tolerability, pharmacokinetic (PK) properties and pharmacodynamic response (lymphopenia) of ascending doses of APD334 when administered as a single oral dose to healthy adult subjects. The study was a randomised, double-blind, doseescalation design. For each dose a separate cohort of up to 8 subjects were randomised, 6 to APD334 and 2 to placebo. Dosing started at 0.1 mg and was planned to escalate to 0.35, 1, 3, 5, 10, 20, and 40 mg. Subjects were healthy adult men and women, 18 to 45 years, non-smokers, no prescription medications with a body weight of 50 to 100 kg. Following a screening period of up to 21 days a single dose was administered on day 1 with prior and subsequent inpatient observations and procedures undertaken until at least day 7/Exit. Results: Forty subjects were enrolled and completed the study; 30 subjects were included in the PK analyses. APD334 doses of 0.1, 0.35, 1, 3, and 5 mg were assessed. APD334 was well tolerated at the 0.1, 0.35, 1, and 3 mg dose levels. In the 5 mg APD334 cohort, 1 subject experienced first degree Atrioventricular (AV) block and second degree AV block with bradycardia, and 2 subjects experienced first degree AV block, 1 of which was associated with bradycardia. These events, although asymptomatic, led to discontinuation of further dose escalation. Dose-related declines in blood pressure and heart rate from baseline compared to placebo were noted. Only the decline in heart rate at the 3.0 and 5.0 mg doses was statistically significant (P < 0.05). These declines resolved during follow-up, without intervention. PK parameters for 0.1, 0.35, 1, 3, and 5 mg doses were Cmax (mg/mL), mean (SD); 0.00173 (0.00061), 0.00628 (0.00036), 0.0172 (0.0055), 0.0605 (0.0117), 0.102 (0.019); AUC0-inf (mg$h/mL) 0.0798 (0.0213), 0.268 (0.031), 0.793 (0.168), 2.60 (0.84), 4.39 (0.61) and demonstrate dose-proportionality. Tmax (h), median (range) was; 6 (4.00–12.00), 7 (1.50–24.0), 6 (2.00–8.00), 3.5 (1.50–8.00), 4 (3.00–6.00). The mean terminal half-life of APD334 was consistent between dose groups, ranging from 30.7 to 37.4 hours. APD334 at 0.1, 0.35, and 1 mg had little effect on total T, B, and Natural Killer (NK) cell counts when compared to baseline or placebo at each dose, as was observed for total lymphocyte counts. Dose-related decreases in total lymphocyte and T cell counts were observed at 3 and 5 mg. There were no other clinically significant safety issues with respect to; vital signs, electrocardiograms, pulmonary function, ophthalmoscopy, or clinical laboratory tests. Conclusions: The study demonstrates that APD334 was well tolerated when orally administered to healthy volunteers at dose levels 0.1 mg up to 3 mg and supports evaluation of APD334 in further clinical studies across this dose range.