Orally administered LYT-300 achieved blood
levels of allopregnanolone at or above those associated with
therapeutic effect.1 Allopregnanolone is a natural neurosteroid
with proven efficacy that is currently only available as a 60-hour
intravenous infusion.
Preliminary pharmacodynamic data indicate that
oral administration of LYT-300 results in allopregnanolone target
engagement with GABAA receptors, which have been shown to regulate
mood and other neurological conditions.
LYT-300 was generally well-tolerated across the
trial with no treatment-related severe or serious adverse events
observed.
PureTech Health plc (Nasdaq: PRTC, LSE: PRTC) ("PureTech" or the
"Company"), a clinical-stage biotherapeutics company dedicated to
changing the treatment paradigm for devastating diseases, today
announced topline results from the completed, multi-part Phase 1
trial of LYT-300 (oral allopregnanolone).
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the full release here:
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PureTech announced topline results for
LYT-300 (oral allopregnanolone), a therapeutic candidate in
development for neurological and neuropsychological conditions. The
results show that oral administration of LYT-300 achieved blood
levels of allopregnanolone at or above those associated with
therapeutic benefit and results in exposure-dependent target
engagement of GABAA receptors. Additional data from the Phase 1
trial will be presented in a scientific forum, and a Phase 1b/2a
trial is expected to begin in the first half of 2023. (Graphic:
Business Wire)
Topline results announced today show that oral administration of
LYT-300 achieved blood levels of allopregnanolone at or above those
associated with therapeutic benefit1 and resulted in
exposure-dependent target engagement with γ-aminobutyric-acid type
A (GABAA) receptors. Earlier this year, PureTech announced that
LYT-300 also demonstrated oral bioavailability of allopregnanolone
approximately ninefold greater than third-party reported data with
orally administered allopregnanolone.1 Additional data from the
Phase 1 trial will be presented in a scientific forum, and a Phase
1b/2a trial is expected to begin in the first half of 2023.
“Today’s results make us very excited about the potential of
LYT-300 to unlock the full therapeutic benefit of allopregnanolone,
which to date has been limited to a small subset of patients,” said
Julie Krop, M.D., Chief Medical Officer at PureTech. “Using our
proprietary Glyph platform, orally administered LYT-300 has
demonstrated a favorable safety profile at allopregnanolone levels
that have been shown to be associated with therapeutic benefit.
This, along with evidence of exposure-dependent target engagement,
brings us one step closer to potentially addressing the needs of
patients across a range of neurological and neuropsychiatric
conditions.”
Allopregnanolone is a natural neurosteroid with well-validated
biological effects. It has demonstrated a rapid onset of action for
the treatment of depression, as well as the potential to treat
other neurological conditions, but its poor oral bioavailability
has limited its therapeutic potential. The United States Food and
Drug Administration (FDA) has approved a 60-hour intravenous
infusion formulation of allopregnanolone for the treatment of
postpartum depression (PPD), though this method of administration
has inherent limitations. To overcome this, synthetic oral analogs
of allopregnanolone have been developed, though these may not
capture the full therapeutic potential of natural allopregnanolone.
To potentially harness the broad applicability of this natural
neurosteroid through oral administration, PureTech has applied its
GlyphTM platform, which is designed to enable the oral
administration of certain therapeutics with low oral
bioavailability due to first pass metabolism. The Glyph platform
has yielded two candidates to date.
72 healthy volunteers were dosed in the multi-part, Phase 1
clinical trial, which was designed to evaluate oral
bioavailability, safety and tolerability of LYT-300 across a range
of doses, and to inform dose selection moving forward. As part of
the trial, single and multiple ascending doses were evaluated along
with cohorts to evaluate the effect of food on oral absorption. The
impact of LYT-300 on b-EEG and other markers of GABAA target
engagement were also assessed. LYT-300 was generally well-tolerated
with no treatment-related severe or serious adverse events
observed. Doses have been selected to carry forward into the
planned Phase 1b/2a clinical trial.
A second candidate from the Glyph platform, LYT-310, an oral
cannabidiol (CBD), is designed to greatly expand the therapeutic
application and potential of CBD. LYT-310 has demonstrated a three
to fourfold increase in oral exposure versus unmodified CBD in
multiple preclinical models, including large animal and non-human
primate. This has the potential to translate into improved safety
and reduced side effects. Lymphatic transport has also been
confirmed in preclinical models, with up to 30% of LYT-310 entering
the lymphatics, compared to 5% for unmodified CBD – which further
supports the novel Glyph mechanism of enhancing oral
bioavailability. LYT-310 is expected to enter the clinic in Q4 of
2023.
About LYT-300
LYT-300 is a clinical therapeutic candidate that is in
development as a potential treatment for a range of neurological
and neuropsychological conditions. Developed using PureTech's
GlyphTM technology platform, LYT-300 is an oral prodrug of natural
allopregnanolone. An intravenous formulation of allopregnanolone is
approved by the United States Food and Drug Administration and
administered as a 60-hour infusion for the treatment of postpartum
depression. Allopregnanolone is a positive allosteric modulator of
γ-aminobutyric-acid type A (GABAA) receptors and has been shown to
regulate mood and other neurological conditions. PureTech completed
a Phase 1 clinical trial of LYT-300 in 2022, which demonstrated
oral bioavailability, tolerability and GABAA receptor target
engagement in healthy volunteers. Allopregnanolone is a neuroactive
steroid and positive allosteric modulator (PAM) of GABAA receptors.
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 Dual intra-
and extra-synaptic GABA PAMs have been shown to not only improve
sleep,3 but also mood.1
About the GlyphTM Platform
Glyph is PureTech’s synthetic lymphatic-targeting chemistry
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)
enable direct modulation of the immune system via drug targets
present in mesenteric lymph nodes and (2) 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 Phase 1 clinical trial in 2022, and a Phase 1b/2a
clinical trial is expected to begin in the first half of 2023. A
second therapeutic candidate, LYT-310 (oral cannabidiol), is
expected to enter the clinic in Q4 of 2023. PureTech has a robust
intellectual property portfolio that includes licensed patents as
well as wholly owned patents, 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 biotherapeutics company dedicated to changing the
treatment paradigm for devastating diseases. The Company has
created a broad and deep pipeline through the expertise of its
experienced research and development team and its extensive network
of scientists, clinicians and industry leaders. This pipeline,
which is being advanced both internally and through PureTech's
Founded Entities, is comprised of 28 therapeutics and therapeutic
candidates, including two (Plenity® and EndeavorRx®) that have
received both U.S. FDA clearance and European marketing
authorization and a third (KarXT) that will soon be filed for FDA
approval, as of the most recent update by the Company. 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
based on unique insights in immunology and drug development.
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 timelines and key
milestones associated with clinical trials for LYT-300, the
therapeutic potential of LYT-300, the potential for improved
tolerability associated with LYT-310 as compared to unmodified CBD,
that such potential improved tolerability and oral dosing could
expand the therapeutic application of CBD across a wider range of
age groups and indications, 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, 2021 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)
Brexanolone NDA 211371 Multi-disciplinary
Review and Evaluation, FDA CDER, 2018.
2)
Ghit, A., Assal, D., Al-Shami, A.S.
Hussein D.E.E. GABAA receptors: structure, function, pharmacology,
and related disorders. J Genet Eng Biotechnol 19, 123 (2021).
https://doi.org/10.1186/s43141-021-00224-0
3)
Bullock, A., Kaul, I., Li, S., Silber, C.,
Doherty, J., & Kanes, S. J. (2021). Zuranolone as an oral
adjunct to treatment of Parkinsonian tremor: A phase 2, open-label
study. Journal of the neurological sciences, 421, 117277.
https://doi.org/10.1016/j.jns.2020.117277
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