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UC. SF. Presenter Disclosure Information. John R. Teerlink, M.D., F.A.C.C., F.A.H.A., F.E.S.C., F.R.C.P. Professor of Medicine, University of California San Francisco Director of Heart Failure, San Francisco Veterans Affairs Medical Center Financial Disclosure

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  1. UC SF Presenter Disclosure Information John R. Teerlink, M.D., F.A.C.C., F.A.H.A., F.E.S.C., F.R.C.P. Professor of Medicine, University of California San Francisco Director of Heart Failure, San Francisco Veterans Affairs Medical Center • Financial Disclosure • This study was funded by Amgen Inc. • J.R. Teerlink has received research grants and/or consulting fees from Amgen, Corthera, Cytokinetics, Merck, Novartis, Sorbent, and Trevena • Unlabeled/unapproved uses disclosure • Use of omecamtiv mecarbil in patients with heart failure is investigational. • The technical support of Karen Driver is acknowledged and was supported by Amgen Inc.

  2. A Phase 2 Study of Intravenous Omecamtiv Mecarbil, A Novel Cardiac Myosin Activator, In Patients With Acute Heart Failure John R. Teerlink, G. Michael Felker, John J. V. McMurray, PiotrPonikowski, Marco Metra, Gerasimos S. Filippatos, Kenneth Dickstein, Justin A. Ezekowitz, John G. Cleland, Jae B. Kim, Lei Lei, Beat Knusel, Andrew A. Wolff, Fady I. Malik and Scott M. Wasserman on behalf of the ATOMIC-AHF Investigators and Patients

  3. Omecamtiv Mecarbil (OM) is a Novel Selective Cardiac Myosin Activator Omecamtiv mecarbil increases the entry rate of myosin into the tightly-bound, force-producing state with actin “More hands pulling on the rope” Mechanochemical Cycle of Myosin Omecamtiv mecarbil Force production Malik FI, et al. Science 2011; 331:1439-43.

  4. Increases in Systolic Ejection Time Underlie Increases in Cardiac Function Healthy Volunteers Δ Stroke Volume (mL) Δ Fractional Shortening (% points) Δ Ejection Fraction (% points) Teerlink JR, et al. Lancet 2011; 378: 667–75. Cleland JGF, et al. Lancet 2011; 378: 676–83. Δ = placebo corrected change from baseline Mean ± SEM Δ SET (msec)

  5. Objective: To evaluate the safety, pharmacokinetics/ pharmacodynamics, and efficacy of IV omecamtiv mecarbil (OM) in patients with acute heart failure (AHF) Hypothesis: At least 1 dose level of IV OM will be well tolerated and will result in improvement of dyspnoea in subjects with left ventricular systolic dysfunction hospitalised for AHF ATOMIC-AHFAcute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure

  6. Study Design: Sequential Dosing Cohort Cohort 1 Cohort 2 Cohort 3 7.5 mg/hr@ 0-4 hr1.5 mg/hr @ 4-48 hr Target: 115 ng/mL Cmax: 30-250 ng/mL SET: ~3-28 msec 15 mg/hr@ 0-4 hr3 mg/hr @ 4-48 hr Target: 230 ng/mL Cmax: 75-500 ng/mL SET: ~8-55 msec 20 mg/hr@ 0-4 hr4 mg/hr @ 4-48 hr Target: 310 ng/mL Cmax: 125-700 ng/mL SET: ~14-78 msec Pharmacokinetic simulations Cohort 1 Cohort 2 Cohort 3 Omecamtiv Omecamtiv Omecamtiv 1:1 Randomization (n≈200) 1:1 randomization (n≈200) 1:1 randomization (n≈200) Placebo Placebo Placebo DMC DMC Teerlink JR, et al. Lancet 2011; 378: 667–75; Cleland JGF, et al. Lancet 2011; 378: 676–83.

  7. Study Design Randomised, double-blind, placebo-controlled, sequential cohort study Randomisation* 1:1 Presentation for AHF Screening Vital Status (phone call) Omecamtiv mecarbil IV Placebo IV M A N D A T O R Y I N - H O S P I T A L S T A Y 0 4 6 15 24 48 72 96 Day 6/DC Month 6 Day 30 EOS Time (hrs) Loading Dose Maintenance Dose Study drug administration 1⁰ EP dyspnoea response Cardiac troponin/CK-MB PK sampling all subjects PK/PD sub-study Echo (PK/PD sub-study) * Randomisation within 24 hours of initial IV diuretic (Amendment 2)

  8. Key Inclusion and Exclusion Criteria Key Exclusion Criteria • Receiving IV vasopressor, inotropic or mechanical support • Acute coronary syndrome (ACS) on presentation • Recent vascular event or cardiac procedure • Severe obstructive valvular or myocardial disease • BP >160/100 or SBP <90 mmHg, or HR >110 or <60 bpm • eGFR (MDRD) <20 mL/min/1.73m2 Key Inclusion Criteria • Male/female ≥ 18 and ≤ 85 y • History of HF and LVEF ≤40% • Hospitalised for AHF requiring IV therapy • Dyspnoea due to HF at rest or with minimal exertion ≥2 hours after iv diuretic • Screening BNP ≥ 400 pg/mL or NT-proBNP ≥ 1600 pg/mL (BNP ≥ 600 pg/mL or NT-proBNP ≥2400 pg/mL, if the subject has atrial fibrillation) Randomised within 24 hours of initial IV diuretic treatment

  9. Efficacy Endpoints Primary: • Dyspnoea symptom response (7-point Likert scale) through 48 hours Secondary: • Death (any cause) and/or worsening heart failure within 7 days • Dyspnoea area under the curve (AUC) (baseline to 5th day or discharge) as measured by subject self-assessed Numerical Rating Scale (NRS) • Dyspnoea by 7-point Likert scale at each scheduled assessment • Patient Global Assessment response through 48 hours • Change from baseline in NT-proBNP • Length of initial hospital stay • Days alive out of hospital until day 30 PK/PD (Echo) Sub-study

  10. Baseline Characteristics (1) *p < 0.05 for a difference in cohorts 1-3 Placebo arms compared to each other

  11. Baseline Characteristics (2) *p < 0.05 for a difference in cohorts 1-3 Placebo arms compared to each other; URL= upper reference limit

  12. Primary Efficacy EndpointDyspnoea Response (Likert Scale) Responder defined as: • Minimally, moderately or markedly better at 6 hours AND • Moderately or markedly better at both 24 and 48 hours WITHOUT • Worsening heart failure or death for any cause by 48 hours

  13. Primary Efficacy Endpoint:Dyspnoea Response (Likert Scale)Pooled Placebo Overall p-value = 0.33 55 51% 47% 50 45 42% 41% 40 35 Dyspnoea Response Rate (% Responders) 30 25 20 15 10 5 0 OM OM OM Pooled Placebo Cohort 1 Cohort 2 Cohort 3 *Ratio of response rate to Pooled Placebo p-value of a CMH test among all 3 Placebo arms = 0.32

  14. Supplemental Primary Analysis: Dyspnoea Response (Likert Scale)Paired Placebo p = 0.03 p = NS 55 51% p = NS 47% 50 46% 45 42% 41% 37% 40 35 Dyspnoea Response Rate (% Responders) 30 25 20 15 10 5 0 Placebo OM Placebo OM Placebo OM Cohort 1 Cohort 2 Cohort 3 Response rate ratio: ratio of response rate to Placebo within each cohort

  15. Exploratory Analyses: Dose and ConcentrationRelationship to Dyspnoea Response * Adjusted for region, cohort, age, baseline NRS, presentation-randomisation duration (continuous)

  16. Secondary Efficacy Endpoint: Worsening Heart Failure (WHF) • *Worsening heart failure is defined as clinical evidence of persistent or deteriorating heart failure requiring at least one of the following treatments: • Initiation, reinstitution or intensification of IV vasodilator • Initiation of IV positive inotropes, or IV vasopressors • Initiation of ultrafiltration, hemofiltration, or dialysis • Initiation of mechanical ventilatory or circulatory support

  17. Other Secondary Efficacy Endpoints All comparisons to Pooled Placebo not significant (p > 0.05)

  18. Supraventricular and Ventricular Tachyarrhythmias

  19. Post-Randomization Adjudicated Events ACS/MI = Acute Coronary Syndrome/Myocardial Infarction. 66 patients had 73 positively adjudicated rehospitalisations.

  20. Troponin-I Change from Baseline (ng/mL) Compared with Pooled Placebo 0.03 0.02 0.01 0.00 –0.01 Troponin Change from Baseline (ng/mL) –0.02 Q3 –0.03 Median –0.04 Q1 –0.05 4 hours 15 hours 24 hours 48 hours Day 4 Day 6 Time

  21. Omecamtiv Mecarbil Concentrations vs. Troponin-I Maximal Change from Baseline Omecamtiv mecarbil AUC0-48 Omecamtiv mecarbil Cmax Red lines represent linear regression line and its +/- SE. Baseline troponin-I is adjusted. Max Troponin Change from Baseline(ng/mL) OM Cmax (ng/mL) OM AUC0-48 (ng*hr/mL) Max Troponin Change from Baseline(ng/mL) p=0.95 p=0.83 OM Cmax (ng/mL) OM AUC0-48 (ng*hr/mL)

  22. Adverse Events N = Number of patients in the analysis set; IP = Investigational Product. * Cardiac failure includes both “Cardiac failure” and “Cardiac Failure Congestive” Preferred Terms.

  23. PK/PD Substudy Endpoint:Change in Systolic Ejection Time (SET) Baseline systolic ejection time for all patients was 258 msec. N: number of patients in the bin, n: number of observations in the bin; Control = observations in Placebo + PK below quantification limit; PK bin concentration analysis: repeated measures analysis of covariance; Linear regression slope analysis: repeated measures multiple linear regression.

  24. Change in Heart Rate and SBP N: number of patients in the bin, n: number of observations in the bin. Heart rate measured by ECG. Control = observations in Placebo + PK below quantification limit. PK bin concentration analysis: repeated measures analysis of covariance. Linear regression slope analysis: repeated measures multiple linear regression.

  25. Summary • Efficacy • OM did not meet the 1° endpoint of dyspnoea relief • Appeared to improve dyspnoea in Cohort 3 • Trends towards reduction of worsening HF • Safety • Overall SAE profile and tolerability similar to placebo • Increase in troponin; no clear relationship to OM concentration • Numerical imbalance in MIs in Cohort 3 • No evidence of pro-arrhythmia • Pharmacology • PK similar to healthy volunteers and stable HF patients • Systolic ejection time significantly increased consistent with MOA • Small fall in heart rate & rise in systolic BP at higher doses

  26. Committees • Data Monitoring Committee: • Henry Dargie • Barry Greenberg • James Januzzi (Advisor) • Julie Johnson (Advisor) • Marv Konstam (Chair) • Joseph Massaro • Barry Massie • Executive Committee: • Michael Felker • John McMurray • John Teerlink (Chair) • Steering Committee: • John Cleland • Kenneth Dickstein • Justin Ezekowitz • Gerasimos Filippatos • Marco Metra • Piotr Ponikowski

  27. Investigators Joanna Szachniewicz, Mikhail Kotelnikov, Zhanna Kobalava, Jindrich Spinar, Veselin Mitrovic, Janos Tomcsanyi, Bela Merkely, Dinesh Gupta, Mason Weiss, Kalman Toth, Pranas Serpytis, Andrzej Wysokinski, Alain Cohen Solal, Kirkwood Adams, Michel Galinier, Gintare Sakalyte, Hans Vandekerckhove, Fedya Nikolov, Marco Metra, Steven Krueger, Boycho Boychev, Eustathios Iliodromitis, Ioannis Nanas, Jooyoung Shin, Javed Butler, Petar Lazov, Guy Proulx, Gaetano De Ferrari, Dmitry Zateyshchikov, Ivan Gordeev, Boris  Goloshchekin, Peter MacDonald, Borislav Atzev, Assen Goudev, Jan Belohlavek, Kumudha Ramasubbu, Nina Shehova-Iankova, Haissam Haddad, Richard Isnard, Kenneth Dickstein, Jadwiga Nessler, Svetlana Boldueva, Glenn Hamroff, John Morrow, Lynne Wagoner, Jiri Vitovec, Jans Stevlik, Stephen Gottlieb, Frank McGrew, Arthur Eberly, Thao Huynh, Henning Ebelt, Thomas Heitzer, Panagiotis Vardas, Dirk Lok, Sergey Tereshenko, Nina Novikova, Marian Hranai, Debra Weinstein, Eugene Chung, David Lanfear, Denise Barnard, Chetan Patel, Mark Dunlap, James Maher, Inder Anand, Marc Vanderheyden, Michel de Ceuninck, Ditmar Raev, Robert Stewart, Pavel Cervinka, Angelika Costard-Jäckle, Athanasios Manolis, Jaroslaw Kasprak, Vladimir Simanenkov, David Smull, Mitchell Saltzberg, Peter McCullough, Andrew Wilson, Filip Charlier, Serge Lepage, Justin Ezekowitz, Gordon Moe, Manohara Senaratne, David Zemanek, Pascal De Groote, Rémi Sabatier, Christian Hengstenberg, Tim Schäufele, Andreas Zeiher, Stephan  Felix, Dimitrios Alexopoulos, Bela Herczeg, Laszlo Zoltan, Eelko Ronner, Wlodzimierz Musial, Piotr Jankowski, Eugeny Shlyakhto, Tatyana Novikova, Elena Vasilieva, Arsenio Rodriguez, John Teerlink, Alexander Adler, Andrew McRae, Garrie Haas, Daniel Lenihan, Henry Krum, Carmine De Pasquale, Dariusz Korczyk, Aleksandra Bankova, Stefan Denchev, Debra Isaac, John David Parker, Veli-Pekka Harjola, Heikki Ukkonen, François Roubille, Gérald Roul, Michael Böhm, Ruth Strasser, Sebastian Maier, Gerhard Cieslinski, Hans-Georg Olbrich, Noemi Nyolczas, Maurizio Porcu, Claudio Fresco, Folkert Asselbergs, Lars Gullestad, Andrzej Rynkiewicz, Grigory Aroutiounov, Daniel Pella, Jozef Kaluzay, John Cleland, Hugh Bethell, Angus Nightingale, John McMurray, Philip Adamson, Todd Kovach, Jalal Ghali, Andrew Keller, Adrian Van Bakel, James Mudd, Gregory Ewald, Stephanie Dunlap, Edward McMillan, Freidoon Ghazi, Glenn Barquet, Joshua Larned, Rami Alharethi

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