omecamtiv mecarbil in heart failure
TRANSCRIPT
Slides templateJohn R. Teerlink, M.D. FACC, FAHA, FESC, FHFA,
FHFSA, FRCP(UK)
Professor of Medicine, University of California San Francisco
Director of Heart Failure, San Francisco Veterans Affairs Medical Center
San Francisco, CA, USA
Omecamtiv Mecarbil in Heart Failure: Where Does it Fit in the Management of Heart Failure?
• Consulting Fee: Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, Windtree Therapeutics
• Contracted Research: Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cytokinetics, Medtronic, Novartis, Windtree Therapeutics
Disclosures
Decreased Systolic Function
Isolated epinephrine in 1897
Jokichi Takamine, Japan Isolated pure, stable, crystalline form of epinephrine in 1900 –
‘adrenaline’
Latin ad and renal – “near the kidneys”
Improving LV systolic function has been pursued as a therapeutic target since the discovery of epinephrine
Modified from: Kaye and Krum Nature Reviews Drug Discovery 2007;6:127–139.
The Inotrope Cemetery
(catecholamines, phosphodiestase-3 inhibitors, etc.)
• Myotropes – affect the molecular motor and scaffolding
Improving Cardiac Performance: Calcitropes, Mitotropes, and Myotropes
Psotka MA, et al. J Am Coll Cardiol 2019;73:2345-53.
Omecamtiv Mecarbil (OM): A Novel Selective Cardiac Myosin Activator
Increases duration of systole
No change in dP/dtmax
No increase in MVO2
OM stabilizes myosin in the Pre- Powerstroke State, increasing the entry rate of myosin into the tightly-bound,
force-producing state with actin
“More hands pulling on the rope”
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.
Mechanochemical Cycle of Myosin
– With omecamtiv mecarbil • More “hands” (myosin heads) to
grasp the “rope” (actin filament) and pull, leading to more force produced
Teerlink JR, et al. JACC Heart Fail 2020;8:329-340.
Cardiac Myosin Activator Mechanism of Action: an Analogy
Dose adjustment
R an
d o
m iz
at io
Sc re
e n
in g
3 0
D ay
25 mg BID (n = 150)
En d
o f
Expansion Phase
Dose escalation from 25 mg BID to 50 mg BID based on OM trough concentration at Week 2
Titration was blinded
NYHA class II or III
LVEF ≤ 40%
LVEF, left ventricular ejection fraction; LVFS, left ventricular fractional shortening; SE, standard error; SET, systolic ejection time
SET Stroke Volume LVFS LVEF
Improved LV Systolic Function
Left Ventricular Size
LVESD left ventricular end systolic diameter LVEDD left ventricular end diastolic diameter LVESV left ventricular end systolic volume LVEDV left ventricular end diastolic volume
LVESD LVESV LVEDD LVEDV
Teerlink JR, et al. Lancet 2016; 388:2895-2903.
Heart Rate and NT-proBNP
Failure
• History of chronic heart failure (HF)
• New York Heart Association class II to IV
• LVEF ≤35%
• BNP ≥ 125 pg/mL or NT-proBNP ≥ 400 pg/mL (atrial fibrillation/flutter: BNP ≥ 375 pg/mL or NT-proBNP ≥ 1200 pg/mL)
• Managed with standard HF therapies
• Currently hospitalized for HF (Inpatients) OR
Urgent ED visit or hospitalization for HF within 1 year prior to screening (Outpatients)
Key exclusion criteria
• Systolic blood pressure < 85 mmHg
• Estimated GFR < 20 mL/min/1.73 m2
• Recent ACS events or CV procedures (including planned procedures) within last 3 months
• Other conditions that would adversely affect participation in the trial
Teerlink JR, et al. JACC Heart Fail 2020;8:32940.
Multicenter, international, randomized, double-blind, placebo-controlled, event-driven Phase 3 study
Screening: • Chronic HF, NYHA II-IV
• LVEF ≤35%
• Managed with Standard HF therapies
• Currently hospitalized for HF (Inpatients) OR Urgent ED visit or hospitalization for HF within 1 year prior to screening (Outpatients)
Randomization (1:1)
outpatient – Region
Omecamtiv Mecarbil + Standard HF Therapy Starting dose: 25 mg PO BID; Pharmacokinetic-guided dose selection
(25, 37.5 or 50 mg PO BID)
Placebo + Standard HF Therapy
D1 W2 W4 W6 W8 W12 W24 W36 W48 Q16W
Pharmacokinetic assessment for dose adjustment
Study Visits
Hypothesis: Selectively improving cardiac function with the cardiac myosin activator, omecamtiv mecarbil, will improve clinical outcomes in patients with HFrEF
Baseline Characteristics
Teerlink JR, et al. Eur J Heart Fail 2020:22:2160-2171.
Primary Composite Endpoint
Placebo 4112 3310 2889 2102 1349 647 141
Omecamtiv mecarbil 4120 3391 2953 2158 1430 700 164
Patients at risk, n Months (30 days) since randomization
C u
m u
la ti
ve in
ci d
en ce
50
40
30
20
10
0
Placebo
Teerlink JR, et al. N Engl J Med 2021;384:105-16.
23.7
5.8
21.2
6.3
0
5
10
15
20
25
Change in Kansas City Cardiomyopathy Questionnaire Total Symptom Score from Baseline to Week 24
Joint test P = 0.028
Cardiovascular Death HR = 1.01 (95% CI, 0.92–1.11) P = 0.86
First Heart Failure Event HR = 0.93 (95% CI, 0.86–1.00) P = 0.06
+2.5 (95% CI, 0.54–4.46)
-0.5 (95% CI, -1.40–0.48)
Primary Composite Components and KCCQ TSS
Teerlink JR, et al. N Engl J Med 2021;384:105-16.
Primary Outcome: Subgroup Results
Primary Outcome: Subgroup Results
Interaction P-value = 0.003
1.0 1.3 0.7
Primary Outcome: EF Subgroup Results
21
22
Variable
Vital signs, laboratory values: change from baseline to Week 24
Systolic BP, mmHg, mean (SD) 1.4 (15.3) 1.5 (15.6) -0.1 (-0.9, 0.6)
Heart rate, bpm, mean (SD) -2.1 (12.6) -0.5 (12.8) -1.6 (-2.2, -1.0)
Potassium, mmol/L, mean (SD) -0.01 ± 0.57 -0.01 ± 0.57 0.00 (-0.03, 0.03)
Creatinine, mg/dL, mean (SD) 0.03 ± 0.33 0.02 ± 0.32 0.01 (-0.01, 0.02)
NT-proBNP, pg/mL, median (Q1, Q3) -251
(-1180, 295) -180
Cardiac troponin I, ng/mL, median (Q1, Q3)
0.004 (-0.002, 0.021)
0.000 (-0.009, 0.008)
0.004 (0.003, 0.005)
No negative impact on renal function or potassium
Teerlink JR, et al. N Engl J Med 2021;384:105-16.
Adverse Events
Adverse event
Relative Risk (95% CI)
Any serious AE, n (%) 2373 (57.7) 2435 (59.4) 0.97 (0.94, 1.01)
Drug discontinuation due to AE, n (%) 371 (9.0) 382 (9.3) 0.97 (0.85, 1.11)
Adverse events of interest
Ventricular tachyarrhythmias 290 (7.1) 304 (7.4) 0.95 (0.82, 1.11)
Torsade de pointes/QT prolongation 176 (4.3) 195 (4.8) 0.90 (0.74, 1.10)
SAE of ventricular arrhythmia requiring treatment 119 (2.9) 127 (3.1) 0.93 (0.73, 1.20)
Adjudicated major cardiac ischemic events, n (%) 200 (4.9) 188 (4.6) 1.06 (0.87, 1.29)
Myocardial infarction 122 (3.0) 118 (2.9) -- Hospitalized for unstable angina 25 (0.6) 12 (0.3) -- Coronary revascularization 115 (2.8) 117 (2.9) --
Adjudicated Strokes 76 (1.8) 112 (2.7) 0.68 (0.51, 0.91)
24
Arrhythmic Adverse Events
Any Treatment Group
Adverse Events Occurring in
Treatment Group
Teerlink JR, et al. N Engl J Med 2021;384:105-16.
Conclusions
•The pattern of adverse events, including myocardial ischemia and ventricular arrhythmias, were similar in the omecamtiv mecarbil and placebo groups
•Preliminary analyses suggest that there may be groups of patients who would derive even greater benefit from Omecamtiv mecarbil.
Multicenter Exercise Tolerance Evaluation of Omecamtiv Mecarbil Related to Increased Contractility
in Heart Failure
• ~270 subjects randomized 2:1 (omecamtiv mecarbil : placebo)
• 20-week treatment, 10 study visits, two CPETs, four 2-week actigraphy sets
• PK-guided dose titration of omecamtiv mecarbil (identical to GALACTIC-HF)
Primary Endpoint • ΔpVO2 at W20 Secondary Endpoints • Change in Exercise
Capacity • Change in
So… Where does Omecamtiv Mecarbil fit?
• Should Omecamtiv mecarbil replace any of the “four pillars” of HFrEF Medical therapy?
ARNi Beta- Blocker
ARNi Beta- Blocker
MRA SGLT2i
• Should Omecamtiv mecarbil replace any of the “four pillars” of HFrEF Medical therapy? NO!!
So… Where does Omecamtiv Mecarbil fit?
• Should Omecamtiv mecarbil replace any of the “four pillars” of HFrEF Medical therapy?
• Who should receive Omecamtiv mecarbil? EF≤35% Currently hospitalized for HF or urgent treatment for
HF within 1 year Receiving tolerated “four pillars” HF therapy
So… Where does Omecamtiv Mecarbil fit?
• Should Omecamtiv mecarbil replace any of the “four pillars” of HFrEF Medical therapy?
• Who should receive Omecamtiv mecarbil? • When should Omecamtiv mecarbil be initiated?
• No adverse effect on: Blood pressure Heart rate Kidney function Potassium homeostasis
• Should not interfere with initiation or up-titration of other GDMT
So… Where does Omecamtiv Mecarbil fit?
•Selectively targeting the cardiac sarcomere with omecamtiv mecarbil, the first-in-class myotrope, is a novel approach to improving cardiac function that translates into improved clinical outcomes
•Further analyses of GALACTIC-HF will provide greater insight into subgroups who may demonstrate greater benefit, such as patients with lower ejection fraction or more advanced heart failure in whom improving cardiac function may have a greater role
San Francisco Veterans Affairs Medical Center
Thank you!
Professor of Medicine, University of California San Francisco
Director of Heart Failure, San Francisco Veterans Affairs Medical Center
San Francisco, CA, USA
Omecamtiv Mecarbil in Heart Failure: Where Does it Fit in the Management of Heart Failure?
• Consulting Fee: Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, Windtree Therapeutics
• Contracted Research: Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cytokinetics, Medtronic, Novartis, Windtree Therapeutics
Disclosures
Decreased Systolic Function
Isolated epinephrine in 1897
Jokichi Takamine, Japan Isolated pure, stable, crystalline form of epinephrine in 1900 –
‘adrenaline’
Latin ad and renal – “near the kidneys”
Improving LV systolic function has been pursued as a therapeutic target since the discovery of epinephrine
Modified from: Kaye and Krum Nature Reviews Drug Discovery 2007;6:127–139.
The Inotrope Cemetery
(catecholamines, phosphodiestase-3 inhibitors, etc.)
• Myotropes – affect the molecular motor and scaffolding
Improving Cardiac Performance: Calcitropes, Mitotropes, and Myotropes
Psotka MA, et al. J Am Coll Cardiol 2019;73:2345-53.
Omecamtiv Mecarbil (OM): A Novel Selective Cardiac Myosin Activator
Increases duration of systole
No change in dP/dtmax
No increase in MVO2
OM stabilizes myosin in the Pre- Powerstroke State, increasing the entry rate of myosin into the tightly-bound,
force-producing state with actin
“More hands pulling on the rope”
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.
Mechanochemical Cycle of Myosin
– With omecamtiv mecarbil • More “hands” (myosin heads) to
grasp the “rope” (actin filament) and pull, leading to more force produced
Teerlink JR, et al. JACC Heart Fail 2020;8:329-340.
Cardiac Myosin Activator Mechanism of Action: an Analogy
Dose adjustment
R an
d o
m iz
at io
Sc re
e n
in g
3 0
D ay
25 mg BID (n = 150)
En d
o f
Expansion Phase
Dose escalation from 25 mg BID to 50 mg BID based on OM trough concentration at Week 2
Titration was blinded
NYHA class II or III
LVEF ≤ 40%
LVEF, left ventricular ejection fraction; LVFS, left ventricular fractional shortening; SE, standard error; SET, systolic ejection time
SET Stroke Volume LVFS LVEF
Improved LV Systolic Function
Left Ventricular Size
LVESD left ventricular end systolic diameter LVEDD left ventricular end diastolic diameter LVESV left ventricular end systolic volume LVEDV left ventricular end diastolic volume
LVESD LVESV LVEDD LVEDV
Teerlink JR, et al. Lancet 2016; 388:2895-2903.
Heart Rate and NT-proBNP
Failure
• History of chronic heart failure (HF)
• New York Heart Association class II to IV
• LVEF ≤35%
• BNP ≥ 125 pg/mL or NT-proBNP ≥ 400 pg/mL (atrial fibrillation/flutter: BNP ≥ 375 pg/mL or NT-proBNP ≥ 1200 pg/mL)
• Managed with standard HF therapies
• Currently hospitalized for HF (Inpatients) OR
Urgent ED visit or hospitalization for HF within 1 year prior to screening (Outpatients)
Key exclusion criteria
• Systolic blood pressure < 85 mmHg
• Estimated GFR < 20 mL/min/1.73 m2
• Recent ACS events or CV procedures (including planned procedures) within last 3 months
• Other conditions that would adversely affect participation in the trial
Teerlink JR, et al. JACC Heart Fail 2020;8:32940.
Multicenter, international, randomized, double-blind, placebo-controlled, event-driven Phase 3 study
Screening: • Chronic HF, NYHA II-IV
• LVEF ≤35%
• Managed with Standard HF therapies
• Currently hospitalized for HF (Inpatients) OR Urgent ED visit or hospitalization for HF within 1 year prior to screening (Outpatients)
Randomization (1:1)
outpatient – Region
Omecamtiv Mecarbil + Standard HF Therapy Starting dose: 25 mg PO BID; Pharmacokinetic-guided dose selection
(25, 37.5 or 50 mg PO BID)
Placebo + Standard HF Therapy
D1 W2 W4 W6 W8 W12 W24 W36 W48 Q16W
Pharmacokinetic assessment for dose adjustment
Study Visits
Hypothesis: Selectively improving cardiac function with the cardiac myosin activator, omecamtiv mecarbil, will improve clinical outcomes in patients with HFrEF
Baseline Characteristics
Teerlink JR, et al. Eur J Heart Fail 2020:22:2160-2171.
Primary Composite Endpoint
Placebo 4112 3310 2889 2102 1349 647 141
Omecamtiv mecarbil 4120 3391 2953 2158 1430 700 164
Patients at risk, n Months (30 days) since randomization
C u
m u
la ti
ve in
ci d
en ce
50
40
30
20
10
0
Placebo
Teerlink JR, et al. N Engl J Med 2021;384:105-16.
23.7
5.8
21.2
6.3
0
5
10
15
20
25
Change in Kansas City Cardiomyopathy Questionnaire Total Symptom Score from Baseline to Week 24
Joint test P = 0.028
Cardiovascular Death HR = 1.01 (95% CI, 0.92–1.11) P = 0.86
First Heart Failure Event HR = 0.93 (95% CI, 0.86–1.00) P = 0.06
+2.5 (95% CI, 0.54–4.46)
-0.5 (95% CI, -1.40–0.48)
Primary Composite Components and KCCQ TSS
Teerlink JR, et al. N Engl J Med 2021;384:105-16.
Primary Outcome: Subgroup Results
Primary Outcome: Subgroup Results
Interaction P-value = 0.003
1.0 1.3 0.7
Primary Outcome: EF Subgroup Results
21
22
Variable
Vital signs, laboratory values: change from baseline to Week 24
Systolic BP, mmHg, mean (SD) 1.4 (15.3) 1.5 (15.6) -0.1 (-0.9, 0.6)
Heart rate, bpm, mean (SD) -2.1 (12.6) -0.5 (12.8) -1.6 (-2.2, -1.0)
Potassium, mmol/L, mean (SD) -0.01 ± 0.57 -0.01 ± 0.57 0.00 (-0.03, 0.03)
Creatinine, mg/dL, mean (SD) 0.03 ± 0.33 0.02 ± 0.32 0.01 (-0.01, 0.02)
NT-proBNP, pg/mL, median (Q1, Q3) -251
(-1180, 295) -180
Cardiac troponin I, ng/mL, median (Q1, Q3)
0.004 (-0.002, 0.021)
0.000 (-0.009, 0.008)
0.004 (0.003, 0.005)
No negative impact on renal function or potassium
Teerlink JR, et al. N Engl J Med 2021;384:105-16.
Adverse Events
Adverse event
Relative Risk (95% CI)
Any serious AE, n (%) 2373 (57.7) 2435 (59.4) 0.97 (0.94, 1.01)
Drug discontinuation due to AE, n (%) 371 (9.0) 382 (9.3) 0.97 (0.85, 1.11)
Adverse events of interest
Ventricular tachyarrhythmias 290 (7.1) 304 (7.4) 0.95 (0.82, 1.11)
Torsade de pointes/QT prolongation 176 (4.3) 195 (4.8) 0.90 (0.74, 1.10)
SAE of ventricular arrhythmia requiring treatment 119 (2.9) 127 (3.1) 0.93 (0.73, 1.20)
Adjudicated major cardiac ischemic events, n (%) 200 (4.9) 188 (4.6) 1.06 (0.87, 1.29)
Myocardial infarction 122 (3.0) 118 (2.9) -- Hospitalized for unstable angina 25 (0.6) 12 (0.3) -- Coronary revascularization 115 (2.8) 117 (2.9) --
Adjudicated Strokes 76 (1.8) 112 (2.7) 0.68 (0.51, 0.91)
24
Arrhythmic Adverse Events
Any Treatment Group
Adverse Events Occurring in
Treatment Group
Teerlink JR, et al. N Engl J Med 2021;384:105-16.
Conclusions
•The pattern of adverse events, including myocardial ischemia and ventricular arrhythmias, were similar in the omecamtiv mecarbil and placebo groups
•Preliminary analyses suggest that there may be groups of patients who would derive even greater benefit from Omecamtiv mecarbil.
Multicenter Exercise Tolerance Evaluation of Omecamtiv Mecarbil Related to Increased Contractility
in Heart Failure
• ~270 subjects randomized 2:1 (omecamtiv mecarbil : placebo)
• 20-week treatment, 10 study visits, two CPETs, four 2-week actigraphy sets
• PK-guided dose titration of omecamtiv mecarbil (identical to GALACTIC-HF)
Primary Endpoint • ΔpVO2 at W20 Secondary Endpoints • Change in Exercise
Capacity • Change in
So… Where does Omecamtiv Mecarbil fit?
• Should Omecamtiv mecarbil replace any of the “four pillars” of HFrEF Medical therapy?
ARNi Beta- Blocker
ARNi Beta- Blocker
MRA SGLT2i
• Should Omecamtiv mecarbil replace any of the “four pillars” of HFrEF Medical therapy? NO!!
So… Where does Omecamtiv Mecarbil fit?
• Should Omecamtiv mecarbil replace any of the “four pillars” of HFrEF Medical therapy?
• Who should receive Omecamtiv mecarbil? EF≤35% Currently hospitalized for HF or urgent treatment for
HF within 1 year Receiving tolerated “four pillars” HF therapy
So… Where does Omecamtiv Mecarbil fit?
• Should Omecamtiv mecarbil replace any of the “four pillars” of HFrEF Medical therapy?
• Who should receive Omecamtiv mecarbil? • When should Omecamtiv mecarbil be initiated?
• No adverse effect on: Blood pressure Heart rate Kidney function Potassium homeostasis
• Should not interfere with initiation or up-titration of other GDMT
So… Where does Omecamtiv Mecarbil fit?
•Selectively targeting the cardiac sarcomere with omecamtiv mecarbil, the first-in-class myotrope, is a novel approach to improving cardiac function that translates into improved clinical outcomes
•Further analyses of GALACTIC-HF will provide greater insight into subgroups who may demonstrate greater benefit, such as patients with lower ejection fraction or more advanced heart failure in whom improving cardiac function may have a greater role
San Francisco Veterans Affairs Medical Center
Thank you!