PPD drug with Monash tech enters Phase 2a trial

A drug delivery technology designed to enable the oral administration of allopregnanolone for postpartum depression (PPD) has reached the next phase of clinical trials.

Allopregnanolone is the only FDA-approved medication on the market specifically for the treatment of PPD and has also been shown to be effective for the treatment of depression and potentially other neurological conditions. The use of allopregnanolone, however, is limited by negligible oral bioavailability and it is currently only approved as a 60-hour intravenous infusion for the treatment of PPD. This is likely to limit broader application.

Now, oral allopregnanolone, ‘LYT-300’, is set to enter a placebo-controlled, Phase 2a, proof-of-concept social anxiety trial in healthy volunteers in the first half of 2023.

The Australian technology, invented by Monash University researchers in partnership with PureTech Health plc, will also enter a Phase 2a, open-label, proof-of-concept study in women with postpartum depression in the second half of 2023.

The 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.

To potentially harness the broad applicability of allopregnanolone through oral administration, the team behind the trial has applied the Glyph platform, which is designed to enable the oral administration of certain therapeutics with low oral bioavailability due to first pass metabolism.

The LYT-300 trial is the first clinical validation of the Glyph technology in humans. The platform, developed by Professor Chris Porter and his team at the Monash Institute of Pharmaceutical Sciences, piggybacks onto lipid absorption pathways, targeting drug absorption to the lymphatic system and away from the liver. This provides patients an opportunity to switch from invasive intravenous administration to a simple oral capsule.

Topline results from a Phase 1 trial of LYT-300 were announced in December 2022 and showed that when orally administered using Glyph, 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 data¹.

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.

“Anxiety disorders are particularly prevalent in Australia, affecting around 17%² of the population. Likewise, PPD impacts around 1 in 6³ women in their first year after birth, yet a big gap remains when it comes to effective and accessible treatments,” Porter said.

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.

“It’s exciting to see LYT-300 a step closer to becoming a simple oral capsule to treat a broad range of neurological conditions,” Porter concluded.

Julie Krop, MD, Chief Medical Officer at PureTech, said, “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.

“Using our proprietary Glyph platform, we have made natural allopregnanolone orally bioavailable without 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.”

^{[1] Brexanolone NDA 211371 Multi-disciplinary Review and Evaluation, FDA CDER, 2018.}

^{[2] https://www.abs.gov.au/statistics/health/mental-health/national-study-mental-health-and-wellbeing/latest-release}

^{[3] https://www.mentalhealthcommission.gov.au/news-and-media/media-releases/2022/march/international-women-s-day-snapshot-of-women-s-ment}

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