LYT-300

 

Our programs 1
Discovery
Preclinical
Phase 1
Phase 2
Phase 3
LYT-300
Oral Allopregnanolone
Neurological indications

1

Neurological indications


LYT-300 is designed to unlock the validated biology of allopregnanolone to potentially offer a new, oral treatment option for a range of conditions where there is significant patient need. Allopregnanolone is a natural neurosteroid that is a positive allosteric modulator of γ-aminobutyric-acid type A (GABAA) receptors, which are known to play a key biological role in depression, epilepsy and other neurological and neuropsychological conditions. Natural allopregnanolone has poor oral bioavailability, thus limiting its development as a therapeutic. An injectable formulation of allopregnanolone is approved by the United States Food and Drug Administration (FDA) as a 60-hour infusion for the treatment of post-partum depression, though the method of administration has limitations.

Phase completedPhase in progressRegistration-enabling studies to begin in 1H2022

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 and achieve significant oral bioavailability of natural allopregnanolone in preclinical models. We initiated a Phase 1 clinical study of LYT-300 in late 2021 for the potential treatment of neurological and neuropsychological conditions with significant unmet need, such as depression, anxiety, sleep disorders, fragile X tremor-associated syndrome, essential tremor and epileptic disorders, among others.

  • Key Points of Innovation & Differentiation
    • Allopregnanolone has therapeutic potential across a wide range of neurological conditions like seizures, sleep and neuropsychological disorders, but has poor oral bioavailability as a result of first-pass liver metabolism.
    • An injectable formulation of allopregnanolone is approved by the U.S. Food and Drug Administration (FDA) as a 60-hour infusion for the treatment of post-partum depression, though the method of administration has limitations.
    • Natural allopregnanolone is an effective positive allosteric modulator of GABAA receptors, which are known to play a key biological role in depression, epilepsy and other neurological and neuropsychological conditions. Natural allopregnanolone has poor oral bioavailability, thus limiting its development as a therapeutic. To overcome this, researchers have applied medicinal chemistry approaches to synthesize analogs to make them orally bioavailable. There are several chemically modified analogs of allopregnanolone in clinical development that have demonstrated varying degrees of clinical activity across indications. One possible reason for the variable clinical activity may be that the chemical modifications could potentially be affecting receptor engagement and subsequently their mode of action via the GABAA pathway in the central nervous system and beyond. As a result, these chemically distinct analogs of allopregnanolone may not have the same pharmacologic effects as the natural neurosteroid.
    • Using our proprietary Glyph technology, which is designed to allow for lymphatic targeting and to avoid first-pass metabolism, we have developed LYT-300, an oral prodrug of the endogenous neurosteroid, allopregnanolone.
    • Results from preclinical studies conducted thus far have demonstrated that LYT-300 is orally bioavailable and that relevant concentrations may be achievable in human plasma. One example of the data we have generated in non-human primates is shown below. 

  • 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 a range of neurological and neuropsychological conditions including depression, anxiety, sleep disorders, fragile X tremor-associated syndrome, essential tremor and epileptic disorders, among others. 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
    • The recent approval of Zulresso, which requires a 60-hour IV 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. 

  • Milestones Achieved & Development Status
    • In December 2021, we announced the initiation of a clinical study of LYT-300 (oral allopregnanolone), for the potential treatment of neurological and neuropsychological conditions, including depression, anxiety, sleep disorders, fragile X tremor-associated syndrome, essential tremor and epileptic disorders, among others. The Phase 1 study of LYT-300 involves multiple parts, including the evaluation of a single ascending dose, multiple ascending doses and the effect of food on oral absorption of the prodrug in healthy volunteers. Safety, tolerability and pharmacokinetics (PK) will be assessed. Given the GABAA receptor modulating activity of allopregnanolone, the study will also explore the impact of LYT-300 on β-EEG, a marker of GABAA target engagement, thus potentially providing early insights into the mechanistic effects of LYT-300.
    • 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 pharmacokinetic 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.
    • No drug-related adverse effects have been noted in preclinical studies to date at therapeutically relevant doses. IND-enabling studies are underway to advance LYT-300 towards the clinic.
  • Expected Milestones
    • Results from the Phase 1 clinical study of LYT-300 are expected in the second half of 2022 and will be used to inform the design of possible future studies evaluating LYT-300 in indications that could include depression, anxiety, sleep disorders, fragile X tremor-associated syndrome, essential tremor and epileptic disorders, among others.
  • 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 two patent families comprising one international PCT application and three U.S. patent applications as of December 31, 2020, all of which are co-owned with Monash University. Any patents to issue from these patent applications are expected to expire in 2039 or 2041, 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.

LYT-300 is an oral lipid prodrug of natural allopregnanolone. By trafficking via the lymphatics, LYT-300 is able to be orally administered and enable the allopregnanolone payload to overcome first-pass metabolism by the liver.