CONCLUSIONS

1. Δlog(Sway) A study with a partial subtype selective GABAA α2,3 agonist, using quantitative pharmacodynamic measurements in healthy subjects ΔVAS alertness AZD7325 2 mg AZD7325 10 mg Poster copy • Chen, X1,2, Jaeger, J 3*, Lappalainen, J 4, Maruff, P 3, Smith, MA 5*, Cross, AJ4, van Gerven, JMA21Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, China; 2Centre for Human Drug Research ,Leiden, The Netherlands; 3Cogstate, Melbourne Australia and New Haven CT, USA;4AstraZeneca, R&D, Wilmington Delaware and Cambridge MA; 5Shire Pharmaceuticals, PA, USA 90.00 low high • INTRODUCTION • Does AZD7325, a novel α2,3-subtype selective GABAA modulator produce a benzodiazepine-like profile on cognition and neurophysiologic biomarkers at doses that result in high GABAA receptor occupancy? • RESULTS • Neither dose of AZD7325 affected VASalertness, SPV, sway, smooth pursuit, tracking, or any cognitive measures (Figure 1), which were all robustly impaired by lorazepam 2mg (all p<0.05). • The slopes of the regression lines were flatter for AZD7325, particularly for the ΔLog(Sway)-ΔSPV relation and the ΔVASalertness-ΔSPV relation, compared to lorazepam (Figure 2). 80.00 loraz placebo 70.00 60.00 • AIM • To investigate the effects of AZD7325 on cognitive, visuo-motor, neurophysiological and postural stability measures relative to lorazepam at doses that result in comparable or higher occupancy. 50.00 group mean (SE) Errors) 40.00 30.00 low 2.86 high • METHODS • Design: single-dose, randomized,double-blind, • 4-way crossover study in 16 healthy men • Treatments: AZD7325 10mg, AZD7325 2 mg, • Lorazepam 2 mg, Placebo • CogState battery: 2.84 loraz Identification 20.00 placebo 2.82 2.80 2.78 10.00 2.76 group mean (SE) speed (log10RT) 2.74 2.72 2.70 0.00 2.68 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 2.66 2.64 ΔSPV ΔSPV -3 -2 -1 0 1 2 3 4 5 6 7 8 9 hours hours Figure 2.:ΔSPV-ΔVASalertness and ΔSPV-Δlog(Sway) relation 1.00 0.95 0.90 0.85 0.80 • CONCLUSIONS • The characteristic ΔSPV-relative effect profiles of AZD7325 vs. lorazepam suggests anxio-selectivity related to α2,3-selective GABAAagonism. However, exploration of higher doses may be warranted. • The lack of effects on most CNS-PD parameters suggests lower cognitive and neurophysiological side-effect burden than non-selective benzodiazepines. 0.75 group mean (SE) prop correct (arcsine) 0.70 0.65 0.60 0.55 low Visual Learning Executive Functioning high 0.50 loraz 0.45 placebo 0.40 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 hours • CNS-PD test battery: • Neurophysiological function: saccadic peak velocity (SPV), smooth pursuit • Postural balance: Body sway • Eye-hand coordination: Adaptive tracking • Subjective effect: Visual analogue scales, VASalertness Figure 1:Group mean (+SE) performance on CogState measures at each of the time points. Note: Detection and Chase test profiles were very similar to that observed on Identification task, shown above. The authors report no conflicts of interest for this work