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Chronic Oral Study of Myosin Activation to Increase ... Eligibility Criteria – Inclusion ......
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HFSA, Las Vegas, Nevada; September 14 – 17, 2014 © Amgen Inc. 2014 Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): A Double-blind, Randomized, Placebo-controlled, Multicenter, Dose Escalation Study John R. Teerlink, 1 G. Michael Felker, 2 John J. V. McMurray, 3 Scott D. Solomon, 4 Maria Laura Monsalvo, 5 Daya Gulabani, 5 Qinfen Yu, 5 Fady I. Malik, 6 Jae B. Kim 5 1 Section of Cardiology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, CA, USA; 2 Division of Cardiology, School of Medicine, Duke University Medical Center, Durham, NC, USA; 3 Division of Cardiology and Medical Sciences, University of Glasgow, UK; 4 Harvard University, Boston, MA, USA; 5 Amgen, Thousand Oaks, CA, USA; 6 Cytokinetics, Inc., South San Francisco, CA, USA Background • Heart failure (HF) is a progressive disorder with a natural history punctuated by frequent recurrent hospitalizations and ultimately death. • 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 Study Organization COSMIC-HF: Primary Objectives • 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 • To characterize its pharmacokinetics (PK) over 20 weeks of treatment COSMIC-HF: Secondary 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 over 20 weeks of oral dosing with OM • To evaluate the effect over 20 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 References 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. COSMIC-HF is a Global Study Current Study Status COSMIC-HF: How to Participate and Key Sponsor Contact KEY Eligibility Criteria – Inclusion • Male/female ≥ 18 and ≤ 85 years of age • History of chronic stable HF and left ventricular systolic dysfunction (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% • At screening, NT-proBNP ≥ 200 pg/mL (≥ 23.6 pmol/L); ≥ 1200 pg/mL (≥ 141.6 pmol/L) 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 – Exclusion • 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 • Acute myocardial infarction, 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 m 2 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) Figure 1. Omecamtiv Mecarbil is a Novel, First-in-Class Cardiac Myosin Activator Figure 4. Figure 2. Dose Escalation Phase (Cohorts 1-3*) Figure 3. Expansion Phase • 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. Force-production Myosin Actin The Actin–Myosin Cycle Omecamtiv Increases the transition rate from weak to strong binding states COSMIC-HF Trial: Study Design • Multicenter, randomized, double-blind, placebo-controlled, dose escalation • Dose escalation phase to select 1 of 3 OM oral formulations in 2 dose escalation cohorts, compared with placebo BID, for 7 days each. – Cohort 1: 25 mg BID – Cohort 2: 50 mg BID – A third cohort (contingent) of 75 mg BID was determined not to be necessary based on pharmacokinetic data from cohorts 1 and 2 • Following completion of the escalation phase, an expansion phase to evaluate 20 weeks of administration of the selected formulation at 2 target dose levels • Up to approximately 530 subjects with HF and left ventricular systolic dysfunction – 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 450 subjects in expansion phase randomized 1:1:1 to receive the selected OM formulation at 1 of 2 target dose levels or placebo COSMIC-HF Trial: Study Design *Cohort 3 was contingent upon PK data from cohorts 1 and 2 and was not enrolled EOS = end of study; IP = investigational product Echo = echocardiographic parameters; EOS = end of study; IP = investigational product *Subjects randomized to omecamtiv mecarbil 50 mg BID target dose will initiate administration at 25 mg BID until week 8; pre-dose plasma omecamtiv mecarbil plasma concentrations and IP compliance at week 2 will determine whether subjects are up-titrated to 50 mg BID or remain at 25 mg BID. • 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 “Patient Questionnaire” to: Kelly Simmons Amgen Global Study Management +1 805 447 8038 [email protected] • Or contact the Global Study Manager Daya Gulabani Amgen Global Study Management Tel: +1 (805) 447-8619 Email: [email protected] • 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 • Data Monitoring Committee Chair: Marvin A. Konstam, MD, FACC Tufts Medical Center/Tufts University School of Medicine Boston, MA 02111 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) • 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 Omecamtiv Mecarbil Formulation B 10 Subjects Placebo 10 Subjects EOS Omecamtiv Mecarbil Formulation C 10 Subjects PK Sampling (Day): D1 D5 D6 D7 D9 D35 D8 D10 Randomization 1:1:1:1 Screening Period Maximally 30 days Omecamtiv Mecarbil Formulation A 10 Subjects IP Administration: D14 Mandatory Visit: Omecamtiv Mecarbil 25 mg BID 150 Subjects Placebo 150 Subjects EOS Omecamtiv Mecarbil 50 mg BID Target Dose* 150 Subjects Study Visits (Day, Week): D1 W2 W8 W12 W16 W20 W24 Randomization 1:1:1 Screening Period Maximally 30 days Echo: Intensive PK Sampling: IP Administration: Cohort 1 Cohort 2 Expansion Phase N 49 47 Enrolling Age (years), mean (SD) 66.5 (8.5) 63.9 (9.9) Enrolling Female, % 16 26 Enrolling Canada United States United Kingdom Germany Belgium Italy Lithuania Poland Czech Republic Hungary Bulgaria Australia Netherlands
Transcript of Chronic Oral Study of Myosin Activation to Increase ... Eligibility Criteria – Inclusion ......
HFSA, Las Vegas, Nevada; September 14 – 17, 2014© Amgen Inc. 2014
Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): A Double-blind, Randomized, Placebo-controlled, Multicenter, Dose Escalation Study
John R. Teerlink,1 G. Michael Felker,2 John J. V. McMurray,3 Scott D. Solomon,4 Maria Laura Monsalvo,5 Daya Gulabani,5 Qinfen Yu,5 Fady I. Malik,6 Jae B. Kim5 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, USA
Background• Heart failure (HF) is a progressive disorder with a natural history punctuated by frequent
recurrent hospitalizations and ultimately death.• 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
Study Organization
COSMIC-HF: Primary Objectives• 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• To characterize its pharmacokinetics (PK) over 20 weeks of treatment
COSMIC-HF: Secondary 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 over 20 weeks of oral dosing with OM
• To evaluate the effect over 20 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
References1. 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.
COSMIC-HF is a Global Study
Current Study Status
COSMIC-HF: How to Participate and Key Sponsor Contact
KEY Eligibility Criteria – Inclusion• Male/female ≥ 18 and ≤ 85 years of age• History of chronic stable HF and left ventricular systolic dysfunction (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%• At screening, NT-proBNP ≥ 200 pg/mL (≥ 23.6 pmol/L); ≥ 1200 pg/mL (≥ 141.6 pmol/L)
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 – Exclusion• 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• Acute myocardial infarction, 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)
Figure 1. Omecamtiv Mecarbil is a Novel, First-in-ClassCardiac Myosin Activator
Figure 4.
Figure 2. Dose Escalation Phase (Cohorts 1-3*)
Figure 3. Expansion Phase
• 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.
Force-production
MyosinActin
The Actin–Myosin Cycle
Omec
amtiv Increases the
transition rate from weak to
strong binding states
COSMIC-HF Trial: Study Design• Multicenter, randomized, double-blind, placebo-controlled, dose escalation • Dose escalation phase to select 1 of 3 OM oral formulations in 2 dose escalation cohorts,
compared with placebo BID, for 7 days each.– Cohort 1: 25 mg BID– Cohort 2: 50 mg BID– A third cohort (contingent) of 75 mg BID was determined not to be necessary based on
pharmacokinetic data from cohorts 1 and 2• Following completion of the escalation phase, an expansion phase to evaluate 20 weeks of
administration of the selected formulation at 2 target dose levels• Up to approximately 530 subjects with HF and left ventricular systolic dysfunction
– 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 450 subjects in expansion phase randomized 1:1:1 to receive the selected OM formulation at 1 of 2 target dose levels or placebo
COSMIC-HF Trial: Study Design
*Cohort 3 was contingent upon PK data from cohorts 1 and 2 and was not enrolledEOS = end of study; IP = investigational product
Echo = echocardiographic parameters; EOS = end of study; IP = investigational product*Subjects randomized to omecamtiv mecarbil 50 mg BID target dose will initiate administration at 25 mg BID until week 8; pre-dose plasma omecamtiv mecarbil plasma concentrations and IP compliance at week 2 will determine whether subjects are up-titrated to 50 mg BID or remain at 25 mg BID.
• 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 “Patient Questionnaire” to:
Kelly Simmons Amgen Global Study Management +1 805 447 8038 [email protected]
• Or contact the Global Study Manager Daya Gulabani Amgen Global Study Management Tel: +1 (805) 447-8619 Email: [email protected]
• 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• Data Monitoring Committee Chair: Marvin A. Konstam, MD, FACC Tufts Medical Center/Tufts University School of Medicine Boston, MA 02111 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)
• 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
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 BID150 Subjects
Placebo150 Subjects
EOSOmecamtiv Mecarbil 50 mg BID Target Dose*
150 Subjects
Study Visits (Day, Week): D1 W2 W8 W12 W16 W20 W24
Rand
omiza
tion
1:1:
1
ScreeningPeriod
Maximally30 days
Echo:
Intensive PK Sampling:IP Administration:
Cohort 1 Cohort 2 Expansion PhaseN 49 47 EnrollingAge (years), mean (SD) 66.5 (8.5) 63.9 (9.9) EnrollingFemale, % 16 26 Enrolling
Canada
United States
UnitedKingdom
Germany
BelgiumItaly
LithuaniaPolandCzech Republic
HungaryBulgaria
Australia
Netherlands
