IQ-CSRC PROSPECTIVE STUDY RESULTS. Steve Riley, PharmD, PhD IQ-CSRC meeting December 12, 2014

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1 IQ-CSRC PROSPECTIVE STUDY RESULTS Steve Riley, PharmD, PhD IQ-CSRC meeting December 12, 2014

2 IQ-CSRC prospective study - Design 20 male and female healthy subjects 3 treatment periods 9 subjects were to receive each drug, 6 on placebo Target to have at least 6 on active and 5 on placebo Study drugs: 5 QT-positive drugs, well characterized from previous studies 1 QT negative Placebo Dosing on 2 days: Day 1: Dose intended to give app. 10 to 12 ms QTc effect Day 2: Dose intended to give app. 15 to 20 ms effect ECG methodology as in TQT studies Primary analysis: Based on exposure-response analysis

3 Number of evaluable subjects Day 1 Day 2 Ondansetron 9 9 Quinine 9 6 Dolasetron 9 9 Moxifloxacin 9 9 Dofetilide 9 9 Levocetirizine 8 8 Placebo 6 6 Quinine: 1 subject withdrew after dosing on Day 1 due to AEs 2 subjects not dosed on Day 2 due to QTc prolongation Levocetirizine: 1 subject withdrawn prior to dosing in Period 3 due to administrative exclusion criterion

4 Mean QTcF Day 1 Day 2 90% Mean QTcF 90% Ondansetron 12.2 (7.1, 17.4) 10.2 (4.0, 16.5) Quinine* 13.3 (4.2, 22.4) 22.1 (13.3, 30.9) Dolasetron 6.5 (1.5, 11.5) 12.2 (3.8, 20.5) Moxifloxacin 11.9 (6.3, 17.5) 33.4 (28.2, 38.6) Dofetilide 14.2 (9.0, 19.4) 24.5 (15.7, 33.3) Levocetirizine 1.8 (-4.1, 7.6) 3.1 (-4.6, 10.7) : confidence interval; ΔΔQTcF: Placebo adjusted change from baseline QTcF; *: After the 1st dose on Day 1, i.e. within 8 hours;

5 Criteria for the absence of hysteresis met for all drugs Test for nonlinearity not significant except for dofetilide An Emax model provided a better fit to dofetilide data based on AIC

6 Slope, mean ms per ng/ml Red bars denote observed median (IQR) QTcF within each concentration decile Cmax Day 1, ng/ml Projected QTc effect mean, ms Criteria * ** Met *: The positive slope is statistically significant **: QTc effect above 10 ms at the Cmax of Day 1 cannot be excluded ( using bootstrap, variability of Cmax included)

7 Slope, mean ms per ng/ml Red bars denote observed median (IQR) QTcF within each concentration decile Cmax Day 1, ng/ml Projected QTc effect mean, ms Criteria * ** Met *: The positive slope is statistically significant **: QTc effect above 10 ms at the Cmax of Day 1 cannot be excluded ( using bootstrap, variability of Cmax included)

8 Slope, mean ms per ng/ml Red bars denote observed median (IQR) QTcF within each concentration decile Cmax Day 1, ng/ml Projected QTc effect mean, ms Criteria * ** Met *: The positive slope is statistically significant **: QTc effect above 10 ms at the Cmax of Day 1 cannot be excluded ( using bootstrap, variability of Cmax included)

9 Slope, mean ms per ng/ml Red bars denote observed median (IQR) QTcF within each concentration decile Cmax Day 1, ng/ml Projected QTc effect mean, ms Criteria * ** Met *: The positive slope is statistically significant **: QTc effect above 10 ms at the Cmax of Day 1 cannot be excluded ( using bootstrap, variability of Cmax included)

10 QTcF (msec) E Slope, mean ms per ng/ml Dofetilide Concentration (ng/ml) Red bars denote observed median (IQR) QTcF within each concentration decile Dofetilide Concentration (ng/ml) Cmax Day 1, ng/ml Projected QTc effect mean, ms Criteria * ** Met *: The positive slope is statistically significant **: QTc effect above 10 ms at the Cmax of Day 1 cannot be excluded ( using bootstrap, variability of Cmax included)

11 QTcF based on descriptive statistics Day Peak QTc* (ms) *: Change from baseline QTcF analyzed by time point with a linear model with treatment as factor and baseline as covariate

12 *: QTc effect above 10 ms can be excluded at the geometric mean Cmax on Day 2 ( using bootstrap, variability of Cmax included) Slope, mean ms per ng/ml Red bars denote observed median (IQR) QTcF within each concentration decile Cmax Day 2, ng/ml Projected QTc effect mean, ms Criteria * Met

13 Drug Slope, mean ms per ng/ml Positive drugs (Day 1) Ondansetron Day 1 only Quinine Day 1 only Dolasetron Day 1 only Moxifloxacin Day 1 only Dofetilide* Day 1 only Negative drug (Day 2) Levocetirizine Day 2 only *: Slope from linear model for comparison.

14 *: Prediction from linear model for comparison. Predicted effect for dofetilide using Emax model: 11.6 ms; 90% 7.0 to 16.0 Drug Cmax Day 1, ng/ml Projected QTc effect mean, ms * * Ondansetron Positive drugs (Day 1) Day 1 only Quinine Day 1 only Dolasetron Day 1 only Moxifloxacin Day 1 only Dofetilide* Day 1 only Negative drug (Day 2) Levocetirizine Day 2 only

15 Drug Slope, mean ms per ng/ml Positive drugs (Day 1) Ondansetron Parallel Design (n = 7)** Quinine Parallel Design (n = 7) ** Dolasetron Parallel Design (n = 7) ** Moxifloxacin Parallel Design (n = 7) ** Dofetilide* Parallel Design (n = 7) ** Negative drug (Day 2) Levocetirizine Parallel Design (n = 6) ** *: Slope from linear model for comparison. **: subjects also dosed with placebo excluded

16 Drug Cmax Day 1, ng/ml Projected QTc effect mean, ms * * Positive drugs (Day 1) Ondansetron Parallel Design (n = 7)** Quinine Parallel Design (n = 7) ** Dolasetron Parallel Design (n = 7) ** Moxifloxacin Parallel Design (n = 7) ** Dofetilide* Parallel Design (n = 7) ** Negative drug (Day 2) Levocetirizine Parallel Design (n = 6) ** *: Prediction from linear model for comparison. Predicted effect for dofetilide using Emax model: 11.6 ms; 90% 7.0 to 16.0

17 Largest mean ΔΔPR interval: 8.9 ms for quinine on Day 1* 16 ms for quinine and dolasetron on Day 2 All other treatments, mean ΔΔPR was < 6 ms Largest mean ΔΔQRS interval after dosing with quinine and dolasetron: 7.7 ms for quinine on Day ms for dolasetron on Day 2 All other mean ΔΔQRS were < 5 ms *: During the first 8 hours on Day 1

18 All 5 positive drugs met the pre-specified criteria, i.e., the study was able to demonstrate a druginduced QT effect at the pre-specified dose The negative drug, levocetirizine, also met the criterion, i.e., a QT effect above 10 ms could be excluded Effect on PR and QRS intervals observed with quinine and dolasetron