LYT-300

 

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

Preclinical

Neurological indications


Oral form of allopregnanolone, a natural neurosteroid, that we believe may be applicable to a range of neurological conditions. An IV version of allopregnanolone, also known as brexanolone, is approved by the FDA to treat postpartum depression.
Phase completedPhase in progressRegistration-enabling development plans 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 and achieve significant oral bioavailability of natural allopregnanolone in preclinical models. We plan to advance LYT-300 for the treatment of a range of neurological and neuropsychological conditions with significant unmet need, such as epileptic disorders, fragile X syndrome, fragile X tremor-associated syndrome, anxiety, depression, essential tremor and sleep 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 is not orally bioavailable as a result of first-pass liver metabolism.
    • An intravenous infusion formulation of allopregnanolone is approved for the treatment of postpartum depression and available in the U.S. as Zulresso®. However, since a 60-hour infusion is required, Zulresso usage has seen limited uptake.
    • Natural allopregnanolone is an effective positive allosteric modulator of the GABA-A receptor, as has been clinically demonstrated with the approval of Zulresso, but natural neurosteroids like allopregnanolone are not orally bioavailable. 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 GABA-A 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 such as epileptic disorders, fragile X syndrome, fragile X tremor-associated syndrome, anxiety, depression, essential tremor and sleep 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
    • 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
    • We expect to initiate a clinical trial by the end of 2021. The initial objective of the clinical program is to characterize the safety, tolerability and PK of orally administered LYT-300 in a Phase 1 clinical trial in healthy volunteers. This study may include exploratory endpoints such as beta wave power electroencephalography (ß-EEG), a marker of GABAA target engagement. Data from this study will be used to define a range of future studies and planned indications, which could include those discussed in the above section regarding unmet needs.
  • 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.