PureTech Health, a clinical-stage biotherapeutics company, will advance therapeutic candidate LYT-300 (oral allopregnanolone) for the potential treatment of anxiety disorders and postpartum depression (PPD).
A social anxiety clinical trial in healthy volunteers is expected to begin in the first half of 2023, with results anticipated by the end of 2023; a clinical trial in women with PPD is expected to initiate in the second half of 2023.
Trial design
The placebo-controlled, Phase IIa, proof-of-concept trial will evaluate short-term changes in anxiety-related patient reported outcomes in approximately 50 healthy volunteers. The trial will be conducted using a validated clinical model that simulates social anxiety.
The open-label, Phase IIa, proof-of-concept trial will evaluate LYT-300 in a small number of patients with moderate to severe PPD. It is designed to inform dose selection of LYT-300 in this population given the known efficacy of allopregnanolone in this population, and it will evaluate scores on the HAM-D scale as well as other relevant pharmacodynamic markers.
Results
Topline results from a Phase I trial of LYT-300 were announced in December 2022 and showed that oral administration of LYT-300 achieved blood levels of allopregnanolone at or above those associated with therapeutic benefit in PPD and ninefold greater than orally administered allopregnanolone, based on third-party published data.1 The results also demonstrated exposure-dependent target engagement with γ-aminobutyric-acid type A (GABAA) receptors, which have been shown to regulate mood and other neurological conditions.
Background
Allopregnanolone is a natural neurosteroid with well-validated biological effects. It has demonstrated a rapid onset of action for the treatment of depression, as well as the potential to treat other neurological conditions, including anxiety, but its poor oral bioavailability has limited its therapeutic potential.
The United States Food and Drug Administration (FDA) has approved a 60-hour intravenous infusion formulation of allopregnanolone for the treatment of PPD, though this method of administration has inherent limitations. To overcome this, oral chemically modified analogs of allopregnanolone have been developed, though these may not capture the full therapeutic potential of natural allopregnanolone. To potentially harness the broad applicability of this natural neurosteroid through oral administration, PureTech has applied its Glyph platform, which is designed to enable the oral administration of certain therapeutics with low oral bioavailability due to first pass metabolism.
Official comments
“I am exceptionally proud of the progress we’ve made with the Glyph platform, which has yielded two exciting therapeutic candidates to date, and I believe it will be a rich source of additional candidates for our Wholly Owned Pipeline going forward,” said Dr Joe Bolen, a member of PureTech’s Research and Development Committee and recently retired Chief Scientific Officer. “PureTech’s unique model includes moving resources toward the programs with the most promise. To that end, and with a focus on translational and clinical work, we have recently deprioritized our Orasome Technology Platform following a key go/no go experiment. I look forward to continuing to work with the team as a member of the R&D Committee to advance big ideas, and I am honored to be a part of such an innovative organization with a deep commitment to serving patients in need.”
“We believe LYT-300 is the most advanced oral prodrug of natural allopregnanolone and, as such, has the potential to unlock the full therapeutic benefit of allopregnanolone,” said Julie Krop, M.D., Chief Medical Officer at PureTech. “Using our proprietary GlyphTM platform, we have made natural allopregnanolone orally bioavailable without permanently chemically modifying the natural neurosteroid. This differentiated approach, which harnesses the validated, fast-acting efficacy of allopregnanolone, may offer an enhanced therapeutic benefit to patients with a wide range of neurological and neuropsychiatric conditions, including anxiety and postpartum depression.”
