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

Phase 1

Completed

Brief Summary: 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.

Detailed Description: 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).

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Participants received matching placebo dose regimens by subcutaneous injection.
Evolocumab	Evolocumab	Participants received one of 5 dose levels of evolocumab administered as multiple subcutaneous doses.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events	From the first dose of study drug until Day 85	The relationship of each adverse event to the investigational product was assessed by the investigator. A serious adverse event (SAE) is defined as an adverse event that * is fatal * is life threatening (places the subject at immediate risk of death) * requires in-patient hospitalization or prolongation of existing hospitalization * results in persistent or significant disability/incapacity * is a congenital anomaly/birth defect * other significant medical hazard.
Number of Participants With Anti-Evolocumab Antibodies	From the first dose of study drug until Day 85	Serum samples were analyzed by an electrochemiluminescence (ECL)-based immunoassay for anti-evolocumab binding antibodies. Positive samples were subsequently tested in a receptor-ligand binding bioassay for anti-evolocumab neutralizing antibodies

Secondary Outcome Measures

Name	Time	Method
Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Evolocumab	Day 29 predose (last dose for Cohorts 3-7) and Days 36 (predose for Cohorts 1 and 2), 40, 43, 50, 57, 64, 71, 78, and 85	Area under the unbound evolocumab serum concentration-time curve from time of last dose to time of last quantifiable concentration following the last dose of evolocumab.
Percent Change From Baseline to End of the Dosing Interval in LDL-C	Baseline and Day 43 for QW and Q2W groups or Day 57 for Q4W group
Maximum Observed Plasma Concentration (Cmax) of Evolocumab	Day 1, predose and Days 4, 8, 15, 22, 29, 36, 40, 43, 50, 57, 64, 71, 78, and 85	Serum concentrations of evolocumab were measured by a validated enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 800 ng/mL.
Percent Change From Baseline to End of the Dosing Interval in PCSK9	Baseline and Day 43 for QW and Q2W groups or Day 57 for Q4W group	Serum PCSK9 concentrations were determined by using a qualified enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 15 ng/mL.