UNCORRECTED PROOF 0055 A new translational, noninvasive cardiac risk biomarker — Index of cardiac electrophysiological balance (iCEB) from preclinical models to patients Hua Rong Lu a , David J. Gallacher a , Gan-Xin Yan b,c , Dieter Nuyens d , Stefan Janssens d a Janssen Pharmaceutical NV, Beerse, Belgium b Main Line Health Heart Center, Bryn Mawr, PA, USA c Lankenau Institute for Medical, Bryn Mawr, PA, USA d KU Leuven, Leuven, Belgium A new noninvasive biomarker-index of cardiac-electrophysiolog- ical balance (iCEB) was evaluated in different species including man. The values of iCEB (Mean ± SEM) vary according to the experimental condition: 9 ± 0 (n = 7, in isolated rabbit left ventricular wedge preparations), 6.2 ± 0.5 (n = 6 in isolated rabbit hearts), 4.8 ± 0.2 (n = 8 in anesthetized rats), 4.6 ± 0.1 (n = 7 in anesthetized guinea- pigs), 4.1 ± 0.2 (n = 8 in anesthetized rabbits), 5.5 ± 0.3 (n = 6 in anesthetized dogs), 6.8 ± 0.4 (n = 6 in anesthetized pigs) and 4.1 ± 0.5 (n = 15 in men), respectively. In isolated rabbit hearts and ventricular wedges, the IKr blocker (ibutilide; n = 6) largely increased iCEB and elicited a high incidence of early afterdepolarizations. The Na + channel blocker flecainide (n = 7) markedly reduced iCEB and elicited non-TdP-like ventricular tachycardia/fibrillation (VT/VF). iCEB was also significantly reduced in patients with genotype positive Brugada syndrome (n = 51) (3.57 ± 0.1 vs 4.16 ± 0.1 in the control, n = 47; p b 0.001) and significantly increased in the genotype positive patients with long QT syndrome (n = 64) (5.24 ± 0.5 vs 4.21 ± 0.5 in the control, n = 55; p b 0.001). These data suggest that iCEB is new, non- invasive and translational biomarker, which could potentially be used in preclinical animal models and in patients. doi:10.1016/j.vascn.2014.03.060 0056 Identification of altered cardiovascular function produced by a novel biologic compound in a stand alone safety pharmacology primate study Jonathan Renninger, Loren Kohrs, Eric Rossman, Dennis Murphy GlaxoSmithKline Pharmaceuticals, King of Prussia, PA, USA Safety Pharmacology (SP) in vivo studies with biotechnology- derived molecules, i.e. monoclonal antibodies (mAbs), are generally not conducted because of the perception that mAbs are highly selective for the target and would have no secondary pharmacologic effects. The ICH S6 guidance for the preclinical safety evaluation of biotechnology-derived pharmaceuticals states that SP studies are not required for the non-clinical testing of mAbs. A standalone SP study was conducted in primates to help define the mechanism of a car- diac lesion seen following a dose of a mAb that selectively inhibits ADAMTS5 activity. Assessments included an evaluation of arterial pressure, heart rate, ECG interval durations and ECG waveform analysis using a standard telemetered model. A single intravenous or subcutaneous dose of the mAb produced a dose-dependent increase in mean arterial pressure as well as cardiac conductance abnormal- ities. ECG waveform abnormalities included significant ST segment elevation and an increase in the frequency of ventricular abnormal- ities, including intraventricular conduction delay and VPC bigeminy. The ST segment elevation and increase in mean arterial pressure persisted for at least 4 weeks. A follow-up study was conducted to evaluate lower doses and to evaluate the effect of repeat dosing and affirmed the findings from the first study. In addition, an assessment conducted at approximately 4 months after dosing showed that the effects on pressure and ST elevation were still present in a majority of the animals. These results highlight the need to carefully evaluate the potential effects of mAbs on cardiovascular function prior to administration to humans. doi:10.1016/j.vascn.2014.03.061 0057 Using in vitro pharmacological profiling to inform safety pharmacology design: A case study Michael Rolf, Anna Cronin, Katie Stamp, Jackie Moors, Matthew Skinner, Jon Curwen, Jean-Pierre Valentin AstraZeneca, Macclesfield, UK In vitro pharmacological profiling of a lead compound (AZ1) in an Oncology indication following the ICH S9 route identified off-target activity at a range of molecular targets associated with cardiovascular effects. An integrated package of in vitro and in vivo studies was designed to investigate the potential for cardiovascular liabilities and characterise the mechanisms underlying effects seen in vivo. In an isolated canine myocyte assay, AZ1 enhanced sarcomere shortening, indicating a possible positive inotropic effect. In isolated rat aorta, AZ1 relaxed rings pre-constricted with phenylephrine. In anaesthetised guinea pigs, AZ1 increased heart rate and left ventricular contractility, whilst decreasing arterial blood pressure. With this cardiovascular profile, AZ1 was progressed into regulatory preclinical testing and an enhanced cardiovascular package was employed to further character- ise the compound. Previous findings were confirmed in the dog telemetry study, with increased heart rate, cardiac contractility and decreased blood pressure at free plasma concentrations within 10- fold of the predicted therapeutic free C max . In an in vitro rat isolated Langendorff heart model, AZ1 caused a small increase in coronary flow at 30-fold above the predicted therapeutic free C max , consistent with the effects observed in other studies. Monitoring of blood pressure on the GLP dog toxicology study further confirmed these observations. Using a science-driven approach to generate and integrate in vitro and in vivo data, resulted in the characterisation of AZ1 as a peripheral vasodilator. The understanding of the mechanism was crucial in informing the decision to proceed further into clinical development with this compound. doi:10.1016/j.vascn.2014.03.062 0058 Translational modelling of preclinical cardiovascular findings to patients James Yates, Michael Rolf, Elizabeth Martin, Katie Stamp, Gary Wilkinson, Glen Clack, Paul Howarth, Jean-Pierre Valentin AstraZeneca, Macclesfield, UK AZ1 was developed in an Oncology indication, for elderly pa- tients with life-threatening disease. The integrated preclinical data package showed that the compound was a peripheral vasodilator, with the potential to cause a significant drop in blood pressure in the efficacious dose range. A pharmacokinetic–pharmacodynamic (PK– PD) model was developed to describe cardiovascular effects in dogs. Abstracts 326