Efficacy

Summary⁴

• The CLEAR Harmony trial was a Phase 3, randomised, double-blind, placebo-controlled trial that enrolled patients with ASCVD, HeFH, or both
• After a 2-week screening period, 2,230 patients were randomly assigned 2:1* to oral once-daily NILEMDO® 180 mg or placebo once daily for 52 weeks
• One patient underwent randomisation in error and was excluded from the safety population

Study composition⁴

~93% of patients were treated with moderate- or high-intensity statins

~8% of patients were using ezetimibe

Study design⁴

Key inclusion criteria⁴

• Adults with ASCVD, HeFH or both
• On maximally-tolerated statin therapy^† with or without other LLTs^‡ for at least 4 weeks before screening
• Fasting LDL-C levels of ≥1.8 mmol/L during screening period

Key exclusion criteria^4,9

• Use of gemfibrozil or simvastatin at doses greater than 40 mg per day (although high-intensity atorvastatin and rosuvastatin regimens were permitted)
• Use of any inhibitor of proprotein convertase subtilisin-kexin type 9 (PCSK9) was prohibited starting 4 weeks before trial entry but was permitted after trial Week 24 if the LDL-C level was greater than 170 mg/dL (4.4 mmol/L) and had increased by at least 25% from baseline
• Uncontrolled hypertension: systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg
• Liver disease or dysfunction, including alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥2× ULN, and/or total bilirubin (TB) ≥1.2× ULN at Week -2
• eGFR <30 mL/min/1.73 m² (or renally impaired patients receiving an average daily dose of simvastatin 40 mg with eGFR below <45 mL/min/1.73 m²)
• Total fasting triglyceride ≥500 mg/dL (5.6 mmol/L)
• BMI >50kg/m²

Endpoints⁴

• Primary endpoint (safety): Overall safety, assessed according to the incidence of AEs and changes in safety laboratory variables from receipt of the first dose through 30 days after the last dose
• Principal secondary endpoint (efficacy): % change in LDL-C levels from baseline to Week 12
• Additional key secondary endpoints: % changes in non-HDL-C levels, total cholesterol from baseline to Week 12

Results⁴

Safety⁴

• The incidence of adverse events and serious adverse events was similar between the NILEMDO® and placebo groups: Adverse events (bempedoic acid 78.5% [n=1167]; placebo 78.7% [n=584]); Serious adverse events (bempedoic acid 14 .5% [n=216]; placebo 14.0% [n=104])
• The incidence of adverse events leading to discontinuation of the regimen was higher in the bempedoic acid group than in the placebo group (10.9% [n=162] vs. 7.1% [n=53]), as was the incidence of gout (1.2 % [n=18] vs. 0.3% [n=2])

LDL-C⁴

• NILEMDO® delivered a significant 18.1% (95% CI: 20.0% to 16.1%) LS mean LDL-C reduction (placebo-corrected) vs. placebo at Week 12 (p<0 .001) on top of maximally tolerated statins^† alone or in combination with other LLTs
• The effects of bempedoic acid on LDL-C were still apparent through Week 52 with minimal attenuation of effect in the on-treatment analyses

*Randomisation stratified by baseline statin intensity (low-, moderate-, or high-intensity) and HeFH (present or absent).^4
†Defined as the highest intensity statin regimen that the patient was able to maintain, as determined by the investigator.^4
‡Other LLTs could include ezetimibe or fibrates. The use of PCSK9 inhibitors was prohibited starting 4 weeks before trial entry but was permitted after trial Week 24 if the LDL-C level was greater than 4.4 mmol/L and had increased by at least 25% from baseline.⁴

Summary⁵

• The CLEAR Wisdom trial was a Phase 3, randomised, double-blind, placebo-controlled trial that enrolled patients at high CV risk due to ASCVD and/or HeFH*
• The CLEAR Wisdom trial comprised a 1-week screening period and a 4-week placebo run-in phase, 779 patients were randomly assigned 2:1^† to oral once-daily NILEMDO® 180 mg or placebo for 52 weeks

Study composition⁵

~89% of patients were treated with statins as background therapy

~85% were treated with moderate-or high-intensity statins

~8% of patients were using ezetimibe

Study design⁵

Key inclusion criteria⁵

• While receiving maximally-tolerated LLT:^‡,§
• Fasting levels of:
• ≥2.6 mmol/L at the first screening
• ≥1.8 mmol/L 1 week before randomisation

Key exclusion criteria^5,10

• Maximally tolerated LLT was determined by the investigator and included a maximally tolerated statin dose alone or in combination with other LLTs, excluding simvastatin at an average daily dose of 40 mg or greater, mipomersen (unlicensed in the UK), lomitapide, lipoprotein apheresis, or gemfibrozil
• Uncontrolled hypertension: systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg
• Liver disease or dysfunction, including alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥2x ULN and/or total bilirubin (TB) ≥2x ULN at Week -5
• eGFR <30 mL/min/1.73 m²
• Total fasting triglyceride ≥5.6 mmol/L (500 mg/dL)
• BMI ≥50 kg/m²

Endpoints⁵

• Primary endpoint: % change in LDL-C levels from baseline to Week 12
• Secondary endpoints: % change in non-HDL-C levels and total cholesterol from baseline to Week 12

Results⁵

LDL-C⁵

• NILEMDO® delivered a significant 17.4% (95% CI: 21.0% to 13.9%) LS mean LDL-C reduction (placebo-corrected) from baseline to Week 12 (p<0.001) on top of maximally tolerated LLTs

Safety⁵

• Safety was assessed by continuous monitoring of TEAEs as well as clinical laboratory values, vital sign measurements, weight changes, physical examination findings and electrocardiogram readings
• No difference in overall TEAEs between NILEMDO® (70.1% [n=366]) and placebo (70.8% [n=182]) at Week 52
• The majority of adverse events across both treatment groups (78.5% [n=430]) were mild or moderate in intensity, and most (77.6% [n=425]) were classified as not related or unlikely related to study drug treatment
• TEAEs leading to discontinuation occurred in 10.9% (n=57) of paients taking NILEMDO® vs. 8.6% (n=22) taking placebo

*ASCVD included CHD (acute MI, silent MI, unstable angina, coronary revascularisation or clinically significant CHD diagnosed by invasive or non-invasive testing) or CHD risk equivalents (cerebrovascular atherosclerotic disease or symptomatic peripheral arterial disease).^5
†Randomisation was stratified by presence of HeFH and baseline statin intensity (low-, moderate-, or high-intensity).^5
‡Determined by the investigator and included a maximally-tolerated statin dose alone or in combination with other approved LLTs, excluding simvastatin at an average daily dose of ≥40 mg, mipomersen (unlicensed in UK), lomitapide, lipoprotein apheresis, or gemfibrozil. Background LLT dose could be adjusted or additional LLT added by the investigator from Week 24 if the LDL-C was >4.4 mmol/L and elevated ≥25% from baseline.^5
§Defined as the highest intensity statin regimen that the patient was able to maintain, as determined by the investigator.⁵

Summary⁶

• The CLEAR Serenity trial was a Phase 3, randomised, double-blind, parallel-group, placebo-controlled trial that enrolled 345 patients with hypercholesterolaemia and a history of intolerance to at least two statins (1 at the lowest dose)
• After a 5-week screening period (including a 4-week, single-blind, placebo run-in period), 345 patients were randomly assigned 2:1* to oral once-daily NILEMDO® 180 mg or placebo for 24 weeks
• Patients were permitted the following background LLT if initiated ≥4 weeks prior to screening: ezetimibe, bile acid sequestrants, fibrates (except gemfibrozil in patients receiving a very-low-dose statin), PCSK9 inhibitors (if ≥3 doses were received prior to screening), niacin, or very-low-dose statin therapy (average daily dose of rosuvastatin <5 mg, atorvastatin <10 mg, simvastatin <10 mg, lovastatin <20 mg (unlicensed in UK), pravastatin <40 mg, fluvastatin <40 mg, or pitavastatin <2 mg (unlicensed in UK), either alone or in combination

Study composition⁶

8.4% of patients were treated with very low dose statin

1/3 of patients (n=116) were treated with non-statin LLTs (including ezetimibe)

Study design⁶

Key inclusion criteria⁶

While receiving stable background LLT:^†

• Fasting LDL-C levels of ≥2.6 mmol/L in patients with HeFH and/or a secondary prevention indication^‡
• Fasting LDL-C levels of ≥3.4 mmol/L in primary prevention patients
• A history of statin intolerance (to at least 2 statins including 1 at a low dose)^§,¶

Key exclusion criteria^6,11

• Uncontrolled hypertension: systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg
• eGFR <30 mL/min/1.73 m²
• Liver disease or dysfunction, including alanine aminotransferase (ALT) ≥2× ULN, aspartate aminotransferase (AST) ≥2× ULN, and/or total bilirubin (TB) ≥1.2× ULN at Week -5
• Total fasting triglyceride ≥5.6 mmol/L (500 mg/dL)
• BMI ≥50 kg/m²

Endpoints⁶

• Primary endpoint: % change in LDL-C levels from baseline to Week 12
• Secondary endpoints: % change in LDL-C levels from baseline to Week 24 and % change in non-LDL-C levels and total cholesterol from baseline to Week 12

Results⁶

LDL-C⁶

• NILEMDO® delivered a significant 21.4% (95% CI: 25.1% to 17.7%) LDL-C LS mean reduction vs. placebo (placebo-corrected) from baseline at Week 12 (p<0.001) in statin-intolerant patients

Safety⁶

• Safety was assessed by continuous monitoring of TEAEs, clinical safety laboratory findings, vital sign measurements, physical examinations, electrocardiograph readings, and cardiovascular event rates
• Overall rates of TEAEs were 64.1% (n=150) in the NILEMDO® group vs. 56.8% (n=63) in the placebo group at Week 24
• The majority of AEs in both the NILEMDO® and placebo groups were mild to moderate in intensity
• TEAEs leading to discontinuation occurred in 18.4% (n=43) in the NILEMDO® group vs. 11.7% (n=13) in the placebo group at Week 24

*Randomisation was stratified by treatment indication (primary prevention vs. secondary prevention and/or HeFH).^6
†Patients were permitted the following background LLT if initiated ≥4 weeks prior to screening: ezetimibe, bile acid sequestrants, fibrates (except gemfibrozil in patients receiving a very-low-dose statin), PCSK9 inhibitors (if ≥3 doses were received prior to screening), niacin, or very-low-dose statin therapy (average daily dose of rosuvastatin <5 mg, atorvastatin <10 mg, simvastatin <10 mg, lovastatin <20 mg (unlicensed in UK), pravastatin <40 mg, fluvastatin <40 mg, or pitavastatin <2 mg (unlicensed in UK), either alone or in combination.^6
‡Including coronary artery disease, symptomatic peripheral arterial disease, and/or cerebrovascular atherosclerotic disease.^6
§Average daily dose of rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg (unlicensed in UK), pravastatin 40 mg, fluvastatin 40 mg, or pitavastatin 2 mg (unlicensed in UK).^6
¶Due to a prior adverse event that started or increased during statin therapy and resolved or improved when statin therapy was discontinued.⁶

Summary⁷

• The CLEAR Tranquility trial was a Phase 3, randomised, double-blind, placebo-controlled trial that enrolled 269 patients with an LDL-C ≥2.6 mmol/L while on no more than low-dose statin therapy (which could include no statin) and with a history of statin intolerance (not tolerating at least one statin) requiring additional LDL-C lowering
• During a 4-week run-in phase, patients received open-label ezetimibe 10 mg once daily and single-blind placebo to confirm tolerance to ezetimibe and compliance with protocol-directed therapy
• After the run-in period, individuals were randomised 2:1 to treatment with oral once-daily NILEMDO® 180 mg or placebo added to once-daily ezetimibe 10 mg/day for 12 weeks

Study composition⁷

~31% of patients (32.6% NILEMDO; 27.6% placebo) were receiving stable background lipid-modifying therapy (inclusive of a low-dose or very low-dose statin and/or permitted non-statin agents)

100% of patients were treated with study-provided open-label ezetimibe 10 mg once daily, maintained throughout the study

Study design⁷

Key inclusion criteria⁷

While receiving low-dose statin therapy,^† which could also include no statin:

• Fasting LDL-C levels of ≥2.6 mmol/L at screening
• A history of statin intolerance (to at least 1 statin)

Key exclusion criteria^7,12

• Liver disease or dysfunction, including: alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥2× ULN, and/or total bilirubin (TB) ≥2× ULN at Week -5
• Uncontrolled hypertension: systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg
• eGFR <30 mL/min/1.73 m²
• Total fasting triglyceride ≥5.6 mmol/L (500 mg/dL)
• BMI ≥50 kg/m²

Endpoints⁷

• Primary endpoint: % change in LDL-C levels from baseline to Week 12
• Secondary endpoints: % change in non-LDL-C levels and total cholesterol from baseline to Week 12

Results⁷

LDL-C⁷

• NILEMDO® delivered a significant 28.5% (95% CI: 34.4% to 22.5%) LS mean LDL-C reduction vs. placebo (placebo-corrected) from baseline to Week 12 (p<0.001) in statin-intolerant patients taking ezetimibe +/- other LLT

Safety⁷

• Safety was assessed by continuous monitoring of TEAEs, clinical safety laboratory findings, vital sign measurements, physical examinations, electrocardiograph readings, and weight measurements and were judged to be not related or unlikely related to investigational study drug
• TEAEs were reported by 48.6% (n=88) and 44.8% (n=39) of patients in the NILEMDO® and placebo groups, respectively
• The majority of TEAEs in the NILEMDO® group and the placebo group were mild to moderate in intensity and were judged to be not related or unlikely related to investigational study drug
• Serious TEAEs occurred in 2.8% (n=5) and 3.4% (n=3) of patients in the bempedoic acid and placebo treatment groups, respectively
• TEAEs leading to discontinuation occurred in 6.1% (n=11) in the NILEMDO® group vs. 5.7% (n=5) in the placebo group

*Patients with ≤80% adherence and/or who experienced a study drug-related adverse event during the placebo and ezetimibe run-in period did not proceed to randomisation.^7
†Low-dose statin therapy was defined as an average daily dose of rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg (unlicensed in UK), pravastatin 40 mg, fluvastatin 40 mg, or pitavastatin 2 mg (unlicensed in UK).⁷

Summary¹³

• A randomised, double-blind, placebo-controlled Phase 3 study to assess the effects of NILEMDO® (180mg bempedoic acid) on the occurrence of major CV events in patients with, or at high risk for, CVD who are unable or unwilling to take guideline-recommended statins

Study design¹³

*All patients provided written informed consent. Eligible patients had to report being unable or unwilling to receive statins owing to an adverse effect that had started or increased during statin therapy and resolved or improved after statin therapy was discontinued (“statin-intolerant” patients). The patients were required to provide written confirmation that they were statin intolerant and aware of the benefits of statins in reducing the risk of CV events, including death, as well as acknowledge that many patients who are unable to receive an administered statin can receive a different statin or dose; the site investigators were also required to confirm and acknowledge these statements with respect to the patients.^13
†Patients were permitted the following background LLT without unacceptable adverse effects if initiated ≥4 weeks prior to screening: ezetimibe, niacin, bile acid resins, fibrates and/or PCSK9 inhibitors, or very-low-dose statin therapy (average daily dose of rosuvastatin <5 mg, atorvastatin <10 mg, simvastatin <10 mg, lovastatin <20 mg (unlicensed in UK), pravastatin <40 mg, fluvastatin <40 mg, or pitavastatin <2 mg (unlicensed in UK), either alone or in combination.^13
‡Including CV death, non-fatal MI, non-fatal stroke or coronary revascularisation.^13
§Including CV death, non-fatal MI or non-fatal stroke.¹³

Primary efficacy endpoint¹³

• The primary endpoint was a four-component composite of major adverse CV events (MACE-4), defined as death from CV causes, non-fatal MI, non-fatal stroke or coronary revascularisation, as assessed in a time-to-first event analysis

Key secondary time-to-event endpoints¹³

• A three-component composite of major adverse CV events (MACE-3) defined as death from CV cause, non-fatal MI or non-fatal stroke
• Fatal or non-fatal MI
• Coronary revascularisation
• Fatal or non-fatal stroke
• Death from CV causes
• Death from any cause

Key inclusion criteria¹³

• A previous CV event (secondary-prevention patients) or clinical features that placed patients at high risk for a CV event (primary-prevention patients)
• Unable or unwilling to tolerate statins due to an adverse event that started or increased during statin therapy and resolved or improved when statin therapy was discontinued (“statin intolerance”)
• Written confirmation by both patient and investigator that the patient is statin intolerant as defined above, aware of the benefit of statin use to reduce the risk of MACE including death, and also aware that many other patients who are unable to tolerate a statin are able to tolerate a different statin or dose

Key exclusion criteria^13,14

• Forms of CVD that include recent (90 days prior to or during screening) acute CVD events including transient ischemic attack (TIA), MI, coronary revascularisation, peripheral arterial revascularisation, ischaemic stroke, carotid endarterectomy, carotid stenting; recent (90 days of screening) unstable or symptomatic cardiac arrhythmia; NYHA Functional Classification Class IV heart failure, uncontrolled hypertension: systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg; planned coronary revascularisation
• Liver disease or dysfunction, including alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥2x ULN at Week -5
• eGFR <30 mL/min/1.73 m² at Week -5
• Total fasting triglyceride >500 mg/dL (5.6 mmol/L) at Week -5

Baseline change in secondary lipid and biomarker efficacy endpoints¹³

• Percent change in LDL-C and hsCRP
• Absolute change in HbA1c in patients with diabetes and HbA1c ≥7% at baseline
• Development of new diagnosis of diabetes in patients with prediabetes at baseline

Results¹³

Safety¹³ (Safety population N=13,965)

• The safety population included all patients who underwent randomisation and received at least one dose of bempedoic acid or placebo; patients who received any dose of double-blind bempedoic acid were placed in the bempedoic acid group in the safety analyses
• No difference in the overall incidence of AEs between bempedoic acid 86.3% (n=6,040/7,001) and placebo 85% (n=5,919/6,964)
• AEs leading to discontinuation occurred in 10.8% (n=759/7,001) of patients receiving bempedoic acid vs. 10.4% (n=722/6,964) receiving placebo
• Incidences of prespecified AEs of special interest were similar between bempedoic acid and placebo, except for myalgia (5.6% [n=393/7,001] vs. 6.8% [n=471/6,964], respectively), elevations in hepatic enzyme levels (4.5% [n=317/7,001] vs. 3.0% [n=209/6,964], respectively) and renal impairment (11.5% [n=802/7,001] vs. 8.6% [n=599/6,964], respectively)
• The incidence of hyperuricemia was higher in the bempedoic acid group than in the placebo group (10.9% [n=763/7,001] vs. 5.6% [n=393/6,964], respectively), as were the incidences of gout (3.1% [n=215/7,001] vs. 2.1% [n=143/6,964], respectively) and cholelithiasis (2.2% [n=152/7,001] vs. 1.2% [n=81/6,964], respectively)

Table

Adapted from Nissen SE, et al. 2023.¹³