HFSA Congress, Orlando, FL; September 22-25, 2013© Amgen Inc. 2013

Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): A Double-blind, Randomized, Placebo-controlled, Multicenter, Dose Escalation Study

1Section of Cardiology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, CA, USA; 2Division of Cardiology, School of Medicine, Duke University Medical Center, Durham, NC, USA; 3Division of Cardiology and Medical Sciences, University of Glasgow, UK; 4Harvard University, Boston, MA, USA; 5Amgen, Thousand Oaks, CA, USA; 6Cytokinetics, Inc., South San Francisco, CA, USAJohn R. Teerlink,1 G. Michael Felker,2 John J. V. McMurray,3 Scott D. Solomon,4 Maria L. Monsalvo,5 Daya Gulabani,5 Lei Lei,5 Fady I. Malik,6 Jae B. Kim5

• Heart failure (HF) is a progressive disorder with a natural history punctuated by frequent recurrent hospitalizations and high mortality rates.

• HF is a condition most commonly marked by cardiac systolic dysfunction.• While several interventions have been shown to reduce the rate of HF hospitalizations and improve

mortality, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, aldosterone antagonists, coronary revascularization, and biventricular pacing,1 mortality and morbidity still remain high.

• Another target for treatment of HF is to improve myocardial contractility.2

• Omecamtiv mecarbil (OM) is a novel therapy to increase cardiac contractility. It increases stroke volume, decreases filling pressures, and improves ventricular volumes by increasing the left ventricular systolic ejection time, without increasing the rate of left ventricular pressure development or heart rate, and without noticeable effect upon myocardial oxygen uptake, blood pressure, or coronary blood flow.3-7

• OM increases entry rate of myosin into force-producing state; hence increasing the number of “force generators” (myosin heads) interacting with actin.4

• OM prolongs duration of systole.• OM increases stroke volume, decreases filling pressures, and improves left ventricular volumes.

• To select an oral modified release (MR) formulation and dose of OM for chronic twice daily (BID) dosing in subjects with HF and left ventricular systolic dysfunction (LVSD)

• To characterize its pharmacokinetics (PK) after 12 weeks of treatment

• Multicenter, randomized, double-blind, placebo-controlled, dose escalation • Dose escalation phase to select 1 of 3 OM oral formulations in at least 2 dose escalation cohorts,

compared with placebo BID, for 7 days each.– Cohort 1: 25 mg BID– Cohort 2: 50 mg BID– Cohort 3: 75 mg BID (will enroll depending on PK parameters achieved in cohorts 1 and 2)

• Following completion of the escalation phase, an expansion phase to evaluate 12 weeks of administration of the selected formulation at 2 dose levels

• Up to approximately 420 subjects with HF and LVSD– 40 subjects in each dose escalation cohort randomized 1:1:1:1 to receive 1 of 3 OM formulations (A, B,

or C) or placebo– Approximately 300 subjects in expansion phase randomized 1:1:1 to receive the selected OM

formulation at 1 of 2 dose levels or placebo

Background

COSMIC-HF: Primary Objectives

• To evaluate the safety and tolerability of oral OM• To measure changes in systolic ejection time (SET), stroke volume, left ventricular end-systolic diameter

(LVESD), left ventricular end-diastolic diameter (LVEDD), and heart rate after 12 weeks of oral dosing with OM

• To evaluate the effect of 12 weeks of oral dosing with OM on N-terminal pro-B-type natriuretic peptide (NT-proBNP)

• To evaluate the PK of OM metabolites with oral OM dosing

COSMIC-HF: Secondary Objectives

• Male/female ≥ 18 and ≤ 85 years of age• History of chronic HF (defined as requiring treatment for HF for a minimum of 4 weeks prior to screening)• Treated for HF with stable, optimal pharmacological therapy

– Optimal therapy will include a beta-blocker and an ACE inhibitor and/or an angiotensin receptor blocker at doses shown to be efficacious in HF trials, unless not tolerated.

– Stable therapy is defined as having no new HF drug class introduced or uptitrated ≤ 4 weeks prior to randomization.

• LVEF ≤ 40%• NT-proBNP ≥ 200 pg/mL (≥ 1200 pg/mL if the subject has atrial fibrillation at presentation)• Subjects enrolled in expansion phase must have NYHA class II or III symptoms and an acceptable image

quality of screening echocardiogram per central echo core laboratory

KEY Eligibility Criteria – Inclusion

• Cardiac resynchronization therapy (CRT) or implantable cardioverter defibrilator (ICD) implantation within 30 days prior to enrollment

• NYHA class IV• Hospitalization for any reason within 30 days prior to randomization• Likely to receive within 3 months after randomization, in the opinion of the Investigator, planned

revascularization, implantation of ICD or CRT, ventricular assist device, continuous or intermittent inotropic therapy, hospice care, or cardiac transplant

• Severe uncorrected valvular heart disease• Hypertrophic obstructive cardiomyopathy, active myocarditis, or constrictive pericarditis, or clinically

significant congenital heart disease• Unstable angina or persistent angina at rest within 30 days prior to randomization• Chronic antiarrhythmic therapy, with the exception of amiodarone• Routinely scheduled outpatient IV infusions for HF (eg, inotropes, vasodilators [eg, nesiritide], diuretics) or

routinely scheduled ultrafiltration• Systolic BP > 160 mmHg or < 90 mmHg, or diastolic BP > 90 mmHg, or HR > 110 beats per minute (bpm)

or HR < 50 bpm at screening• Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 at screening• Currently taking, or has taken a potent CYP3A4 inhibitor (within 14 days prior to randomization) or potent

CYP3A4 inducer (within 28 days prior to randomization)

KEY Eligibility Criteria – Exclusion

COSMIC-HF Trial: Study Design

COSMIC-HF is a Global Study

Study Organization

COSMIC-HF Trial: Study Design

1. Krum H, Teerlink JR. Medical therapy for chronic heart failure. Lancet. 2011;378:713-721.2. Hasenfuss G, Teerlink JR. Cardiac inotropes: current agents and future directions. Eur Heart J. 2011;32:1838-1845.3. Teerlink JR. A novel approach to improve cardiac performance: cardiac myosin activators. Heart Fail Rev. 2009;14:289-298.4. Malik FI, Hartman JJ, Elias KA, et al. Cardiac myosin activation: a potential therapeutic approach for systolic heart failure. Science.

2011;331:1439-1443.5. Shen YT, Malik FI, Zhao X, et al. Improvement of cardiac function by a cardiac myosin activator in conscious dogs with systolic heart failure.

Circ Heart Fail. 2010;3:522-527.6. Teerlink JR, Clarke CP, Saikali KG, et al. Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator,

omecamtiv mecarbil: a first-in-man study. Lancet. 2011;378:667-675.7. Cleland JG, Teerlink JR, Senior R, et al. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart

failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet. 2011;378:676-683.

References

Figure 1. Omecamtiv Mecarbil is a Novel, First-in-ClassCardiac Myosin Activator

Force-production

MyosinActin

The Actin–Myosin Cycle

Omec

amtiv Increases the

transition rate from weak to

strong binding states

COSMIC-HF Trial: How to Participate and Key Sponsor ContactFigure 2. Dose Escalation Phase (Cohorts 1-3*)

Figure 3. Expansion Phase

Figure 4.

*Cohort 3 is optional depending on PK parameters achieved in cohorts 1 and 2EOS = end of study; IP = investigational product

EOS = end of study; IP = investigational product

Omecamtiv Mecarbil Formulation B10 Subjects

Placebo10 Subjects

EOS

Omecamtiv Mecarbil Formulation C10 Subjects

PK Sampling (Day): D1 D5 D6 D7 D9 D35D8 D10

Rand

omiza

tion

1:1:

1:1

Screening Period

Maximally 30 days

Omecamtiv Mecarbil Formulation A10 Subjects

IP Administration:

D14Mandatory Visit:

Omecamtiv Mecarbil 25 mg or 50 mg BID100 Subjects

Placebo 100 Subjects

EOSOmecamtiv Mecarbil 50 mg or 75 mg BID

100 Subjects

Study Visits (Day, Week): D1 W1 W4 W8 W12 W16

Vita

l Sta

tus P

hone

Call

M6

Rand

omiza

tion

1:1:

1

Screening Period

Maximally 30 days

Echocardiogram:

Intensive PK Sampling:

IP Administration:

Canada

United States

UnitedKingdom

Germany

BelgiumItaly

LithuaniaPolandCzech Republic

HungaryBulgaria

Australia

Netherlands

• The COSMIC-HF Study is conducted by Amgen in collaboration with Cytokinetics.• Study Sponsor: Amgen Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Phone: +1 866 572 6436 FAX +1 805 480 1291 http://www.amgen.com• ClinicalTrials.gov NCT01786512

• If interested in becoming a study site, or interested in a list of sites in your area that are accepting patients for enrollment:

• Please complete and fax the “Interest Questionnaire” to: Kelly Simmons Amgen Global Study Management +1 805 447 8038 kelly.simmons@amgen.com• Or contact the Global Study Manager Daya Gulabani Amgen Global Study Management Tel: +1 (805) 447-8619 Email: daya.gulabani@amgen.com

• Executive Committee: John R. Teerlink, MD, FACC, FAHA, FESC, FRCP (Chair) San Francisco VA Medical Center/ UCSF San Francisco, CA 94121-1545 USA Michael Felker, MD, MHS, FACC Duke Clinical Research Institute Durham, NC 27710 USA John J V McMurray, MD, FRCP, FACC, FESC, FRSE Western Infirmary Glasgow G11 6NT, United Kingdom Scott David Solomon, MD Brigham & Women’s Hospital Boston, MA 02115 USA

• National Leaders: Kirkwood Adams (USA), John Cleland (United Kingdom), Justin Ezekowitz (Canada), Assen Goudev (Bulgaria),

Peter McDonald (Australia), Marco Metra (Italy), Veselin Mitrovic (Germany), Piotr Ponikowski (Poland), Jindrich Spinar (Czech Republic), Janos Tomcsanyi (Hungary), Hans Vanderckhove (Belgium), Adriaan Voors (Netherlands)

• Data Monitoring Committee Chair: Marvin A. Konstam, MD, FACC Tufts Medical Center/Tufts University School of Medicine Boston, MA 02111 USA