Study of Evinacumab (REGN1500) in Participants With Persistent Hypercholesterolemia

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the reduction of LDL-C by evinacumab in comparison to placebo after 16 weeks in patients with primary hypercholesterolemia (HeFH, or non-HeFH with a history of clinical ASCVD) with persistent hypercholesterolemia despite receiving maximally-tolerated LMT. Persistent hypercholesterolemia is defined as LDL-C ≥70 mg/dL (1.81 mmol/L) for those patients with clinical ASCVD and LDL-C ≥100 mg/dL (2.59 mmol/L) for those patients without clinical ASCVD.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Varying Doses and Dose Regimens of Evinacumab in Patients With Persistent Hypercholesterolemia Despite Maximally Tolerated Lipid Modifying Therapy

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: Evinacumab
* Drug: Matching placebo
* Other: Background Lipid Modifying Therapy (LMT)


Participation Criteria
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Eligibility Criteria
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The inclusion/ exclusion criteria below, include, but are not limited to, the following: Key Inclusion Criteria: Men and women, ages 18 through 80 at the screening visit Diagnosis of primary hypercholesterolemia, either HeFH or non-HeFH with clinical ASCVD A history of clinical ASCVD, for those patients who are non-HeFH. Receiving a stable maximally tolerated statin (± ezetimibe) for at least 4 weeks at screening For those patients with HeFH who are not receiving a statin at screening, documentation of inability to tolerate at least 2 statins. Receiving alirocumab 150 mg SC Q2W, OR evolocumab 140 mg SC Q2W or 420 mg SC Q4W for at least 8 weeks prior to the screening visit For those patients with a history of clinical ASCVD, serum LDL-C ≥ 70 mg/dL at screening (1 repeat lab is allowed) For those patients without a history of clinical ASCVD, serum LDL-C ≥ 100 mg/dL at screening (1 repeat lab is allowed) Provide signed informed consent Key Exclusion Criteria: Known history of homozygous FH (clinically, or by previous genotyping) Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins Newly diagnosed diabetes (within 3 months prior to screening) Use of thyroid medications (except for replacement therapy which has been stable for at least 12 weeks before screening) Laboratory findings during screening period (not including randomization labs): Triglycerides > 400 mg/dL (> 4.52 mmol/L) for patients without a known history of diabetes mellitus; OR Triglycerides > 300 mg/dL (> 3.39 mmol/L) for patients with a known history of diabetes mellitus Positive test for Hepatitis B surface antigen and/or Hepatitis C antibody (associated with a positive HCV ribonucleic acid [RNA] polymerase chain reaction) Positive serum beta-human chorionic gonadotropin or urine pregnancy test in women of childbearing potential Estimated glomerular filtration rate < 30 mL/min/1.73 m^2 TSH > 1.5 x ULN Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 x ULN Systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg at screening visit or time of randomization History of heart failure (New York Heart Association [NYHA] Class III-IV) within 12 months before screening History of MI, unstable angina leading to hospitalization, CABG surgery, PCI, uncontrolled cardiac arrhythmia, carotid surgery or stenting, stroke, TIA, carotid revascularization, endovascular procedure or surgical intervention for peripheral vascular disease within 3 months prior screening History of cancer within the past 5 years (except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer) Having received LDL apheresis within 2 months before screening Pregnant or breast-feeding women Women of childbearing potential who are unwilling to practice a highly effective birth control method Men who are sexually active with women of childbearing potential (WOCBP) and are unwilling to consistently use condoms during the study drug treatment period regardless of vasectomy status.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: dosing regimen 1<br>SC Evinacumab QW for 16 weeks | Drug: Evinacumab<br>* SC or IV administration<br>* Other names: REGN1500;Other: Background Lipid Modifying Therapy (LMT)<br>* All participants should be on a stable, maximally tolerated statin throughout the duration of the study. The dose of statin and of PCSK9 inhibitor, such as alirocumab or evolocumab, as well as other LMT (if applicable), should remain stable throughout the study duration, from screening through the end of study (EOS) visit.<br>|
| Experimental: Group A: dosing regimen 2<br>SC Evinacumab Q2W for 16 weeks (alternating with matching placebo on opposite weeks) | Drug: Evinacumab<br>* SC or IV administration<br>* Other names: REGN1500;Other: Background Lipid Modifying Therapy (LMT)<br>* All participants should be on a stable, maximally tolerated statin throughout the duration of the study. The dose of statin and of PCSK9 inhibitor, such as alirocumab or evolocumab, as well as other LMT (if applicable), should remain stable throughout the study duration, from screening through the end of study (EOS) visit.<br>|
| Experimental: Group A: dosing regimen 3<br>SC Evinacumab QW for 16 weeks | Drug: Evinacumab<br>* SC or IV administration<br>* Other names: REGN1500;Other: Background Lipid Modifying Therapy (LMT)<br>* All participants should be on a stable, maximally tolerated statin throughout the duration of the study. The dose of statin and of PCSK9 inhibitor, such as alirocumab or evolocumab, as well as other LMT (if applicable), should remain stable throughout the study duration, from screening through the end of study (EOS) visit.<br>|
| Experimental: Group A: matching placebo<br>Placebo SC QW for 16 weeks | Drug: Matching placebo<br>* SC or IV administration<br>Other: Background Lipid Modifying Therapy (LMT)<br>* All participants should be on a stable, maximally tolerated statin throughout the duration of the study. The dose of statin and of PCSK9 inhibitor, such as alirocumab or evolocumab, as well as other LMT (if applicable), should remain stable throughout the study duration, from screening through the end of study (EOS) visit.<br>|
| Experimental: Group B: dosing regimen 1<br>Intravenous (IV) Evinacumab Q4W for 24 weeks | Drug: Evinacumab<br>* SC or IV administration<br>* Other names: REGN1500;Other: Background Lipid Modifying Therapy (LMT)<br>* All participants should be on a stable, maximally tolerated statin throughout the duration of the study. The dose of statin and of PCSK9 inhibitor, such as alirocumab or evolocumab, as well as other LMT (if applicable), should remain stable throughout the study duration, from screening through the end of study (EOS) visit.<br>|
| Experimental: Group B: dosing regimen 2<br>IV Evinacumab Q4W for 24 weeks | Drug: Evinacumab<br>* SC or IV administration<br>* Other names: REGN1500;Other: Background Lipid Modifying Therapy (LMT)<br>* All participants should be on a stable, maximally tolerated statin throughout the duration of the study. The dose of statin and of PCSK9 inhibitor, such as alirocumab or evolocumab, as well as other LMT (if applicable), should remain stable throughout the study duration, from screening through the end of study (EOS) visit.<br>|
| Experimental: Group B: matching placebo<br>Placebo IV Q4W for 24 weeks | Drug: Matching placebo<br>* SC or IV administration<br>Other: Background Lipid Modifying Therapy (LMT)<br>* All participants should be on a stable, maximally tolerated statin throughout the duration of the study. The dose of statin and of PCSK9 inhibitor, such as alirocumab or evolocumab, as well as other LMT (if applicable), should remain stable throughout the study duration, from screening through the end of study (EOS) visit.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol (LDL-C) at Week 16 (Intent-to-Treat [ITT] Estimand) |  | Baseline and Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 16 (ITT Estimand) |  | Baseline and Week 16 | 
| Percent Change From Baseline in Apo B at Week 24 (ITT Estimand) |  | Baseline and Week 24 | 
| Percent Change From Baseline in Non High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 16 (ITT Estimand) |  | Baseline and Week 16 | 
| Percent Change From Baseline in Non-HDL-C at Week 24 (ITT Estimand) |  | Baseline and Week 24 | 
| Percentage of Participants With >= 30% Reduction in Calculated LDL-C at Week 16 (ITT Estimand) |  | Week 16 | 
| Percentage of Participants With >= 50% Reduction in Calculated LDL-C at Week 16 (ITT Estimand) |  | Week 16 | 
| Percentage of Participants With Calculated LDL-C < 50 mg/dL (1.30 mmol/L) at Week 16 (ITT Estimand) | Percentage of Participants with Calculated LDL-C < 50 milligrams/deciliter (mg/dL) [1.30 Millimoles per liter (mmol/L)] at Week 16 (ITT Estimand) | Week 16 | 
| Percent Change From Baseline in Calculated LDL-C at Week 24 (ITT Estimand) |  | Baseline and Week 24 | 
| Percent Change From Baseline in Total Cholesterol (TC) at Week 16 (ITT Estimand) |  | Baseline and Week 16 | 
| Percent Change From Baseline in Total Cholesterol at Week 24 (ITT Estimand) |  | Baseline and Week 24 | 
| Percent Change From Baseline in Fasting Triglycerides at Week 16 (ITT Estimand) |  | Baseline and Week 16 | 
| Percent Change From Baseline in Fasting Triglycerides at Week 24 (ITT Estimand) |  | Baseline and Week 24 | 
| Percent Change From Baseline in Lipoprotein a [Lp(a)] at Week 16 (ITT Estimand) |  | Baseline and Week 16 | 
| Percent Change From Baseline in Lipoprotein (a) [Lp(a)] at Week 24 (ITT Estimand) |  | Baseline and Week 24 |