TIDMPRTC
PureTech Health PLC
14 June 2022
14 June 2022
PureTech Meets Milestone of Achieving Oral Bioavailability of
Allopregnanolone in Healthy Adults Dosed with LYT-300
LYT-300 achieved systemic blood levels approximately nine-fold
greater compared to previous reports with oral allopregnanolone.(1)
Allopregnanolone is a neurosteroid with proven efficacy that is
currently only approved as a 60-hour intravenous infusion.
LYT-300, an orally administered prodrug of allopregnanolone, is
designed to be differentiated from synthetic analogs, which may not
replicate the full target engagement profile of natural
allopregnanolone.
These clinical data establish proof-of-principle for PureTech's
Glyph(TM) platform for enabling oral administration of a range of
therapeutics.
PureTech Health plc (Nasdaq: PRTC, LSE: PRTC) ("PureTech" or the
"Company"), a clinical-stage biotherapeutics company dedicated to
discovering, developing and commercializing highly differentiated
medicines for devastating diseases, today announced the achievement
of proof-of-principle for its Glyph(TM) platform in a healthy adult
study of LYT-300 (oral allopregnanolone), PureTech's wholly-owned
therapeutic candidate for the potential treatment of a range of
neurological and neuropsychological conditions. This is a key
milestone for the candidate, which is designed to overcome the
normally poor oral bioavailability of allopregnanolone to deliver
its proven efficacy via simple, convenient oral dosing. This is
also the first mechanistic proof-of-principle in the clinic for
PureTech's Glyph lymphatic targeting platform, which is designed to
bypass first-pass metabolism to help maximize the therapeutic
potential of validated targets and drugs where oral bioavailability
has been a barrier. The Glyph platform is also designed to have
additional applications through its ability to selectively traffic
therapeutics into the lymphatic system, potentially enabling more
direct targeting of the immune system.
"Natural allopregnanolone has demonstrated efficacy for the
treatment of postpartum depression (PPD) and other
neuropsychological conditions, but up to now has required IV
delivery due to high first-pass liver metabolism. LYT-300 is
designed to unlock the validated pharmacology of natural
allopregnanolone with a potential oral treatment option for PPD and
a range of other neurological and neuropsychological conditions,"
said Julie Krop, M.D., Chief Medical Officer of PureTech.
"Achieving significant systemic exposure of allopregnanolone with
orally administered LYT-300 is also a key validation for our Glyph
lymphatic targeting platform and represents proof-of-principle for
being able to administer drugs orally that currently require IV
administration due to first-pass liver metabolism."
PureTech has previously presented data in non-human primates
with LYT-300 demonstrating significantly greater oral
bioavailability than orally administered allopregnanolone. Data
from this Phase 1 program reaffirmed this finding in humans,
showing bioavailability of allopregnanolone that was approximately
nine-fold greater than that of orally administered
allopregnanolone, based on previously published data.(1) In the
PureTech study, fasted healthy adults were given LYT-300 containing
the equivalent of 53 mg of allopregnanolone, achieving plasma
exposure levels with an AUC(inf) of 352 ng*hr/mL. This represents a
nine-fold increase in dose-adjusted exposure when compared to a
previously published study in fasted healthy adults in which 30 mg
of allopregnanolone was orally dosed, resulting in an AUC(inf) of
21 ng*hr/mL.(1)
Allopregnanolone is a natural neurosteroid with well-established
biology that has demonstrated efficacy for the treatment of
epilepsy, depression and other neurological indications, but its
poor oral bioavailability has limited its development as a
therapeutic. The United States Food and Drug Administration (FDA)
has approved a 60-hour intravenous infusion formulation of
allopregnanolone for the treatment of PPD, though this method of
administration has inherent limitations. The Glyph platform is
designed to leverage the body's natural lipid absorption and
transport process to overcome these limitations to enable oral
administration. Demonstrating oral bioavailability with the Glyph
platform opens up the possibility of developing other natural
neurosteroids and a number of bioactive molecules as oral therapies
to treat a range of serious diseases.
"Due to a relative paucity of newly FDA-approved molecules in
recent decades, significant patient needs exist, and we are
experiencing a national mental health crisis that makes these needs
even greater. Achieving an orally bioavailable prodrug of
allopregnanolone may prove promising in the treatment of mood
disorders such as postpartum depression - and potentially a range
of related neurological and neuropsychiatric conditions," said
Maurizio Fava, M.D., Psychiatrist-in-Chief at Massachusetts General
Hospital.
"Given the proven efficacy of allopregnanolone in postpartum
depression and its potential in a range of other conditions,
significant effort has been put into delivering oral formulations
for the molecule, without success. This has led to synthetic
approaches that may not capture the full therapeutic potential of
natural allopregnanolone," said Scott Reines, M.D., Ph.D., former
Senior Vice President, J&J Pharmaceutical Research &
Development. " I am excited by the data generated with PureTech's
LYT-300 and believe it could represent an exciting step towards
enabling bioavailability for this and other classes of
therapeutics."
The multi-part Phase 1 program of LYT-300 has three primary
objectives - to demonstrate oral bioavailability, evaluate safety
and tolerability across a range of doses, and to identify a dose to
take forward. With the achievement of the first objective,
additional dose exploration and the effect of food on oral
absorption of the prodrug are progressing, and assessments of
safety, tolerability, pharmacokinetics ( PK) and pharmacodynamics
(PD) will be measured. Dose escalation continues as no
dose-limiting toxicities have been observed to date.
As allopregnanolone is a modulator of the GABA (A) receptor, the
Phase 1 program will also explore the impact of LYT-300 on b-EEG,
and other markers of GABA (A) target engagement, thus potentially
providing further early insights into the mechanistic effects of
LYT-300 and its potential in a range of indications where GABA (A)
receptors play a key biological role. Completion of the rest of the
Phase 1 program is expected by the end of 2022, and - if data are
favorable - a Phase 1b/2a study is planned to initiate in 2023.
Results from the Phase 1 program will be shared in future
scientific forums.
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 Glyph
technology platform, LYT-300 is an oral prodrug of natural
allopregnanolone. An IV 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
<GAMMA>-aminobutyric-acid type A (GABA (A) ) receptors and
has been shown to regulate mood and other neurological conditions.
PureTech initiated a Phase 1 clinical study of LYT-300 in late
2021, which is designed to characterize the safety, tolerability,
PK and PD of orally administered LYT-300 in healthy volunteers.
Allopregnanolone is a neuroactive steroid and positive allosteric
modulator (PAM) of GABA(A) 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 Glyph(TM) Technology 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 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 orally administered drugs that
would otherwise be reduced by first-pass liver metabolism. PureTech
is leveraging validated biology to accelerate the development of a
Glyph portfolio, prioritizing highly characterized drugs to enhance
with the Glyph technology based on the potential value unlocked in
improving their oral bioavailability or lymphatic targeting. Glyph
has achieved mechanistic proof-of-principle in the clinic with the
first Glyph-generated therapeutic candidate, LYT-300 (oral
allopregnanolone), which is being evaluated in a Phase 1 study.
PureTech has exclusively licensed 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 , Frontiers in Pharmacology 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 discovering, developing and commercializing highly
differentiated medicines for devastating diseases, including
inflammatory, fibrotic and immunological conditions, intractable
cancers, lymphatic and gastrointestinal diseases and neurological
and neuropsychological disorders, among others. 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 27
therapeutics and therapeutic candidates, including two that have
received both U.S. FDA clearance and European marketing
authorization, as of the date of PureTech's most recently filed
Annual Report and corresponding Form 6-K. 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 statements that are or may be
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
those related to the design and applicability of the Glyph
lymphatic targeting platform, including other potential development
options and applications of the platform, the potential treatments
associated with LYT-300, our LYT-300 clinical development plans and
programs, including our Phase 1 program and expected timing
associated therewith, 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
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
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