Ascending Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Evolocumab (AMG 145) in Adults With Hyperlipidemia on Stable Doses of a Statin

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Ascending Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 145 in Subjects With Hyperlipidemia on Stable Doses of a Statin

The purpose of the study is to evaluate the safety and tolerability of multiple doses of evolocumab when given as an add-on to stable statin therapy.

Participants receiving low-to-moderate-dose statins were randomized in a 1:3 ratio to receive subcutaneous placebo or evolocumab and enrolled sequentially into one of 5 dose-escalation cohorts:

1. Evolocumab 14 mg/placebo once weekly (QW) × 6 doses
2. Evolocumab 35 mg/placebo once weekly (QW) × 6 doses
3. Evolocumab 140 mg/placebo every 2 weeks (Q2W) × 3 doses
4. Evolocumab 280 mg/placebo every 2 weeks (Q2W) × 3 doses
5. Evolocumab 420 mg/placebo every 4 weeks (Q2W) × 2 doses.

Participants receiving high-dose statins were randomized 1:3 to receive subcutaneous placebo or evolocumab 140 mg every 2 weeks × 3 doses (Cohort 6).

Participants diagnosed with familial hypercholesterolemia (HeFH) were randomized 1:2 to receive subcutaneous placebo or evolocumab 140 mg every 2 weeks × 3 doses (Cohort 7).

Inclusion Criteria:

• Men and women ages 18 to 70 years (inclusive) at the time of screening with hyperlipidemia
• Body mass index (BMI) ≥18 and ≤ 35 kg/m^2 at the time of screening
• Low-density lipoprotein cholesterol (LDL-C) level of 70-220 mg/dL (inclusive) at screening as measured by direct assay
• For Cohorts 1-5: On a stable dose of rosuvastatin (Crestor) < 40 mg/day, atorvastatin (Lipitor) < 80 mg/day, or simvastatin (Zocor) 20-80 mg/day for ≥ 1 month prior to enrollment and expected to remain on this dose for the remainder of the study
• For Cohort 6: On a stable dose of rosuvastatin (Crestor) 40 mg/day or atorvastatin (Lipitor) 80 mg/day for ≥ 1 month prior to enrollment and expected to remain on this dose for the remainder of the study
• For Cohort 7: Diagnosis of heterozygous familial hypercholesterolemia, based on a score of ≥ 9 points using the World health Organization (WHO) criteria

Exclusion Criteria:

• Diagnosis of homozygous familial hypercholesterolemia

• History of heart failure, coronary artery bypass graft, or cardiac arrhythmia

• History of acute coronary syndrome (e.g. myocardial infarction, hospitalization for unstable angina) or percutaneous coronary intervention, within 12 months prior to enrollment

• Planned cardiac surgery or revascularization

• Known aortic, peripheral vascular or cerebrovascular disease (including history of stroke or transient ischemic attack)

• Diabetes mellitus with any of the following:

  1. known microvascular or macrovascular disease
  2. HbA1c > 8.0% at screening
  3. use of any hypoglycemic medication other than metformin

• Uncontrolled hypertension (systolic blood pressure ≥ 150 or diastolic blood pressure ≥ 90 mmHg) either on or off therapy at screening or at baseline