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 studies planned

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 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 an oral lipid prodrug version of allopregnanolone, LYT-300. By trafficking via the lymphatics, we are able to overcome first-pass metabolism by the liver and have achieved significant oral bioavailability of natural allopregnanolone in preclinical models. We plan to advance this preclinical therapeutic candidate, LYT-300, for a range of neurological and neuropsychological conditions.

  • Key Points of Differentiation
    • Allopregnanolone has therapeutic potential across a wide range of neurological conditions like seizures, sleep and neuropsychiatric disorders. The problem is allopregnanolone is not orally bioavailable, as a result of first-pass metabolism in the liver.
    • An intravenous infusion formulation of allopregnanolone is approved for the treatment of postpartum depression and available in the U.S. as Zulresso®. As a 60-hour infusion, Zulresso usage has been limited in postpartum depression and would likely be similarly limited for other indications.
    • 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 form of the endogenous neurosteroid, allopregnanolone.
    • In preclinical studies conducted thus far, we have demonstrated oral bioavailability with LYT-300 and have observed plasma exposures that suggest therapeutically relevant human plasma levels of free allopregnanolone may be achieved. 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 neurosteroids in general as a class of potent endogenous natural small molecules, have been recognized over the past three decades for their therapeutic 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 an oral formulation due to first-pass metabolism by the liver; and
      • The inability to administer these chronically to patients – essential for treating CNS disorders.
    • The recent approval of Zulresso, a 60-hour IV infusion requiring regular monitoring for sudden loss of consciousness, to treat postpartum depression, speaks to the challenges that limit the scope of translation of this class of compounds to treat neurological and neuropsychological disorders.
    • An oral form of allopregnanolone and other neurosteroids would enable the development of these natural molecules for the potential treatment of a range of neurological and neuropsychological conditions.

     

  • Milestones Achieved & Development Status
    • We created a library of lipid prodrugs of allopregnanolone and showed that orally dosing these prodrugs achieved therapeutically relevant plasma levels in small and large animal models. These studies, coupled with our other preclinical studies, support the potential utility of this approach for enabling natural allopregnanolone as an orally-dosed drug as well as for numerous other potential therapeutics with intrinsic hepatic first-pass metabolism liabilities and oral absorption limitations.
    • No drug-related adverse effects have been noted in preclinical studies to date at therapeutically relevant doses. Formal safety studies are being pursued as a part of the first-in-human-enabling package of studies. To support these studies, dose escalation studies have been performed in rats and dogs, and dose proportionality has been observed in both species.
  • Expected Milestones
    • The initial objective of the LYT-300 clinical program is to characterize the safety, tolerability and PK of orally administered LYT-300 in a Phase 1 clinical trial in healthy volunteers. We expect to initiate a clinical trial by the end of 2021. 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 version of allopregnanolone. By trafficking via the lymphatics, we are able to overcome first-pass metabolism by the liver and have achieved significant oral bioavailability of natural allopregnanolone in preclinical models. We believe that an oral form of allopregnanolone and other neurosteroids would enable the development of natural molecules for the potential treatment of a range of neurological and neuropsychological conditions.