GlyphAgo demonstrated 6.8-fold bioavailability and 10-fold reduced variability versus unmodified agomelatine at doses projected to mitigate liver exposure in humans

Introduction & Aims:Agomelatine, a clinically validated MT1/MT2 melatonin receptor agonist and serotonin 2C receptor antagonist, is an effective anxiolytic and antidepressant approved for treatment of generalized anxiety disorder (GAD; Australia) and major depressive disorder (MDD; Australia and EU). However, over 90% of unmodified agomelatine is lost to first-pass metabolism, resulting in low bioavailability, variable systemic exposure, and dose-dependent elevations in liver enzymes prompting the need for routine liver monitoring [1-3]. To address these limitations, GlyphAgo™ (SPT-320 or GlyphAgomelatine), an oral prodrug of agomelatine, is being developed using the Glyph™ platform to shift absorption from a hepatic route to the gut lymphatic system to avoid first-pass metabolism and reduce liver exposure. Here, we present proof-of-concept pharmacokinetic (PK) data from a phase 1 trial of GlyphAgo.

Methods

The safety, tolerability, and PK of oral GlyphAgo was evaluated in a multipart, first-in-human phase 1 trial in healthy volunteers. Part A was an open-label, single dose design to assess the PK profile of the approved 25 mg dose of agomelatine. Part B was a randomized, double-blind, placebo-controlled single ascending dose study of GlyphAgo across six cohorts. Part C was an open-label, randomized 3-period, 2-sequence, crossover portion (Part C) to assess the effect of food on the PK profile of GlyphAgo and agomelatine exposure after administration of GlyphAgo or 25 mg of agomelatine. Participants were randomized 1:1 to one of two treatment sequences where they received oral GlyphAgo under fed and fasted states in the first two periods before a single dose of agomelatine in the third period with a 5-to-7-day washout between periods. This portion included participants taking estrogen-containing oral contraceptives (OC) which increase exposure of unmodified agomelatine due to liver drug-drug interactions. Part D is a multiple ascending dose portion to further characterize the safety and PK of repeat-dosing of GlyphAgo.

Results

In Parts A and B, GlyphAgo achieved higher dose-normalized exposure of agomelatine (AUC_0-24/D: 9.6x–14.5x; C_max/D: 2.3x–3.7x) compared to unmodified agomelatine, and agomelatine exposures increased with dose of GlyphAgo. In Part C, GlyphAgo demonstrated a statistically significant 6.8-fold increase (90% CI: 4.7x–10.0x) in bioavailability (as quantified by dose-normalized exposure) and a significantly lower PK variability (10-fold) compared to unmodified agomelatine. No effect of OC on GlyphAgo was observed. Following GlyphAgo dosing, the geometric mean ratio of fed:fasted plasma agomelatine indicated no observed food effect (AUC_0-24: 1.01; C_max: 0.968). GlyphAgo was generally well tolerated across all dose levels, with no serious or severe adverse events (AEs) observed. There were no changes in liver-related laboratory parameters during the study treatment period or liver-related AEs.

Conclusions

GlyphAgo administration achieved 6.8x dose-normalized agomelatine exposures compared to unmodified agomelatine administration in healthy volunteers. GlyphAgo demonstrated a 10x reduction in PK variability which may enhance the consistency of treatment response in patients. GlyphAgo exposure was also unaffected by oral contraceptives, further supporting the ability of GlyphAgo to bypass first-pass metabolism and decrease liver exposure which could reduce or eliminate the need for liver function testing as well as avoid drug-drug interactions that occur in the liver.

References

1. Slee A et al. 2019; Lancet, 393: 768-77.
2. Perlemuter G et al. 2016; CNS Drugs, 30(9): 877-888.
3. Committee for Human Medicinal Products (CHMP). Assessment Report for Valdoxan. November 2008.