The end of the TQT era – the role of ion channel assays and systems models Derek Leishman, Global PK/PD & Pharmacometrics

Outline

Breaking down the original problem

The pieces of a new assessment

Bringing it all together

What would success look like?

Next Steps

THE PROBLEM

Torsade Silent in Drug Development

TdP Emerges

Post-marketing

Adult rats and mice don’t use

IKr for repolarization – Not Fatal in Rats

IKr block does not sufficiently prolong QTc in dogs – Not

Fatal in Dogs

TdP induced in primate self-reverts to sinus rhythm – Not

Fatal in Primates

hERG is pharmacologically promiscuous c.f. Cyp 3A4

hERG block favoured by lipophilic amines –

common pharmacophore for biobenic amine GPCR

targets

Promiscuity and shared binding to Cyps and PGP

raises DDI issue

TdP is sufficiently rare to be difficult to detect in

Phase 3

DDIs may be under-represented in clinical trials

Technology and understanding of QT

interval measurement was under-developed

How Big Was The Problem TdP Likely

TdP Possible

hERG Block

QTc prolongation

• hERG Block – 60-70% of compounds had hERG block IC50 <10µM?

• QTc Prolongation – 40% of compounds may have prolonged QTc by a small amount?

• TdP Likely – around 1% of approved drugs were withdrawn owing to TdP

• TdP Possible – around 10% of approved drugs may be linked to TdP under certain circumstances

• To find a small subset of molecules need a sensitive test but also a very specific test

• Need to be able to distinguish the special circumstances which make TdP more likely

Screening And Published Experience

Initial estimates suggest 60-70% of compounds may have had IC50<10µM.

Changing Chemical Space

Incidence of potent hERG block has diminished with time

y = -2.854x + 68.185 R² = 0.7913

0 10 20 30 40 50 60 70 80

0 5 10 15 20 25 Prop

ortio

n of

Tes

ted

Com

poun

ds

(%)

Time (Quarter Years)

Missed Cut (IC50 < 10 µM)

Trend over recent 5 year period

Human QTc vs. Log Concentration

1 10 100 1000 10000 100000-10

0

10

20

30

40

50

60

70

80

90

Chan

ge in

QTc

(ms)

Concentration (ng/ml)

dofetilide terodiline terfenadine cisapride sotalol halofantrine bepridil verapamil moxifloxacin E-4031

Key compounds in different therapeutic classes have been linked to QT prolongation. Prolongation is strongly concentration-dependent and large, passing 25ms and 10% change.

Correlation Between Human QTc & HERG

HERG IC50 vs QTc Change

y = 1.0109x - 0.6974R2 = 0.9075

4

5

6

7

8

9

10

4 5 6 7 8 9 10

-Log10 Concentration for 25ms QTc Change

-Log

10 H

ERG

IC50

Strong correlation between QTc prolonging (>25ms) concentrations and hERG IC50. Data suggests [(IC50)/5 ] associated with measurable QTc change.

Around IC15 in hERG assay gives 25ms QTc prolongation

Consistent with Jonker et al (2005) data on dofetilide

Physiological and Pharmacological Effects on QTc

Stimulus ΔHeart Rate ΔQTcf Reference Day/Night Difference -23 +27 Molnar et al (1996)

Standing from Supine +12 -18 Cuomo et al (1997)

Head Tilt +16 -5 Nakagawa et al (1999)

Hand Grip +7 +16 Frederiks et al (2001)

Exercise +67 -35 Davey et al (2000)

Food +11 +25 Nagy et al (1997)

Atropine +30, +35 +14, -12 Annila et al (1993), Cuomo et al (1997)

Propranolol -7 +3 Cuomo et al (1997)

Adrenaline +15 +39 Lee et al (2003)

Isoprenaline +22 +23 Cuomo et al (1997)

Autonomic Blockade +12, +31 -2, -6 Cappato et al (1993), Burke et al (1997)

Ganglion Blockade +30 +7 Diedrich et al (2002)

Based on literature reports and where necessary back converted to QTcF

Effects Of Manipulation Of Autonomic Tone Or Direct IKr Blockade On QTcF And HR

Direct

-40

-20

0

20

40

60

80

100

-40 -20 0 20 40 60 80 Change in Heart Rate (bpm)

Cha

nge

in Q

Tcf (

ms)

Atropine Atropine (2) Propranolol Isoprenaline

Adrenaline Autonomic Blockade Autonomic Blockade (2) Ganglion Blockade Exercise Day/Night Sotalol Terfenadine Terodiline Bepridil Mibefradil Verapamil

E-4031

Identifying Different Phenotypes

It appears at least 3 or 4 different phenotypes

may exist

The latter two categories may or may not be associated with

arrhythmias

How do we distinguish the first from the rest?

•hERG blockers with substantial QTc prolongation and associated with TdP •hERG blockers with substantial QTc prolongation and NOT associated with TdP •associated with non-direct effects on ion channels and some modest QTc prolongation •associated with effects on other ion channels and with some modest QTc prolongation

•current experience would suggest less likely to be undetected by current safety measures

Don’t Forget The PK In The PKPD

• Calculating a margin has been a common practice – focus on the quality of the numerator has also been

common (can you believe the IC50?) – What about the denominator?

• Need increased awareness of pharmacokinetics and physiologically-based PK – Understand the concentrations in the effect

compartment (cardiac cell) – Understand the potential for drug-drug interactions – Understand the potential ranges of exposure in

animals and man

THE COMPONENTS OF THE TESTING PARADIGM

Components

ICH S7B • Quality in vivo ECG

assessment • A hERG assessment

Quality QTc evaluation in man

(TQT or FHD)

PK understanding and PBPK CiPA

CIPA: Goal • Develop a new non-clinical paradigm for cardiac safety

evaluation of new drugs that utilizes high throughput methods and provides a more comprehensive assessment of direct proarrhythmic potential by: – evaluating effects on multiple cardiac ionic currents (inward and

outward currents) – provide a more complete (and accurate) assessment of potential

effects on human cardiac electrophysiology – Focus: proarrhythmia rather than QT prolongation

• Message to Pharma Industry: leverage nonclinical CV data

more – Implication: S7B core + CIPA → low risk → obtain waiver for

TQT study • Waiver would require robust QT data from Phase 1 studies

Comprehensive In Vitro ProArrhythmia Assay (CiPA) What It Is: Proposal to evaluate proarrhythmic risk based on mechanistic electrophysiologic understanding of proarrhythmia with two primary components

In vitro drug effects, multiple cardiac channels

In silico reconstruction of electrical effects

Confirmation using human stem-cell derived cardiomyocytes

What It is Not: Approach that negates well-controlled preclinical in vivo ECG assessment in preclinical studies

Nonclinical ECGs – CV study and/or toxicology study

Clinical ECGs

Understanding of PK

Current

Sodium Calcium (L-Type) Calcium (T-Type)

I TO1 I TO2 I Ks I Kr I Kur

Clone

hH1 α 1C α 1G

Kv4.2/4.3 ? KvLQT1 HERG Kv1.5

LQTS

LQT3

LQT1 LQT2

Acquired LQT?

+

+ +++

Adapted from Snyders (1999) Cardiovascular Research, 42, 377-390

Cardiac Ion Channels

Example Simulated Ventricular APs

Presentation Title | Date xx.xx.xx | Company Confidential © 2013 19

Which Ion Channels

Need a pragmatic solution

• Is it all ion channels possibly involved? •Most sensitive solution •How to put together •Most expensive solution

• Is it all channels where there is a single example compound modulator? • Is it those channels a medicinal chemist has the highest probability of having selectivity issues for? •More modest list • Less expensive •May need a fail safe – use substantial QTc prolongation in animals and man as the alert that something

may have been missed? Use a real cardiac myocyte recording as the fail safe? •Current plan will use a myocyte as a confirmatory step

A survey of pharma companies gathered a list perhaps most relevant to the middle category above •7 channels of interest currently chosen •Potential to narrow that list following initial work

Ion Channels Currently Included

• the common target of drugs known to cause torsade de pointes (TdP) hERG

•other key repolarization current, existing compounds known to block KvLQT1

•blockers known, impact conduction but also influence action potential morphology in other ways Fast sodium current

•known to impact QTc but less likely to be proarrhythmic (e.g. ranolazine) Late sodium current

•known blockers which may mitigate risk of TdP ICa – L type

•precedented block IT0

•key role in membrane potential maintenance and some precedented block IK1

Some Less Obvious Changes

Do we need a perfectly predictive protocol for each channel?

• Predictive of what? Shifting from trying to predict TQT outcome but need general active range relative to human heart exposure

• Need a protocol which can describe the affinity, kinetics and state-dependence of interaction of drug with the channel

Need an in silico model which can use this information

Will require some iterations in the modeling/ion channel and myocyte electrophysiology

Will need a protocol which is practical and sufficiently informative

CIPA: Science Questions • What is the index of proarrhythmia if it is not

simply a repolarization duration? • Which computational model? • What are the inputs to the model, is it likely

IC50 alone is insufficient? Need kinetic info? • Which myocyte, are stem cell-derived

cardiomyocytes a viable option? • Role of myocyte recordings, does a myocyte

only approach suffice?

BRINGING THE PIECES TOGETHER

Sensitivity and Specificity • The overall incidence of compounds associated

with torsade de pointes (TdP) is relatively low – Less than 1% of drugs approved since 1950

withdrawn – Around 10% of approved drugs having at least a

conditional link to TdP • Appear to have eradicated false negatives using

current paradigm but at the potential costs of many false positives

• IN A LOW PREVALENCE ENVIRONMENT FALSE POSITIVES ARE COMMON

• Need to emphasize specificity and will need a highly specific assessment paradigm – unlikely to be any single assay but a combination and integration of information

Effect of Specificity on Predictive Value Where Prevalence is Low (10%)

Prevalence set at 10% Sensitivity set at 99% 1000 compounds tested

Cost in False Positives and Negatives

Prevalence set at 10% Sensitivity set at 99% 1000 compounds tested

Integrated Risk • Guidelines invariably use expressions like “science-driven”, “case-

by-case” and “integrated” assessments • Integration often seems relatively basic – if two or more assays are

used it is often “AND” or “OR” type integration – Positive in either assay or in both

• Some assays or tests are inherently more informative or impactful – In clinical diagnostics the sensitivity and specificity combine in to a

Likelihood Ratio – Likelihood ratios can inform on the strength of a positive or negative

finding in indicating the likely presence or absence of a clinical outcome – Diagnosing whether a compound will prolong QTc or be proarrhythmic is

very analogous – Leads to a probabilistic type assessment – Likelihood ratios will integrate findings across multiple tests giving most

weight to the most informative test • May need an assay which is apparently of sensitivity >99% and a

specificity also >99% - this can be exceeded integrating 4 assays where these values are only 80%

Integrated Risk 2 • May need ‘strategy tables’ to differentiate testing paradigm used for

different types of drug molecules or targets – Already do little for large molecules – Drugs targeted to the CNS often have properties making ion channel

interaction more likely and often have larger exposure in the periphery than target potency in CNS

– Drugs targeted at ion channels will have selectivity limitations making off-target ion channel interactions more likely

– Already have experience that peripherally targeted receptor antagonists and enzyme inhibitors can successfully be made absent ion channel effects e.g. fexofenadine vs terfenadine

• Combining probabilistic assessments and strategy tables could give the desired case-by-case and integrated approach likely to be necessary in a way which can be easily communicated

• This also minimizes the overall cost in resources and time of testing without undermining quality

WHAT WOULD SUCCESS LOOK LIKE

Implementation Questions When a compound has a clinical or animal QT signal but no effect in the CIPA assay what do we conclude? •There is no evidence of proarrhythmic potential? •We’ve missed an ion channel activity? •Need clarity: what is to be considered a negative package?

What about a compound with +ve CIPA assessment but no QTc effect? Unlikely based on current hERG-oriented assessment but the CIPA assessment is new

Likely need the integrated assessment to differentiate the probability of being proarrhythmic AND the probability of prolonging the QT interval •Why both? •Demonstrating an understanding of both probabilities means that a QTc prolongation becoming apparent

in the clinic need not be alarming or confusing • If the proarrhythmia potential is predicted low and QTc prolongation is predicted high – Clinical QTc

prolongation if it occurred was anticipated • If both proarrhythmia and QTc prolongation potentials are predicted low – Clinical QTc prolongation if it

occurred would trigger more evaluations

Overall want to detect proarrhythmic compounds early, prioritize information gaps when data unclear and minimize lost opportunity cost of false positives

Next Steps

CiPA 1 Iterative interaction between in silico modeling – ion channel electrophysiology –

myocyte electrophysiology 2 Identify appropriate compound sets to build, test and validate the approach 3 Identify characteristics of myocyte electrophysiology indicative of TdP potential

IQ

Analyze and report results of FHD to TQT prediction study