PureTech Health to develop oral allopregnanolone to treat anxiety disorders and postpartum depression

PureTech Health plc, a clinical-stage biotherapeutics company dedicated to changing the treatment paradigm for devastating diseases, announced that it will advance LYT-300 (oral allopregnanolone), a clinical therapeutic candidate in development as a potential treatment for anxiety disorders and postpartum depression (PPD). A placebo-controlled, phase 2a proof-of-concept social anxiety clinical trial in healthy volunteers is set to begin in the first half of 2023, with results expected by the end of the year.

Allopregnanolone is a confirmed natural neurosteroid that is now only available as a 60-hour intravenous infusion. “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, MD, chief medical officer at PureTech. “Using our proprietary Glyph 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.”

The placebo-controlled, phase 2a, 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. A placebo-controlled, phase 2a, proof-of-concept, 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. An open-label, phase 2a, proof-of-concept clinical trial in women with postpartum depression is expected to initiate in the second half of 2023. The open-label, phase 2a, 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. In a healthy volunteer study, LYT-300 achieved blood levels of allopregnanolone at or above those associated with therapeutic effect in postpartum depression and was generally well-tolerated. Topline results from a phase 1 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 nine fold greater than orally administered allopregnanolone, based on third-party published data.1

The results also demonstrated exposure-dependent target engagement with ?-aminobutyric-acid type A (GABAA) receptors, which have been shown to regulate mood and other neurological conditions. Allopregnanolone 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. “

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 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 programmes 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.” Anxiety disorders are the most common mental disorder, affecting nearly 30% of adults. 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.

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. Glyph is PureTech’s lymphatic-targeting chemistry platform which is designed to employ the lymphatic system’s natural lipid absorption and transport process to enable the oral administration of certain therapeutics. Glyph 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. PureTech believes this technology has the potential to enable direct modulation of the immune system via drug targets present in mesenteric lymph nodes and provide a broadly applicable means of enhancing the bioavailability of certain orally administered drugs that would otherwise be limited by first-pass liver metabolism. PureTech is accelerating development of a Glyph portfolio that leverages validated efficacy, prioritizing highly characterized drugs to evaluate the ability of the Glyph technology to improve oral bioavailability or lymphatic targeting.