LYT-300

 

Our programs 1
Discovery
Preclinical
Phase 1
Phase 2
Phase 3
LYT-300
Oral Allopregnanolone
Neurological and neuropsychological conditions

1

Neurological and neuropsychological conditions


Designed to unlock the validated efficacy of allopregnanolone to potentially offer a new, oral treatment option for a range of conditions where there is significant patient need. Allopregnanolone, a positive allosteric modulator of GABAA receptors, has therapeutic potential across a wide range of neurological conditions like depression, epilepsy and other neurological and neuropsychological conditions, but has poor oral bioavailability as a result of first-pass liver metabolism. An intravenous formulation of allopregnanolone is approved by the FDA as a 60-hour infusion for the treatment of post-partum depression, though the method of administration has significant limitations.

Phase completedPhase in progress

1 The FDA and corresponding regulatory authorities will ultimately review our clinical results and determine whether our wholly-owned therapeutic candidates are safe and effective. No regulatory agency has made any such determination that LYT-300 is safe or effective for use by the general public for any indication.

An oral form of natural allopregnanolone for the potential treatment of neurological and neuropsychological conditions

Using our Glyph™ platform (see here), which harnesses the natural trafficking of dietary lipids via the lymphatics, we have developed LYT-300, an oral lipid prodrug version of allopregnanolone. By trafficking LYT-300 via the lymphatics, we are able to overcome first-pass metabolism by the liver to help maximize the therapeutic potential of validated targets and drugs where oral bioavailability has been a barrier. In 2021, we initiated a Phase 1 clinical study of LYT-300 in healthy volunteers as part of our ongoing strategy for developing this agent as a potential treatment for neurological and neuropsychological conditions. In 2022, we achieved proof-of-principle for our Glyph platform in the ongoing healthy adult clinical trial of LYT-300.

  • Key Points of Innovation & Differentiation
    • Allopregnanolone, a positive allosteric modulator of GABAA receptors, has therapeutic potential across a wide range of neurological conditions like depression, epilepsy and other neurological and neuropsychological conditions, but has poor oral bioavailability as a result of first-pass liver metabolism.
    • An intravenous formulation of allopregnanolone is approved by the FDA as a 60-hour infusion for the treatment of postpartum depression, though the method of administration has significant limitations.
    • To overcome the poor oral bioavailability of allopregnanolone, medicinal chemistry approaches have been applied to synthesize orally bioavailable analogs. Several of these modified allopregnanolone analogs have demonstrated varying degrees of clinical activity across different indications. The variable clinical activity of these compounds may be due to the possibility that chemical modifications are interfering with optimal GABAA receptor engagement and consequently their on-target mode of action. Hence, these chemically distinct analogs of allopregnanolone may not have the same pharmacologic effects as the natural unmodified allopregnanolone.
    • Using our proprietary Glyph technology, 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, we have developed LYT-300, an oral prodrug of the endogenous, natural neurosteroid, allopregnanolone.
  • Program Discovery Process by the PureTech Team
    • LYT-300 is the most advanced therapeutic candidate developed from our synthetic lymphatic-targeting chemistry platform called Glyph (see here), which employs the body’s natural lipid absorption and transport process to orally administer drugs via the lymphatic system.
  • Patient Need & Market Potential
    • Allopregnanolone and related endogenous neurosteroids have been recognized for their potential to treat epilepsy, depression and other neurological indications. The major hurdles associated with the translation of these compounds have been:
      • The inability to create oral formulations of these neurosteroids; and
      • The inability to chronically administer compounds to patients
    • An injectable formulation of allopregnanolone, which was approved by the FDA as a 60-hour infusion to treat postpartum depression, speaks to the challenges that limit the scope of clinical translation with this class of compounds.
    • Oral formulations of allopregnanolone and other neurosteroids could potentially have significant advantages for the potential treatment of a range of neurological and neuropsychological conditions, addressing the significant unmet medical need for more effective treatments for psychiatric conditions, such as postpartum depression and MDD, which impact 400,000 and over 20 million patients in the U.S. each year, respectively.

  • Milestones Achieved & Development Status
    • In June 2022, we achieved proof-of-principle for the Glyph platform in a healthy adult study of LYT-300. This was the first mechanistic proof-of-principle in the clinic for the Glyph lymphatic targeting platform.
      • Data from this Phase 1 program of LYT-300 showed bioavailability of allopregnanolone that was approximately nine-fold greater than that of orally administered allopregnanolone, based on previously published data.3 In the study, fasted healthy adults were given LYT-300 containing the equivalent of 53 mg of allopregnanolone, achieving plasma exposure levels with an AUCinf 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 AUCinf of 21 ng*hr/mL.3
      • 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 inform dose selection moving forward. With the achievement of the first objective, additional dose exploration and assessments of safety, tolerability, PK and pharmacodynamics will be measured.
    • In December 2021, we initiated a Phase 1 clinical study of LYT-300 in healthy volunteers as part of our ongoing strategy to develop this agent as potential treatment for neurological and neuropsychological conditions.
    • In December 2021, we presented preclinical proof-of-concept data at the 60th American College of Neuropsychopharmacology (ACNP) Annual Meeting that support the clinical advancement of LYT-300 for the potential treatment of neurological and neuropsychological conditions. The data presented at ACNP showed that systemic exposure of natural allopregnanolone was achieved after oral administration of LYT-300 in multiple preclinical models of increasing complexity. In contrast, systemic levels of allopregnanolone were not observed following oral administration of natural unmodified allopregnanolone. These results
      demonstrate the potential of the Glyph technology platform to enhance the systemic absorption of natural bioactive molecules and other small molecules with poor oral bioavailability.
    • Oral bioavailability of LYT-300 has been confirmed in small and large animal PK studies. Results support the potential utility of this prodrug approach for oral administration of natural allopregnanolone and other small molecule therapeutics with intrinsic liabilities related to hepatic first-pass metabolism.
  • Expected Milestones
    • We expect to complete the multi-part Phase 1 program of LYT-300 by the end of 2022, and - based on the data - a Phase 1b/2a clinical trial is planned to initiate in 2023.
  • Intellectual Property
    • Within the extensive Glyph intellectual property portfolio (see here), which covers a wide range of novel linker chemistries, LYT-300 is specifically covered by four patent families comprising one international PCT application, seven foreign patent applications, and six U.S. patent applications as of December 31, 2021, two of which families are co-owned with Monash University and two of which are PureTech owned. Any patents to issue from these patent applications are expected to expire in 2039 or 2042, exclusive of possible patent term adjustments or extensions or other forms of exclusivity.

2 Zulresso® is a trademark of Sage Therapeutics and is not owned by or affiliated with PureTech Health. LYT-300 is an investigational drug not approved by any regulatory authority.
3 Brexanolone NDA 211371 Multi-disciplinary Review and Evaluation, FDA CDER, 2018.

Allopregnanolone is a natural neurosteroid with well-established biology that has demonstrated efficacy for treatment of epilepsy, depression and other neurological indications. However, it is not orally bioavailable and is commercially formulated to be administered as a cumbersome 60-hour IV infusion. We have applied our innovative Glyph technology to generate LYT-300, which is an orally bioavailable prodrug of natural allopregnanolone. Our Glyph technology platform is based on the natural process of dietary lipid transport in the body. We use the Glyph technology to design prodrugs of natural bioactive molecules, such as allopregnanolone, for oral administration of drugs, that are transported via the lymphatic system and bypass first-pass liver metabolism. LYT-300 has been shown in preclinical models to enable allopregnanolone to be bioavailable.