PureTech Health plc announced topline results from its Phase 2a, randomized, placebo-controlled, proof-of-concept trial of LYT-300 (oral allopregnanolone). The trial was designed to evaluate the salivary cortisol response in the Trier Social Stress Test (TSST), a validated clinical model of anxiety in healthy volunteers. Oral administration of LYT-300 achieved the trial?s primary endpoint of a statistically significant reduction versus placebo in the increase from baseline to peak levels of the stress hormone salivary cortisol (p=0.0001).

The LYT-300 treatment effect size versus placebo was 0.72, as measured by Cohen?s d, which is one of the most common ways to measure effect size. LYT-300 showed a similar effect size to previously observed results for alprazolam, a benzodiazepine drug indicated for treatment of anxiety disorders, when assessed following the TSST procedure. An increase in cortisol levels after the TSST is a physiological response and an objective biomarker of acute stress.

Eighty healthy volunteers were randomized and treated with either LYT-300 or placebo in a 1:1 ratio. LYT-300 was well tolerated, with all treatment-related adverse events transient, mild or moderate and consistent with the known pharmacology profile of allopregnanolone. Additional data from the study will be presented in a scientific forum.

LYT-300 is an oral prodrug of allopregnanolone, an endogenous neurosteroid. Allopregnanolone has been recognized for its potential to treat a range of neurological and neuropsychiatric indications with a well-established rapid onset of action in mood disorders. The major hurdles associated with endogenous neurosteroids in the past have been their lack of oral bioavailability and inability to chronically administer them to patients, which means they otherwise can only be administered via a long, cumbersome intravenous infusion.

To overcome the challenges with this method of administration, medicinal chemistry approaches have been applied to synthesize orally bioavailable chemical analogs of allopregnanolone. These oral analogs may have different pharmacological effects than endogenous allopregnanolone and therefore may not capture its full therapeutic potential. LYT-300 is designed to achieve oral administration of an endogenous allopregnanolone that has the potential to capture the breadth of the natural biological response.

These results further validate PureTech?s Glyph platform, which is designed to employ the lymphatic system's natural lipid absorption and transport process to enable the oral administration of certain therapeutics that otherwise cannot be administered orally. PureTech has generated seven CNS programs based on its Glyph platform, including LYT-300 and LYT-310 (oral cannabidiol), which is currently in development for the treatment of epilepsies and other neurological indications.