph™ platform, which harnesses the
body’s natural lipid absorption and transport process to enable the
oral administration of certain therapeutics that otherwise cannot
be administered orally.
FXTAS, which was discovered by Dr. Randi Hagerman and her
colleagues at the University of California, Davis, is a devastating
neurological condition that is closely related to, but distinct
from, Fragile X syndrome (FXS). Both conditions are the result of
repeated elements in the Fragile X Messenger Ribonucleoprotein Gene
1 (FMR1) gene. While FXS is associated with intellectual disability
and autism, FXTAS leads to neurodegeneration in otherwise normally
developed, aging individuals who carry a premutation of the FMR1
gene.
“FXTAS is a devastating, late-onset neurodegenerative condition
characterized by cognitive decline, tremors in the hands and
balance problems. Currently, there are no primary treatments for
FXTAS, though IV-administrated allopregnanolone has demonstrated
therapeutic potential,” said Dr. Randi Hagerman, M.D., F.A.A.P.,
Medical Director of the UC Davis MIND Institute, Chair in Fragile X
Research and co-primary investigator for the LYT-300 trial. “I am
excited to be working with PureTech to evaluate their oral prodrug
of allopregnanolone (LYT-300), and I am optimistic that this award
will help accelerate the development of this potential first
therapy for FXTAS.”
An exploratory, open-label trial of six men with FXTAS,
evaluated IV-administration of allopregnanolone across multiple
neuropsychological and emotional tests. In addition to being
well-tolerated, allopregnanolone showed signals of pharmacologic
benefit across multiple neurological endpoints, including the
Behavioral Dyscontrol Scale, which measures executive, cognitive
and motor function, and demonstrated improvement compared to
baseline (p=0.009).1 IV administration is not feasible in most
indications, especially for a chronic therapy, and there remains a
need for treatments that can address this debilitating condition.
PureTech plans to evaluate LYT-300 in a placebo-controlled trial to
demonstrate the safety, tolerability and efficacy of the drug in
people with FXTAS.
“This award from the DoD allows us to expand our evaluation of
LYT-300, a candidate with a wide variety of potential indications,
into FXTAS, an area of tremendous need where otherwise normally
developed, aging individuals suffer from significant
neurodegeneration,” said Eric Elenko, Ph.D., Chief Innovation
Officer at PureTech Health. “We look forward to collaborating with
Dr. Randi Hagerman and her team at UC Davis to bring the potential
of allopregnanolone to the thousands of individuals with FXTAS in
need of a treatment.”
PureTech’s capital efficient strategy includes the pursuit of
non-dilutive funding in the form of grants. This is the fourth DoD
grant that PureTech has secured on behalf of its Wholly Owned
Programs in addition to five grants secured on behalf of its
Founded Entities. This work is supported by the Office of the
Assistant Secretary of Defense for Health Affairs and the Defense
Health Agency J9, Research and Development Directorate, or the U.S.
Army Medical Research Acquisition Activity at the U.S. Army Medical
Research and Development Command through the Peer Reviewed Medical
Research Program (PRMRP) under Award No. HT94252310598, with a
total program budget of up to $11.4 million for both the planning
and clinical study phases. The PRMRP supports research across the
full range of science and medicine, with an underlying goal of
enhancing the health, care and well-being of military service
members, veterans, retirees and their family members. Opinions,
interpretations, conclusions and recommendations are those of the
author and are not necessarily endorsed by the Department of
Defense.
In addition to LYT-300, which is being advanced in three
indications, PureTech is progressing multiple CNS-focused programs
derived from its Glyph platform. These include LYT-310, an oral
form of cannabidiol that is expected to enter a Phase 1 clinical
trial in the fourth quarter of 2023, as well as programs that are
in various stages of preclinical development.
About Fragile X-associated Tremor/Ataxia Syndrome Fragile
X-associated Tremor/Ataxia Syndrome (FXTAS) was discovered at the
MIND Institute by researcher Dr. Randi Hagerman and her colleagues
in 2001. It is one of the most devastating of the Fragile X
Spectrum Disorders, which result from a trinucleotide expansion in
the FMR1 gene. FXTAS is a late onset condition that can occur in up
to 75% of males with the premutation by the eighth decade of life
and in approximately 16% of females, but the clinical signs
typically emerge when individuals are in their early 60s. The
clinical features of FXTAS include tremor in the hands with action
or at rest, balance problems (ataxia) that lead to frequent
falling, and cognitive decline that is sometimes misdiagnosed as
Alzheimer’s disease. No specific treatment for FXTAS is
efficacious, though a variety of medications may improve
psychiatric issues or the severity of tremor. Carriers are common
in the general population, occurring in 1 in 150 to 200 women and 1
in 400 men, but FXTAS is often mistakenly diagnosed as Parkinson’s
disease.
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, postpartum depression and Fragile X-associated
Tremor/Ataxia Syndrome. Developed using PureTech’s Glyph™
technology platform, LYT-300 is an oral prodrug of endogenous
allopregnanolone that is designed to overcome its poor oral
bioavailability. PureTech completed a Phase 1 clinical trial of
LYT-300 in 2022, which demonstrated oral bioavailability,
tolerability and γ-aminobutyric-acid type A (GABAA) receptor target
engagement in healthy volunteers.
Allopregnanolone is a positive allosteric modulator (PAM) of
GABAA receptors and has been shown to regulate mood and other
neurological conditions. Unlike benzodiazepines, allopregnanolone
can provide both transient and longer-term normalization of
overactive neural circuits because it also acts at GABA receptors
outside of synapses.2 An intravenous formulation of
allopregnanolone is approved by the U.S. Food and Drug
Administration as a 60-hour infusion for the treatment of
postpartum depression, though the method of administration has
significant challenges and limits the scope of clinical translation
with this class of compounds. To overcome this, 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.
About the Glyph™ 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 (1) provide a broadly applicable means of enhancing the
bioavailability of certain orally administered drugs that would
otherwise be limited by first-pass liver metabolism and (2) enable
direct modulation of the immune system via drug targets present in
mesenteric lymph nodes. 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 Phase 1 clinical trial in 2022. A
placebo-controlled, Phase 2a, proof-of-concept trial using a
validated clinical model of anxiety in healthy volunteers initiated
in June 2023, with results anticipated by the end of 2023. An
open-label, Phase 2a, proof-of-concept clinical trial in women with
postpartum depression is expected to initiate in the second half of
2023 and planning is underway for a Phase 2 clinical trial in
FXTAS. A second therapeutic candidate, LYT-310 (oral cannabidiol),
is expected to enter the clinic in Q4 of 2023. 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, Ph.D., 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 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®
and EndeavorRx®) that have received both US FDA clearance and
European marketing authorization and a third (KarXT) that is
expected to be filed soon 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 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,
including for FXTAS, the therapeutic potential of LYT-300, our
expectations regarding the Glyph™ technology platform including the
potential for new treatment applications, the applicability of
preclinical results to human subjects, our product 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.
1 Wang, J., Trivedi, A. M., Carrillo, N. R., Yang, J.,
Schneider, A., Giulivi, C. R., Adams, P. D., Tassone, F., Kim, K.,
Rivera, S. M., Lubarr, N., Wu, C. Y., Irwin, R. S., Brinton, R. D.,
Olichney, J. M., Rogawski, M. A., & Hagerman, R. J. (2017).
Open-Label Allopregnanolone Treatment of Men with Fragile
X-Associated Tremor/Ataxia Syndrome. Neurotherapeutics, 14(4),
1073–1083. https://doi.org/10.1007/s13311-017-0555-6
2 Ghit, A. (2021, August 21). GABAA receptors: structure,
function, pharmacology, and related disorders - Journal of Genetic
Engineering and Biotechnology. SpringerOpen.
https://jgeb.springeropen.com/articles/10.1186/s43141-021-00224-0
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