P2‐031: SAFETY, TOLERABILITY AND HUMAN PHARMACOKINETICS OF SUVN‐502, A POTENT AND PURE 5‐HT6 RECEPTOR ANTAGONIST

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SUVN-502 is a novel and pure 5-HT6 receptor antagonist with potent receptor affinity and high degree of selectivity. SUVN-502 is orally bioavailable and has adequate brain penetration in preclinical species. In animal models of cognition, SUVN-502 acts on all three phases of cognition (acquisition, consolidation & retention) and it increases the brain acetylcholine levels. SUVN-502 also enhances spatial memory in aged rats. SUVN-502 has adequate margin of safety in long-term toxicity studies. SUVN-502 is being developed for the treatment of cognitive deficits associated with Alzheimer's disease (AD). SUVN-502 was studied in a single-center, multi-faceted, phase-1 clinical trial (US IND) to evaluate its safety, tolerability, and pharmacokinetics after multiple ascending doses by healthy elderly male subjects. Subjects were dosed with 50 or 100 mg orally for 14 days. The effect of gender and food on SUVN-502 pharmacokinetics following 100 mg single oral dose was also evaluated in healthy subjects. SUVN-502 and its active metabolite M1 of SUVN-502 were quantified in plasma using a validated LC-MS/MS method. SUVN-502 was well tolerated up to the highest tested dose of 100 mg/day following single or multiple oral administration in healthy elderly subjects. There were no clinically relevant or serious adverse events noted. There was no significant effect of gender and food on the pharmacokinetics of SUVN-502 and M1 of SUVN-502 after single oral administration of 100 mg SUVN-502. Following multiple administration of SUVN-502, steady state was reached within 2–4 days for SUVN-502 and 4–6 days for metabolite M1 of SUVN-502. The exposure of SUVN-502 was comparable between Day 14 and Day 1, while metabolite M1 of SUVN-502 exposure was approximately 2 fold higher on Day 14 compared to Day 1. SUVN-502 has shown a favorable safety and pharmacokinetic profile after single and repeated dose administration. Gender and food did not have significant effect on SUVN-502 pharmacokinetic parameters. SUVN-502 and M1 of SUVN-502 achieved the projected efficacy concentrations and attained steady state within seven days upon multiple administrations in elderly subjects. SUVN-502 is well tolerated in humans with adequate plasma exposure for efficacy and favorable pharmacokinetics suitable for once a day oral administration.