SUVN-G3031, A SELECTIVE H3 RECEPTOR INVERSE AGONIST: ASSESSMENT OF SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HEALTHY HUMAN VOLUNTEERS

Abstract

SUVN-G3031, a potent and selective histamine H3 receptor inverse agonist is being developed for the treatment of cognitive deficits associated with Alzheimer's disease. SUVN-G3031 demonstrated cognitive enhancement and relevant neurochemical modulation without affecting the sleep in rodent models. SUVN-G3031 was studied in a single-center, multi-faceted, phase 1 clinical study (US IND) to evaluate its safety, tolerability, and pharmacokinetics after single and multiple ascending doses in healthy adult subjects. For single dose evaluation, subjects dosed with 0.1 mg to 20 mg of SUVN-G3031 tablets. For multiple ascending dose evaluation, once daily doses of 1 mg to 6 mg were administered for 14 days. Effect of food on pharmacokinetics was evaluated under fed and fasted conditions in healthy adult male subjects. For evaluation of gender and age effect, SUVN-G3031 was administered under fasted conditions in healthy female and elderly subjects. SUVN-G3031 was quantified in plasma using a validated LC-MS/MS method. Safety and tolerability was assessed throughout the study by incidence and severity of AEs, abnormalities in vital signs, ECG and clinical laboratory assessments. SUVN-G3031 was well tolerated up to the highest tested dose of 20 mg single dose or 12 mg/ day repeated dose in healthy adult subjects. During single ascending dose studies, exposures were observed to be dose-proportional at the tested doses between 0.1 mg to 20 mg. During multiple ascending dose studies, SUVN-G3031 has shown an excellent pharmacokinetic profile. SUVN-G3031 achieved the projected efficacy concentrations and attained steady state on day 6. At a tested dose of 6 mg, food, gender and age had no effect on human pharmacokinetics of SUVN-G3031. SUVN-G3031 was well tolerated and there were no clinically relevant or serious adverse events observed in different population. SUVN-G3031 has excellent safety and pharmacokinetic profile in healthy human volunteers after single and multiple dose administration for 14 days. Food, gender and age had no effect on SUVN-G3031 pharmacokinetics in human. Long term safety studies are completed and SUVN-G3031 is ready for phase-2 clinical evaluation.