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Steven E. Nissen MD MACC
Study Sponsor:
Esperion Therapeutics, Inc.
Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen
The CLEAR Outcomes Trial
On behalf of the CLEAR investigators and our extraordinary patients
A Michael Lincoff
Co-Principal Investigator
John J.P. Kastelein
Paul D. Thompson
Leslie Cho
Harold E. Bays
Jorge Plutzky
2
Stephen Nicholls
Co-Principal Investigator
Kausik K. Ray
Peter Libby
Patrick M. Moriarty
Michael J. Louie (non-voting)
Executive Committee
Steven E. Nissen
(Study Chair)
Diederick E. Grobbee Denise Mason Maggie Horner & LeAnne Bloedon
European ARO Partner C5Research Lead Project Manager Esperion Lead Managers
Background
• Statin intolerance is a vexing problem that prevents many patients
from achieving LDL-C levels associated with cardiovascular benefits.
• Bempedoic acid, an ATP citrate lyase inhibitor, inhibits hepatic
cholesterol synthesis upstream of HMG-Co-A reductase, the enzyme
inhibited by statins.
• Bempedoic acid is a pro-drug activated in the liver, but not peripheral
tissues, resulting in a low incidence of muscle-related adverse events.
• Although approved for lowering LDL-C, the effects of bempedoic acid
on cardiovascular outcomes has not been assessed .
CLEAR Outcomes Trial Design
Bempedoic Acid 180 mg/day
Matching Placebo
•≥1,620 primary
4-component MACE
•≥810 key secondary
3-component MACE
•≥24 months follow up
Primary or secondary
prevention patients
with LDL-C ≥ 100 mg/dL
4
• Statin intolerance: An adverse effect that started or increased
during statin therapy and resolved or improved after therapy discontinued.
• Intolerance to 2 or more statins or 1 statin if unwilling to attempt
a second statin or advised by physician to not attempt second statin.
Very low dose statin therapy permitted (< lowest approved dose).
Statin Intolerance Confirmation Form
• Patient must confirm and sign:
– “…I can’t tolerate these medications (called statins) even though
I know they would reduce my risk of a heart attack or stroke or death.
My doctor has explained and I am aware that many patients who are
unable to tolerate a single statin medication may also be able to
tolerate a different statin or dose.”
• Signed provider statement:
– “…in my opinion, this patient is unable to tolerate statin therapy (except
possibly at very low average daily doses)….based on my review of the
medical and medication histories and discussion with the patient."
Primary and Key Secondary Endpoints
• Primary endpoint 4-component MACE: nonfatal MI, nonfatal
stroke, coronary revascularization or cardiovascular death
• Hierarchical testing of key secondary endpoints:
1) 3-component MACE (MI, stroke or CV death)
2) Fatal and nonfatal MI
3) Coronary revascularization
4) Fatal and nonfatal stroke
5) Cardiovascular death
6) All-cause mortality
Sequential
Testing
• 13,970 patients randomized at 1250 sites in 32 countries.
• Patients enrolled December 2016 to August 2019 with a median
duration of follow-up 40.6 months.
• Despite the pandemic, complete assessment for the primary
endpoint in 95.3% and vital status in 99.4% of patients.
• 4-component MACE occurred in 1746 patients and 3-component
MACE in 1238 patients.
Study Milestones
Characteristic
Bempedoic Acid
N=6992
Placebo
N=6978
Mean Age (years) 65.5 65.5
Female sex 48.1% 48.4%
White 91.5% 90.8%
LDL cholesterol (mg/dL) 139.0 139.0
HDL cholesterol (mg/dL) 49.6 49.4
hsCRP (mg/L) 2.3 2.3
High Risk Primary Prevention 30.0% 30.2%
Secondary Prevention 70.0% 69.8%
Diabetes 45.0% 46.3%
Baseline statin use 22.9% 22.5%
Selected Baseline Characteristics
Effect of Trial Regimens on LDL-C and hsCRP
2.4%
0.0%
-1.6%
-22.2%
-20.6%
-19.4%
-25%
-20%
-15%
-10%
-5%
0%
5%
Month 6 Month 12 End of Study
Mean
Percent
Change
(%)
Percent Change in hsCRP
Placebo Bempedoic Acid
-21.7%
-19.7%
-26.1%
-0.6%
-4.90%
-10.60%
-30%
-25%
-20%
-15%
-10%
-5%
0%
0 6 12 18 24 30 36 42 48 54 60
Mean
Percent
Change
(%)
Months Since Randomization
Percent Change in LDL-C over Time
Bempedoic Acid Placebo
3
Primary and First Key Secondary Cardiovascular End Points
Patients
with
an
Event
(%)
3-component MACE
Months Since Randomization
HR 0.85 (95% CI 0.76-0.96)
P=0.006
Absolute risk reduction 1.3%
Placebo
Bempedoic Acid
Patients
with
an
Event
(%)
4-component MACE
Months Since Randomization
HR 0.87 (95% CI 0.79-0.96)
P=0.004
Absolute risk reduction 1.6%
NNT=63
Placebo
Bempedoic Acid
Key Secondary End Point: MI and Coronary Revascularization
Patients
with
an
Event
(%)
Coronary Revascularization
Months Since Randomization
HR 0.81 (95% CI 0.72-0.92)
P=0.001
Absolute risk reduction 1.4%
Placebo
Bempedoic Acid
Patients
with
an
Event
(%)
Fatal and Nonfatal MI
Months Since Randomization
HR 0.77 (95% CI 0.66-0.91)
P=0.002
Absolute risk reduction 1.1%
Placebo
Bempedoic Acid
Effect on Stroke and Hospitalization for Unstable Angina
Patients
with
an
Event
(%)
Hospitalization for Unstable Angina
Months Since Randomization
Patients
with
an
Event
(%)
Fatal and Nonfatal Stroke
Months Since Randomization
HR = 0.66 (95% CI 0.50 – 0.86)
Placebo
Bempedoic Acid
HR 0.85 (95% CI 0.67-1.07)
Placebo
Bempedoic Acid
Effects of Trial Regimens on Mortality End Points
Patients
with
an
Event
(%)
All-cause Mortality
Months Since Randomization
Patients
with
an
Event
(%)
Cardiovascular Death
Months Since Randomization
HR 1.03 (95% CI 0.90-1.18)
HR 1.04 (95% CI 0.88-1.24)
Placebo
Bempedoic Acid
Placebo
Bempedoic Acid
HR 1.03 (95% CI 0.90-1.18)
Investigator-Reported Adverse Effects
Characteristic
Bempedoic Acid
N=7001
Placebo
N=6964
Serious Treatment Emergent Adverse event 25.2% 24.9%
Adverse event leading to drug discontinuation 10.8% 10.4%
Any muscle disorder 15.0% 15.4%
New onset diabetes 16.1% 17.1%
Elevated hepatic enzymes 4.5% 3.0%
Prespecified renal events 11.5% 8.6%
Gout 3.1% 2.1%
Cholelithiasis 2.2% 1.2%
Adjudicated tendon rupture 1.2% 0.9%
Primary MACE-4 End Point in Selected Subgroups
Favors Treatment Favors Placebo
Endpoints
Age
<65
≥65 to <75
>75
Sex
Male
Female
CVD Risk Category
Secondary Prevention
Primary Prevention
Baseline LDL-C
<130
≥130 to <160
≥160
Baseline glycemic status
Normoglycemic
Prediabetes
Diabetes
Hazard Ratio
0.87
0.83
0.95
0.87
0.86
0.91
0.68
0.88
0.79
0.98
0.84
0.94
0.83
Limitations
• The trial enrolled only patients with documented statin
intolerance. Effects in other populations were not studied.
• Addition of other therapies (including PCSK9 inhibitors)
narrowed the LDL-C differences between bempedoic acid
and placebo over time.
• The pandemic created challenges in achieving complete
follow up, although full outcome data were available in 95.3%
of patients and vital status determined in 99.4%.
Conclusions
• Bempedoic acid was well-tolerated in a mixed population of primary
and secondary prevention patients unable or unwilling to take statins
• Bempedoic acid lowered LDL-C by 21.7% and hsCRP by 22.2%
with small increases in the incidence of gout and cholelithiasis.
• The primary end point, 4-component MACE was reduced 13%,
3-component MACE 15%, myocardial infarction 23% and coronary
revascularization 19%.
• These findings establish bempedoic acid as an effective approach
to reduce major cardiovascular events in statin intolerant patients.
A Final Thought
Management of patients unable or unwilling to take
statins represents a challenging and frustrating clinical
issue.
Regardless whether this problem represents the nocebo
effect or actual intolerance, these high-risk patients need
effective alternative therapies.
The CLEAR Outcomes trial provides a sound rationale
for use of bempedoic acid to reduce major adverse
cardiovascular outcomes in patients intolerant to statins.
Backup
21
Summary of All LMT Cross-ins During the Trial
LMT Category
Bempedoic Acid
(N = 6992)
Placebo
(N = 6978)
Any LMT 660 ( 9.4%) 1089 (15.6%)
Statins* 283 (4.0%) 456 (6.5%)
PCSK9 inhibitors -mAb 194 (2.8%) 306 (4.4%)
Selective Cholesterol Absorption
Inhibitors (Ezetimibe)
189 (2.7%) 382 (5.5%)
Fibrates 72 (1.0%) 91 (1.3%)
Bile Acid Sequestrants 11 (0.2%) 17 ( 0.2%)
Bempedoic Acid 11 (0.2%) 10 (0.1%)
Fixed Dose Combination: Bempedoic
Acid + Ezetimibe
6 (0.1%) 3 (<0.1%)
PCSK9-siRNA 4 (0.1%) 5 (0.1%)
Niacin derivatives 4 (0.1%) 6 (0.1%)
22
* At the end of the study <4% patients receiving a moderate or high intensity statin
Time to Cross-in to Additional Lipid Modifying Therapy
0%
10%
20%
Probability
of
Starting
Additional
Therapy
Placebo
Bempedoic Acid
0 12 24 36 48 60
Months Since Randomization
CTTC End Point Calculation
Bempedoic Acid (N=6992), n (%) Placebo (N=6978), n (%) HR P-value
703 (10.1) 816 (11.7) 0.85 (0.77,0.94) 0.001
Bempedoic Acid (N=6992) Placebo (N=6978)
Baseline, n 6992 6978
Mean (SD) 139.0 (34.9) 139.0 (35.2)
Month 12, n 5977 5824
Mean (SD) 107.2 (37.8) 133.2 (41.4)
Change from baseline, LS Mean (SE) -28.5 (0.42) -2.47 (0.43)
Difference of LS Means (SE) -26.1 (0.59) mg/dl (0.67 mmol/L)
CTTC calculation = Expected HR for 0.67 mmol/L LDL-C reduction = 0.846
Outcomes: Non-Statin LDL-C Lowering Therapies
3-Component
MACE
Nonfatal MI
Ezetimibe 0.90 0.87
Evolocumab 0.80 0.73†
Alirocumab 0.86* 0.86
Bempedoic Acid 0.85 0.73
*Trial used all-cause mortality rather than CV death †Fatal and nonfatal MI

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1030am-CLEAR-OUTCOMES-acc-2023- Bemp.pdf

  • 1. Steven E. Nissen MD MACC Study Sponsor: Esperion Therapeutics, Inc. Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen The CLEAR Outcomes Trial On behalf of the CLEAR investigators and our extraordinary patients
  • 2. A Michael Lincoff Co-Principal Investigator John J.P. Kastelein Paul D. Thompson Leslie Cho Harold E. Bays Jorge Plutzky 2 Stephen Nicholls Co-Principal Investigator Kausik K. Ray Peter Libby Patrick M. Moriarty Michael J. Louie (non-voting) Executive Committee Steven E. Nissen (Study Chair) Diederick E. Grobbee Denise Mason Maggie Horner & LeAnne Bloedon European ARO Partner C5Research Lead Project Manager Esperion Lead Managers
  • 3. Background • Statin intolerance is a vexing problem that prevents many patients from achieving LDL-C levels associated with cardiovascular benefits. • Bempedoic acid, an ATP citrate lyase inhibitor, inhibits hepatic cholesterol synthesis upstream of HMG-Co-A reductase, the enzyme inhibited by statins. • Bempedoic acid is a pro-drug activated in the liver, but not peripheral tissues, resulting in a low incidence of muscle-related adverse events. • Although approved for lowering LDL-C, the effects of bempedoic acid on cardiovascular outcomes has not been assessed .
  • 4. CLEAR Outcomes Trial Design Bempedoic Acid 180 mg/day Matching Placebo •≥1,620 primary 4-component MACE •≥810 key secondary 3-component MACE •≥24 months follow up Primary or secondary prevention patients with LDL-C ≥ 100 mg/dL 4 • Statin intolerance: An adverse effect that started or increased during statin therapy and resolved or improved after therapy discontinued. • Intolerance to 2 or more statins or 1 statin if unwilling to attempt a second statin or advised by physician to not attempt second statin. Very low dose statin therapy permitted (< lowest approved dose).
  • 5. Statin Intolerance Confirmation Form • Patient must confirm and sign: – “…I can’t tolerate these medications (called statins) even though I know they would reduce my risk of a heart attack or stroke or death. My doctor has explained and I am aware that many patients who are unable to tolerate a single statin medication may also be able to tolerate a different statin or dose.” • Signed provider statement: – “…in my opinion, this patient is unable to tolerate statin therapy (except possibly at very low average daily doses)….based on my review of the medical and medication histories and discussion with the patient."
  • 6. Primary and Key Secondary Endpoints • Primary endpoint 4-component MACE: nonfatal MI, nonfatal stroke, coronary revascularization or cardiovascular death • Hierarchical testing of key secondary endpoints: 1) 3-component MACE (MI, stroke or CV death) 2) Fatal and nonfatal MI 3) Coronary revascularization 4) Fatal and nonfatal stroke 5) Cardiovascular death 6) All-cause mortality Sequential Testing
  • 7. • 13,970 patients randomized at 1250 sites in 32 countries. • Patients enrolled December 2016 to August 2019 with a median duration of follow-up 40.6 months. • Despite the pandemic, complete assessment for the primary endpoint in 95.3% and vital status in 99.4% of patients. • 4-component MACE occurred in 1746 patients and 3-component MACE in 1238 patients. Study Milestones
  • 8. Characteristic Bempedoic Acid N=6992 Placebo N=6978 Mean Age (years) 65.5 65.5 Female sex 48.1% 48.4% White 91.5% 90.8% LDL cholesterol (mg/dL) 139.0 139.0 HDL cholesterol (mg/dL) 49.6 49.4 hsCRP (mg/L) 2.3 2.3 High Risk Primary Prevention 30.0% 30.2% Secondary Prevention 70.0% 69.8% Diabetes 45.0% 46.3% Baseline statin use 22.9% 22.5% Selected Baseline Characteristics
  • 9. Effect of Trial Regimens on LDL-C and hsCRP 2.4% 0.0% -1.6% -22.2% -20.6% -19.4% -25% -20% -15% -10% -5% 0% 5% Month 6 Month 12 End of Study Mean Percent Change (%) Percent Change in hsCRP Placebo Bempedoic Acid -21.7% -19.7% -26.1% -0.6% -4.90% -10.60% -30% -25% -20% -15% -10% -5% 0% 0 6 12 18 24 30 36 42 48 54 60 Mean Percent Change (%) Months Since Randomization Percent Change in LDL-C over Time Bempedoic Acid Placebo 3
  • 10. Primary and First Key Secondary Cardiovascular End Points Patients with an Event (%) 3-component MACE Months Since Randomization HR 0.85 (95% CI 0.76-0.96) P=0.006 Absolute risk reduction 1.3% Placebo Bempedoic Acid Patients with an Event (%) 4-component MACE Months Since Randomization HR 0.87 (95% CI 0.79-0.96) P=0.004 Absolute risk reduction 1.6% NNT=63 Placebo Bempedoic Acid
  • 11. Key Secondary End Point: MI and Coronary Revascularization Patients with an Event (%) Coronary Revascularization Months Since Randomization HR 0.81 (95% CI 0.72-0.92) P=0.001 Absolute risk reduction 1.4% Placebo Bempedoic Acid Patients with an Event (%) Fatal and Nonfatal MI Months Since Randomization HR 0.77 (95% CI 0.66-0.91) P=0.002 Absolute risk reduction 1.1% Placebo Bempedoic Acid
  • 12. Effect on Stroke and Hospitalization for Unstable Angina Patients with an Event (%) Hospitalization for Unstable Angina Months Since Randomization Patients with an Event (%) Fatal and Nonfatal Stroke Months Since Randomization HR = 0.66 (95% CI 0.50 – 0.86) Placebo Bempedoic Acid HR 0.85 (95% CI 0.67-1.07) Placebo Bempedoic Acid
  • 13. Effects of Trial Regimens on Mortality End Points Patients with an Event (%) All-cause Mortality Months Since Randomization Patients with an Event (%) Cardiovascular Death Months Since Randomization HR 1.03 (95% CI 0.90-1.18) HR 1.04 (95% CI 0.88-1.24) Placebo Bempedoic Acid Placebo Bempedoic Acid HR 1.03 (95% CI 0.90-1.18)
  • 14. Investigator-Reported Adverse Effects Characteristic Bempedoic Acid N=7001 Placebo N=6964 Serious Treatment Emergent Adverse event 25.2% 24.9% Adverse event leading to drug discontinuation 10.8% 10.4% Any muscle disorder 15.0% 15.4% New onset diabetes 16.1% 17.1% Elevated hepatic enzymes 4.5% 3.0% Prespecified renal events 11.5% 8.6% Gout 3.1% 2.1% Cholelithiasis 2.2% 1.2% Adjudicated tendon rupture 1.2% 0.9%
  • 15. Primary MACE-4 End Point in Selected Subgroups Favors Treatment Favors Placebo Endpoints Age <65 ≥65 to <75 >75 Sex Male Female CVD Risk Category Secondary Prevention Primary Prevention Baseline LDL-C <130 ≥130 to <160 ≥160 Baseline glycemic status Normoglycemic Prediabetes Diabetes Hazard Ratio 0.87 0.83 0.95 0.87 0.86 0.91 0.68 0.88 0.79 0.98 0.84 0.94 0.83
  • 16. Limitations • The trial enrolled only patients with documented statin intolerance. Effects in other populations were not studied. • Addition of other therapies (including PCSK9 inhibitors) narrowed the LDL-C differences between bempedoic acid and placebo over time. • The pandemic created challenges in achieving complete follow up, although full outcome data were available in 95.3% of patients and vital status determined in 99.4%.
  • 17. Conclusions • Bempedoic acid was well-tolerated in a mixed population of primary and secondary prevention patients unable or unwilling to take statins • Bempedoic acid lowered LDL-C by 21.7% and hsCRP by 22.2% with small increases in the incidence of gout and cholelithiasis. • The primary end point, 4-component MACE was reduced 13%, 3-component MACE 15%, myocardial infarction 23% and coronary revascularization 19%. • These findings establish bempedoic acid as an effective approach to reduce major cardiovascular events in statin intolerant patients.
  • 18.
  • 19. A Final Thought Management of patients unable or unwilling to take statins represents a challenging and frustrating clinical issue. Regardless whether this problem represents the nocebo effect or actual intolerance, these high-risk patients need effective alternative therapies. The CLEAR Outcomes trial provides a sound rationale for use of bempedoic acid to reduce major adverse cardiovascular outcomes in patients intolerant to statins.
  • 20.
  • 22. Summary of All LMT Cross-ins During the Trial LMT Category Bempedoic Acid (N = 6992) Placebo (N = 6978) Any LMT 660 ( 9.4%) 1089 (15.6%) Statins* 283 (4.0%) 456 (6.5%) PCSK9 inhibitors -mAb 194 (2.8%) 306 (4.4%) Selective Cholesterol Absorption Inhibitors (Ezetimibe) 189 (2.7%) 382 (5.5%) Fibrates 72 (1.0%) 91 (1.3%) Bile Acid Sequestrants 11 (0.2%) 17 ( 0.2%) Bempedoic Acid 11 (0.2%) 10 (0.1%) Fixed Dose Combination: Bempedoic Acid + Ezetimibe 6 (0.1%) 3 (<0.1%) PCSK9-siRNA 4 (0.1%) 5 (0.1%) Niacin derivatives 4 (0.1%) 6 (0.1%) 22 * At the end of the study <4% patients receiving a moderate or high intensity statin
  • 23. Time to Cross-in to Additional Lipid Modifying Therapy 0% 10% 20% Probability of Starting Additional Therapy Placebo Bempedoic Acid 0 12 24 36 48 60 Months Since Randomization
  • 24. CTTC End Point Calculation Bempedoic Acid (N=6992), n (%) Placebo (N=6978), n (%) HR P-value 703 (10.1) 816 (11.7) 0.85 (0.77,0.94) 0.001 Bempedoic Acid (N=6992) Placebo (N=6978) Baseline, n 6992 6978 Mean (SD) 139.0 (34.9) 139.0 (35.2) Month 12, n 5977 5824 Mean (SD) 107.2 (37.8) 133.2 (41.4) Change from baseline, LS Mean (SE) -28.5 (0.42) -2.47 (0.43) Difference of LS Means (SE) -26.1 (0.59) mg/dl (0.67 mmol/L) CTTC calculation = Expected HR for 0.67 mmol/L LDL-C reduction = 0.846
  • 25. Outcomes: Non-Statin LDL-C Lowering Therapies 3-Component MACE Nonfatal MI Ezetimibe 0.90 0.87 Evolocumab 0.80 0.73† Alirocumab 0.86* 0.86 Bempedoic Acid 0.85 0.73 *Trial used all-cause mortality rather than CV death †Fatal and nonfatal MI