how did i get here? a perspective from a cardiologist in...

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How Did I Get Here? A Perspective From a Cardiologist in

Biotech

Fady Malik MD, PhD, FACCSenior Vice President

Research & Early DevelopmentCytokinetics

Associate Clinical ProfessorDivision of Cardiology

UCSF

My Scientific Roots

How lucky can one be? A perspective from a young scientist at the right place at the right timeRonald D Vale (2012 Lasker Awardee)Volume 18, Number 10, October 2012, Nature Medicine

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“Wonderful stuff – but I doubt this will have any use in medicine”- Fady Malik after handing in his thesis

10 Lessons for the Young Scientist1. Find good mentors, learn from them and then

develop your own style.2. Pick an important problem.3. Get ahead but then take a chance: seek adventure.4. Read the literature but don’t be crippled by it.5. You don’t need a fancy lab to do good science.6. Work hard, play hard and squeeze in time to do your

laundry.7. Persistence is more important than brilliance.8. No project or career is immune from mistakes.9. Don’t be afraid to change your life plans.10. Science is moving fast: hold on and enjoy the ride.

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Cytokinetics Corporate History

• Commenced operations in 1998 with focus to cytoskeletal biology• First to develop small molecule inhibitors of mitotic kinesins• Next focused on the discovery and development of novel small

molecule therapeutics that modulate muscle contractility• Strategic decision in 2008 to focus on a muscle biology portfolio• Located in South San Francisco, California• NASDAQ: CYTK (IPO in 2004)• To date, five drug candidates arising from the company’s research

activities have been progressed into clinical development• Corporate strategy:

• Fully-integrated biopharmaceutical company• First-in-class novel mechanism compounds

Rule #3: Get ahead but then take a chance: seek adventure.Rule #9: Don’t be afraid to change your life plans.

Pharmaceutical targeting of motor proteins has therapeutic potential!!!

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Indirect Mechanisms

Small Molecules Can Improve Cardiac Function…

PKA phosphorylates proteins throughout

the myocyte

Intracellular [Ca2+]increases

NE βAR

βarrestin

Giα

AD or MUSCReceptor

AC

HA

DChannel

I KACH

(L-type)

Gsαβ γ

Ca2+ Channel

AT1

Receptor Gαqβγ

All

Gαqβγ

α1 Receptor

NE

Adenylyl Cyclase

Ca2+ATPase

Metabolic Enzymes

Phospholamban

Phospholamban-P

Ca2+

Ca2+

SR

Ca2+ Release Channel

Cardiac Sarcomere

PKA

IonChannels

Ca2+

K+

(-)γβ

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… But They Compromise Cardiac Performance

Indirect MechanismsPKA phosphorylates proteins throughout

the myocyte

Intracellular [Ca2+]increases

NE βAR

βarrestin

Giα

AD or MUSCReceptor

AC

HA

DChannel

I KACH

(L-type)

Gsαβ γ

Ca2+ Channel

AT1

Receptor Gαqβγ

All

Gαqβγ

α1 Receptor

NE

Adenylyl Cyclase

Ca2+ATPase

Metabolic Enzymes

Phospholamban

Phospholamban-P

Ca2+

Ca2+

SR


Cardiac Sarcomere

PKA

IonChannels

Ca2+

K+

(-)γβ

ContractilityHeart rate

Blood PressureO2 DemandEfficiency

ArrhythmiasDobutamine (β-agonist), Milrinone (PDE3i)

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Potential Advantages of Targeting the Sarcomere

Effective Drug?

Therapeutic Hypothesis

Directly target the sarcomere

Ø PKA activation

Intracellular [Ca2+]unchanged

ContractilityHeart rate?

Blood Pressure?O2 Demand?Efficiency?

Arrhythmias?

NE βAR

βarrestin

Giα

AD or MUSCReceptor

AC

HA

DChannel

I KACH

(L-type)

Gsαβ γ

Ca2+ Channel

AT1

Receptor Gαqβγ

All

Gαqβγ

α1 Receptor

NE

Adenylyl Cyclase

Ca2+ATPase

Metabolic Enzymes

Phospholamban

Phospholamban-P

Ca2+

Ca2+

SR


PKA

IonChannels

Ca2+

K+

(-)γβ

Cardiac Sarcomere

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Why Focus on Cardiac Function?

Systolic dysfunction is at the “heart” of the matter

Renin-Angiotensin System

Sympathetic Nervous SystemCardiacContractility

Rule #2: Pick an important problem.Rule #4: Read the literature but don’t be crippled by it.

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Why Focus on Cardiac Function?

• Improving cardiac function works (at least for devices)!– Cardiac Resynchronization Therapy

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The SarcomereThe Basic Contractile Unit of Muscle

ThinFilament

ThickFilament

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The Sarcomere Can Be ReconstitutedIn Vitro Motility Assay

FluorescentActin/ThinFilaments

MyosinCoated

Glass SurfaceMyosinSpudich, et al, Nature 1985Toyoshima, et al, Nature 1987

KinesinVale, et al, Cell 1985

2012 Lasker Awardees

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High Throughput Screening of a Functional Sarcomere

Activator!

Malik and MorganJMCC 2011

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Lead Optimization is Complex!


Compound Design and

Synthesis

Assess In Vitro ActivityFunctional Cardiac Sarcomere

Cardiac Myocyte Profiling

Assess Drug-Like PropertiesDrug Metabolism and Pharmacokinetics

Solubility

Rule out Undesired ActivitiesAlteration of Ca2+ Transient

PDE III Inhibition

Demonstrate In Vivo ActivityRat Efficacy Model

Instrumented Dog Model of Heart FailurePreclinical evaluation

DrugCandidate

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Key Milestones Leading to Drug Candidate


N

O NH

NO2

O

FCK-0156636

N

O NH

F

O

NH

N

CK-1032100

N

O NH

F

O

NH

N

H3C O

CK-1122534

O NH

F

O

NH

NNSNO

OH3C

H3C

CK-1213296

NN

NH

O

NH

NH3CO

OCH3N

NNH

O

NH

NH3CO

OCH3

FCK-1317138 Omecamtiv Mecarbil

(CK-1827452)

1

2

3

4

5

>1700 Compounds Synthesized and Tested

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How Does a Cardiac Myosin Activator Work?The Chemical and Mechanical Cycles are Linked

The Actin–Myosin Cycle

Weak Binding to Strong Binding

Transition

Omecamtiv mecarbil increases the number of independent force generators (myosin heads) interacting with the actin filament

“More hands pulling on the rope”

Malik et al, 2011

Omecamtiv mecarbil increases the transition rate from

weak to strong binding states

10- 8 10- 7 10- 6 10- 5 10- 40

2

4

6

8

10

Omecamtiv mecarbil (mol/L)

k obs

(s-1

)

A + M + ATP A•M•ADP + Pi

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Omecamtiv MecarbilA Cardiac Myosin Activator

• Key Characteristics– Selective activator of cardiac myosin– Prolongs duration of systole by

o Increasing entry rate of myosin into force-producing stateo Thus increasing overall number of active cross-bridges

– No increase in myocyte calcium– Increases stroke volume– No change in dP/dtmax– No increase in MVO2

Omecamtiv Mecarbil(MW = 401.43)

Vale and Milligan, Science 2000

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Time-dependent Elastance [E(t)]

0

0.5

1.0

0 0.1 0.2 0.3 0.4

Time (sec)

Nor

mal

ized

E(t

) Dobutamine

Baseline

TEmax

TEmin

0 0.1 0.2 0.3 0.4

Baseline

Omecamtiv mecarbil

TEmin

TEmax

Time (sec)

0

0.5

1.0

MVO2 Increased MVO2 Unchanged

Omecamtiv Mecarbil: Dog Heart Failure Model Increases Duration but not Velocity of Contraction

Malik et al, 2011

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Clinical Experience with a Selective Cardiac Myosin Activator(Omecamtiv Mecarbil)

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CY 1111 Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous CK-1827452in Healthy Volunteers

Lancet 2011; 378: 667–75

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Increases in Systolic Ejection Time Underlie Increases in Cardiac Function

Systolic Ejection Time

500 1000 1500

-50

0

50

100

150

200

[omecamtiv mecarbil] (ng/mL)

Cha

nge

from

Bas

elin

e(m

secs

)

-5

0

5

10

15

20

0

4

8

12

16

0 20 40 60 80 100-4

0

4

8

12

Δ SET (msec)

Δ Stroke Volume(mL)

Δ Fractional Shortening(% points)

Δ Ejection Fraction(% points)

Δ SET (msec)Δ = placebo corrected change from baseline

Mean ± SEM

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CY 1121 Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous CK-1827452in Patients with Stable Heart Failure

Lancet 2011; 378: 676–83

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Increases in Systolic Ejection Time…

300 600 900 1200

-80

-40

0

40

80

120

160

24 hr1.5 hr

SET vs. [Omecamtiv Mecarbil] (ng/mL)Cohorts 1, 2, 3, 4, and 5 at times 1.5 and 24 hours

[Omecamtiv mecarbil] (ng/mL)

SET

(mse

c)C

hang

e fr

om B

asel

ine

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Baseline 24 hours

CY 1121: Effect of Omecamtiv Mecarbil in a Subject with Stable Heart Failure

24 hour infusionPeak [omecamtiv mecarbil] = 378 ng/mL

SET (msec) LVOT SV (mL) EF (%) HR (bpm) – supine ECG

Baseline 24 hrs Baseline 24 hrs Baseline 24 hrs Baseline 24 hrs

Omecamtiv mecarbil 216 311 23 54 18 23 88 57

Placebo 234 225 26 24 18 18 85 86

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The Systolic Ejection Time PK/PD Response is the Same in HF Patients and Healthy Volunteers

300 600 900 1200

-80

-40

0

40

80

120

160

Healthy Volunteers vs. Heart Failure Patients

SET Heart FailureSET Healthy Vol

[Omecamtiv mecarbil] (ng/mL)

SET

(mse

c)C

hang

e fr

om B

asel

ine

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Targeting Muscle ContractilityDiversity of Contractile Function

Smooth Muscle– Bronchial tone – Pulmonary vascular tone– Systemic vascular tone

– Strength– Mobility

Cardiac Muscle

Skeletal Muscle

– Ventricular ejection– Ventricular filling

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Targeting Muscle ContractilityDiversity of Therapeutic Application

Cardiac Muscle– Systolic heart failure– Diastolic heart failure

Smooth Muscle– Asthma/COPD– Pulmonary hypertension– Systemic hypertension

– Neuromuscular dysfunction– Muscle weakness/wasting

Skeletal Muscle

Russell et al, 2012

Rule #7: Persistence is more important than brilliance!Rule #10: Science is moving fast: hold on and enjoy the ride.

In Conclusion

While science is a combination of skill and luck...

In the fields of observation, chance favors only the prepared mind.

- Louis Pasteur, Lecture, University of Lille (7 December 1854)

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Acknowledgements

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• Too numerous to count…– A large group of people at Cytokinetics and Amgen

– Academic Collaborators

– Clinical Investigators

– Healthy Volunteers

– and of course the Patients for whom the therapy is intended

Rule #1: Find good mentors, learn from them and then develop your own style.

How Did I Get Here? �A Perspective From a Cardiologist in Biotech My Scientific Roots10 Lessons for the Young ScientistCytokinetics Corporate HistorySmall Molecules Can Improve Cardiac Function…… But They Compromise Cardiac PerformancePotential Advantages of Targeting the SarcomereWhy Focus on Cardiac Function?Why Focus on Cardiac Function?The Sarcomere�The Basic Contractile Unit of MuscleThe Sarcomere Can Be Reconstituted�In Vitro Motility AssayHigh Throughput Screening of a Functional SarcomereLead Optimization is Complex!Key Milestones Leading to Drug CandidateHow Does a Cardiac Myosin Activator Work?Omecamtiv Mecarbil�A Cardiac Myosin ActivatorSlide Number 17Clinical Experience with a Selective Cardiac Myosin Activator�(Omecamtiv Mecarbil)CY 1111 �Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous CK-1827452 in Healthy VolunteersIncreases in Systolic Ejection Time Underlie Increases in Cardiac FunctionCY 1121 �Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous CK-1827452 in Patients with Stable Heart FailureIncreases in Systolic Ejection Time…CY 1121: Effect of Omecamtiv Mecarbil in a Subject with Stable Heart Failure The Systolic Ejection Time PK/PD Response is the Same in HF Patients and Healthy VolunteersTargeting Muscle Contractility�Diversity of Contractile FunctionTargeting Muscle Contractility�Diversity of Therapeutic ApplicationIn ConclusionAcknowledgements

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