SUVN-D4010: A POTENT AND SELECTIVE 5-HT4 RECEPTOR PARTIAL AGONIST— ASSESSMENT OF SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HEALTHY HUMAN VOLUNTEERS

Abstract

SUVN-D4010 is a potent, selective and orally bioavailable 5-HT4 receptor partial agonist being developed for the treatment of Alzheimer's disease (AD). SUVN-D4010 has shown to improve the memory in preclinical animal models. SUVN-D4010 also produced significant increase in the brain acetylcholine levels and cortical sAPPα with simultaneous decrease in amyloid-β protein levels. SUVN-D4010 was studied in a single-center, multi-faceted, phase 1 clinical trial (US IND) to evaluate its safety, tolerability, and pharmacokinetics after single or multiple ascending doses in healthy male subjects. For single dose evaluation, subjects were dosed with 5 mg, 15 mg, 30 mg or 45 mg of SUVN-D4010 tablets, once. For multiple ascending dose evaluation, the once daily doses of 10, 25 and 40 mg SUVN-D4010 were administered for 14 days. SUVN-D4010 was administered at a dose of 25 mg for evaluation of food, gender and age effect. Effect of food on SUVN-D4010 pharmacokinetics was evaluated under fed and fasted conditions in healthy adult male subjects. For evaluation of gender and age effect, SUVN-D4010 was administered under fasted conditions in healthy female and elderly subjects. SUVN-D4010 was quantified in plasma using a validated LC-MS/MS method. Safety and tolerability was assessed by incidence and severity of AEs, abnormalities in vital signs, ECG and laboratory assessments. SUVN-D4010 was well tolerated up to the highest tested dose of 45 mg single dose or 40 mg/day multiple doses in healthy male subjects. There were no clinically relevant or serious adverse events reported. During single ascending dose studies, the absorption of SUVN-D4010 was rapid and exposures (Cmax and AUC) were dose proportional. During multiple ascending dose studies, SUVN-D4010 achieved steady state on day 3 in the tested population. SUVN-D4010 has excellent safety and pharmacokinetic profile following single or multiple dose administration for 14 days in healthy male subjects. Projected efficacy concentrations of SUVN-D4010 achieved during multiple ascending dose studies. SUVN-D4010 is currently being evaluated for long term safety in animal models.