UNLOCKING MEDICINES FOR NEUROPSYCHIATRY BY ENHANCING ORAL ABSORPTION USING A LYMPHATIC-TARGETING PRODRUG TECHNOLOGY

Introduction

Depression and anxiety are disabling mental health conditions with a significant need for new treatment options. The Glyph™ platform, a lymphatic-targeting prodrug technology, can be applied to overcome limitations such as high first-pass metabolism, low oral bioavailability, and/or side effects, which may otherwise present barriers to patient use. The platform reversibly conjugates a drug of interest to a dietary fat molecule using proprietary chemistry, shifting absorption toward intestinal lymphatics to avoid first-pass hepatic metabolism and enhance oral bioavailability while reducing dose. GlyphAllo™ (SPT-300 or Glyph Allopregnanolone), an oral prodrug of allopregnanolone, is designed to overcome allopregnanolone’s poor oral bioavailability from substantial first-pass hepatic metabolism. Allopregnanolone is an endogenous neurosteroid that has been clinically validated as a rapidly acting antidepressant with anxiolytic and sleep-promoting effects through its pharmacology as a GABAA receptor positive allosteric modulator. Here, we discuss how GlyphAllo was developed using the Glyph platform and present initial proof-of-concept and safety results from phase 1 and phase 2a clinical trials in healthy volunteers.

Methods

A series of lymphatic-targeting allopregnanolone prodrugs was evaluated by screening for in vitro plasma release and assessing plasma levels after oral administration across species. GlyphAllo was evaluated in a multipart phase 1 clinical trial (NCT05129865) of healthy volunteers including single and multiple ascending dose components. Safety, pharmacokinetic data, and pharmacodynamic assessments, including the Stanford Sleepiness Scale (SSS), quantitative EEG (qEEG), and video-oculography for saccadic eye velocity (SEV), were collected. GlyphAllo’s potential to reduce physiological stress in healthy volunteers was evaluated in an initial proof-of-concept phase 2a (NCT05129865) pharmacodynamic trial using the Trier Social Stress Test (TSST), a clinical validated model of anxiety.

Results

Based on the discovery and preclinical screening methods, GlyphAllo (SPT-300) was selected as the lead development candidate. In a phase 1 clinical trial in healthy volunteers, oral dosing of GlyphAllo was generally well-tolerated and resulted in a > nine-fold increase in allopregnanolone plasma levels compared to previously reported bioavailability of oral allopregnanolone. Peak allopregnanolone plasma levels and pharmacodynamic markers, including increased beta EEG power and reduced SEV, were observed 3-5 hours post-dose. GlyphAllo demonstrated initial proof-of-concept in a phase 2a TSST clinical trial, significantly blunting the salivary cortisol stress response compared to placebo in healthy volunteers (p=0.0001). No treatment-related severe or serious adverse events were reported. The most common adverse event was somnolence, which was mild or moderate and transient in all cases. SSS scores returned to baseline by six hours post dose.

Conclusion

These data validate the Glyph platform’s ability to enhance oral bioavailability and confirm that the pharmacodynamic activity of GlyphAllo is consistent with the pharmacology of allopregnanolone. A phase 2b, placebo-controlled trial (BUOY-1) is currently underway to evaluate the efficacy and safety of GlyphAllo in patients with major depressive disorder, with or without anxious distress (NCT07065240). GlyphAllo’s development and demonstration of enhanced oral bioavailability provides an initial proof-of-concept supporting the wider applicability of the lymphatic-targeting prodrug approach to therapeutic molecules with previous limitations.