UC SF A Phase 2 Study of Intravenous Omecamtiv Mecarbil, A Novel - PowerPoint PPT Presentation

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. UC SF

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, Piotr Ponikowski, 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

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

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)

ATOMIC-AHF A cute T reatment with O mecamtiv M ecarbil to I ncrease C ontractility in A cute H eart F ailure 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

Study Design: Sequential Dosing Cohort 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 Pharmacokinetic simulations Cohort 1 Cohort 2 Cohort 3 7.5 mg/hr @ 0-4 hr 15 mg/hr @ 0-4 hr 20 mg/hr @ 0-4 hr 1.5 mg/hr @ 4-48 hr 3 mg/hr @ 4-48 hr 4 mg/hr @ 4-48 hr Target: 115 ng/mL Target: 230 ng/mL Target: 310 ng/mL Cmax: 30-250 ng/mL Cmax: 75-500 ng/mL Cmax: 125-700 ng/mL SET: ~3-28 msec SET: ~8-55 msec SET: ~14-78 msec Teerlink JR, et al. Lancet 2011; 378: 667–75; Cleland JGF, et al. Lancet 2011; 378: 676–83.

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

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

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 5 th 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

Baseline Characteristics (1) Pooled Cohort 1 Cohort 2 Cohort 3 Placebo OM OM OM Characteristic (N = 303) (N = 103) (N = 99) (N = 101) Age , mean (SD) 66 (11) 65 (12) 67 (10) 68 (10) Gender – male, % 76 76 82 76 Region, % * Eastern Europe 53 45 56 62 North America 25 37 24 18 Australia 2 0 1 0 Western Europe 21 18 19 20 Ischaemic heart disease, % 62 62 59 66 Years from HF diagnosis, mean (SD) 6 (6) 6 (6) 6 (5) 6 (5) Most recent LVEF (%), mean (SD) 26 (8) 26 (8) 25 (7) 28 (7) Persistent Atrial Fibrillation or Flutter, % 33 29 32 36 Diabetes Mellitus, % 45 49 41 42 Hypertension, % 81 84 81 82 * p < 0.05 for a difference in cohorts 1-3 Placebo arms compared to each other

Baseline Characteristics (2) Pooled Cohort 1 Cohort 2 Cohort 3 Placebo OM OM OM Characteristic (N = 303) (N = 103) (N = 99) (N = 101) Systolic BP (mmHg), mean (SD) 119 (18)* 118 (18) 117 (17) 117 (15) Heart rate (beats/min), mean (SD) 78 (13) 78 (13) 79 (13) 78 (14) Dyspnoea Numerical Rating Scale (NRS), Mean (SD) 6 (2) 6 (2) 6 (2) 6 (2) ACE inhibitors/Angiotensin Receptor Blockers, % 78 79 74 84 Beta blocker, % 86* 90 87 90 Digoxin, % 20 28 26 22 Mineralocorticoid Receptor Antagonist, % 55 54 59 58 Ivabradine, % 3 4 4 6 Troponin-I, median (URL 0.04 ng/mL) 0.044* 0.060 0.044 0.056 NT-proBNP (pg/mL), median 9026 7674 10488 10416 eGFR (mL/min/1.73m 2 ), mean (SD) 53 (18)* 52 (18) 53 (19) 50 (18) Time from presentation to randomisation, mean (SD) 15 (8)* 12 (8) 16 (10) 15 (9) * p < 0.05 for a difference in cohorts 1-3 Placebo arms compared to each other; URL= upper reference limit

Primary Efficacy Endpoint Dyspnoea 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

Primary Efficacy Endpoint: Dyspnoea Response (Likert Scale) Pooled Placebo Overall p-value = 0.33 55 51% Dyspnoea Response Rate 47% 50 45 42% 41% (% Responders) 40 35 30 25 20 15 10 5 0 Pooled OM OM OM Placebo Cohort 1 Cohort 2 Cohort 3 Response Rate 1.03 1.15 1.23 Ratio* 95% CI (0.79, 1.35) (0.90, 1.47) (0.97, 1.55) *Ratio of response rate to Pooled Placebo p-value of a CMH test among all 3 Placebo arms = 0.32

Supplemental Primary Analysis: Dyspnoea Response (Likert Scale) Paired Placebo p = 0.03 p = NS 55 51% p = NS Dyspnoea Response Rate 47% 50 46% 45 42% 41% (% Responders) 40 37% 35 30 25 20 15 10 5 0 Placebo OM Placebo OM Placebo OM Cohort 1 Cohort 2 Cohort 3 Response 1.02 1.02 1.41 Rate Ratio 95% CI (0.74, 1.42) (0.76, 1.37) (1.02, 1.93) Response rate ratio: ratio of response rate to Placebo within each cohort

Exploratory Analyses: Dose and Concentration Relationship to Dyspnoea Response Response Rate For Increases Ratio of… Increases… 95% CI P-value 50 mg total OM Dose* 5.5% 0.7% – 10.6% 0.025 administered Plasma 4000 hr*ng/mL 6.4% 1.7% – 11.4% 0.007 concentration* AUC48h * Adjusted for region, cohort, age, baseline NRS, presentation-randomisation duration (continuous)

Secondary Efficacy Endpoint: Worsening Heart Failure (WHF) Pooled Cohort 1 Cohort 2 Cohort 3 Placebo OM OM OM Within 7 days of IP initiation (N = 303) (N = 103) (N = 99) (N = 101) Death or WHF* Yes - n(%) 52 (17) 13 (13) 9 (9) 9 (9) Relative risk 0.67 0.54 0.54 (95% CI) (0.38, 1.18) (0.28, 1.04) (0.27, 1.08) p-value 0.151 0.054 0.067 WHF* Yes - n(%) 51 (17) 13 (13) 8 (8) 9 (9) Relative risk 0.68 0.49 0.55 (95% CI) (0.38, 1.21) (0.24, 0.98) (0.28, 1.09) p-value 0.179 0.034 0.075 *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