Media release

From: Monash University

A Monash-invented oral version of the drug ‘allopregnanolone’ called ‘LYT-300’ has successfully completed a Phase 2a clinical trial, conducted by Boston-based biotherapeutics company PureTech Health plc (Nasdaq: PRTC, LSE: PRTC).

The randomised, placebo-controlled, proof-of-concept trial has achieved a statistically significant reduction in stress hormone response among healthy volunteers, compared to placebo. 

Designed to evaluate the salivary cortisol (a hormone that manages stress) response in the Trier Social Stress Test (TSST) - a validated clinical model of anxiety in healthy volunteers - the trial enlisted eighty volunteers who were randomised and treated with either LYT-300 or placebo in a 1:1 ratio. 

Oral administration of LYT-300 achieved the trial’s primary goal of a statistically significant reduction (versus placebo) in the peak levels of the stress hormone cortisol in saliva (p=0.0001). 

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[1]. Importantly, however, LYT-300 is based on an endogenous neurosteroid and therefore has different pharmacology to traditional benzodiazepines. 

LYT-300 employs PureTech’s GlyphTM platform, 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 has been recognised for its potential to treat a range of neurological and neuropsychiatric indications and has a well-established rapid onset of action in mood disorders. However, historically there have been major hurdles associated with the development of endogenous neurosteroids as medicines. Most notably, a lack of oral bioavailability and a need to administer intravenously. This makes convenient dosing to patients over an extended period of time in chronic diseases extremely difficult,” Professor Porter said.

“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. These data validate that LYT-300 has the potential to become a simple oral capsule for people living with anxiety, a condition where there’s been a dearth of innovation.” 

Murray Stein, MD, MPH, FRCPC, Distinguished Professor of Psychiatry and Public Health at the University of California San Diego and an advisor to PureTech said: “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. 

“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.”

In the trial 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.  

ENDS

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 GlyphTM 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 γ-aminobutyric-acid type A (GABAA) receptor target engagement in healthy volunteers.

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 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 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.