Media release

From: Monash University

A unique drug delivery platform developed by Monash University researchers in partnership with PureTech Health plc (Nasdaq: PRTC, LSE: PRTC), has reached another exciting milestone, with the initiation of a Phase 2a clinical trial of LYT-300 (oral allopregnanolone) in healthy volunteers using a validated clinical model of anxiety, with results anticipated by the end of 2023. 

LYT-300 is an oral prodrug of allopregnanolone that employs PureTech’s GlyphTM platform. The Glyph technology was initially developed by Professor Chris Porter and his team at the Monash Institute of Pharmaceutical Sciences (MIPS) and exclusively licensed to PureTech Health in 2017. 

Allopregnanolone and related endogenous neurosteroids have been recognized for their potential to treat depression and other neurological and neuropsychiatric indications with a rapid onset of action. The use of allopregnanolone, however, is limited by negligible oral bioavailability and is currently only approved as a 60-hour intravenous infusion for the treatment of post-partum depression (PPD). This delivery method is likely to limit broader application.

The Glyph platform harnesses the body’s natural lipid absorption and transport process to enable the oral administration of therapeutics like allopregnanolone that otherwise cannot be administered orally. 

Topline results from a Phase 1 trial of LYT-300 were announced in December 2022 and showed that oral administration of LYT-300 resulted in blood levels of allopregnanolone at or above those associated with therapeutic benefit in PPD and ninefold greater than orally administered allopregnanolone, based on third-party published data1[1]. The results also demonstrated exposure-dependent target engagement with γ-aminobutyric-acid type A (GABAA) receptors, which have been shown to regulate mood and other neurological conditions.

“Despite the prevalence of anxiety disorders throughout the community, few advancements in new safe and effective treatments have emerged over the last 20 years,” said Professor Porter. ‘It is our hope that LYT-300 will become a simple oral capsule that is able to treat a range of neurological conditions including anxiety and PPD.”

Eric Elenko, Ph.D., Chief Innovation Officer at PureTech, said “We believe that our Glyph technology platform is positioned to unlock the therapeutic potential of a range of molecules, beginning with allopregnanolone, and we look forward to the results of this study as well as the initiation of a study with LYT-300 in postpartum depression later this year.”

Results for the placebo-controlled, Phase 2a, proof-of-concept trial using a validated clinical model of anxiety in healthy volunteers are anticipated by the end of 2023. Additionally, the open-label, Phase 2a, proof-of-concept clinical trial in patients with postpartum depression is expected to begin in the second half of 2023. 

Ends

About LYT-300
LYT-300 is a clinical therapeutic candidate that is in development as a potential treatment of neurological and neuropsychiatric disorders, including anxiety disorders and postpartum depression. Developed using PureTech's Glyph™ technology platform, LYT-300 is an oral prodrug of endogenous 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. 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 positive allosteric modulator of γ-aminobutyric-acid type A (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] Dual intra- and extra-synaptic GABA PAMs have been shown to not only improve sleep,[3] but also mood.

About the Glyph™ Platform
Glyph is PureTech's 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. Results from a placebo-controlled, Phase 2a, proof-of-concept, trial using a validated clinical model of anxiety in healthy volunteers are anticipated by the end of 2023.  An open-label, Phase 2a, proof-of-concept clinical trial in patients with PPD is expected to begin in the second 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 the Monash Institute of Pharmaceutical Sciences (MIPS)
MIPS houses over 450 researchers and graduate students across five major themes of activity in Pharmaceutical Sciences – Drug Discovery Biology, Medicinal Chemistry, Drug Candidate Optimisation, Drug Delivery, Disposition and Dynamics and Medicine Use and Safety. Therapeutically, MIPS strengths lie in neuroscience and mental health, cardiovascular and metabolic health, and global health. Major capabilities lie in G-protein coupled receptor (GPCR) biology, synthetic medicinal chemistry, fragment-based drug design, ADME-informed lead optimisation, drug formulation and delivery (including nanomedicine), and optimised medicine use and safety in community and clinical settings. MIPS is committed to research translation and industry engagement and recent successes include the spin out/start-up companies Cincera, Septerna, Ankere and Inosi and significant ongoing relationships with local and international companies including Takeda, Servier, CSL, Starpharma, PureTech and Polyactiva.

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.

[1] Brexanolone NDA 211371 Multi-disciplinary Review and Evaluation, FDA CDER, 2018.

[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

[3] Bullock, A. (2021, February 15). Zuranolone as an oral adjunct to treatment of Parkinsonian tremor: A phase 2, open-label study. Journal of the Neurological Sciences. https://www.jns-journal.com/article/S0022-510X(20)30613-4/fulltext