LIVE WEBINAR: March 1, 2018 Sponsor: www.vivaquant.com Comprehensive assessment of ECG intervals and arrhythmias is now practical in both preclinical and clinical research studies. A subset of the available information is currently required by the FDA, and researchers are challenged to balance the value of knowing more against potential liabilities of evaluating and submitting incremental data. During this webinar, sponsored by VivaQuant, experts review advances in ECG safety assessment including reductions in interval measurement variability, reductions in confidence limits in concentration effect models and accurate reporting of up to 20 common arrhythmias. The clinical perspective is delivered by Dr. Jay W. Mason. He discusses reductions in interval measurement variability and confidence limits in concentration effect models and review the implications for clinical TQT studies and Phase I (IQ-CSRC) studies supporting TQT waivers, stressing why tighter confidence limits and more accurate measurements matter. Following, Mike Gralinski, CEO of CorDynamics, offers a preclinical perspective on the potential of incorporating detailed assessment of arrhythmias for every cardiovascular study, and shares his thoughts on how and when this additional information should be leveraged. He discusses the value of knowledge versus liability of disclosure, the potential value of pre-study arrhythmia screening and incorporating baseline/control arrhythmia assessment. Key topics covered during this webinar include: Opportunities to improve FDA acceptance of phase I (IQ-CSRC) studies in support of TQT waivers. How and when comprehensive arrhythmia assessment should be leveraged in preclinical safety assessment. Why accurate interval measurements and tighter confidence limits matter.

1. Improving Preclinical and Clinical Regulatory
Submissions Through Enhanced ECG Interval
and Arrhythmia Assessment
Experts in preclinical and clinical ECG safety
assessment discuss how advances in
arrhythmia detection and concentration
effects modelling improve study outcomes.
#LifeScienceWebinar #ISCxVivaQuant

2. Improving Preclinical and Clinical Regulatory
Submissions Through Enhanced ECG Interval
and Arrhythmia Assessment
#LifeScienceWebinar #ISCxVivaQuant
Michael Gralinski, Ph.D.
CEO and Co-Founder
CorDynamics
info@cordynamics.com
Jay W. Mason, MD
Professor of Medicine
University of Utah
jwm@jaymason.com

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5. Copyright 2018 J. Mason and InsideScientific. All Rights Reserved.
Jay W. Mason, MD
Professor of Medicine
University of Utah
jwm@jaymason.com
Concentration – ECG Effect Modeling:
Enhanced Measurement Methods
for Drug Development

6. 1. The Thorough QT Study (TQTS)
Required for most drug approvals
Prior to initiation of Phase 3
3. FDA CiPA Project
Comprehensive in vitro proarrhythmia assay project
ECG biomarkers: QTc, J-Tpeakc and Tpeak-Tend
2. Concentration-QT (C-ECG) modeling
An acceptable alternative to a TQTS (waiver)
First in Human dose escalation
The Electrocardiogram in Drug Development

7. The objective of this presentation is to examine two algorithms for
ECG biomarker measurements:
✓ The FDA algorithm
✓ The Rhythm Express algorithm (VivaQuant), in the context of C-ECG modeling
To do so, we will analyze a dataset with both software algorithms that was made
publicly available by the FDA.
✓ Twenty-two subjects
✓ 5-armed crossover design
✓ Treatments: Placebo, dofetilide, quinidine ranolazine and verapamil
Objective

8. Analytical Differences
FDA
Signal averaged beat to reduce noise
Intervals measured on a signal averaged
beat from 10-sec ECG
Decision tree, rule-based classification of
T-wave morphology
Use 1st derivative to identify T-offset
Tp is the largest detected peak in T-wave
(usually the first)
Rhythm Express
Spatially selective denoising
Intervals measured as the average of all
beat values from 10-sec ECG
Machine learning to classify T-wave
morphology
Detect T-offset using a wavelet-based
emphasis signal
Tp is the last significant peak prior to
offset

9. T-Wave Segmentation
Click here to watch the
webinar on-demand

10. • The two analysis methods yielded generally similar results.
o Dofetilide and quinidine (strong hERG K channel blockers) prolonged
QTc by lengthening both J-Tpc and Tp-Te to a similar degree.
o Ranolazine (K channel and late sodium blocker) had a minimal effect
on QTc because it shortened J-Tpc while lengthening Tp-Te.
o Verapamil (calcium and K) had little effect on the T-wave.
Clinical Pharmacology
& Therapeutics
Clinical Trial
Differentiating Drug-Induced Multichannel
Block on the Electrocardiogram:
Randomized Study of Dofetilide, Quinidine,
Ranolazine, and Verapamil
L Johannesen, J Vicente, J W Mason, C Sanabria,
K Waite-Labott, M Hong, P Guo, J Lin, J S Sørensen,
L Galeotti, J Florian, M Ugander, N Stockbridge,
D G Strauss
First published: 23 July 2014
Article
Comparison of Two Highly Automated ECG
Algorithms for Detection of Drug-Induced
Cardiac Ion Channel Block
Marina Brockway, Anthony A. Fossa, Jay W Mason
First published: 8 December 2017
• The similarity in results is a corroboration of FDA’s methods and findings.
• BUT, there were some interesting and important differences in certain
details of the findings.

11. FDA
Rhythm Express
Differences in Interval
Measurements
• No difference in the two methods for J-Tpc,
but QTcF and Tp-Te were shorter for
dofetilide and quinidine in the Rhythm
Express analysis compared to that of the
FDA.
• These shorter values are explained by two
evident differences in algorithm results:
• The FDA software often included part
or all of the U-wave, when present, as
part of the QT interval, resulting in
shorter mean QTcF for Rhythm Express.
• The FDA software usually identified the
first peak of bifid T-waves as Tpeak,
while Rhythm Express consistently
identified the second peak, resulting in
shorter Tp-Te for Rhythm Express.

12. 𝑠 𝑟 = ෍
𝑖=1
𝑝 𝑠𝑖
2
𝑝
Repeatability Standard Deviation
• The triplicate measurements at each time point were considered repeated measurements
• The absolute difference between measurement will be below the RSD with 95% probability
Differences in Measurement Consistency
Repeatability
SD FDA
Repeatability
SD RE
Percent
Difference
QTcF 5.85 5.79 1%
JTp 5.98 5.67 5%
TpTe 3.63 2.55 42%
Average 16%

13. 11 – 31% reductions in 95% CI for quinidine and dofetilide; 39% for dofetilide QTcF (not shown)
Visibly Smaller Confidence Intervals for RE

14. Effect of SD on
Sample Size
We want to detect test score
improvement from 75 to 80.
How many students are needed?
Null hypothesis µ = 75;
actual µ = 80; α = 0.05
33% improvement in SD reduces
sample size requirement from 57
to 23 (60%) to detect a mean
change of 5 (7%)

15. ↓ SD ↓ Sample Size ↓ ECG Number
16.6% 27.5% 52%
33% 50% 76%
Consider a crossover with 40 subjects with a ddQTcF SD of 12 msec and 3 ECGs per
time point. If the SD of ddQTcF can be reduced, either the required enrollment or
the required number of ECGs can be reduced without loss of power.
Effect of SD on Sample Size or Number of ECGs

16. ✓ The FDA method of concentration – effect analysis of QTcF and
T-wave segments was corroborated by performance of the same analyses
using Rhythm Express software.
✓ Both software methods can be used in concentration-effect modeling for drug
approval and for identification of the ion channels affected by the drug.
✓ Rhythm Express results had lower variance and therefore better repeatability.
This allows for reduced sample size or reduced number of ECGs.
✓ Given the emphasis in CiPA on pre-clinical studies, it would make sense to extend
the use of C-ECG modeling to preclinical animal models.
Conclusions

17. Thank you to our event sponsor, VivaQuant, LLC
VivaQuant provides continuous beat-
to-beat analysis services for
ambulatory ECGs from preclinical
and clinical research studies.
Services include restitution analysis,
predictive modeling, and complex
statistics.
More information >
VivaQuant AE-1010 software for
arrhythmia and beat-to-beat interval
analysis of preclinical ECGs is fast,
accurate, easy to learn, and easy to
validate - saving you time and
money. Process a 24-hour recording
in 10-20 seconds.
More information >
VivaQuant licenses MDSP technology
for select fields of use and is available
for both Windows PC platforms and
ultra-low-power ARM Cortex
embedded platforms for heart rate
measurement and arrhythmia
detection.
More information >
ECG Services ECG Analysis Software Technology Licensing

18. Advances in Fully Automated and
Semi-Automated Detection of
Arrhythmias in Preclinical Studies
Michael Gralinski, Ph.D.
CEO and Co-Founder
CorDynamics
info@cordynamics.com
Copyright 2018 M. Gralinski and InsideScientific. All Rights Reserved.

19. 1997: ICH M3
• ’safety pharmacology and pharmacodynamic studies should be conducted’
1997: ICH S6
• ’…to reveal any functional effects on the major physiological systems (e.g., cardiovascular…)…’
2000: ICH S7A
• 2.2.1: ’…(proarrhythmia is a common feature of antiarrhythmic agents)…’
• 2.7.2: ‘Effects of the test substance on the cardiovascular system should be assessed appropriately. Blood
pressure, heart rate, and the electrocardiogram should be evaluated. In vivo, in vitro and/or ex vivo
evaluations, including methods for repolarization and conductance abnormalities, should also be considered.’
• Note 3: ‘There is no scientific consensus on the preferred approach to, or internationally recognized guidance
on, addressing risks for repolarization - associated ventricular tachyarrhythmia (e.g., Torsade de Pointes).
Proarrhythmia - History

20. 2005: ICH S7B
• 2.2: ’proarrhythmic effects measured in isolated cardiac preparations or animals’
• 3.1.4: ‘Directly assessing the proarrhythmic risk of pharmaceuticals that prolong the QT interval would be a
logical undertaking.’’
2017, Pugsley et al, Journal of Pharm. and Tox. Methods 86 (2017) 34–43
1. 88% of pharmaceutical industry using ECG recordings from implantable telemetry
2. Yet only 22-44% of industry detailed attempt of arrhythmia examination
3. From the above, “have you encountered drug-induced arrhythmia?’:
PVC: 80% (dog), 59% (NHP) VT: 79% (dog), 58% (NHP)
VF: 55% (dog), 55% (NHP) AVB: 77% (dog), 41% (NHP)
4. WHAT IS HAPPENING IN THE 56-78% MISSING FROM POINT TWO??
5. ’Unfortunately, the sensitivity of pre-clinical safety models to drug-induced arrhythmia development has
been erroneously perceived to be lower than the sensitivity in the human population…’
Proarrhythmia - History

21. Case Study – 2007 (Roche)
Investigation of mechanism of drug-induced cardiac injury and torsades de pointes in cynomolgus monkeys.
DL Misner, C Frantz, L Guo, MR Gralinski, PB Senese, J Ly, M Albassam, KL Kolaja
BRITISH JOURNAL OF PHARMACOLOGY, 165 (8) April 2012, 2771–2786
• CCR5 antagonist two week repeat dosing resulted in morbidity and mortality in NHP
• Moderate myocardial degen lesions at >=250 mg/kg (out of 50, 250, 750 mg/kg)
• Effects at 250 mg/kg noted in tox study:
• 1F/2: Day 8 mortality (no other signs)
• 1M/2: euth. in extremis
• ECG (transient): decrease HR, increase PR and QTc
• No changes in hematology or clinical pathology
• Hypoactivity and CNS signs
• What caused the mortality in this study?
• What may have happened prior to mortality?
• Was there a biomarker?
Click here to watch the
webinar on-demand

22. Case Study – 2007 (Roche)
A follow up 2 and 8 day telemetry study was conducted in NHP…
• 0, 50 and 250 mg/kg
• 23 NHP total
• All subjects received vehicle Day 0, then separated to 3 groups as above
• Telemetry recorded continuously (24h for 3-10 days)
• Automated output of ECG intervals
However, MANUAL review of cardiac cycles to look for arrhythmias
• no reliable software in 2007
• Average HR24h of NHP is ~106
• Math tells us that in the above study….
• ~18,927,360 heart beats to analyze
Manual visual
review took multiple
scientists a few
weeks to complete!

23. Case Study –
2007 (Roche)
Here is what our scientists found…
Pre-Dose Day 1
Telemetry
#7428F
250 mg/kg

24. Case Study –
2007 (Roche)
Post-Dose Day 3
Telemetry
#7428F
250 mg/kg
Here is what our scientists found…

25. Case Study –
2007 (Roche)
6h Post-Dose Day 3
Telemetry
#7428F
250 mg/kg
Here is what our scientists found…

26. Case Study –
2007 (Roche)
Post-Dose Day 5
Telemetry
#7428F
250 mg/kg
Here is what our scientists found…

27. Case Study –
2007 (Roche)
4h Post-Dose Day 8
Telemetry
#7428F
250 mg/kg
Here is what our scientists found…

28. Here is what our scientists found…
after weeks of manual overread to identifyCase Study –
2007 (Roche)
4h Post-Dose Day 8
Fatal VF
Telemetry
#7428F
250 mg/kg

29. Case Study – 2007 (Roche)
1. What caused the mortality in this study?
• Fatal cardiac arrhythmia
2. What may have happened prior to mortality?
• ECG changes as soon as Day 3
3. Was there an identifiable biomarker?
• YES, but it took WEEKS of manual human
resources to identify
• Timelines extended, scientist ‘burn out’.
DL Misner, C Frantz, L Guo, MR Gralinski, PB Senese, J Ly, M Albassam, KL
Kolaja. Investigation of mechanism of drug-induced cardiac injury and torsades
de pointes in cynomolgus monkeys. BRITISH JOURNAL OF PHARMACOLOGY, 165 (8)
April 2012, 2771–2786

30. There must be a better way?
Case Study 2017

31. Subject Monkey 1 Monkey 2
Day Vehicle Low Dose Mid Dose High Dose Vehicle Low Dose Mid Dose High Dose
Mean % Sinus Rhythm 99.6 98.5 91 87.3 97.5 95.4 80.4 78.7
Ventricular Ectopy (#) 2 0 1 4 0 1 0 0
Late Beats (#) 15 287 1017 1265 345 749 8129 6288
Dropped Beats (#) 1 14 1350 95 4 9 112 163
SVE (#) 18 345 7299 10430 37 2918 14787 15668
Tachy (#) 0 0 0 0 0 0 0 0
Average 5 min Rate (#) 122 109 92 76 125 105 90 87
Brady (#) 0 0 0 5 0 0 24 48
Pause (#) 0 0 0 0 0 1 1 0
Compete AV Block (%) 0 0 0 0 0 0 0 0
Subject Monkey 3 Monkey 4
Day Vehicle Low Dose Mid Dose High Dose Vehicle Low Dose Mid Dose High Dose
Mean % Sinus Rhythm 99.5 98.8 97.3 92.1 99.9 86.5 82.1 86.5
Ventricular Ectopy (#) 1 0 0 1 1 2 0 7
Late Beats (#) 6 85 355 1128 27 196 692 657
Dropped Beats (#) 1 4 6 64 1 21 1 100
SVE (#) 94 923 3662 9340 6 214 1573 2253
Tachy (#) 2 2 3 1 0 0 0 0
Average 5 min Rate (#) 120 108 107 96 97 79 77 67
Brady (#) 0 0 0 0 0 18 71 418
Pause (#) 0 2 1 1 0 0 2 1
Compete AV Block (%) 0 0 0 0 0 3.6 17.8 4.8
VivaQuant Rhythm Express Software
Used previously in our labs
(ex: monkey CV study) to analyze
1:1 AV conduction
• Queried telemetry
waveforms to interrogate for
supraventricular arrhythmias
• Appx 2,800,000 cardiac
cycles analyzed by software
in minutes to hours
Internal Reference

32. Case Study – 2017: Cardiovascular Safety Study of “CorD1”
• Designed a subsequent dog CV safety
pharmacology study
1. Can we characterize the apparent
risk from the in vitro and in vivo
findings?
2. Can we stratify a monitorable ECG
change ideally PRIOR to AV block?
3. Can we quantitate ECG changes
with high degree of fidelity?
4. Can we identify dose-response to
the above?
• No appreciable antagonism against cardiac
ionic channels
• Including cardiac conduction mechanisms
• Toxicology studies identified ↑ in PR interval
and QRS duration
• Highest doses (HIGH+ mg/kg), included
visually apparent AV block
• Isolated rabbit heart subsequently showed
concentration-dependent…
• PR interval and QRS duration prolongation
• Negative inotropic activity
• Loss of 1:1 AV conduction

33. 1. ECG changes were
quantified with high
fidelity?
YES
 D / R?
YES
Case Study – 2017: Cardiovascular Safety Study of “CorD1”

34. Hour
offset SVE
VE (non
Prem)
VE
Prem
AV
Block
Wencke-
bach Brady Pause Tachy
VE
Bigeminy
VE
Couplets
VE
Runs
1 0 0 0 0 0 0 0 0 0 0 0
2 0 0 0 0 0 0 0 0 0 0 0
3 0 0 0 0 0 0 0 0 0 0 0
4 0 0 0 0 0 0 0 0 0 0 0
5 0 0 0 0 0 0 0 0 0 0 0
6 0 0 0 0 0 0 0 0 0 0 0
7 0 0 0 0 0 0 0 0 0 0 0
8 0 0 0 0 0 0 0 0 0 0 0
9 0.25 0 0 0 0 0 0 0 0 0 0
10 0 0 0 0 0 0 0 0 0 0 0
11 0 0 0 0 0 0 0 0 0 0 0
12 0 0 0 0 0 0 0 0 0 0 0
13 0 0 0 0 0 0 0 0 0 0 0
14 0 0 0 0 0 0 0 0 0 0 0
15 0 0 0 0 0 0 0 0 0 0 0
16 0 0 0 0 0 0 0 0 0 0 0
17 0 0 0 0 0 0 0 0 0 0 0
18 0 0 0 0 0 0 0 0 0 0 0
19 0 0 0 0 0 0 0 0 0 0 0
20 0 0 0 0 0 0 0 0 0 0 0
21 0.25 0 0 0 0 0 0 0 0 0 0
22 0 0 0 0 0 0 0 0 0 0 0
23 0.25 0 0 0 0 0 0 0 0 0 0
24 0 0 0 0 0 0 0 0 0 0 0
25 0 0 0 0 0 0 0 0 0 0 0
Control Average Arrhythmia (n=4) Mid Dose Average Arrhythmia (n=4)
Hour
offset SVE
VE
(non
Prem)
VE
Prem
AV
Block
Wencke-
bach Brady Pause Tachy
VE
Bigeminy
VE
Couplets
VE
Runs
1 0 0 0 0 0 0 0 0 0 0 0
2 0 0 0 0 0 0 0 0 0 0 0
3 0 0 0 0 0 0 0 0 0 0 0
4 0 0 0 0 0 0 0 0 0 0 0
5 0 0 0 0 0 0 0 0 0 0 0
6 0 0 0 0 0 0 0 0 0 0 0
7 0 0 0 0 0 0 0 0 0 0 0
8 0 0 0 0 0 0 0 0 0 0 0
9 0 0 0 0 0 0 0 0 0 0 0
10 0 0 0 0 0 0 0 0 0 0 0
11 0 0 0 0 0 0 0 0 0 0 0
12 0 0 0 0 0 0 0 0 0 0 0
13 0 0 0 0 0 0 0 0 0 0 0
14 0 0 0 0 0 0 0 0 0 0 0
15 0 0 0 0 0 0 0 0 0 0 0
16 0 0 0 0 0 0 0 0 0 0 0
17 0 0 0 0 0 0 0 0 0 0 0
18 0 0 0 0 0 0 0 0 0 0 0
19 0 0 0 0 0 0 0 0 0 0 0
20 0 0 0 0 0 0 0 0 0 0 0
21 0 0 0 0 0 0 0 0 0 0 0
22 0 0 0 0 0 0 0 0 0 0 0
23 0 0 0 0 0 0 0 0 0 0 0
24 0 0 0 0 0 0 0 0 0 0 0
25 0 0 0 0 0 0 0 0 0 0 0
2. Were ECG
changes
PRIOR to
arrhythmia?
YES
Case Study – 2017: Cardiovascular Safety Study of “CorD1”

35. Mid Dose Average Arrhythmia (n=4)
Hour
offset SVE
VE
(non
Prem)
VE
Prem
AV
Block
Wencke-
bach Brady Pause Tachy
VE
Bigeminy
VE
Couplets
VE
Runs
1 0 0 0 0 0 0 0 0 0 0 0
2 0 0 0 0 0 0 0 0 0 0 0
3 0 0 0 0 0 0 0 0 0 0 0
4 0 0 0 0 0 0 0 0 0 0 0
5 0 0 0 0 0 0 0 0 0 0 0
6 0 0 0 0 0 0 0 0 0 0 0
7 0 0 0 0 0 0 0 0 0 0 0
8 0 0 0 0 0 0 0 0 0 0 0
9 0 0 0 0 0 0 0 0 0 0 0
10 0 0 0 0 0 0 0 0 0 0 0
11 0 0 0 0 0 0 0 0 0 0 0
12 0 0 0 0 0 0 0 0 0 0 0
13 0 0 0 0 0 0 0 0 0 0 0
14 0 0 0 0 0 0 0 0 0 0 0
15 0 0 0 0 0 0 0 0 0 0 0
16 0 0 0 0 0 0 0 0 0 0 0
17 0 0 0 0 0 0 0 0 0 0 0
18 0 0 0 0 0 0 0 0 0 0 0
19 0 0 0 0 0 0 0 0 0 0 0
20 0 0 0 0 0 0 0 0 0 0 0
21 0 0 0 0 0 0 0 0 0 0 0
22 0 0 0 0 0 0 0 0 0 0 0
23 0 0 0 0 0 0 0 0 0 0 0
24 0 0 0 0 0 0 0 0 0 0 0
25 0 0 0 0 0 0 0 0 0 0 0
Hour
offset SVE
VE (non
Prem)
VE
Prem
AV
Block
Wencke-
bach Brady Pause Tachy
VE
Bigeminy
VE
Couplets
VE
Runs
1 0 0 0 0 0 0 0 0 0 0 0
2 0 0 0 0.75 0 0 0 0 0 0 0
3 0 0 0 0.25 0 0 0 0 0 0 0
4 0 0 0 0 0 0 0 0 0 0 0
5 0 0 0 0 0 0 0 0 0 0 0
6 0 0 0 0 0 0 0 0 0 0 0
7 0 0 0 0 0 0 0 0 0 0 0
8 0 0 0 0 0 0 0 0 0 0 0
9 0.25 0 0 0 0 0 0 0 0 0 0
10 0 0 0 0 0 0 0 0 0 0 0
11 0.25 0 0 0 0 0 0 0 0 0 0
12 0 0 0 0 0 0 0 0 0 0 0
13 0 0 0 0 0 0 0 0 0 0 0
14 0 0 0 0 0 0 0 0 0 0 0
15 0 0 0 0 0 0 0 0 0 0 0
16 0 0.25 0 0 0 0 0 0 0 0 0
17 0 0 0 0 0 0 0 0 0 0 0
18 0 0 0 0 0 0 0 0 0 0 0
19 0 0 0 0 0 0 0 0 0 0 0
20 0 0 0 0 0 0 0 0 0 0 0
21 0 0 0 0 0 0 0 0 0 0 0
22 0 0 0 0 0 0 0 0 0 0 0
23 0 0 0 0 0 0 0 0 0 0 0
24 0 0 0 0 0 0 0 0 0 0 0
25 0 0 0 0 0 0 0 0 0 0 0
High Dose Average Arrhythmia (n=4)
3. Were ECG
changes
PRIOR to
arrhythmia?
YES
Case Study – 2017: Cardiovascular Safety Study of “CorD1”

36. Subject Dose (mg/kg) IVCD Duration
J-point
Elevation Notes
A 0 N NA NA NA
B 0 N NA NA NA
C 0 N NA NA NA
D 0 N NA NA NA
A LOW N NA NA NA
B
LOW
N NA NA NA
C
LOW
N NA NA NA
D
LOW
N NA NA NA
A MID N NA NA NA
B
MID
N NA NA NA
C
MID
N NA NA NA
D
MID
N NA NA NA
A HIGH Y <5 hours post dose N NA
B
HIGH
N NA NA NA
C
HIGH
Y <6 hours post dose Y Sinus tachycardia
D
HIGH
N NA NA NA
4. Were ECG
changes
observed
PRIOR to
arrhythmia?
YES
Case Study – 2017: Cardiovascular Safety Study of “CorD1”

37. Summary: Integrated Risk Assessment of “CorD1”
• Progressive cardiovascular effect as dose (plasma levels) increased
• ↑ in PR interval and QRS duration
• Present in multiple animal models
• Dose (concentration) responsive
• Automated ECG and arrhythmia analysis delivered
• Characterization of the risk (ECG changes & arrhythmia burden)
• Stratified clinically monitorable ECG changes PRIOR to arrhythmia
• Allowed calculation of safety margin, inclusion of biomarker
Case Study – 2017: Cardiovascular Safety Study of “CorD1”

38. Conclusions
Automated ECG Interval Analysis and Arrhythmia Interrogation
1. Should be included on all IND enabling CV telemetry
assessments
• Arrhythmias are commonly encountered in
preclinical studies
• Critical component of the integrated CV risk
assessment
• Can readily compare pre-study/time control vs
active cohorts
2. Provides evidence vis a vis lack of pro-
arrhythmogenesis
• Somewhat limited by study design construct,
still vitally important
3. Stratify presence of rhythm disturbances
• Identify ‘escalation’ of arrhythmogenesis
(time and dose dependent)
• Interrogate presence and usability of ECG
‘biomarkers’ (ex: intervals)
4. Are also used in screening and non-GLP
paradigms
5. Results in MINUTES to HOURS, enabling critical
decision-making

39. #LifeScienceWebinar #ISCxVivaQuant
Michael Gralinski, Ph.D.
CEO and Co-Founder
CorDynamics
info@cordynamics.com
Jay W. Mason, MD
Professor of Medicine
University of Utah
jwm@jaymason.com
For additional information on the products and
applications presented during this webinar
please visit www.vivaquant.com
Thank You