Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): Results from a Double-blind, Randomized, Placebo-controlled, Multicenter Study John R. Teerlink, 1 G. Michael Felker, 2 John J. V. McMurray, 3 Scott D. Solomon, 4 Maria Laura Monsalvo, 5 Jason Legg, 5 Fady I. Malik, 6 Narimon Honarpour 5 for the COSMIC-HF Investigators 1 San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA; 2 Duke University School of Medicine, Durham, NC; 3 University of Glasgow, Glasgow, UK; 4 Brigham & Women’s Hospital and Harvard Medical School, Boston, MA; 5 Amgen, Inc., Thousand Oaks, CA; 6 Cytokinetics, Inc., South San Francisco, CA, USA
Omecamtiv Mecarbil (OM) is a Novel Selective Cardiac Myosin Activator Mechanochemical Cycle of Myosin OM increases the entry rate of myosin into the tightly-bound, force-producing state with actin “More hands pulling on the rope” Increases duration of systole Increases stroke volume No increase in myocyte calcium No change in dP/dt max Force production No increase in MVO 2 Malik FI, et al. Science 2011; 331:1439-43
OM-induced Increases in Systolic Ejection Time (SET) Underlie the Improvements in Cardiac Function Healthy Volunteers Healthy Volunteers vs. Stable HF Patients Δ Stroke Volume (mL) C h a n g e fro m B a s e lin e S E T (m s e c ) Δ Fractional Shortening (% points) Δ Ejection Fraction (% points) 1. Teerlink JR, et al. Lancet 2011; 378: 667–75. Δ = placebo corrected 2. Cleland JGF, et al. Lancet 2011; 378: 676–83. change from baseline Mean ± SEM SEM, standard error of the mean Δ SET (msec)
COSMIC-HF Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure • Primary Objectives – To select an oral modified release formulation and dose for chronic twice daily (BID) dosing in patients with HFrEF (Escalation Phase) – To characterize pharmacokinetics (PK) over 20 weeks of treatment with selected formulation (Expansion Phase) • Secondary Objectives – To evaluate the safety and tolerability of the oral formulation – To measure changes in SET, stroke volume, left ventricular end- systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), and heart rate (HR) over 20 weeks of oral dosing – To evaluate the effect over 20 weeks of oral dosing on N-terminal pro-B-type natriuretic peptide (NT-proBNP)
Study Design Escalation Phase Expansion Phase Select a modified-release Evaluate a PK-based titration formulation and dose(s) regimen vs placebo Dosing for 7 days Dosing for 20 weeks Intensive PK Echocardiograms ~40 patients/cohort ~450 patients Cohort 1 Cohort 2 Expansion Cohort (3 formulations) (3 formulations) (1 formulation) Matrix-F 1 Matrix-F 1 25 mg BID 50 mg BID Matrix-F 1 25 mg BID Matrix-F 2 Matrix-F 2 25 mg BID 50 mg BID Matrix-F 1 25 mg then 50 mg BID SCT-F 2 SCT-F 2 25 mg BID 50 mg BID Placebo Placebo Placebo BID, twice a day
Expansion Phase 25 mg BID (n = 150) End of Study Visit Randomization Administration Screening End of IP 25 mg BID 50 mg BID (PK-titration; n = 149) 30 Days 1:1:1 Dose adjustment Placebo (n = 149) 12 Time (wk) 0 2 8 16 20 24 Study drug administration Dose escalation from 25 mg BID to 50 mg BID based on OM trough concentration at Week 2 Titration was blinded PK sampling Echo Intensive PK sampling Echo, echocardiographic parameters; IP, investigational product
Key Inclusion and Exclusion Criteria • Key Inclusion Criteria − ≥ 18 and ≤ 85 years of age − History of chronic HF − Treated with stable, optimal heart failure therapy − NYHA class II or III − LVEF ≤ 40% − NT-proBNP ≥ 200 pg/mL (≥ 1200 pg/mL if AFib at screening) • Key Exclusion Criteria − NYHA class IV − Severe uncorrected valvular heart disease − Acute MI, unstable angina, or persistent angina at rest within 30 days prior to randomization − Systolic BP > 160 mmHg or < 90 mmHg, or diastolic BP > 90 mmHg, or HR > 110 bpm or HR < 50 bpm at screening − eGFR < 30 mL/min/1.73 m 2 at screening AFib, Atrial fibrillation; BP, blood pressure; bpm, beats per minute; eGRF, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA; New York Heart Association
Key Baseline Demographics and Disease Characteristics 448 Patients Enrolled Placebo OM 25 mg BID All PK Titration (n = 149) (n = 150) (n = 149) Demographics Age (years), mean (SD) 64 (10) 63 (10) 63 (12) Male, % 80 85 84 White, % 91 95 94 Disease characteristics Ischemic heart disease, % 60 65 67 LVEF (%), mean (SD) 29 (7) 29 (8) 29 (7) NYHA class II, % 70 68 72 NYHA class III, % 30 32 28 Persistent atrial fibrillation or flutter, % 22 19 16 Diabetes mellitus, % 41 47 37 SD, standard deviation
Key Baseline Concomitant Medications and Lab Values Placebo OM 25 mg BID All PK Titration (n = 149) (n = 150) (n = 149) Laboratory parameters Troponin I (ng/mL), median 0.025 0.022 0.022 (Q1, Q3) (0.016, 0.041) (0.016, 0.039) (0.016, 0.042) NT-proBNP (pg/mL), median 1719 1538 1719 (Q1, Q3) (699, 3242) (634, 3427) (881, 3060) eGFR (mL/min/1.73m 2 ), mean (SD) 65 (19) 63 (19) 65 (19) Concomitant medications, % ACE inhibitors 71 69 65 ARBs 24 28 27 Beta-blockers 98 97 97 MRAs 59 58 63 Diuretics other than MRAs 84 85 90
Preliminary PK Results PK-titration PK-titration 25 mg OM 25 mg OM 25 to 50 mg OM All PK-Titration (n = 58) a (n = 78) a (n = 141) a Week 12 (n = 146) C predose, mean (SD), ng/mL 160 (72) 221 (87) 289 (126) 261 (116) C max, mean (SD), ng/mL 197 (75) 258 (85) 359 (137) 317 (141) • The maximum concentration was 453 ng/mL and 812 ng/mL for the 25 mg BID and the PK-titration groups, respectively. a includes data from only those subjects with available PK data C predose , concentration prior to OM administration; C max , maximum observed concentration
Efficacy of OM LS mean (SE) Change (msec) 4.0 40 40 8 SET Stroke Volume PK-Titration Group PK-Titration Group LS Mean (SE) Change (msec) LS Mean (SE) Change (mL) 3.5 35 6 p = 0.004 p < 0.001 30 3.0 30 p = 0.022 4 25 2.5 20 2.0 20 2 p = 0.001 15 1.5 0 10 10 1.0 -2 0.5 5 25 50 mg Placebo 25 mg 25 mg All PK 0 0.0 -4 25 mg 25 50 mg 25 mg All PK Placebo (no titration) Titration (no titration) Titration 7 PK-Titration Group 5 LVFS LVEF LS Mean (SE) Change (%) LS Mean (SE) Change (%) PK-Titration Group 6 4 p = 0.025 5 p = 0.063 p = 0.013 p = 0.017 3 4 3 2 2 1 1 0 0 25 50 mg Placebo 25 mg 25 mg All PK 25 50 mg 25 mg Placebo 25 mg All PK (no titration) Titration (no titration) Titration LVEF, left ventricular ejection fraction; LVFS, left ventricular fractional shortening; SE, standard error; SET, systolic ejection time
Efficacy of OM LVESD LVESV 0 0 LS Mean (SE) Change (mm) LS Mean (SE) Change (mL) -1 -5 -2 -10 -3 -4 p = 0.019 p = 0.173 -15 p = 0.005 -5 p = 0.003 -20 -6 -7 -25 25 50 mg 25 50 mg Placebo 25 mg 25 mg All PK Placebo 25 mg 25 mg All PK (no titration) Titration (no titration) Titration 1.5 10 LVEDD LVEDV LS Mean (SE) Change (mL) LS Mean (SE) Change (mm) 1.0 5 0.5 0 0.0 p = 0.190 -5 -0.5 -10 p = 0.062 -1.0 p = 0.021 p = 0.013 -15 -1.5 -2.0 -20 25 50 mg 25 50 mg Placebo 25 mg 25 mg All PK Placebo 25 mg 25 mg All PK (no titration) Titration (no titration) Titration LVESD left ventricular end systolic diameter LVEDD left ventricular end diastolic diameter LVESV left ventricular end systolic volume LVEDV left ventricular end diastolic volume
Efficacy of OM Heart Rate NT-proBNP 2 1000 800 LS Mean (SE) Change (pg/mL) 1 LS Mean (SE) Change (bpm) 600 0 400 200 -1 0 p = 0.218 -2 -200 -400 -3 -600 p = 0.007 p = 0.021 -4 -800 p = 0.007 -5 -1000 25 50 mg 25 50 mg Placebo 25 mg 25 mg All PK Placebo 25 mg 25 mg All PK (no titration) Titration (no titration) Titration NT-proBNP, N-terminal of the prohormone brain natriuretic peptide
Cardiac Troponin I PK-guided titration arm All PK Troponin I Placebo 25 mg 25 mg 50 mg Titration Pooled OM (n = 146) a (ng/mL) (n = 149) (n = 150) (n = 58) (n = 78) (n = 296) Baseline Median 0.025 0.022 0.024 0.021 0.025 0.022 Q1, Q3 0.016, 0.041 0.016, 0.039 0.016, 0.034 0.016, 0.046 0.016, 0.042 0.016, 0.040 Change to Week 20 Median 0.000 0.001 0.006 0.007 0.006 0.004 Q1, Q3 -0.007, 0.004 0.000, 0.012 0.000, 0.022 0.000, 0.024 0.000, 0.024 0.000, 0.019 Change to Week 24 Median 0.000 0.000 0.001 0.000 0.000 0.000 Q1, Q3 -0.006, 0.008 -0.002, 0.009 -0.002, 0.016 -0.005, 0.005 -0.003, 0.010 -0.003, 0.009 Number of increased troponin events adjudicated by CEC for MI = 0/278 • cTnI > 0.04 ng/mL (99%URL) when prior undetectable OR • cTnI > 0.03 ng/mL (10%CoV) greater than prior when prior detectable a Excludes 3 patients that were not dosed
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