LYT-300

An oral prodrug of allopregnanolone being advanced for the potential treatment of anxiety disorders and postpartum depression

< WHOLLY OWNED PIPELINE

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Discovery

Preclinical

Phase 1

Phase 2

Phase 3

LYT-300

Oral Allopregnanolone

Depression, anxiety & related indications

Phase:
1

Initial Indications:
Depression, anxiety & related indications

Patient Population:

Key Differentiations:

Designed to overcome the poor oral bioavailability of allopregnanolone to advance what we believe could be a best-in-class new medicine for treating anxiety and depression. Allopregnanolone is a positive allosteric modulator of GABA_A receptors that has therapeutic potential across a wide range of neurological conditions, including depression and anxiety disorders, though its therapeutic application has been limited due to high first pass metabolism. Our Glyph platform reversibly links a drug to a dietary fat molecule, creating a novel prodrug. We believe 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.

More about LYT-300

Phase completed

Phase 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 prodrug of allopregnanolone being advanced for the potential treatment of anxiety disorders and postpartum depression

LYT-300, an oral prodrug of allopregnanolone, is being advanced for the potential treatment of anxiety disorders and postpartum depression. We developed LYT-300 using our Glyph™ platform, which harnesses the body’s natural lipid absorption and transport process to enable the oral administration of certain therapeutics that otherwise cannot be administered orally.

Key Points of Innovation & Differentiation
- We are developing LYT-300 to advance what we believe could be a best-in-class new medicine for treating anxiety and depression. LYT-300 is designed to overcome the poor oral bioavailability of allopregnanolone. LYT-300 has demonstrated oral bioavailability in healthy adults, achieving blood levels of allopregnanolone at or above those associated with therapeutic effect and nine times greater than orally administered allopregnanolone, based on third-party published data.¹ LYT-300 has also demonstrated favorable tolerability in addition to target engagement with GABA_A receptors, which are known to regulate mood and other neurological conditions.
- Allopregnanolone is a positive allosteric modulator of GABA_A receptors that has therapeutic potential across a wide range of neurological conditions, including depression and anxiety disorders, though its therapeutic application has been limited due to high first pass metabolism. To overcome this, the industry has developed oral chemical analogs of allopregnanolone, though these may not capture the full therapeutic potential of endogenous allopregnanolone.
- Our Glyph platform 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. We believe 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.
Program Discovery Process by the PureTech Team
- We sought out different approaches that could selectively transport therapeutic molecules through the lymphatic system to target cells in the lymph nodes. Based on insights gained internally and via unpublished findings through our network of collaborators, we became aware of a technology being developed at Monash University that had the potential to selectively target the lymphatic system. We obtained an exclusive license to this technology and the related intellectual property. We have since further developed the platform and have generated our own intellectual property associated with the Glyph technology platform.
- We conducted a systematic analysis of compounds and indications that could benefit from the application of our Glyph platform. We prioritized areas of high unmet patient need where the broad application of treatment options with validated efficacy was untapped due to poor oral bioavailability. We believe LYT-300 may unlock the full therapeutic potential of allopregnanolone across a range of neurological and psychiatric conditions.
Patient Need & Market Potential
- Anxiety disorders are the most common mental disorder, affecting nearly 30% of adults.² There are several types of anxiety disorders, including generalized anxiety disorder, panic disorder and social anxiety disorder. They are characterized by feelings of excessive fear and may impact a person’s ability to function normally.
- Postpartum depression (PPD) is a debilitating condition that affects over 400,000 women who have given birth in the United States.³ It is characterized by feelings of extreme sadness, changes in energy, sleep and appetite, and it can impact a mother’s ability to care for her child.
- Allopregnanolone and related endogenous neurosteroids have been recognized for their potential to treat depression and other neurological indications with a rapid onset of action. The major hurdles associated with the translation of these compounds have been the inability to create oral formulations of these neurosteroids and chronically administer compounds to patients.
  − 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 challenges and limits the scope of clinical translation with this class of compounds.
  − Medicinal chemistry approaches have been applied to synthesize orally bioavailable analogs of allopregnanolone. The variable clinical activity of these compounds may be due to the possibility that chemical modifications are interfering with optimal GABA_A 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 endogenous allopregnanolone.
Milestones Achieved & Developmental Status
- In February 2023, we announced plans to advance LYT-300 (oral allopregnanolone) for the potential treatment of anxiety disorders and postpartum depression (PPD).
- In December 2022, we announced topline results from the completed, multi-part Phase 1 trial of LYT-300. The results showed that oral administration of LYT-300 achieved blood levels of allopregnanolone at or above those associated with therapeutic benefit and resulted in exposure-dependent target engagement with γ-aminobutyric-acid type A (GABA_A) receptors.
- 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 ninefold greater than that of orally administered allopregnanolone, based on previously published data.
- In December 2021, we presented preclinical proof-of-concept data at the 60th American College of Neuropsychopharmacology (ACNP) Annual Meeting that supported 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 endogenous 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 endogenous allopregnanolone. These results demonstrated the potential of the Glyph technology platform to enhance the systemic absorption of natural bioactive molecules and other small molecules with poor oral bioavailability.
Expected Milestones
- A placebo-controlled, Phase 2a, proof-of-concept, trial using a validated clinical model of anxiety in healthy volunteers is expected to begin in the first half of 2023, with results anticipated by the end of 2023.
- An open-label, Phase 2a, proof-of-concept clinical trial in women with postpartum depression is expected to begin in the second half of 2023.
Intellectual Property
- Within the extensive Glyph intellectual property portfolio, which covers a wide range of novel linker chemistries, LYT-300 is specifically covered by four patent families comprising six US patent applications and 16 foreign patent applications as of December 31, 2022, which are co-owned with Monash University or PureTech owned. Any patents to issue from these patent applications are expected to expire in 2039 through 2043, exclusive of possible patent term adjustments or extensions or other forms of exclusivity.

¹ Brexanolone NDA 211371 Multi-disciplinary Review and Evaluation, FDA CDER, 2018.

² Any Anxiety Disorder. (n.d.). National Institute of Mental Health (NIMH). https://www.nimh.nih.gov/health/statistics/any-anxiety-disorder

³ Any Anxiety Disorder. (n.d.). National Institute of Mental Health (NIMH). https://www.nimh.nih.gov/health/statistics/any-anxiety-disorder

Allopregnanolone is a positive allosteric modulator of GABA_A receptors that has therapeutic potential across a wide range of neurological conditions, including depression and anxiety disorders, though its therapeutic application has been limited due to high first pass metabolism. To overcome this, the industry has developed oral chemical analogs of allopregnanolone, though these may not capture the full therapeutic potential of endogenous allopregnanolone. Our Glyph platform 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. We believe 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.

Press Releases

February 14, 2023

PureTech to Advance LYT-300 (Oral Allopregnanolone) for the Potential Treatment of Anxiety Disorders and Postpartum Depression

December 19, 2022

PureTech's LYT-300 (Oral Allopregnanolone) Demonstrates Oral Bioavailability, Tolerability and GABAA Receptor Target Engagement in Healthy Volunteers

June 14, 2022

PureTech Meets Milestone of Achieving Oral Bioavailability of Allopregnanolone in Healthy Adults Dosed with LYT-300

December 8, 2021

PureTech Presents Preclinical Proof-of-Concept Data for LYT-300 (Oral Allopregnanolone) as Potential Treatment for Neurological and Neuropsychological Conditions

December 7, 2021

PureTech Advances Wholly-Owned Candidate LYT-300 (Oral Allopregnanolone) into Clinical Study for Potential Treatment of Neurological and Neuropsychological Conditions

February 25, 2021

PureTech Announces Publication of Glyph™ Platform Preclinical Proof-of-Concept Study in Journal of Controlled Release