Natural allopregnanolone made orally bioavailable

PureTech Health has announced it will advance its oral allopregnanolone candidate LYT-300, for the potential treatment of anxiety and postpartum depression (PPD). 

A placebo-controlled, Phase IIa, proof-of-concept, social anxiety clinical trial is expected to begin in the first half of 2023. The results are anticipated by the end of 2023. An open-label, Phase IIa, proof-of-concept clinical trial in women with PPD is expected to initiate in the second half of 2023.

At present, a 60-hour intravenous infusion is the only available drug delivery method for the natural neurosteroid allopregnanolone. According to the company’s research, the neurosteroid is a positive allosteric modulator of γ-aminobutyric-acid type A (GABAA) receptors and has been shown to regulate mood and other neurological conditions.

How was oral allopregnanolone made bioavailable?

Dr Julie Krop, Chief Medical Officer at PureTech shared that the company used its platform designed to employ the lymphatic system’s natural lipid absorption and transport process, to enable the oral administration of certain therapeutics with low oral bioavailability.

The 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. Instead, it moves from the gut into the lymphatic vessels that normally process dietary fats.

Ultimately, Dr Krop explained, “… 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.”

PureTech stated that topline results from a Phase 1 trial of LYT-300 announced in December 2022 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.

The results also demonstrated exposure-dependent target engagement with GABAA receptors, which have been shown to regulate mood and other neurological conditions.