Phase 1, Single-Center, Double-Blind, Randomized, Placebo-Controlled Studies of the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Oral Doses of the Sirtuin 6 Activator SP-624 in Healthy Adults.

Abstract

Sirtuin 6 activation is a novel epigenetic mechanism proposed for treatment of depression. Two Phase 1 studies, SP-624-101 and SP-624-102, examined the pharmacokinetics and safety of SP-624, an orally active sirtuin 6 activator, in healthy adults. SP-624-101 was a single-ascending-dose study. In Part A, participants were randomized 6:2 to SP-624 (single oral doses of 3, 10, or 30 mg) or placebo. Part B compared results in 8 participants receiving SP-624 while fasting or after a high-fat, high-calorie breakfast. In SP-624-102, a multiple-ascending-dose study, participants were randomized 6:2 to SP-624 (3 or 10 mg SP-624 daily) or placebo for 5 days and 5:2 to SP-624 20 mg daily or placebo for 10 days. At all doses, maximum concentration (C_max) exceeded predicted target plasma concentrations of 3.28 ng/mL. Area under the concentration-time curve and C_max increased dose proportionally. A food effect resulted in significantly lower C_max, later time to maximum concentration_, and comparable AUC for fed versus fasting participants. No serious adverse events were observed. In SP-624-101 and SP-624-102, respectively, 3 (12%) and 5 (29%) SP-624-treated participants experienced treatment-emergent adverse events. SP-624 was well tolerated and reached target concentrations in healthy adults, supporting progression of SP-624 20 mg daily into Phase 2 studies of major depressive disorder.