501 Clinical PK of XW10172 for Once Nightly Therapy in Patients with Narcolepsy or Sleep Disorders in Neurodegenerative Diseases

Abstract

Abstract Introduction Patients with narcolepsy and patients with sleep disorders secondary to neurodegenerative diseases have been shown to respond to oxybate. To overcome the limitations of current oxybate therapies, we designed XW10172, a new chemical entity and GABA-B agonist with no sodium or other cation content and for once nightly dosing. The objectives of two clinical studies were to assess the XW10172 pharmacokinetics (PK), pharmacodynamics (PD) and safety/tolerability in normal study participants. Methods Two XW10172 studies in healthy participants assessed ascending single and multiple doses, comparison to sodium oxybate in immediate release (IR) and extended release (ER) formulations. PK parameters were calculated from concentration vs. time data. Safety and tolerability were assessed by monitoring adverse events, laboratory tests, and vital signs. Results To date, 84 study participants received XW10172 and the PK from single and multiple dose administration showed doses of 0.1 to 7.25 g had a mean oxybate half-life range of 0.5 to 1.3 hours. Oxybate levels from the drug were about 6-fold higher than XW10172 levels. Oxybate PK from XW10172 (IR) was the same as from equal molar doses of sodium oxybate. XW10172 (ER) formulations showed delayed Tmax with extended oxybate exposure compatible with single nightly dose therapy. PK-PD assessment of somnolence, the desired pharmacologic effect, showed a concentration-effect relationship (Cmax p=0.0004, AUC p<0.0001). XW10172 was generally well tolerated and adverse events were those known to be associated with oxybate. Conclusion These data support progression of XW10172 (ER) in further clinical development studies to assess this once nightly GABA-B agonist therapy for the treatment of patients with various sleep disorders. Support (if any) XWPharma