An oral allopregnanolone prodrug bypasses liver metabolism via lymphatic transport enabling bioavailability in animals and humans.

Abstract

Allopregnanolone, an endogenous neuroactive steroid, has antidepressant and anxiolytic activity but poor oral bioavailability because of substantial first-pass hepatic metabolism. To address the broader challenge of oral bioavailability across clinically validated therapeutics in neuropsychiatry, we developed a lymphatic-targeting prodrug technology platform called Glyph in which a drug of interest is conjugated to a dietary lipid molecule using specifically designed linker chemistry to shift drug absorption to the gut lymphatic system, thus bypassing hepatic metabolism. A series of allopregnanolone prodrugs with different functional linker elements was designed, synthesized, and screened in vitro for gut lymphatic transport and plasma release. Multiple prodrugs achieved therapeutically relevant plasma allopregnanolone concentrations after oral dosing in small- and large-animal models consistent with results from in vitro screening. A triglyceride-mimetic prodrug, GlyphAllo (SPT-300 or Glyph Allopregnanolone), was selected and tested in a phase 1/2a clinical trial (NCT05129865) in 189 healthy participants. Single- and multiple-ascending oral dosing showed that this prodrug could generate therapeutically relevant plasma concentrations in trial participants. GlyphAllo was generally well tolerated and resulted in delivery of allopregnanolone to the systemic circulation and exposure-dependent pharmacodynamic effects via GABA_A (γ-aminobutyric acid type A) receptor positive allosteric modulation. In a subsequent randomized, double-blind, placebo-controlled phase 2a trial using the Trier Social Stress Test (TSST), a validated clinical test for anxiety, GlyphAllo was reported to reduce the salivary cortisol stress response compared with placebo at all post-TSST time points. Collectively, these data support further investigation of GlyphAllo for treating mood and anxiety disorders.