LYT-300

A range of neurological and neuropsychological conditions, including anxiety, mood disorders and Fragile X-associated Tremor/Ataxia Syndrome

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Discovery

Preclinical

Phase 1

Phase 2

Phase 3

LYT-300

Oral Allopregnanolone

Neuropsychiatric and rare CNS conditions

Phase:
2a

Initial Indications:
Neuropsychiatric and rare CNS conditions

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, mood disorders and Fragile X-associated Tremor/ Ataxia Syndrome. Allopregnanolone is a positive allosteric modulator of GABA_A receptors that has therapeutic potential across a wide range of neurological conditions, including anxiety and Fragile X-associated Tremor/ Ataxia Syndrome, though its therapeutic application has been limited due to high first pass metabolism. Our Glyph platform reversibly links a drug to a lipid, 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.

A range of neurological and neuropsychological conditions, including anxiety, mood disorders and Fragile X-associated Tremor/Ataxia Syndrome

LYT-300, an oral prodrug of allopregnanolone, is being advanced for the potential treatment of anxiety, mood disorders and Fragile X-associated Tremor/ Ataxia Syndrome. 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, mood disorders and Fragile X-associated Tremor/ Ataxia Syndrome. 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, 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 lipid, 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 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 our Glyph platform should enable us to retain the potency of endogenous allopregnanolone in a more convenient oral form and potentially enable us to unlock the therapeutic potential of allopregnanolone across a range of neurological and neuropsychiatric conditions.
Patient Need & Market Potential
- Anxiety Disorders
  - 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.
- Mood Disorders
  - ~9.6% of adults are affected by mood disorders in a lifetime globally³
- Fragile X-associated Tremor/ Ataxia Syndrome (FXTAS)
  - FXTAS is one of the most devastating of the Fragile X Spectrum Disorders, which result from a trinucleotide expansion in the FMR1 gene. It is a late onset condition that can occur in up to 75% of males and approximately 16% of females with the premutation, and the clinical signs typically emerge when individuals are in their early 60s. The clinical features of FXTAS include tremor in the hands with action or at rest, balance problems (ataxia) that lead to frequent falling, and cognitive decline that is sometimes misdiagnosed as Alzheimer’s disease. No specific treatment for FXTAS is efficacious, though a variety of medications may improve psychiatric issues or the severity of tremor.
- Lower levels of allopregnanolone have been documented in patients with mood disorders, such as depression, and there is evidence that allopregnanolone has therapeutic potential in both anxiety and depression.⁴ 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 has limited the scope of clinical use for allopregnanolone.
  - Medicinal chemistry approaches have been applied to synthesize orally bioavailable chemical analogs of allopregnanolone. These oral analogs may have different pharmacological effects than endogenous allopregnanolone and therefore may not capture its full therapeutic potential, though one of them was recently approved in PPD.
Milestones Achieved & Development Status
- In November 2023, we announced topline results from the Phase 2a randomized, proof-of-concept trial of LYT-300. The trial was designed to evaluate the salivary cortisol response in the Trier Social Stress Test (TSST), a validated clinical model of anxiety in healthy volunteers. Oral administration of LYT-300 achieved the trial’s primary endpoint of a statistically significant reduction versus placebo in the increase from baseline to peak levels of the stress hormone salivary cortisol (p=0.0001).
- In August 2023, we announced a grant from the U.S. Department of Defense of up to $11.4 million to advance LYT-300 for the treatment of Fragile X-associated Tremor/ Ataxia Syndrome (FXTAS). The funds will support a Phase 2 trial of LYT-300 in collaboration with the University of California, Davis (UC Davis).
- In February 2023, we announced plans to advance LYT-300 for the potential treatment of anxiety and depression.
- 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
- LYT-300 is advancing into a Phase 2 clinical trial for the treatment of Fragile X-associated Tremor/ Ataxia Syndrome (FXTAS), which is a rare neurological disease. A Phase 2 trial is expected to initiate in 2024.
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 Zachary Steel and others, The global prevalence of common mental disorders: a systematic review and meta-analysis 1980–2013, International Journal of Epidemiology, Volume 43, Issue 2, April 2014, Pages 476–493, https://doi.org/10.1093/ije/dyu038.

⁴ Schüle, C., Nothdurfter, C., & Rupprecht, R. (2014). The role of allopregnanolone in depression and anxiety. Progress in Neurobiology, 113, 79–87. https://doi.org/10.1016/j.pneurobio.2013.09.003

Allopregnanolone is a positive allosteric modulator of GABA_A receptors that has therapeutic potential across a wide range of neurological and neuropsychological conditions, including anxiety, mood disorders and Fragile X-associated Tremor/ Ataxia Syndrome, though its therapeutic application has been limited due to high first pass metabolism. To overcome this, medicinal chemistry approaches have been applied to synthesize orally bioavailable chemical analogs of allopregnanolone. These oral analogs may have different pharmacological effects than endogenous allopregnanolone and therefore may not capture its full therapeutic potential, though one of them was recently approved in PPD. We believe our Glyph platform should enable us to retain the potency of endogenous allopregnanolone in a more convenient oral form and potentially enable us to unlock the therapeutic potential of allopregnanolone across a range of neurological and neuropsychiatric conditions.