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, Uni...
A Phase 2 Study of
Intravenous Omecamtiv Mecarbil,
A Novel Cardiac Myosin Activator,
In Patients With Acute Heart Failure
...
Omecamtiv Mecarbil (OM) is a Novel
Selective Cardiac Myosin Activator
Malik FI, et al. Science 2011; 331:1439-43.
Mechanoc...
Increases in Systolic Ejection Time
Underlie Increases in Cardiac Function
Δ Stroke Volume
(mL)
Δ Fractional Shortening
(%...
Objective:
•To evaluate the safety, pharmacokinetics/ pharmacodynamics,
and efficacy of IV omecamtiv mecarbil (OM) in pati...
Study Design: Sequential Dosing Cohort
Cohort 1 Cohort 2 Cohort 3
Omecamtiv
Placebo
1:1 Randomization (n≈200)
Omecamtiv
Pl...
Study Design
Placebo IVPlacebo IV
0 72484Time (hrs)
M A N D A T O R Y I N - H O S P I T A L S T A YM A N D A T O R Y I N -...
Key Inclusion and Exclusion Criteria
Key Inclusion Criteria
•Male/female ≥ 18 and ≤ 85 y
•History of HF and LVEF ≤40%
•Hos...
Primary:
•Dyspnoea symptom response (7-point Likert scale) through 48 hours
Secondary:
•Death (any cause) and/or worsening...
Characteristic
Pooled
Placebo
(N = 303)
Cohort 1
OM
(N = 103)
Cohort 2
OM
(N = 99)
Cohort 3
OM
(N = 101)
Age , mean (SD) 6...
Characteristic
Pooled
Placebo
(N = 303)
Cohort 1
OM
(N = 103)
Cohort 2
OM
(N = 99)
Cohort 3
OM
(N = 101)
Systolic BP (mmHg...
Responder defined as:
•Minimally, moderately or markedly better at 6 hours
AND
•Moderately or markedly better at both 24 a...
Primary Efficacy Endpoint:
Dyspnoea Response (Likert Scale)
Pooled Placebo
Response Rate
Ratio*
1.03 1.15 1.23
95% CI (0.7...
Supplemental Primary Analysis:
Dyspnoea Response (Likert Scale)
Paired Placebo
Response
Rate Ratio
1.02 1.02 1.41
95% CI (...
For Increases
of…
Response Rate
Ratio
Increases… 95% CI P-value
Dose*
50 mg total OM
administered
5.5% 0.7% – 10.6% 0.025
...
Within 7 days of IP initiation
Pooled
Placebo
(N = 303)
Cohort 1
OM
(N = 103)
Cohort 2
OM
(N = 99)
Cohort 3
OM
(N = 101)
D...
Pooled
Placebo
(N = 303)
Cohort 1
OM
(N = 103)
Cohort 2
OM
(N = 99)
Cohort 3
OM
(N = 101)
Dyspnoea Numerical Response AUC
...
Preferred Term
Patient Incidence, n (%)
Pooled
Placebo
(N = 303)
Pooled
OM
(N = 303)
Cohort 1
OM
(N = 103)
Cohort 2
OM
(N ...
Patient Incidence, n (%)
Pooled
Placebo
(N = 303)
Pooled
OM
(N = 303)
Cohort 1
OM
(N = 103)
Cohort 2
OM
(N = 99)
Cohort 3
...
Troponin-I Change from Baseline (ng/mL)
Compared with Pooled Placebo
Baseline TnI (ng/mL)
Pooled
Placebo Cohort 1 Cohort 2...
Omecamtiv Mecarbil Concentrations vs.
Troponin-I Maximal Change from Baseline
Red lines represent
linear regression line
a...
Adverse Events (AEs),
Patient Incidence, n (%)
Pooled
Placebo
(N = 303)
Pooled
OM
(N = 303)
Cohort 1
OM
(N = 103)
Cohort 2...
PK/PD Substudy Endpoint:
Change in Systolic Ejection Time (SET)
PK Concentration Bin Analysis Control
OM
Concentration
Bin...
Change in Heart Rate and SBP
PK Concentration Bin Analysis Control OM Conc. Bin 1 OM Conc. Bin 2 OM Conc. Bin 3
OM concent...
• Efficacy
– OM did not meet the 1° endpoint of dyspnoea relief
– Appeared to improve dyspnoea in Cohort 3
– Trends toward...
• Executive Committee:
– Michael Felker
– John McMurray
– John Teerlink (Chair)
• Steering Committee:
– John Cleland
– Ken...
Investigators
Joanna Szachniewicz, Mikhail Kotelnikov, Zhanna Kobalava, Jindrich Spinar, Veselin Mitrovic, Janos
Tomcsanyi...
Presenter Disclosure Information
of 28

Presenter Disclosure Information

Presenter Disclosure Information
Published on: Mar 4, 2016
Published in: Health & Medicine      
Source: www.slideshare.net


Transcripts - Presenter Disclosure Information

  • 1. 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. UCSF
  • 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, 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
  • 3. Omecamtiv Mecarbil (OM) is a Novel Selective Cardiac Myosin Activator Malik FI, et al. Science 2011; 331:1439-43. Mechanochemical Cycle of Myosin Force production Omecamtiv mecarbil increases the entry rate of myosin into the tightly-bound, force-producing state with actin “More hands pulling on the rope”
  • 4. Increases in Systolic Ejection Time Underlie Increases in Cardiac Function Δ Stroke Volume (mL) Δ Fractional Shortening (% points) Δ Ejection Fraction (% points) Δ = placebo corrected change from baseline Mean ± SEM 300 600 900 1200 -80 -40 0 40 80 120 160 Healthy Volunteers vs. Heart Failure Patients SET Heart Failure SET Healthy Volunteers [Omecamtiv mecarbil] (ng/mL) SET(msec) ChangefromBaseline Δ SET (msec) Cleland JGF, et al. Lancet 2011; 378: 676–83. Teerlink JR, et al. Lancet 2011; 378: 667–75. Healthy Volunteers
  • 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-AHF Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure
  • 6. Study Design: Sequential Dosing Cohort Cohort 1 Cohort 2 Cohort 3 Omecamtiv Placebo 1:1 Randomization (n≈200) Omecamtiv Placebo 1:1 randomization (n≈200) Placebo Omecamtiv 1:1 randomization (n≈200) DMC DMC Cohort 1 Cohort 2 Cohort 3 15 mg/hr @ 0-4 hr 3 mg/hr @ 4-48 hr Target: 230 ng/mL Cmax: 75-500 ng/mL SET: ~8-55 msec 20 mg/hr @ 0-4 hr 4 mg/hr @ 4-48 hr Target: 310 ng/mL Cmax: 125-700 ng/mL SET: ~14-78 msec 7.5 mg/hr @ 0-4 hr 1.5 mg/hr @ 4-48 hr Target: 115 ng/mL Cmax: 30-250 ng/mL SET: ~3-28 msec Pharmacokinetic simulations Teerlink JR, et al. Lancet 2011; 378: 667–75; Cleland JGF, et al. Lancet 2011; 378: 676–83.
  • 7. Study Design Placebo IVPlacebo IV 0 72484Time (hrs) M A N D A T O R Y I N - H O S P I T A L S T A YM A N D A T O R Y I N - H O S P I T A L S T A Y Day 30 EOSLoading Dose Omecamtiv mecarbil IVOmecamtiv mecarbil IV Month 6 * Randomisation within 24 hours of initial IV diuretic (Amendment 2) Randomised, double-blind, placebo-controlled, sequential cohort study 6 15 24 Day 6/ DC Study drug administration 1⁰ EP dyspnoea response PK sampling all subjects PK/PD sub-study Echo (PK/PD sub-study) Maintenance Dose 96 Cardiac troponin/CK-MB
  • 8. Key Inclusion and Exclusion Criteria 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) 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 Randomised within 24 hours of initial IV diuretic treatment
  • 9. 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 Efficacy Endpoints
  • 10. Characteristic Pooled Placebo (N = 303) Cohort 1 OM (N = 103) Cohort 2 OM (N = 99) Cohort 3 OM (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 Baseline Characteristics (1) * p < 0.05 for a difference in cohorts 1-3 Placebo arms compared to each other
  • 11. Characteristic Pooled Placebo (N = 303) Cohort 1 OM (N = 103) Cohort 2 OM (N = 99) Cohort 3 OM (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/1.73m2 ), 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) Baseline Characteristics (2) * p < 0.05 for a difference in cohorts 1-3 Placebo arms compared to each other; URL= upper reference limit
  • 12. 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)
  • 13. Primary Efficacy Endpoint: Dyspnoea Response (Likert Scale) Pooled Placebo Response Rate Ratio* 1.03 1.15 1.23 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 Overall p-value = 0.33 Pooled Placebo OM Cohort 1 OM Cohort 2 OM Cohort 3 DyspnoeaResponseRate (%Responders) 0 5 10 15 20 25 30 35 40 45 50 55 42% 47% 51% 41%
  • 14. Supplemental Primary Analysis: Dyspnoea Response (Likert Scale) Paired Placebo Response Rate Ratio 1.02 1.02 1.41 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 Cohort 1 OM OM OM 42%41% Cohort 2 47%46% Cohort 3 Placebo 51% 37% DyspnoeaResponseRate (%Responders) 0 5 10 15 20 25 30 35 40 45 50 55 PlaceboPlacebo p = NS p = NS p = 0.03
  • 15. For Increases of… Response Rate Ratio Increases… 95% CI P-value Dose* 50 mg total OM administered 5.5% 0.7% – 10.6% 0.025 Plasma concentration* 4000 hr*ng/mL AUC48h 6.4% 1.7% – 11.4% 0.007 Exploratory Analyses: Dose and Concentration Relationship to Dyspnoea Response * Adjusted for region, cohort, age, baseline NRS, presentation-randomisation duration (continuous)
  • 16. Within 7 days of IP initiation Pooled Placebo (N = 303) Cohort 1 OM (N = 103) Cohort 2 OM (N = 99) Cohort 3 OM (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 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. Pooled Placebo (N = 303) Cohort 1 OM (N = 103) Cohort 2 OM (N = 99) Cohort 3 OM (N = 101) Dyspnoea Numerical Response AUC through Day 6, mean (95% CI) 3.5 (3.3, 3.8) 3.5 (3.1, 3.9) 3.6 (3.2, 4.0) 3.7 (3.3, 4.0) Patient Global Assessment response, n (%) 127 (42) 44 (43) 48 (48) 51 (50) Length of initial hospital stay, median days (95% CI) 9 (8, 9) 8 (7, 9) 7 (7, 8) 9 (8, 10) Days alive out of hospital through 30 days, median (95% CI) 22 (21, 23) 23 (21, 24) 23 (23, 24) 22 (21, 23) NT-proBNP change from BL (pg/mL) at 48 hours, median (95% CI) -1805 (-2271, -1370) -2076 (-2746, -1292) -2161 (-4273, -1336) -1742 (-2517, -1017) Other Secondary Efficacy Endpoints All comparisons to Pooled Placebo not significant (p > 0.05)
  • 18. Preferred Term Patient Incidence, n (%) Pooled Placebo (N = 303) Pooled OM (N = 303) Cohort 1 OM (N = 103) Cohort 2 OM (N = 99) Cohort 3 OM (N = 101) Number of subjects reporting AEs of Supraventricular or Ventricular Tachyarrhythmia 34 (11.2) 26 (8.6) 13 (12.6) 5 (5.1) 8 (7.9) Supraventricular Tachyarrhythmias 20 (6.6) 10 (3.3) 6 (5.8) 0 (0.0) 4 (4.0) Atrial Fibrillation or Atrial Flutter 15 (5.0) 6 (2.0) 3 (2.9) 0 (0.0) 3 (3.0) Atrial Tachycardia 3 (1.0) 1 (0.3) 1 (1.0) 0 (0.0) 0 (0.0) Sinus Tachycardia 1 (0.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Supraventricular Tachycardia 2 (0.7) 4 (1.3) 3 (2.9) 0 (0.0) 1 (1.0) Ventricular Tachyarrhythmias 18 (5.9) 17 (5.6) 8 (7.8) 5 (5.1) 4 (4.0) Ventricular Arrhythmia 4 (1.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Ventricular Extrasystoles 1 (0.3) 2 (0.7) 1 (1.0) 1 (1.0) 0 (0.0) Ventricular Fibrillation 2 (0.7) 1 (0.3) 0 (0.0) 1 (1.0) 0 (0.0) Ventricular Tachyarrhythmia 0 (0.0) 1 (0.3) 1 (1.0) 0 (0.0) 0 (0.0) Ventricular Tachycardia 11 (3.6) 13 (4.3) 7 (6.8) 3 (3.0) 3 (3.0) Extrasystoles 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0) 1 (1.0) Supraventricular and Ventricular Tachyarrhythmias
  • 19. Patient Incidence, n (%) Pooled Placebo (N = 303) Pooled OM (N = 303) Cohort 1 OM (N = 103) Cohort 2 OM (N = 99) Cohort 3 OM (N = 101) Death 10 (3.3) 8 (2.6) 1 (1.0) 4 (4.0) 3 (3.0) Cardiovascular 10 (3.3) 8 (2.6) 1 (1.0) 4 (4.0) 3 (3.0) ACS/MI (fatal) 0 1 (0.3) 0 0 1 (1.0) All Rehospitalisations 37 (12.2) 29 (9.6) 11 (10.7) 11 (11.1) 7 (6.9) Acute MI 1 (0.3) 1 (0.3) 1 (1.0) 0 0 Unstable angina 0 0 0 0 0 Heart failure 19 (6.3) 22 (7.3) 6 (5.8) 11 (11.1) 5 (5.0) Other 18 (5.9) 7 (2.3) 4 (3.9) 0 3 (3.0) All Index hospitalisation MI (non-fatal) 2 (0.7) 5 (1.7) 1 (1.0) 0 4 (4.0) Investigator reported 0 (0.0) 2 (0.7) 0 (0.0) 0 2 (2.0) Troponin triggered 2 (0.7) 3 (1.0) 1 (1.0) 0 2 (2.0) Total MIs (Fatal + Rehosp + Nonfatal Index Hosp) 3 (1.0) 7 (2.3) 2 (1.9) 0 5 (5.0) 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 Baseline TnI (ng/mL) Pooled Placebo Cohort 1 Cohort 2 Cohort 3 Median 0.044 0.060 0.044 0.056 (Q1, Q3) 0.023, 0.080 0.028, 0.141 0.030, 0.084 0.026, 0.092 4 hours 15 hours 24 hours 48 hours Day 4 Day 6 Time TroponinChangefromBaseline(ng/mL) Q3 Median Q1 0.03 0.02 0.01 0.00 –0.01 –0.02 –0.03 –0.04 –0.05
  • 21. Omecamtiv Mecarbil Concentrations vs. Troponin-I Maximal Change from Baseline Red lines represent linear regression line and its +/- SE. Baseline troponin-I is adjusted. Omecamtiv mecarbil Cmax Omecamtiv mecarbil AUC0-48 p=0.83p=0.95 MaxTroponin ChangefromBaseline(ng/mL) MaxTroponin ChangefromBaseline(ng/mL) OM Cmax (ng/mL) OM Cmax (ng/mL) OM AUC0-48 (ng*hr/mL) OM AUC0-48 (ng*hr/mL) 0 200 400 600 800 1000 1200 1400 -40 -20 0 20 40 60 80 100 0 200 400 600 800 1000 1200 1400 -4 -2 0 2 4 0 10000 20000 30000 40000 -40 -20 0 20 40 60 80 100 0 10000 20000 30000 40000 -4 -2 0 2 4
  • 22. Adverse Events (AEs), Patient Incidence, n (%) Pooled Placebo (N = 303) Pooled OM (N = 303) Cohort 1 OM (N = 103) Cohort 2 OM (N = 99) Cohort 3 OM (N = 101) All AEs 187 (61.7) 175 (57.8) 73 (70.9) 49 (49.5) 53 (52.5) 3 most common AEs Cardiac Failure* 53 (17.5) 46 (15.2) 17 (16.5) 14 (14.1) 15 (14.9) Hypokalaemia 18 (5.9) 20 (6.6) 7 (6.8) 7 (7.1) 6 (5.9) Hypotension 14 (4.6) 24 (7.9) 14 (13.6) 5 (5.1) 5 (5.0) Serious AEs 69 (22.8) 66 (21.8) 24 (23.3) 24 (24.2) 18 (17.8) 3 most common serious AEs Cardiac Failure* 29 (9.6) 26 (8.6) 8 (7.8) 11 (11.1) 7 (6.9) Renal Failure Acute 4 (1.3) 6 (2.0) 2 (1.9) 2 (2.0) 2 (2.0) Hypotension 0 (0.0) 3 (1.0) 3 (2.9) 0 (0.0) 0 (0.0) Deaths 11 (3.6) 9 (3.0) 2 (1.9) 4 (4.0) 3 (3.0) AEs leading to discontinuation of IP 15 (5.0) 15 (5.0) 7 (6.8) 4 (4.0) 4 (4.0) 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) PK Concentration Bin Analysis Control OM Concentration Bin 1 OM Concentration Bin 2 OM Concentration Bin 3 OM concentration range (ng/ml) ≥88-200 >200-300 >300-787 Change in SET (msec) N(n) 45 (88) 10 (18) 15 (23) 12 (19) LS mean -6.7 16.6 26.9 46.4 Difference from control 23.4 33.6 53.2 95% CI (7.4, 39.4) (19.8, 47.4) (38.0, 68.3) p-value 0.005 <0.0001 <0.0001 Linear regression slope p < 0.0001 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 PK Concentration Bin Analysis Control OM Conc. Bin 1 OM Conc. Bin 2 OM Conc. Bin 3 OM concentration range (ng/ml) ≥88-200 >200-300 >300-787 Heart Rate (beats/min) LS means -4.3 -4.4 -6.3 -6.5 Difference from control -0.1 -2.0 -2.3 95% CI (-1.4, 1.1) (-3.6, -0.4) (-3.9, -0.6) p-value 0.835 0.016 0.008 Linear regression slope p < 0.0001 SBP (mmHg) LS means -4.6 -4.4 -4.0 -2.2 Difference from control 0.3 0.6 2.4 95% CI (-1.2, 1.7) (-1.2, 2.4) (0.6, 4.2) p-value 0.719 0.521 0.009 Linear regression slope p = 0.0017 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. • 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 Summary
  • 26. • Executive Committee: – Michael Felker – John McMurray – John Teerlink (Chair) • Steering Committee: – John Cleland – Kenneth Dickstein – Justin Ezekowitz – Gerasimos Filippatos – Marco Metra – Piotr Ponikowski Committees • Data Monitoring Committee: – Henry Dargie – Barry Greenberg – James Januzzi (Advisor) – Julie Johnson (Advisor) – Marv Konstam (Chair) – Joseph Massaro – Barry Massie
  • 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

Related Documents