IQ-CSRC Study Results -

Presentation to the CSRC Scientific Oversight Committee

December 4, 2014

Borje Darpo MD, PhD

Co-chair SoC

iCardiac Technologies

• CSRC has entered a collaboration with the IQ-consortium to

prospectively evaluate whether ‘Early QT assessment’ can be

used to generate QT data with the same confidence as the

TQT study

• A prospective study in healthy volunteers has been conducted

in a setting designed to provide similarities with a routine

single ascending dose (SAD) study

• The objective of the study is to evaluate whether ECG

assessment in early phase clinical studies can replace, or

serve as an alternative to the TQT study

Background

History of Project

CSRC Think Tank Meeting (Feb 2012)• https://www.cardiac-safety.org/think-tanks/november-2011/thinktank-

meeting-on-qt-assessment-in-early-clinical-development

FDA-IQ Clinical Pharmacology Leadership Meetings• May 2012. FDA’s retrospective analysis was presented and prospective

study was discussed as a path forward.• Sep 2012. Study design concepts and analyses were discussed. FDA

agreed to select drugs to be tested.

CSRC-IQ Clinical Pharmacology Collaboration (Dec 2012)• September 2013: FTF meeting with FDA at which design and analyses

were agreed.

CSRC-IQ Steering Committee

IQ Consortium Clinical Pharmacology Leadership Group

• Nenad Sarapa (Bayer)

• Venkat Jarugula (Novartis)

• Jim Keirns (Astellas)

• Charles Benson (Lilly)

CSRC

• Christine Garnett (Certara)

• Borje Darpo (iCardiac)

• Catherine Ortemann-Renon (Sanofi)

• Corina Dota (AstraZeneca)

OQT Working Group (SAP)

• Steve Riley (Pfizer)

• Georg Ferber (Consultant)

• DCRI• Cindy Green

FDA

• Kevin Krudys

• Lars Johannesen

• 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

IQ-CSRC prospective study - Design

Study treatments (1)

DrugTQT Study Design and

Results

Dose JustificationDay 1 Day 2

ZOFRAN

(ondansetron

HCl)

QTc interval prolongation was studied in a

TQT study. The maximum mean (95%

upper CI) difference in QTcF from placebo

after baseline-correction was 19.5(21.8)

ms and 5.6 (7.4) ms after 15 minute

intravenous infusions of 32 mg and 8 mg

ZOFRAN, respectively.

52 mg oral**

Dose has not been tested in TQT

study. Anticipated effect is 10 to

12 ms.

Expected Cmax: 281 ng/mL

32 mg given by 15

min IV infusionBased on TQT study

results, mean ΔΔQTc=

19.5 ms.

QUALAQUIN

(quinine

sulphate)

QTc interval prolongation was studied in a

double-blind, multiple dose, placebo- and

positive-controlled crossover study in

young (N=13, 20 to 39 years) and elderly

(N=13, 65 to 78 years) subjects. After 7

days of dosing with QUALAQUIN 648 mg

three times daily, the maximum mean

(95% upper confidence bound) differences

in QTcI from placebo after baseline

correction was 27.7 (32.2) ms.

648 mg oral**

In a PK study in HV (n=24) the

mean change from baseline QTc

at Tmax was 12 ms (from old

Qualaquin label).

The Cmax on day 1 is about 3.9

µg/mL with an expected increase

in QTc of 12 ms based on the

PK/PD model.

648 mg q8h x 4

After the 4th dose (75% of

Cmax), the anticipated

concentration is 5.1 µg/mL

and the anticipated QTc is

19 ms.

ANZEMET

(dolasetron)

QTcF interval was evaluated in a TQT

study with IV dolasetron. The maximum

mean (95% upper confidence bound)

differences in QTcF from placebo after

pre-dose baseline-correction were 14.1

(16.1) and 36.6 (38.6) ms for 100 mg and

supratherapeutic 300 mg ANZEMET

administered intravenously, respectively.

100 mg PO**

Target Cmax for hydrodolasetron

~ 278 ng/mL.

150 mg IV by 15

min infusionTarget Cmax ~ 440 ng/mL

**Dose suggested by FDA

Study treatments (2)

DrugTQT Study Design

and Results

Dose JustificationDay 1 Day 2

Moxifloxacin NA 400 mg po**

Mean ΔΔQTc = 10-14 ms

Target Cmax ~ 2.95 µg/mL

800 mg IV given

by 60 min IV

infusion

Mean ΔΔQTc = ~20 ms,

Tikosyn

(dofetilide)

Increase in QT interval is

directly related to dofetilide

dose and plasma

concentration. The

relationship in normal

volunteers between dofetilide

plasma concentrations and

change in QTc is linear, with

a positive slope of

approximately 15-25 ms per

ng/mL after the first dose.

0.125 mg oralΔQTc = 10 to 11 ms

Target Cmax ~ 0.7 ng/mL

0.25 mg oral ΔQTc = 20 ms

Xyzal

(levocetirizine)

(negative drug)

A QT/QTc study using a

single dose of 30 mg of

levocetirizine did not

demonstrate an effect on the

QTc interval.

5 mg(therapeutic dose)

30 mgSupra-therapeutic dose

evaluated in TQT study

Target Cmax ~ 1.3

µg/mL

**Dose suggested by FDA

Randomization and Study treatments

A: Ondansetron

B: Quinine

C: Dolasetron

D: Moxifloxacin

E: Dofetilide

F: Levocetirizine (negative)

P: Placebo

P1, P2, P3: Period 1, 2 and 3

Randomization scheme

2 cohorts; placebo pooled from both.

9 subjects on active and 6 on placeboCohort Subject Period 1 Period 2 Period 3

1 1 A B C

1 2 B C A

1 3 C A B

1 4 C B A

1 5 B A C

1 6 A C B

1 7 P C B

1 8 C P A

1 9 B A P

1 10 A B C

2 11 D E F

2 12 E F D

2 13 F D E

2 14 F E D

2 15 E D F

2 16 D F E

2 17 P F E

2 18 F P D

2 19 E D P

2 20 D E F

Objectives and Endpoints

Primary Objective:

• To study the effect of 6 marketed drugs on the QTc interval using

concentration effect modeling.

Secondary Objectives:

• To evaluate the safety of the two single doses of 6 marketed drugs in

healthy subjects.

• To evaluate the effect of the two single doses of 6 marketed drugs on heart

rate, QTc, PR and QRS intervals using a descriptive statistical analysis by

time point by dose.

• To evaluate the pharmacokinetics of the 6 marketed drugs in healthy

subjects

Primary endpoint:

• Change-from-baseline QTcF (∆QTcF)

Secondary endpoints:

• ∆∆QTcF by time point

• Categorical analysis of the QTc outliers

• Effects on heart rate, PR and QRS intervals.

Criteria for QT Assessment

Positive QT assessment(for the positive drugs in this study):

1. The QT effect is detected:

The upper bound of the 2-sided 90% confidence

interval (CI) of the projected placebo-corrected

∆QTcF is above 10 ms at the observed geometric

mean Cmax of the drug.

2. The slope of the ER relationship is statistically

significant:

The lower bound of the 90% confidence interval

for the slope of ∆∆QTcF vs. concentration is

above zero.

Negative QT assessment (to claim that a drug

is negative, e.g. levocetirizine):

• The upper bound of the confidence interval of

the predicted placebo-corrected ∆QTcF at the

observed geometric mean Cmax of the drug is

below 10 ms.0 2000 4000 6000 8000 10000

-10

-50

51

0

Concentration (ng/mL)

QT

CF

(m

s)

Median concentration quantilesMean (90% CI) predicted QTcF prolongation

Results, evaluable subjects

Number of evaluable subjects

Day 1 Day 2

Ondansetron 9 9

Quinine 8-9 6

Dolasetron 9 9

Moxifloxacin 9 9

Dofetilide 9 9

Levocetirizine 8 8

Placebo 6 6

Discontinuations:• 1 subject prior to Dosing on Day 1 of Period 3 due to unknown criminal record (completed

periods 1 and 2)

• 2 subjects before Day 2 due to prolonged QTc (returned for next period)

• 1 subject withdrew the evening of Day 1 (Period 3) prior to the 16hr PD dose The subject

was experiencing AEs of nausea, vomiting, and dizziness.

Top Line Results

• All 5 positive drugs met the prespecified criteria , i.e.

the study was able to demonstrate a drug-induced QT

effect at the dose identified by FDA

• The negative drug, levocetirizine, also met the

criterion, i.e. a QT effect above 10 ms could be

excluded

Results - 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

Prespecified criteria for model selection

• Criteria for the absence of hysteresis met for all drugs

• Test for nonlinearity non significant for all drugs except dofetilide For dofetilide, an Emax model provided a better fit to

the data based on AIC

Moxifloxacin – by timepoint analysis

Day Largest mean ∆∆QTc*

(ms)

1 11.9

2 33.4

Moxifloxacin – Exposure response analysis

Slope, mean

ms per ng/mL

LB 90% CI UB 90%

CI

Treatment effect

(intercept) ms

Cmax

Day 1,

ng/mL

Predicted QTc

effect mean,

ms

LB 90% CI UB 90% CI Criteria

0.0065 0.0059* 0.0072 2.3 1862 14.4 10.6 17.9** Met

*: The positive slope is statistically significant

**: QTc effect above 10 ms at the Cmax of Day 1 cannot be excluded

Red bars denote observed median (IQR) ∆∆QTcF within each concentration decile

Levocetirizine – Exposure response analysis

Slope, mean

ms per ng/mL

LB 90% CI UB 90%

CI

Treatment effect

(intercept) ms

Cmax

Day 2,

ng/mL

Predicted QTc

effect mean,

ms

LB 90% CI UB 90% CI Criterion

0.0014 -0.0013 0.0041 0.7 1005 2.1 -2.3 6.1* Met

*: QTc effect above 10 ms can be excluded at the geometric mean Cmax on Day 2

Results – primary and robustness

Drug

Slope,

mean

ms per

ng/mL

LB 90%

CI

UB 90%

CI

Treat-

ment

effect

ms

Cmax

Day 1,

ng/mL

Projected

QTc effect

mean, ms

LB

90%

CI*

UB

90%

CI*

Positive drugs (Day 1)

Ondansetron 0.033 0.025 0.042 0.2284

9.7 6.2 12.8

Day 1 only 0.032 0.022 0.043 0.3 9.5 7.2 13.5

Quinine 0.004 0.0034 0.0047 -3.03623

11.6 6.8 17.1

Day 1 only 0.004 0.0031 0.0051 -4.9 9.8 6.7 17.3

Dolasetron 0.021 0.013 0.028 3.1211

7.4 3.0 11.0

Day 1 only 0.016 0.0008 0.032 3.3 6.8 3.4 11.6

Moxifloxacin 0.0065 0.0059 0.0072 2.31862

14.5 10.5 17.7

Day 1 only 0.0045 0.0024 0.0065 3.4 11.7 10.6 17.9

Dofetilide* 22.2 18.9 25.6 1.10.42

10.5 6.3 14.9

Day 1 only 28.7 20.6 36.7 -0.9 11.3 6.1 14.6

Negative drug (Day 2)

Levocetirizine 0.0014 -0.0013 0.0041 0.71005

2.1 -2.3 6.1

Day 2 only 0.00042 -0.0032 0.0041 1.6 2.0 -2.6 6.0

*: Slope from linear model for comparison.

Predicted effect for dofetilide using Emax model: 11.6 ms; 90% CI 7.0 to 16.0

We propose using the same criteria as in the ICH E14 for QT assessment

adapted to exposure response analysis:

Criteria for negative QT assessment:

The upper bound of the 2-sided 90% confidence interval (CI) of the predicted

placebo-adjusted ∆QTcF is below 10 ms at clinically relevant plasma levels

of the drug.

The definition of clinically relevant plasma levels must be based on

observations in patients, including high plasma levels seen in the 'worst-case

scenario' and considerations are the same as when discussing the choice of the

supratherapeutic dose in a TQT study.

An advantage of QT assessment if performed in FIH studies is that often high

exposure to the drug is achieved, in many cases reaching maximum tolerated

levels and often higher than in any subsequent clinical trial.

Our proposal for QT assessment in early phase clinical studies

Our proposal for QT assessment in early phase clinical studies

We believe that a successful outcome of the study (as defined below for positive QT assessment) would provide evidence in support of a TQT waiver for drugs with a negative outcome in future phase 1 studies conducted in the same robust fashion (e.g. SAD or MAD studies with exposure response analysis)?

Do you agree?

FDA: Yes (with caveats and provisions)

Question asked at our previous FTF meeting with FDA (September/2013)

• Meeting with all key stakeholders at FDA held

October 8 to discuss results and FDA’s independent

analysis

• Results presented to ICH E14 Discussion group

• Results will be discussed on December 12 at a public

meeting at FDA’s White Oak campus Participation from regulators from all regions

Regulatory Activities

Accepted for publication in Clinical Pharmacology & Therapeutics

MY CONCLUSION

-

EXPECT CHANGE

Publications to-date stemming from the IQ-CSRC initiative

1. Darpo, B., Garnett, C. Early QT assessment - how can our confidence in the data be improved? Br J Clin Pharmacol 76, 642-648 (2012)

2. Darpo, B. et al. Cardiac Safety Research Consortium: Can the thorough QT/QTc study be replaced by early QT assessment in routine clinical pharmacology studies? Scientific update and a research proposal for a path forward.Am. Heart J 168, 262-272 (2014)

3. Darpo, B. et al. The IQ-CSRC prospective clinical Phase 1 study:"Can early QT assessment using exposure response analysis replacethe thorough QT study?“ Ann. Noninvasive Electrocardiol. 19, 70-81 (2014)

4. Ferber, Zhou, Darpo. Detection of QTc effects in small studies - Implications for replacing the thorough QT studyANE 2014; Nov 4. doi: 10.1111/anec.12227. [Epub ahead of print]

5. Darpo, B et al. Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase .Accepted for publication in CPT December, 2014