3. Omecamtiv Mecarbil (OM):
A Novel Selective Cardiac Myosin Activator
Omecamtiv mecarbil stabilizes myosin in the Pre-Powerstroke State, increasing the entry
rate of myosin into the tightly-bound, force-producing state with actin
with no effect on intracellular calcium
Malik FI, et al. Science 2011; 331:1439-43;
Shen YT, et al. Circ Heart Fail 2010;3:522-7;
Planelles-Herrero VJ, et al. Nat Commun 2017;8:190;
Teerlink JR, et al. J Am Coll Cardiol HF 2020;8:329-340.
Without omecamtiv mecarbil
With omecamtiv mecarbil
• More “hands” (myosin heads) to grasp
the “rope” (actin filament)
to produce more force
4. Teerlink JR, et al. Lancet 2011; 378: 667-75.
• Dose-escalating, crossover study
• 34 healthy men with 489 echos
• 6-h double-blind i.v. omecamtiv mecarbil
or placebo once a week for 4 weeks.
• Each sequence consisted of three
ascending omecamtiv mecarbil doses
(ranging from 0.005 to 1.0 mg/kg per h)
with a placebo infusion randomized into
the sequence.
6. Changes in Selected Echocardiographic Variables by
Omecamtiv mecarbil Concentration in Heart Failure
Cleland JGF, et al. Lancet 2011; 378: 676-83.
7. Acute Treatment with Omecamtiv Mecarbil to
Increase Contractility in Acute Heart Failure
• Multi-center, randomized,
double-blind, placebo-
controlled study
• Phase 2b Pharmacokinetic/
Pharmacodynamic dosing study
• 3 sequential cohorts (~200
subjects per cohort) with
ascending target
plasma concentrations
• Randomized 1:1 to 48-hour IV
placebo or omecamtiv mecarbil
(OM).
Teerlink JR, et al. J Am Coll Cardiol 2016; 67:1444–55.
8. Primary Endpoint:
Dyspnea Response through 48h (Likert Scale)
Teerlink JR, et al J Am Coll Cardiol 2016;67:1444-55.
Response rate ratio: ratio of response rate to Placebo within each cohort
9. CY 1221:
Ischemic Cardiomyopathy Trial
Cohort 1
45 patients
Randomized 2:1
Omecamtiv mecarbil at lower dose
i.v. (295 ng/ml) 20 hours
oral (184 ng/ml) 7days or placebo
Cohort 2
45 patients
Randomized 2:1
Omecamtiv mecarbil at higher dose
i.v. (550 ng/ml) 20 hours
Oral (368 ng/ml) 7 days or placebo
Greenberg BH, et al. JACC Heart Fail 2015;3:22-9.
Phase IIa
Patients with Ischemic cardiomyopathy and angina
(Ejection fraction ≤ 35%)
Assess effect of i.v. infusion of omecamtiv mecarbil
on symptom-limited treadmill exercise
tolerability and plasma concentrations of oral formulation
10. Omecamtiv mecarbil in HFrEF
Teerlink JR, et al. Lancet 2016; 388: 2895-903.
149 patients per group
• History of chronic HF
• Treated with stable, optimal HF Rx
• NYHA class II or III
• LVEF ≤ 40%
• NT-proBNP ≥ 200 pg/mL
20-weeks Oral therapy
• Placebo
• Omecamtiv mecarbil
25 50 mg BID (PK-titration)
Serial Echocardiograms
Improved LV
Function
Decreased LV
Volumes
Decreased Neuro-
hormonal Activation
11. LAEF, Left atrial ejection fraction; PASP, Pulmonary artery systolic pressure; RV, Right ventricular;
SE, standard error; SET, systolic ejection time; VTI, Velocity time integral (~Stroke volume).
Improved Right Ventricular
and Left Atrial Function
Biering-Sorensen T, et al. Eur J Heart Fail 2021;23:1052-1056; Biering-Sorensen T, et al. Circulation 2016;134, Abstract.
RV VTI (cm)
SET
(msec)
RVOT VTI/PASP ratio (cm/mmHg)
Placebo Omecamtiv
mecarbil
Placebo
Placebo
Placebo
Omecamtiv
mecarbil
Omecamtiv
mecarbil Omecamtiv
mecarbil
Right Ventricular Function Left Atrial Function
PASP (mmHg)
12. Cardiac Myosin Activator: Omecamtiv Mecarbil
N Engl J Med 2021;384:105-116.
8256 Patients:
• Chronic HF, NYHA II-IV
• LVEF ≤35%
• Elevated BNP/ NTproBNP
• Hospitalized for HF (Inpatients)
OR Urgent ED visit or hospitalization
for HF within 1 year prior to screening
(Outpatients)
• SBP ≥85 mmHg
• eGFR ≥20 mL/min/1.73m2
Randomized 1:1 to:
• Omecamtiv mecarbil
(pharmacokinetically-guided)
• Placebo
13. Baseline Characteristics
Only one patient lost-to-follow-up for vital status
Teerlink JR, et al. Eur J Heart Fail 2020;22:2160-2171.
14. Cardiac Myosin Activator: Omecamtiv Mecarbil
Teerlink JR, et al. N Engl J Med 2021;384:105-116.
Time to first Heart Failure event or Cardiovascular death
Placebo 4112 3310 2889 2102 1349 647 141
Omecamtiv mecarbil 4120 3391 2953 2158 1430 700 164
Patients at risk, n
Cumulative
incidence,
%
6 12 18 24 30
Months (30 days) since randomization
36
0
0
50
40
30
20
10
Hazard ratio = 0.92 (95% CI, 0.86–0.99)
P = 0.0252
Placebo
Omecamtiv
mecarbil
HR = 0.92 (95% CI, 0.86–0.99)
P = 0.025
15. Baseline LVEF
≤ median (28%)
> median (28%)
0.84 (0.77, 0.92)
1.04 (0.94, 1.16)
Interactio
1.0 1.3
n P-value = 0.003
0.7
Cardiac Myosin Activator: Omecamtiv Mecarbil
Teerlink JR, et al. N Engl J Med 2021;384:105-116.
16. Primary Outcome: EF Subgroup Results
Hazard
Ratio
for
HF
Event
or
CV
Death
Ejection Fraction (%)
OM better
Teerlink JR, et al. J Am Coll Cardiol 2021:78:97-108.
Placebo better
Continuous HR
HR=1 (unity)
95%CI
17. Primary Outcome: EF Subgroup Results
NNT ~20
NNT ~12-14
NNT = Number needed to treat
18. Atrial Fibrillation/Flutter Modifies
Treatment Effect of Omecamtiv Mecarbil
Solomon SD, et al. Eur Heart J 2022;43:2212-2220.
Patients without baseline AFF
derived greater benefit from
omecamtiv mecarbil.
P-interaction = 0.007
Patients with baseline AFF,
particularly those who were
receiving Digoxin experienced a
blunted treatment effect from
omecamtiv mecarbil.
P-interaction = 0.012
19. Effect of Omecamtiv Mecarbil on HF Hospitalizations
or CV Death by Systolic Blood Pressure
Metra M, et al. Eur Heart J 2022;43:5006-5016.
20. Felker, GM, et al. JAMA Cardiol 2022;7:26-34.
G. Michael Felker, MD, MHS
21. EF ≤ 30
N = 5842
0.88 (0.81, 0.96);
p=0.002
NYHA III-IV
N = 3864
HR 0.88 (0.80, 0.97);
p=0.007
HF Hosp last 6 mos
N = 6308
HR 0.89 (0.83, 0.97);
p=0.006
Benefit of Omecamtiv Mecarbil by
Severe HF Criteria
Severe HF
N = 2258
HR = 0.80 (0.71, 0.90),
p < 0.001
Absolute risk reduction:
8.3 events/100 pt-years
NNT = 12
Felker GM, et al. JAMA Cardiol 2022;
7:26-34.
22. Effect of Omecamtiv Mecarbil on the Risk of
Non-Fatal and Fatal Stroke
HR 0.65 (0.49, 0.87)
p = 0.004
Cumulative
Incidence,
%
117 events
77 events
HR 0.56 (0.31, 0.99)
p = 0.048
Teerlink JR, et al. AHA 2021.
Non-Fatal and Fatal Stroke Fatal Stroke
32 events
18 events
Placebo Omecamtiv mecarbil
Total Recurrent Stroke events (Negative binomial regression): RR = 0.66 (0.49, 0.89), p=0.006
23. So… Where does Omecamtiv Mecarbil fit?
ARNi Beta- MRA SGLT2i
Blocker
• Should Omecamtiv mecarbil replace any of the “four pillars”
of HFrEF Medical therapy? NO!!
25. HF is a progressive disease and patients with Symptomatic
Chronic HF Are at Risk of Progressive Worsening Over Time1
CRT, cardiac resynchronization therapy; GDMT, guideline-directed medical therapy; HF, heart failure; IV, intravenous; ICD, implantable cardioverter-defibrillator.
1. Modified from Greene SJ et al. Circ Heart Fail. 2020;13:e007132; 2. Butler J et al.J Am Coll Cardiol. 2019;73:935–944.
No Heart
Failure
Baseline
HF Risk
Clinical
Risk
Variable 3–6 Months
(Months – Years)
Initial diagnosis and
treatment (outpatient
or hospital)
Variable
(Months – Years)
Variable
(Months)
Worsening HF
despite
optimal medical
and device
therapy
Advanced
HF Risk
Variable
(Months)
Refractory/intolerant
to GDMT
Consideration for heart
transplantation,
mechanical
circulatory support,
or IV inotrope therapy
Palliative care
Residual
HF Risk
Worsening
HF Risk
Time
Initiation and
titration of GDMT
ICD/CRT as
indicated
Transcatheter mitral
valve repair
as indicated
26. Placebo
Dapagliflozin
HR=0.82 (95% CI 0.69–0.98);
ARR=1.9%
DAPA-HF: Kaplan–Meier curves for components of primary outcomes, according to
study group
DAPA-HF: Patients in the Dapagliflozin Group Are Still at
Risk of CV Death or HFH1
16.3% of patients in the dapagliflozin group experienced CV death or worsening HF over a median follow-up of 18.2 months
Cumulative
incidence
(%)
15
10
5
0 3 6 9 12 15 18
Months since randomisation
21 24
0
Placebo
Dapagliflozin
CV death HFH
HR=0.70 (95% CI 0.59–0.83);
ARR=3.7%
20 20
Cumulative
incidence
(%)
15
10
5
0 3 6 9 12 15 18
Months since randomisation
21 24
0
Number of subjects at risk
Placebo 2371 2330 2279 2230 2091 1636 1219 664 234 Placebo 2371 2264 2168 2082 1924 1483 1101 596 212
Dapagliflozin 2373 2339 2293 2248 2127 1664 1242 671 232 Dapagliflozin 2373 2306 2223 2153 2007 1563 1147 613 210
Number of subjects at risk
ARR, absolute risk reduction; CI, confidence interval; CV, cardiovascular; HF, heart failure; HFH, heart failure hospitalisation; HR, hazard ratio.
1. McMurray JJV et al. N Engl J Med. 2019;381:1995–2008.
27. Even patients receiving all four foundational therapies
have a high residual risk of worsening HF and CV death1
Paitents
experiencing
a
primary
outcome
event
(%)
0
5
10
15
20
19.9
14.3
Triple therapy
Quadruple therapy
14.3% of patients on quadruple therapy had a primary event over the course of the trial*#
~1 in 7 patients experienced a primary
outcome event, despite confirmed use of
quadruple therapy
(ARNi, beta blocker, MRA and SGLT2i)
ARNi
Beta blocker
MRA
Dapagliflozin
ARNi
Beta blocker
MRA
Event rates according to background HF
therapy in DAPA-HF
* Primary outcome was the composite of an episode of worsening HF or CV death, whichever occurred first.
# Median follow-up of 18.2 months.2
ARNi, angiotensin receptor–neprilysin inhibitor; CV, cardiovascular; HF, heart failure; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium–glucose cotransporter 2 inhibitor.
References: 1. Docherty KF et al. Eur Heart J 2020;41:2379–2392; 2. McMurray JJV et al. N Engl J Med 2019;381:1995–2008.
28. Despite improved outcomes with contemporary therapy
in patients with HFrEF, significant residual risk
remains1–4
EMPEROR-Reduced (2020)2,4
N=3,730
ARR=5.2; RRR=25%
p<0.001
Median follow-up: 16 months
Diuretic
ACEi or ARB
ARNi
Beta blocker
MRA
Diuretic
ACEi or ARB
ARNi
Beta blocker
MRA
Empagliflozin
28
23
18
13
8
3
21
15.8
HFH
or
CV
death
(events/100
PY)
Diuretic
Digitalis
ACEi
Beta blocker
MRA
ARB or ARNi
Dapagliflozin
Diuretic
Digitalis
ACEi
Beta blocker
MRA
ARB or ARNi
28
23
18
13
8
3
15.6
11.6
Worsening
HF
or
CV
death
(events/100
PY)
ARR=4.0; RRR=26%
p<0.001
Median follow-up: 18.2 months
PARADIGM-HF (2014)1,2 DAPA-HF (2019)2,3
28
23
18
13
8
3
13.2
10.5
HFH
or
CV
death
(events/100
PY)
N=8,442
ARR=2.7; RRR=20%
p<0.001
Median follow-up: 27 months
Diuretic
Digitalis
Beta blocker
MRA
ACEi
Diuretic
Digitalis
Beta blocker
MRA
ARNi
SoC SoC + new therapy
N=4,744
Major medical therapies listed. Each HF study was conducted independently, and no head-to-head HF studies have been completed that allow for direct comparisons.
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor–neprilysin inhibitor; ARR, absolute rate reduction; CV, cardiovascular; HF, heart failure;
HFH, heart failure hospitalization; HFrEF, heart failure with reduced ejection fraction; MRA, mineralocorticoid receptor antagonist; PY, patient-years; RRR, relative risk reduction; SoC, standard of care.
References: 1. McMurray JJV et al. N Engl J Med 2014;371:993–1004; 2. Butler J et al. Eur J Heart Fail 2020;22:1991–1993; 3. McMurray JJV et al. N Engl J Med 2019;381:1995–2008;
4. Packer M et al. N Engl J Med 2020;383:1413–1424.
29. Use of a sGC Stimulator to Treat HF
GTP cGMP
PDE5
Protein Kinase G
Intracellular Ca2+
Myosin Light chain
phosphatase
Vascular Smooth Muscle Relaxation
VASCULAR
SMOOTH
MUSCLE CELL
Myocardial stiffness Hypertrophy Fibrosis
+
Endothelium
GTP cGMP 5’-GMP
PDE5
MYOCARDIAL
CELL
+
Protein Kinase G mediated
phosphorylation of titin
Sacromere (contractile unit)
Actin
Titin Myosin
P
P
P
P
P
P
sGC
P
P
P
sGC
Nitric Oxide
Pathway Effects
• Counteract
Vasoconstriction
Improved Perfusion to
Vital Organs
Nitric Oxide
Pathway Effects
• Ventricular Relaxation
• Decreased
Contractility
• Anti-hypertrophic and
Anti-fibrotic Effects
Improved Cardiac
Output
Nitric Oxide
L-arginine
Oxidative
Stress
Reduced
Endothelial
NOS Activity
5’-GMP
Increased
cGMP Levels
Increased
cGMP Levels
sGC
Stimulators
+
NO-independent
Nitric Oxide
NO-dependent
+
sGC
Stimulators
+
NO-independent
Nitric Oxide
NO-dependent
+
cGMP = cyclic guanosine monophosphate; GTP = guanosine triphosphate; PDE5 = phosphodiesterase; sGC = soluble guanylate cyclase.
1. Butler J et al. Eur J Heart Fail. 2022;11:2029-2036.
30. VICTORIA Trial: Targeting sGC pathway in those with
worsening HFrEF
7
Key Inclusion Criteria
1. LVEF <45%, NYHA Class II-IV
2. Recent HF event
i. HFH within 6 months
ii. Outpatient IV diuretics within 3 months
3. NT-proBNP > 1000pg/dL
4. Receiving currently available GDMT for HF
1:1
Vericiguat
5 mg QD
Vericiguat
10 mg QD
Vericiguat
2.5 mg QD
Week 0
Placebo
Week 2 Week 4 Week 16 Q16W
Primary end point: Time to first occurrence of the
composite of CV death and HFH
31. VICTORIA demonstrated Significant Reduction in the Annualised
Absolute Rate of Time to HFH or CV Death by 4.2 events/100 patient-yrs1
HR=0.90 (95% CI 0.82–0.98);
p=0.02
ARR=4.2 per 100 patient-yrs
Annual NNT=24*
• Median treatment duration for
primary endpoint: 10.8 months
• Annual event rates for
vericiguat and placebo per
100 patient-yrs were 33.6 and
37.8, respectively
Time to CV death or first HFH
Number of patients at risk
Vericiguat 2526 2099 1621 1154 826 577 348 125 1
Placebo 2524 2053 1555 1097 772 559 324 110 0
12 16 20
Months since randomisation
Cumulative
incidence
rate
8
4
0 24 28 32
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
Vericiguat
Placebo
Vericiguat
Placebo
*Calculations: annual NNT = 100/4.2 = 24.
ARR, absolute rate reduction; CI, confidence interval; CV, cardiovascular; HFH, heart failure hospitalisation; HR, hazard ratio;
NNT, number needed to treat; yr, year.
1. Armstrong PW et al. N Engl J Med. 2020;382:1883–1893.
32. Click to edit Master title style
~1250 pts per group: Q4: Interaction p <0.001
Subgroup
Hazard Ratio (95% CI)
NT-proBNP level
Quartile 1 (≤1,556.0 pg/ML) 0.78 (0.62-0.99)
Quartile 2 (>1,556.0 to ≤2,816.0 pg/ML) 0.73 (0.60-0.90)
Quartile 3 (>2,816.0 to ≤5,314.0 pg/ML) 0.82 (0.69-0.99)
Quartile 4 (>5,314.0 pg/ML)
Vericiguat Placebo
no. of events
128 161
165 201
213 257
355 302 1.16 (0.99-1.35)
Reference: 1. Armstrong PW et al. N Engl J Med 2020;382:1883–1893.
33. Treatment effect of vericiguat on primary outcome by NT-proBNP at randomization1,2
10
A separate continuous analysis of VICTORIA data showed benefit of
vericiguat in patients with NT-proBNP levels up to 8,000 pg/ml1,2
Range of the treatment effect of vericiguat compared with placebo for the primary composite endpoint by NT-proBNP at randomization, adjusted for the MAGGIC risk score.
* Events/100 patients years.
ARR, absolute risk reduction; CI, confidence interval; HR, hazard ratio; MAGGIC, Meta-Analysis Global Group in Chronic Heart Failure; NT-proBNP, N-terminal pro-brain natriuretic peptide.
References: 1. Ezekowitz JA et al. JACC Heart Fail 2020;8:931–939; 2. Ezekowitz JA et al. JACC Heart Fail 2020;8(suppl 1–17):931–939.
Treatment
effect
(vericiguat/placebo),
HR
(95%
CI)
3.0
2.5
2.0
1.5
1.0
0.5
0
25
20
15
10
5
0
10 4,000 8,000 12,000 16,000 20,000
NT-proBNP at randomization (pg/ml)
24,000 28,000 32,000
30
Patients
(%)
HR
(95%
CI)
1.2
1.0
0.8
0.6
0.4
0.2
10 1,000 2,000 3,000 4,000 5,000 6,000 7,000 8,000
NT-proBNP at randomization (pg/ml)
The positive treatment effect of
vericiguat vs placebo on the
primary endpoint was:
• Evident for patients with
NT-proBNP ≤8,000 pg/ml
(86% of VICTORIA population)
• Further amplified in patients
with NT-proBNP ≤4,000 pg/ml
(65% of VICTORIA population)
≤8,000
ARR 5.4*
≤4,000
ARR 6.8*
There was also a positive
treatment effect of vericiguat vs
placebo on CV death for
patients with NT-proBNP
≤8,000 pg/ml
• HR=0.84 (95% CI 0.71–0.99)
34. For Patients With NT-proBNP ≤8000 pg/ml, the Treatment
Effect of Vericiguat Extended to Both CV Death and HFH1,2
CV death HF hospitalization
3.0 30
2.5
2.0
1.5
1.0
0.5
0
25
20
15
10
5
0
Treatment
effect
(vericiguat/placebo),
HR
(95%CI)
Percentage
of
patients
4,000 8,000 12,000 16,000 20,000 24,000 28,000 32,000
NT-proBNP at randomization (pg/ml)
10
3.0 30
2.5
2.0
1.5
1.0
0.5
0
25
20
15
10
5
0
Treatment
effect
(vericiguat/placebo),
HR
(95%
CI)
Percentage
of
patients
10 4,000 8,000 12,000 16,000 20,000 24,000 28,000 32,000
NT-proBNP at randomization (pg/ml)
≤4,000 pg/ml:
HR=0.75 (95% CI 0.60–0.94)
≤8,000 pg/ml:
HR=0.84 (95% CI 0.71–0.99)
>8,000 pg/ml:
HR=1.32 (95% CI 1.01–1.71)
≤4,000 pg/ml:
HR=0.78 (95% CI 0.67–0.90)
≤8,000 pg/ml:
HR=0.84 (95% CI 0.75–0.95)
>8,000 pg/ml:
HR=1.17 (95% CI 0.92–1.48)
References: 1. Ezekowitz JA et al. JACC Heart Fail 2020;8:931–939; 2. Ezekowitz JA et al. JACC Heart Fail 2020;8(suppl 1–17):931–939.
35. 50
45
40
35
30
25
20
15
10
5
0
SoC ARNi
Enalapril
HR=0.80 (95% CI 0.73–0.87)
Contemporary HF Outcome Trials
Primary Endpoint Absolute Rate Reduction
SoC Dapagliflozin
HR=0.74 (95% CI 0.65–0.85)
SoC Empagliflozin
HR=0.75 (95% CI 0.65–0.86) HR=0.92 (95% CI 0.86–0.99)
SoC Omecamtiv
mecarbil
SoC Vericiguat
HR=0.90 (95% CI 0.82–0.98)
First HFH or CV death
ARR=2.7
Worsening HF or
CV death
ARR=4.0
First HFH or CV death
ARR=5.2
First HFH or CV death
ARR=2.1
ARR=4.2
VICTORIA1,6
First HFH or CV death
PARADIGM-HF1,2 DAPA-HF1,3 EMPEROR-Reduced1,4 GALACTIC-HF5
Annualised
event
rate
per
100
patient-years
Each HF study was independently conducted, and no head-to-head HF studies have been completed that allow for direct comparison of the efficacy and/or safety of one drug versus another.
ARNi, angiotensin receptor–neprilysin inhibitor; ARR, absolute rate reduction; CI, confidence interval; CV, cardiovascular; HF, heart failure; HFH, heart failure hospitalisation; HR, hazard ratio; SoC, standard of care.
1. Butler J et al. Eur J Heart Fail. 2020;22:1991–1993; 2. McMurray JJ et al. N Engl J Med. 2014;371:993–1004; 3. McMurray JJV et al. N Engl J Med. 2019;381:1995–2008; 4. Packer M et al. N Engl J Med. 2020;383:1413–1424; 5. Teerlink JR et al. N Engl J Med. 2021;384:105–116; 6. Armstrong PW et al. N Engl J Med. 2020;382:1883–1893.
36. Baseline
NT-proBNP
quartile group
Endpoint
n (%)
Events per
100 PY n (%)
Events per
Events per 100 PY
100 PY
Vericiguat (n=1,798) Placebo (n=1,806) Annualized ARR (%)*
Primary composite (CV death or first HFH) 506 (28.1) 24.5 619 (34.3) 31.7 7.2
CV death 190 (10.6) 7.9 240 (13.3) 10.1 2.2
Q1–3 HFH (first) 406 (22.6) 19.6 504 (27.9) 25.8 6.2
(≤5,314 pg/ml) Total HFH (first and recurrent) 725 (40.3) 30.2 891 (49.3) 37.7 7.5
CV hospitalization 594 (33.0) 31.4 698 (38.6) 39.7 8.3
All-cause death 128 (7.1) 25.8 142 (7.9) 33.1 7.3
Vericiguat (n=616) Placebo (n=585) Annualized ARR (%)*
Primary composite (CV death or first HFH) 355 (57.6) 73.6 302 (51.6) 63.6 –10.0
CV death 208 (33.8) 32.0 169 (28.9) 27.1 –4.9
Q4 HFH (first) 251 (40.7) 52.0 209 (35.7) 44.0 –8.0
(>5,314 pg/ml) Total HFH (first and recurrent) 432 (70.1) 66.8 392 (67.0) 63.1 –3.7
CV hospitalization 304 (49.4) 68.0 271 (46.3) 63.0 –5.0
All-cause death 133 (21.6) 79.6 123 (21.0) 70.0 –9.6
Outcomes by NT-proBNP baseline quartile group for 1 year of treatment with vericiguat and placebo1
Treatment with vericiguat led to substantial risk reductions
in the lowest three quartiles of baseline NT-proBNP1
13
* Vericiguat vs placebo.
ARR, absolute risk reduction; CV, cardiovascular; HFH, heart failure hospitalization; NT-proBNP, N-terminal pro-brain natriuretic peptide; PY, patient-years; Q, quartile.
Reference: 1. Senni M et al. ESC Heart Fail 2022; https://doi.org/10.1002/ehf2.14050.
37. 14
Patients with advanced HF may be refractory to other
pharmacological therapies1
* Advanced HF defined as NYHA class IV symptoms, ≥3 months’ GDMT for HF and/or intolerance to such therapy, EF ≤35%, BNP ≥250 pg/ml or NT-proBNP ≥800 pg/ml, and ≥1 additional objective finding of advanced HF.
# The line within the boxes reflect the median; and the data markers indicate the means.
AUC, area under the curve; BNP, brain natriuretic peptide; EF, ejection fraction; GDMT, guideline-directed medical therapy; HF, heart failure; HFrEF, heart failure with reduced ejection fraction;
NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association.
Reference: 1. Mann DL et al. JAMA Cardiol 2022;7:17–25.
No significant benefit of sacubitril/valsartan vs valsartan in terms of a reduction in NT-proBNP level
or the clinical composite of number of days alive, out of hospital and free from HF events1
NT-proBNP
level
(pg/ml)
Valsartan
Sacubitril/valsartan
2,500
2,000
1,500
1,000
500
0
Baseline Week 2
Number of patients with data
Week 4 Week 8 Week 12 Week 24
Valsartan 162 155 154 144 145 124
Sacubitril/valsartan 161 156 153 143 140 118
Log
AUC
NT-proBNP
ratio
1
0
–1
–2
Valsartan Sacubitril/valsartan
Treatment group
LIFE trial: No benefit of sacubitril/valsartan vs valsartan in patients with advanced HFrEF with
NYHA class IV symptoms*,1
Geometric mean NT-proBNP Log AUC NT-proBNP (primary endpoint)#
2
3,000 Treatment ratio 0.95 (0.84–1.03); p=0.45
38. Patients with HFrEF often suffer from medication side effects,
making adherence to quadruple therapy challenging1,2
15
Patient factors commonly associated with nonuse and subtarget dosing of GDMT1
GDMT, guideline-directed medical therapy; HFrEF, heart failure with reduced ejection fraction.
References: 1. Greene SJ et al. Heart Fail Rev 2022;27:741–753; 2. Brownell NK et al. Card Fail Rev 2021; https://doi.org/10.15420/cfr.2021.18.
Worsening renal
function
Hyperkalemia
Older age Heart rate
Hypotension
K+
39. Latest expert guidance – Worsening heart failure:
Nomenclature, epidemiology and future directions (Greene et al. 2023)1
Central illustration: Considering the definition of worsening HF
40. Medical Management of Worsening Heart Failure with Reduced Ejection Fraction: JACC Review Topic of
the Week
Stephen J. Greene MDa,b,Johann Bauersachs MDc, Jasper J. Brugts MD MSc PhDd, Justin A. Ezekowitz MBBCh MSce, Gerasimos Filippatos
MD PhDf, Finn Gustafsson MD PhDg, Carolyn S.P. Lam MBBS PhDh, Lars H. Lund MD PhDi, Robert J. Mentz MDa,b, Burkert Pieske MDj,
Piotr Ponikowski MD PhDk, Michele Senni MDl, Natalie Skopicki BAm, Adriaan A. Voors MD PhDn, Faiez Zannad MD PhDo, Shelley Zieroth
MDp, Javed Butler MD MPH MBAq,r
41. A high residual risk remains among patients with HFrEF
despite the use of HF medications
HF risk vs ASCVD1
Primary prevention
Primary prevention
Multiple ASCVD events, 7%
or one ASCVD event + @
multiple high-risk 6%
conditions * •/,
Primary or p'E 4%
secondary prevention u .
@
Z
3%
2%
1%
ASCVD
Low risk
Borde rli
HF
Advanced HFrEF
intolerant/refractory
to GDMT, recurrent
HFHs
HFrEF and
recent HFH or
worsening HF
'Stable' outpatient
HFrEF, NYHA class
II, no recent
hospitalizations
•10%
Residual risk across trials2—5
PARADIGM-HF (2014)2 3
Diuretic
Digitalis
BB
MRA
• ARN‹
Diuretic
Digitalis
BB
MRA
ACEi
ARB/ARNi
+ ACEi
+ DAPA
—DAPA
Diuretic
BB
MRA
ACEi/ARB —EMPA
ARNi
+ EMPA
Left-hand side figure adapted from Greene et a/. 2023.
Each HF study was conducted independently, and no head-to-head HF studies have been completed that allow for direct comparisons.
Abbreviations in slide notes.
0
0
0
References: 1. Greene SJ ef a/. JACC 2023;81:413—424; 2. McMurray JJV ef a/. /VEngl J Med 2014;371:993—1004; 3. Butler J ef a/. Eur J Heart
Fail 2020;22:1991—1993; 4. McMurray JJV ef a/. /VEngl J Med 2019;381:1995—2008;5. Packer M ef a/. /VEngl J Med 2020;383:1413—1424.
5 10 15
HFH or CV death (events/100 PY)
DAPA-HF (2019)3 4
20
N=8,442
ARR 2.7; RRR 20%
p<0.001
25
N=4,744
ARR 4.0; RRR 26%
p<0.001
5 10 15 20
Worsening HF or CV death (events/100 PY)
EMPEROR-Reduced (2020)3 5
5 10 15
HFH or CV death (events/100 PY)
20
25
N=3,730
ARR 5.2
RRR 25%
p<0.001
25
9
42. Vericiguat therapy after a worsening HF event
19
ACEi/ARNi
Beta blocker
+ivabradine if in NSR and heart rate ≥ 70/min
SGLT2i
MRA
Vericiguat
Worsening
HF Event
ACEi, angiotensin-converting enzyme inhibitor; ARNi, angiotensin receptor–neprilysin inhibitor; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; IV, intravenous;
MRA, mineralocorticoid receptor antagonist; NSR, normal sinus rhythm; SGLT2i, sodium–glucose cotransporter 2 inhibitor.
Reference: 1. Rao VN, …., Bauersachs J. J Cardiac Fail 2023, in press
Additional medical therapies for patients with HFrEF may also include digoxin, and specifically for patients
of self-identified Black/African American race, hydralazine/long-acting nitrate combination therapy.
43. Where Does Vericiguat Fit?
• On standard of care and develop worsening heart failure
• With standard of care and develop worsening heart failure
• Unable to tolerate standard therapy
Vericiguat is safe and well-tolerated
• Blood pressure
• Heart rate
• Renal function
• Potassium
• Among those with NT-proBNP <8000
Mortality estimates similar to other therapies
• Upstream high-risk population
Definition of worsening HF?
52. Proprietary Assays Measuring Changes in Velocity and Force of Contraction
flourescently-labeled actin being moved by myosin “motor” fixed to well
Control MyoKardia Compound Reduces Contraction
Source: Unpublished Company data
55. Published online May 15, 2021 https://doi.org/10.1016/S0140-6736(21)00763-7
At 30 weeks, the change in KCCQ-OS
score was greater with mavacamten
than placebo (mean score 14·9 [SD 15·8]
vs 5·4 [13·7]; difference +9·1 [95% CI 5·5
–12·8]; p<0·0001)
58. J Am Coll Cardiol 2020;75:2649–60
53% in the pooled mavacamten group vs 1%
34% in the pooled mavacamten group vs 4% incre
59. Mavacamten: a
novel treatment
approach for
HOCM
Unanswered questions:
• Predictors of response?
• Interaction with ß-blockers?
• Impact of aetiology (genetic) on
response and safety?
• Potential in non-obstructive disease?
• Long-term effects?
60. Impact of Alirocumab Added to High-
Intensity Statin on Platelet Function in
Patients with Acute Myocardial Infarction:
A Sub-Study of the PACMAN-AMI Trial
61. Background
• PCSK9 inhibitors reduce LDL-C and MACE
• Previous observational studies have suggested a potential
association of PCSK9 level and platelet reactivity.
• The role of PCSK9 inhibitor alirocumab on platelet
aggregation among patients with AMI remains unknown.
Aims
• We aimed to explore the potential antiplatelet effect of
alirocumab in AMI patients on continued dual antiplatelet
therapy with a potent P2Y12 inhibitor.
62. Methods
Design
• A prespecified, powered, pharmacodynamic
substudy nested within the PACMAN AMI trial
Patients
• Patients enrolled at Bern University Hospital &
receiving DAPT with a potent P2Y12 inhibitor at 4
weeks
Primary endpoint
• P2Y12 Reaction Units (PRU) at 4 weeks as assessed by the VerifyNow
point-of-care assays.
• whole blood sample to measure platelet reactivity by assessing the rate and
extent of changes in light transmittance caused by platelet aggregation.
63. Results: Clinical Baseline Characteristics
Alirocumab
(n=66)
Placebo
(n=73)
P value
Age 58.2±10.6 58.3±8.5 0.91
Gender (Female) 7 (10.6%) 14 (19.2%) 0.24
Body mass index (kg/m2) 27.2±4.3 28.3±4.1 0.12
Diabetes mellitus 6 (9.1%) 9 (12.3%) 0.59
Hypertension 28 (42.4%) 33 (45.2%) 0.86
Current smoking 30 (45.5%) 26 (35.6%) 0.30
Type of myocardial infarction 0.40
STEMI 37 (56.1%) 35 (47.9%)
NSTEMI 29 (43.9%) 38 (52.1%)
Hemoglobin (g/l) 145.7±12.0 142.0±13.3 0.09
Thrombocytes (109/L) 250.0±70.4 241.3±55.9 0.42
Aspirin 5 (7.6%) 1 (1.4%) 0.10
Statin 9 (13.6%) 9 (12.3%) 1.00
66. Limitations
• Platelet function was assessed by VerifyNow only.
• Only ACS patients receiving DAPT with a potent P2Y12
inhibitor were included.
• Platelet reactivity in the current study was intensively
reduced compared with that reported in the previous
studies.
• The timing of blood sampling in relation to the intake of
potent P2Y12 inhibitors was not considered.
67. Conclusion
• Among AMI patients receiving DAPT with a potent P2Y12
inhibitor, alirocumab had no significant effect on platelet
function as assessed by PRU 4 weeks after treatment.
69. ATTR Amyloidosis
3
Liver
Stabilize
• In ATTR, the TTR tetramer dissociates into monomers that then misfold and aggregate into
amyloid fibrils, which accumulate extracellularly in organs and tissues.
Amyloidogenic TTR Cascade
Amyloid Fibril
Formation
Misfolded monomers aggregate
into amyloid fibrils
Deposition of Fibrils
Amyloid fibrils accumulate in
different parts of the body,
such as the heart
TTR
Secreted as a tetramer
TTR Dissociation
Tetramer dissociates into
monomers
Suppress
Synthesis
Remove
71. All Cause Mortality Cox Proportinal Hazards Model
30% reduction in the risk of all-cause mortality with Tafamidis compared with
placebo (HR=0.70; 95% CI, 0.51 to 0.96).
Maurer MS et al, N Engl J Med. 2018
0.0
0.6
0.8
1.0
0 15 18 21 24 27 30 33
Pooled tafamidis meglumine
Placebo
0.4
0.2
Hazard ratio: 0.70 (95% CI: 0.51-0.96), p=0.026
Analysis not adjusted for multiplicity.
3 6 9 12
Relative Risk
Reduction
30%
Number Needed to
Treat: 7.51,†
~8 patients would
need to be treated
to prevent 1 death
within 30 months
73. Survival at 5 years: 53.2%.
Median Follow-up: 58.5 months
Survival at 5 years: 32.4%.
Median Follow-up: 57.1 months
Elliott PM et al. Circ Heart Fail 2022
Survival at 5 years
74. LT data of Tafamidis by NYHA
Garcia-Pavia et al. ESC HF Congress 2022
79. Diflunisal
- 35 patients treated with diflunisal vs 69 without treatment
- 73.8 vs 76.8 years (p = 0.034), BNP, 335±67 vs. 520±296 pg/mL, (p = 0.006), eGFR 67±17 vs
53±18 mL/min/1.73m2 (p = 0.0002)
- Less mortality during follow-up (3.2 years). HR 0.13, 95% CI 0.05 - 0.36 (p < 0.001)
- 14 (40%) discontinued Diflunosal despite only 3 during 1st years.
Siddiqi et al. Amyloid 2022
80. ATTRibute-CM: two-part trial design includes
12-month and 30-month registrable endpoints
14
ATTRibute-CM study schematic
Subjects with
diagnosed ATTR-
CM (WT or mutant)
NYHA Class I-III
Positive biopsy or
99mTc scan
Negative serum/
urine light chain if
dx by 99mTc scan
Key inclusion criteria
800 mg AG10
twice daily
Screening and
randomization
Open label extension
Secondary endpoints include: Kansas City Cardiomyopathy Questionnaire, serum TTR, TTR stabilization
1As local standard of care evolves, concomitant use of approved, indicated therapies may be allowed
6MWD = Six minute walk distance; NYHA = New York Heart Association;
99mTc = Technetium labeled pyrophosphate (PYP) or bisphosphonate (e.g., DPD); dx = diagnosis;
CV hosp = cardiovascular-related hospitalizations
12 month primary endpoint: 30 month primary endpoint:
Change in 6MWD Mortality and CV hosp
Part A Part B1
800 mg AG10 twice daily
N ~ 340
Placebo
N ~ 170
81. Primary end point p-value
Change from baseline in 6MWD 0.76
Mean (SD) Median
Acoramidis (n=321) -9.28m (62.7) -4.83m
Placebo (n=160) -7.04m (59.7) -6.25m
Observed change from baseline in 6MWD at month 12
ATTRibute-MC Did Not Meet Its Month 12 Primary End Point
15
82. Acoramidis Improved NT-proBNP Relative to Placebo
aInference analysis (p-value) based on absolute change from baseline between groups.
BridgeBio, data on file.
Percent change from baseline in NT-proBNP at Month 12 – mITT population
Median 0.6%
vs 24.3%;
nominal
p < 0.05a
PRELIMINARY ANALYSIS – NOT VALIDATED
16
83. Acoramidis Improved KCCQ-OS Relative to Placebo
KCCQ-OS by treatment and visit – MMRM without imputation
Baseline = 71.4
Nominal p < 0.05
BridgeBio, data on file.
17
84. Ioannou et al. Circulation 2022
ATTR prognosis has changed!!
86. Adams D, et al. NEJM 2018;379:11-21
Benson MD, et al. NEJM 2018;379:22-31
ASO
siRNA
87. Pharmacodynamics of siRNA and ASO
Adams D, et al. NEJM 2018;379:11-21
Benson MD, et al. NEJM 2018;379:22-31
88. Effective to treat neurological symptomas in ATTRv
Adams D, et al. EAN Congress 2020
Brannagan, et al. Eur J Neurol 2020
24-months Patisiran Global OLE 24-months Inotersen Global OLE
89.
90. Maurer, et al. ISA Congress 2022
Patisiran in ATTR-CM. APOLLO-B
91. Maurer, et al. ISA Congress 2022
Patisiran in ATTR-CM. APOLLO-B
93. Percentage
of
patients
without
an
event(•
A)
Time to First Event for Patisiran vs Placebo over the 12-Month
Double-Blind Period
All-Cause Hospitalizations, Urgent HF Visits, or Deaths
100
90
80
70
6D
50
40
20
10
0
Racebo
N evaluable
178
„ . Placeb
169
o Patisiran
1ffd 140
+ OS0[Rd
130
Patisiran 1R1 160 152 148 140
3
HR=0.839 (0.557,
1,263)
s 9
Follow-up visit (months)
12
96. 30
• Vutrisiran was compared with the external APOLLO placebo group for the primary and most secondary and exploratory endpoints
• As previously reported, the primary endpoint of change from baseline in mNIS+7 at Month 91 and all secondary endpoints2 were met
• A prespecified cardiac subpopulation (baseline left ventricular wall thickness ≥1.3 cm and no medical history of aortic valve disease or
hypertension) was analysed to determine the effect of vutrisiran on exploratory cardiac parameters
Vutrisiran Phase 3 Study in Patients with Hereditary
Transthyretin-Mediated Amyloidosis with Polyneuropathy
aHigher scores of mNIS+7 indicate more neurologic impairment (range, 0 to 304). bHigher scores of Norfolk QOL-DN indicate worse quality of life (range, −4 to 136). c10-MWT speed (m/s) = 10 meters/mean time (seconds) taken to complete two assessments at each visit, imputed as
0 for patients unable to perform the walk; lower speeds indicate worse ambulatory function. dLower scores of mBMI (weight [in kg/m2] × serum albumin [in g/L]) indicate worse nutritional status. eLower scores of R-ODS indicate more disability (range, 0 to 48). fNon-inferiority analysis.
gChange from baseline to Month 18 vs. external placebo group; hTc scintigraphy was only performed at select sites in the HELIOS-A study, and no external placebo group comparison was available, comparison to baseline only.
10-MWT, 10-meter walk test; ATTRv, hereditary transthyretin (v for variant); IV, intravenous; KPS, Karnofsky performance status; mBMI, modified body mass index; mNIS+7, modified Neuropathy Impairment Score +7; NIS, Neuropathy Impairment Score; Norfolk QOL-DN, Norfolk
Quality of Life-Diabetic Neuropathy; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; PND, polyneuropathy disability; Q3M, every 3 months; Q3W, every 3 weeks; R-ODS, Rasch-built Overall Disability Scale; SC, subcutaneous; TTR,
transthyretin. 1. Adams D et al. Neurology 2021;96(15 Supplement):1234. 2. Adams D, et al. Société Francophone du Nerf Périphérique (SFNP) 2022.
18-Month
Efficacy
Assessment
Patient Population
N=164
• 18–85 years old
• hATTR amyloidosis;
any TTR mutation
• NIS 5–130 and PND ≤IIIB
• KPS ≥60%
• Prior TTR stabilizer use
permitted
• NYHA Class ≤II
3:1
RANDOMIZATION
Stratification:
TTR V30M vs non-V30M
Baseline NIS <50 vs ≥50
n=122
Vutrisiran
25 mg
SC Q3M
Reference
group
(patisiran)
0.3 mg/kg
IV Q3W
or
n=42
Vutrisiran vs APOLLO Placebo
mNIS+7a at Month 9 ✔
Primary Endpoint: Change from baseline in
Secondary Endpoints ✔
Change from baseline in:
• mNIS+7a at Month 18
• Norfolk QOL-DNb at Months 9 and 18
• 10-MWTc at Months 9 and 18
• mBMId at Month 18
• R-ODSe at Month 18
Vutrisiran vs HELIOS-A patisiran
Secondary Endpoint
✔
• % TTR reduction through Month 18f
Selected Exploratory Cardiac Endpoints
Change from baseline in:
• NT-proBNP levels to Month 18g
• Echocardiographic parameters to Month 18g
• Technetium scintigraphy at Month 18h
97. 31
• In both the mITT population and cardiac subpopulation, vutrisiran achieved improvement in NT-proBNP levels at Month 9 with
continued improvement to Month 18 compared with the external placebo group (exploratory endpoint)
NT-proBNP Levels with Vutrisiran vs External Placebo at Month 18
aNT-proBNP is a measure of cardiac stress, with higher values indicating a greater level of cardiac stress. NT-proBNP results shown at Month 9 and Month 18 are MMRM model data. Number of evaluable patients at each timepoint are shown.
CI, confidence interval; MMRM, mixed model for repeated measures; NT-proBNP, N-terminal pro–brain natriuretic peptide.
• Geometric mean level decreased from baseline to Month 18 with vutrisiran in the mITT population (273.01 to 227.15 ng/L) and cardiac
subpopulation (748.07 to 614.37 ng/L), and increased with external placebo (531.30 to 844.40 ng/L; 711.10 to 1116.75 ng/L, respectively)
Better
Worse
Change from Baseline in NT-proBNP
(mITT Population)a
Adjusted
Geometric
Fold
Change
from
Baseline
Baseline Month 9 Month 18
0.5
1
1.5
2
Placebo (APOLLO)
Vutrisiran
1.58
n=65
1.96
n=52
n=122
n=75
0.94
n=114
Adjusted Geometric Fold
Change Ratio (95% CI)
at 18 Months:
0.480 (0.383, 0.600)
p=9.606 × 10–10
1.00
n=113
Adjusted
Geometric
Fold
Change
from
Baseline
Baseline Month 9 Month 18
0.5
1
1.5
2
Placebo (APOLLO)
Vutrisiran
1.58
n=30
Change from Baseline in NT-proBNP
(Cardiac Subpopulation)a
1.93
n=23
n=40
n=34
0.95
n=36
Adjusted Geometric Fold
Change Ratio (95% CI)
at 18 Months:
0.491 (0.337, 0.716)
p=0.0004
1.02
n=37
Garcia-Pavia, et al. ESC HF Congress 2022
98. 32 LS, least squares; LV, left ventricular; mITT, modified intent-to-treat; SE, standard error.
Echocardiographic Parameters with Vutrisiran vs External Placebo at Month 18
• Vutrisiran demonstrated a trend towards improvement of echocardiographic parameters in the mITT population and cardiac
subpopulation at Month 18 compared with the external placebo group (exploratory endpoints)
mITT Population Cardiac Subpopulation
APOLLO Placebo
Vutrisiran
0
-0.2
-0.4
-0.6
-0.8
Cardiac Output (L/min)
p=0.0426
n=33 n=24
0
-5
-10
-15
-20
LV End-Diastolic Volume (mL)
p=0.0607
n=33 n=24
0.04
0.02
0
-0.02
-0.04
-0.06
-0.08
Mean LV Wall Thickness (cm)
p=0.5397
n=35
n=25
0.5
0
-0.5
2
1.5
1
Global Longitudinal Strain (%)
p=0.0781
n=35
n=25
LS
Mean
(SE)
Change
from
Baseline
at
Month
18
0.04
0.03
0.02
0.01
0
-0.01
-0.02
-0.03
Mean LV Wall Thickness (cm)
p=0.5228
n=51
n=105
0
0.2
-0.2
-0.4
-0.6
-0.8
Cardiac Output (L/min)
p=1.144 x10-5
n=105 n=49
1.4
1.2
1
0.8
0.6
0.4
0.2
0
Global Longitudinal Strain (%)
p=0.3182
n=48
n=107
0
5
-5
-10
-15
LV End-Diastolic Volume (mL)
p=4.021 x10-5
n=105 n=50
Garcia-Pavia, et al. ESC HF Congress 2022
99. 33
Reduced Cardiac 99mTc Uptake on Scintigraphy Imaging in Majority of Evaluable
Vutrisiran-Treated Patientsa at Month 18
measure and not improved refers to a >0 increase from baseline. LV, left ventricle; Tc, technetium.
Patients
(%)
Improved Not Improved
100
80
60
40
20
0
68.1
(N=32/47) 31.9
(N=15/47)
Improved Not Improved
100
80
60
40
20
0
Quantitative Assessments of Cardiac 99mTc Uptake at Month 18
99mTc Normalized LV Total Uptakeb 99mTc Heart-to-Contralateral Lung Ratiob
64.6
(N=31/48) 35.4
(N=17/48)
All
Scintigraphy
Patients
100
80
60
40
20
0
Improved Not Improved Improved Not Improved
aAnalysis includes patients from mITT population with evaluable data at baseline and Month 18; bImproved refers to a negative change (<0 increase) from baseline to Month 18 in the chosen
76.9
(N=20/26)
23.1
(N=6/26)
Patients
(%)
100
80
60
40
20
0
100
(N=25/25)
0
Perugini
Grade
≥2
Patients
Garcia-Pavia, et al. ESC HF Congress 2022
100. CRISPR/Cas9 genome editing
Gillmore et al, NEJM 2021
Introduction indels into TTR gene
leading to mutations that prevent
production of TTR protein.
106. Brilliant future but several Open Questions
No head-to-head comparisons
When to start? With what agent? When to switch?
Role for combined treatment?
Long-term safety of TTR depletion