Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure

Abigail Geyer, PharmD, PGY1 Pharmacy Resident

Epidemiology of Heart Failure 1

 Nearly 6.2 million adults have heart failure in the United States
o Lifetime risk of developing heart failure is 20% for adult Americans  40 years old
o Heart failure incidence increases with age
 Mortality and Hospitalizations
o In 2018, heart failure accounted for ~13.4% of US deaths
o Heart failure is the primary diagnosis in > 1 million hospitalizations annually
o Heart failure significantly decreases health-related quality of life
 Heart failure cost the nation over $30 billion in 2012

Guideline Directed Medical Therapy for Systolic Heart Failure 2, 3

Aldosterone Hydralazine +
receptor ACE-I, ARB, ARNI isosorbide
antagonist dinitrate

Diuretics,
ivabradine,
Beta-Blockers SGLT2 inhibitor
digoxin,
inotropes
 Devices
o Implantable cardioverter-defibrillator
o Cardiac resynchronization therapy

Kansas City Cardiomyopathy Questionnaire 4

 23-item (or 12-item) self-administered questionnaire developed to independently measure patient’s perception of their health
status
o Heart failure symptoms
o Impact on physical and social function
o Impact on quality of life
 Interpreting Scores
o All scores are scaled from 0 to 100
o A 5-point change is considered clinically significant

0 to 24 75 to 100
25 to 49 50 to 74
Very poor to Good to
Poor to fair Fair to good excellent
poor
Drug Properties—Omecamtiv Mecarbil 5
 New class of myotropes: cardiac myosin activators
 Mechanism of action
o Selectively activates cardiac myosin
o Increases the rate of transition of myosin from weakly bound to
strongly bound state
 Increase in the rate of actin-dependent phosphate release
 Allows more myosin heads to enter strongly bound force-
producing state during systole
 Oral and IV administration studied

Study Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): A Phase 2,
Pharmacokinetic, Randomized, Placebo-Controlled Trial 6
Study Design Multicenter, randomized, parallel-group, placebo-controlled, double-blind study conducted at 87 sites in 13
 countries
Objective Primary endpoint: maximum concentration of omecamtiv mecarbil at weeks 2 and 12, and pre-dose concentration
at weeks 2, 8, 12, 16, and 20 visits
Secondary endpoints: change from baseline in systolic ejection time, stroke volume, heart rate, NT-proBNP at
week 20.
Results Patients: 149 patients assigned to placebo, 150 assigned to fixed-dose omecamtiv mecarbil 25 mg twice daily, and
149 assigned to the pharmacokinetic-titration group
Pre-Dose Concentration (ng/mL)- mean (SD) Fixed dose (N=147) Titration (N=141)
Week 2 174 (62.2) 179 (68.8)
Week 12 165 (67.9) 263 (116)
Week 20 149 (71.2) 239 (118)
Maximum concentration (ng/mL)- mean (SD)
Week 2 212 (70.4) 212 (81)
Week 12 200 (71.1) 318 (129)

Placebo (N=149) Fixed dose (N=147) Titration (N=141)

Systolic Ejection -- 11 25
(ms)—mean increase 95% CI 5 to 18 95% CI 18 to 32
P=0.007 P<0.0001
Stroke Volume (mL) -1 5 4
—mean increase 95% CI 2 to 8 95% CI 1 to 7
P=0.0036 P=0.0217
NT-proBNP (pg/mL) +500 -822 -970
95% CI -1516 to -127 95% CI -1672 to -268
P=0.0205 P=0.0069
Heart rate (bpm)— +0.5 -1 -2.5
mean P=0.2177 P=0.0070

Safety:
At week 20, cardiac troponin I were increased in patients receiving omecamtiv mecarbil.
 Median change from baseline in fixed dose: 0.001 ng/mL
 Median change from baseline in titration: 0.006 ng/mL
 Plasma concentrations returned to normal within 4 weeks of study drug discontinuation
Conclusion Direct, specific activation of cardiac myosin with omecamtiv mecarbil improved systolic function, lowered NT-
proBNP, and heart rate. Concerns with the increase in troponin I during study period warrants further investigation.
Additional phase 3 study necessary to evaluate clinical outcomes in larger groups of patients.

Reasons for Study

 Issues with current inotropes
o Do not improve mortality (benefits may be seen with morbidity)
o Increase intracellular calcium, increase oxygen demand
 Novel drug potentially addressing a gap in care and new addition to standard heart failure therapy

Citation Teerlink JR, Diaz R, Felker M, et al. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J
Med. 384;105-16.
Objectives

Primary To assess whether treatment with omecamtiv mecarbil in patients with heart failure who had reduced ejection fraction would
lower the risk of heart-failure events and cardiovascular death compared to placebo.
Secondary To assess the impact of omecamtiv mecarbil on cardiovascular death, change in total symptom score on Kansas City
Cardiomyopathy Questionnaire (KCCQ) from baseline to 24 weeks, first heart-failure hospitalization, and death from any
cause in patients with heart failure and reduced ejection fraction compared to placebo.
Methods
Study design Randomized, placebo-controlled, phase 3 trial
 January 6, 2017 to July 9, 2019
 945 sites in 35 countries

Patients
Inclusion  Adults between the ages of 18 and 85 years old
 New York Heart Association (NYHA) functional class II, III, IV symptoms
  Left ventricular ejection fraction  35%
 Current hospitalization for heart failure, made an urgent visit to the emergency department or had been hospitalized
for heart failure within one year before screening
 N-terminal pro-B-type natriuretic peptide (NT-proBNP)  400 pg/mL; or a BNP  125 pg/mL
 Receiving GDMT or device therapy for heart failure
Exclusion  Current hemodynamic or clinical instability leading to the use of mechanical support or intravenous medication
 Systolic blood pressure < 85 mm Hg
 Estimated glomerular filtration rate (eGFR) < 20 mL/minute/1.73 m 2 of body-surface area
 Recent acute coronary syndrome event or cardiovascular procedure
Interventions and Interventions: omecamtiv mecarbil 25 mg, 37.5 mg, 50 mg by mouth twice daily dosed based on plasma drug levels
comparators Comparator: matching placebo
Additional therapy: standard guideline directed medical and device therapy for heart-failure with reduced ejection fraction
Follow-up Assessments Post-randomization assessments were performed at weeks 2, 4, 6, 8, 12, 24, 36, and 48 then every 16 weeks thereafter
Outcomes
Primary Composite of heart-failure event or cardiovascular death
 Heart-failure event defined as urgent clinic visit, emergency department visit, or hospitalization for subjectively and
objectively worsening heart failure leading to treatment intensification
Secondary Cardiovascular death, change in total symptom score on KCCQ from baseline to week 24, first heart-failure hospitalization,
and death from any cause
Safety analysis: serious adverse events, adverse events associated with discontinuation of omecamtiv mecarbil or placebo,
adverse events of interest (ventricular arrhythmias, major cardiac ischemic events)
Statistics
Sample Size  8000 patients would provide a power of 90% to detect a hazard ratio of 0.80 for cardiovascular death in the group
receiving omecamtiv mecarbil
 Trial was event driven with target of approximately 1590 cardiovascular deaths
Statistical Tests  Type I error was 0.05 for two-sided testing across primary and secondary outcomes
o Control for multiple comparisons: if primary outcome met significance then alpha would be divided
unequally between cardiovascular death (0.048) and change in KCCQ scores (0.002)
 Efficacy analysis in the full analysis set of the intention-to-treat population
 Time-to-event data evaluated using Kaplan-Meier estimates and Cox proportional-hazards models
Results
# of patients  11,121 patients underwent screening and 8256 underwent randomization
o 24 patients excluded because of Good Clinical Practice Violations
o 4120 patients assigned to receive omecamtiv mecarbil
o 4112 patients assigned to receive placebo
 Discontinued study
o Omecamtiv mecarbil group: 41 patients
o Placebo group: 50 patients
 Overall median duration of follow-up was 21.8 months
Baseline Characteristic Omecamtiv Mecarbil (N=4120) Placebo (N=4112)
Characteristics Age—yr 64.5 +/- 11.3 64.5 +/- 11.4
Female sex—no. (%) 875 (21.2) 874 (21.3)
Race, White—no. (%) 3196 (77.6) 3201 (77.8)
Inpatient setting—no. (%) 1044 (25.3) 1040 (25.3)
NYHA Classification—no. (%)
II 2195 (53.3) 2173 (52.8)
III 1801 (43.7) 1815 (44.1)
Median total symptom score on KCCQ (IQR) 68.8 (49.0-87.5) 68.8 (49.0-87.5)
Median NT-proBNP (IQR)- pg/mL 1977 (980-40161) 2025 (1000-4105)
Median eGFR (IQR)—mL/min/1.73m2 58.8 (44.3-74.3) 58.7 (43.8-73.7)
Heart Failure Therapy—no. (%)
ACE-I, ARB, ARNI 3583 (87.0) 3576 (87.0)
Beta-blocker 3881 (94.2) 3883 (94.4)
Mineralocorticoid-receptor antagonist 3199 (77.6) 3198 (77.8)
SGLT2 inhibitor 104 (2.5) 114 (2.8)

Primary Objective Omecamtiv Mecarbil Placebo (N=4112) Hazard Ratio (95% CI)
(N=4120) P value
First heart-failure event or death from 1523 (37) 1607 (39.1) 0.92 (0.86 to 0.99)
cardiovascular causes—no. (%) P=0.03
Secondary Objectives
Omecamtiv Placebo Hazard Ratio (95% CI)
 Mecarbil (N=4120) (N=4112) P value
Cardiovascular Death—no. (%) 808 (19.6) 798 (19.4) 1.01 (0.92 to 1.11)
No./100 patient-year 10.9 10.8 P=0.86
Change in KCCQ total symptom score at wk 24
Inpatients Between group difference
Outpatients 23.7 +/- 0.7 21.2 +/- 0.7 2.5 (0.5 to 4.5)
5.8 +/- 0.3 6.3 +/- 0.3 -0.5 (-1.4 to 0.5)
P=0.03
First Hospitalization for Heart Failure—no.
(%) 1142 (27.7) 1179 (28.7) 0.95 (0.87 to 1.03)
No./100 patient-year 18.0 19.1
Death from Any Cause—no. (%) 1067 (25.9) 1065 (25.9) 1.00 (0.92 to 1.09)
No./100 patient-year 14.4 14.4

Other outcomes included effect of omecamtiv mecarbil on vital signs and other laboratory values
 There was no difference noted for change in systolic blood pressure
 Heart rate (beats/minute) was slightly lower in omecamtiv mecarbil group compared to placebo (-2.1 vs -0.5 bpm)
 Median NT-proBNP was lower in omecamtiv mecarbil group compared to placebo (-251 vs -180)
Safety analysis
 Omecamtiv was discontinued in 9% of omecamtiv mecarbil group and 9.3% of placebo group due to adverse event
 Trial agent was withheld because of concern for active myocardial infarction or ischemia in 103 vs 101 patients in
the omecamtiv and placebo groups, respectively
Limitations  Inclusion and exclusion criteria—age, stability
 Baseline characteristics—race, sex, background therapy
 A lot of outcomes evaluated
 Guideline updates for systolic heart failure treatment do not align with baseline characteristics/agents used
Author’s Conclusion Patients receiving omecamtiv mecarbil had a lower risk of primary composite outcome of heart-failure event or death from
cardiovascular causes than those receiving placebo. The trial did not show improvement in the secondary outcomes evaluated.
Additionally, the concern about increased troponin did not provide evidence that omecamtiv mecarbil increases risk of
myocardial infarction or ischemic events.
Conclusion and In this patient population, those with heart failure with reduced ejection fraction receiving guideline directed medical therapy,
Application the addition of omecamtiv mecarbil modestly reduced the risk of the composite primary outcome, first heart-failure event or
death from cardiovascular cause.
 Absolute risk reduction 2.1%, number needed to treat 48
 Results were mostly consistent among the prespecified subgroups. Some subgroups to consider are those with lower
ejection fraction, NYHA III or IV and history of atrial fibrillation
 Consider background therapy
 Will drug levels be required for treatment
 Primary outcome was mostly driven by HF hospitalizations without necessarily affecting mortality
 Place in therapy if omecamtiv mecarbil is approved

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