Industry Experience of the Concentration-QTc Relationship in Phase 1 Studies. Corina Dota, AstraZeneca

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1 Industry Experience of the Concentration-QTc Relationship in Phase 1 Studies Corina Dota, AstraZeneca CSRC-2 th February 2012

2 ICH E Alternative Strategies to Assess QT/QTc Interval Effects Alternatives to the use of the thorough QT/QTc study are under active investigation. Examples include evaluating the relationship between concentration and QT/QTc effects or more intensively evaluating ECGs, based on data collected during early phase clinical studies Analysis of Relationship Between Drug Exposure and QT/QTc Interval Changes Establishing the relationship of drug concentrations to changes in QT/QTc interval may provide additional information to assist the planning and interpretation of studies assessing cardiac repolarization. This area is under active investigation. 2 CSRC 2 Feb 2012

3 QT/QTc Evaluation in AstraZeneca: integrated risk-assessment In silico In vitro In vivo SAD MAD TQT Late-stage monitoring 3 CSRC 2 Feb 2012

4 Current strategy SAD/MAD Criteria for inclusion/exclusion, stopping and time table for frequent coordinated decg and PK measurements are set according to pre-clinical data. High quality decgs and time synchronized decg/pk measurements enable exploration of effects on decg parameters (PR interval, QRS duration, QT interval, RR) in relation to ascending drug concentrations in SAD/MAD studies. 4 CSRC 2 Feb 2012 TQT A negative thorough QT/QTc study is one in which the upper bound of the 95% one-sided confidence interval for the largest-time matched mean effect of the drug on the QTc interval excludes 10 ms. The methods for decg collection, analysis and choice of primary endpoint QTc may depend on drug properties, e.g. increase in heart rate.

5 Current strategy High quality decgs in SAD/MAD/TQT - same high quality and precision methodology for recording and analysis of 12 lead digital ECG recordings in SAD/MAD/TQT - EClysis - Analysis performed by a few, skilled, blinded analysts at a centralised ECG core laboratory - Known precision and variability of the methods and of the analysts 5 CSRC 2 Feb 2012

6 Current strategy: Overview of example of timepoints for decg in a SAD study The decg time points are adjusted to and reflect the PK time points, the decg (10 replicates of 10-sec recordings per 5 min period) are recorded immediately before draw of blood tests, BP measurements or other PD tests. 6 CSRC 2 Feb 2012

7 Questions: - How often do Phase I results fail to detect a signal when there is a positive TQT? - If there is a positive slope identified from Concentration- Response analysis (CR) of Phase I data, how different is that from the slope estimated from TQT data? CSRC-2 th February 2012

8 Case Studies Example 1 Pre-clinical evidence of QT/QTc prolongation risk of AZDxxx confirmed in SAD study herg data Dog telemetry data Predicted free C max at efficacious dose SAD QT/QTc prolongation in SAD compound stopped 8 CSRC 2 Feb 2012

9 Case Studies Example 1 Clinical verification of QT/QTc prolongation QT/QTc prolongation in SAD 9 CSRC 2 Feb 2012

10 Case Studies Example 2: Summary of QT/QTc evaluation in phase 1 studies for AZDyyy before the TQT study No clinically concerning cardiac issues Thorough review of digital ECG and 12 lead ECG data had been performed in phase 1 studies no issues identified No individual or mean changes above the categorical values of concern PK/PD modelling of all available decg data (single and multiple dose) suggested low likelihood of effect in TQT reaching the ICH E14 threshold 10 CSRC 2 Feb 2012

11 Case Studies Example 2 TQT study: 2 dose levels drug, active control and placebo Primary analysis demonstrates a negative TQT outcome at both doses of drug. All upper bounds of the 2-sided 90% CI are below 10 ms. (n= 59) Effect of therapeutic and supratherapeutic dose of AZDyyy on ΔΔQTcF 11 CSRC 2 Feb 2012

12 Case Studies Example 3 PK/PD in phase 1 and Negative TQT No statistically significant QTcF --- AZDzzz concentration relationship for a phase I study with 6D+2P subjects for each of 900 mg and 1260 mg doses No statistically significant QTcF --- AZDzzz concentration relationship for the TQT study for 900 mg dose (supratherapeutic dose) 12 CSRC 2 Feb 2012

13 Summary Preliminary analysis suggests that: Concentration-Response analysis of phase 1 data can detect small effects of compounds on QT/QTc, despite relatively small number of subjects, smaller number of placebo subjects, and absence of positve control for assay sensitivity Absence of effect and non-significant Concentration- QT/QTc relationship from phase 1 studies may indicate a negative TQT study No available in-house data allowing opportunity to evaluate predictivity (and magnitude of effect) of a positive TQT based on QT/QTc- Concentration modeling of phase 1 data 13 CSRC 2 Feb 2012

14 Participation in External Collaborations and Initiatives HESI- Proarrhythmia Working Group- main goal to study the predictive value of non-clinical studies for the outcome of the TQT study, with a sub-group compiling early clinical study data to compare with the TQT study outcome TI Pharma PK/PD modeling platform: University- Industry consortium Other initiatives in the industry 14 CSRC 2 Feb 2012

15 Current In-house Initiatives - Ongoing project: AZ Cardiovascular Exploration (ACE)- preclinical/clinical cardiovascular data exploration platform to enable evaluation of novel approaches to analysis and interpretation of CV data, including translational methodologies - Recently started Predictive Safety project to build a platform where predictive utility (quantitative assessment) of available data from early phase studies for the results of TQTs can be assessed and enhanced designs for SAD/MAD will be evaluated using Modeling and Simulation 15 CSRC 2 Feb 2012

16 Question: Can an integrated approach (preclinical and early clinical data) using a Modeling and Simulation approach (PK/PD and statistical) appropriately characterize the QT/QTc and therefore replace the TQT study for many or most compounds in development? A concerted effort is needed to collaboratively work on this important topic: - Retrospective data - Prospective project(s) 16 CSRC 2 Feb 2012

17 Thank you!