PureTech Health has cleared an early hurdle in its pursuit of Sage Therapeutics, linking its oral prodrug of allopregnanolone to a nine-fold increase in the blood levels achieved by the unmodified molecule. Based on the data, the company is forging ahead with a view to starting a phase 1b/2a clinical trial next year.
Allopregnanolone is a modulator of the GABAA receptor. Sage showed the mechanism may have a role to play in the treatment of depression through the development of the intravenous Zulresso, and is now closing in the approval of zuranolone, its oral take on the molecule. Zuranolone is a synthetic analog of allopregnanolone that is designed to overcome the poor oral bioavailability of the GABAA modulator.
PureTech has taken a different approach to improving the bioavailability of allopregnanolone, specifically by making changes to avoid first-pass metabolism. The prodrug bypasses the liver through absorption via the lymphatic system and then releases the therapeutic molecule upon entering systemic circulation.
The phase 1 trial in healthy adults provides early evidence that the idea translates into humans. In the trial, fasted participants had total plasma exposure levels of 352 ng*hr/mL. PureTech compared the data favorably to the results of a separate study that reported exposure levels of 21 ng*hr/mL in recipients of 30 mg of oral allopregnanolone.
“Achieving significant systemic exposure of allopregnanolone with orally administered LYT-300 is also a key validation for our Glyph lymphatic targeting platform and represents proof-of-principle for being able to administer drugs orally that currently require IV administration due to first-pass liver metabolism,” Julie Krop, chief medical officer at PureTech, said in a statement.
PureTech is now working to wrap up the phase 1 clinical trial, which is designed to explore the impact of LYT-300 on markers of GABAA target engagement. With the company aiming to complete the phase 1 by the end of the year, the plan is to start a phase 1b/2a study in 2023.