| Title: |
An oral allopregnanolone prodrug bypasses liver metabolism via lymphatic transport enabling bioavailability in animals and humans. |
| Authors: |
Simpson, Jamie S.; Quach, Tim; Han, Sifei; Hu, Luojuan; Trevaskis, Natalie L.; Leong, Nathania J.; Sharma, Garima; Zheng, Dan; Paul, Steven M.; Porter, Christopher J. H.; Bonner, Daniel K.; Chen, Michael C. |
| Source: |
Science Translational Medicine; 3/25/2026, Vol. 18 Issue 842, p1-15, 15p |
| Subject Terms: |
Prodrugs; Drug delivery systems; Clinical trials; Pharmacokinetics; Affective disorders; Anxiety disorders; Neuropsychiatry; Pregnanolone |
| 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 GABAA (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. Editor's summary: Many drugs cannot be given orally often because the liver breaks down the drug. In a new study, Simpson et al. developed the Glyph platform for lymphatic targeting of prodrugs in which a drug of interest is conjugated to a dietary lipid molecule, thus bypassing liver metabolism and shifting drug absorption to the gut lymphatic system. The authors use this platform to develop GlyphAllo, a prodrug of the neuroactive steroid antidepressant and anxiolytic drug allopregnanolone. They show through preclinical and clinical testing that oral GlyphAllo safely achieved therapeutic concentrations and reduced stress hormone responses, supporting its potential for treating mood and anxiety disorders. —Orla Smith [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |