Study to Evaluate the Safety, PK, and Pharmacodynamics of LIB003

Study Overview
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Brief Summary
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Randomized, double-blind, placebo-controlled, single ascending dose study in nine (9) separate and sequential dose cohorts (7 SC and 2 IV cohorts) to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of LIB003 in subjects with moderately elevated LDL-C levels.

Detailed Description
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After meeting eligibility criteria within each cohort subjects will be randomized to receive a single dose of LIB003. Seven (7) cohorts will receive LIB003 escalating doses of LIB003, or placebo, by SC injection and 2 cohorts LIB003 or placebo by IV infusion. Dose escalation will be based on the assessment of safety and tolerability data. All cohorts will each first enroll a sentinel group of subjects who will receive LIB003 or placebo in a double-blind fashion with the remaining subjects in that cohort only to be dosed after the safety data on day 4 from the sentinel subjects has been assessed and deemed safe.

Official Title
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Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of LIB003 in Healthy Subjects With Hypercholesterolemia on Diet or Statin Therapy

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Biological: LIB003


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women who are >/=18 and </=70 years of age. Female subjects must be of non-childbearing potential. LDL-C >/=100 mg/dL who are either not on a lipid-lowering therapy or who are on stable statin therapy. Body mass index (BMI) >18 and <38 kg/m2 Mild hypertensives on a stable dose of no more than one antihypertensive drug Exclusion Criteria: History of any prior or concomitant clinical condition or acute and/or unstable systemic disease compromising subject inclusion Systolic blood pressure <90 mmHg or >160 mmHg or diastolic blood pressure <50 or >100 mmHg at screening Positive blood screen for human immunodeficiency virus (HIV), hepatitis B surface antigen, or hepatitis C virus antibody Abnormal liver function test at Screening (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] >2 × the upper limit of normal [ULN] Estimated glomerular filtration rate <60 mL/min/1.73 m2 at screening, as determined by the CKD-EPI Equation History of prescription drug abuse, illicit drug use (including marijuana), or alcohol abuse Unable to spend 4 days in confinement unit History of allergy to protein-based biologics including, but not limited to, mAbs and vaccine Any other finding which, in the opinion of the Investigator, would compromise the subject's safety or participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: single ascending dose with placebo controll
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: cohort 1<br>LIB003 dose 1 SC | Biological: LIB003<br>* LIB003 or placebo<br>|
| Placebo Comparator: cohort 2<br>LIB003 dose 2 SC | Biological: LIB003<br>* LIB003 or placebo<br>|
| Placebo Comparator: cohort 3<br>LIB003 dose 4 SC | Biological: LIB003<br>* LIB003 or placebo<br>|
| Placebo Comparator: cohort 4<br>LIB003 dose 4 SC | Biological: LIB003<br>* LIB003 or placebo<br>|
| Placebo Comparator: cohort 5<br>LIB003 dose 5 SC | Biological: LIB003<br>* LIB003 or placebo<br>|
| Placebo Comparator: cohort 6<br>LIB003 dose 4 IV | Biological: LIB003<br>* LIB003 or placebo<br>|
| Placebo Comparator: cohort 7<br>LIB003 dose 5 IV | Biological: LIB003<br>* LIB003 or placebo<br>|
| Placebo Comparator: cohort 8<br>LIB003 dose 3 SC - statin treated | Biological: LIB003<br>* LIB003 or placebo<br>|
| Placebo Comparator: cohort 9<br>LIB003 dose 4 SC - statin treated | Biological: LIB003<br>* LIB003 or placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence and severity of treatment emergent adverse events (TEAEs) | safety and tolerability will be assessed by the incidence and severity of treatment emergent adverse events | 43 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change in serum unbound (free) proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations over time | Serum free PCSK9 will be measured at baseline and various time points over 43 days | 43 days | 
| Absolute change in serum total PCSK9 over time | Serum total PCSK9 will be measured at baseline and various time points over 43 days | 43 days | 
| Percent change in Low Density Lipoprotein cholesterol (LDL-C) over time | Serum LDL-C will be measured at baseline and various time points over 43 days to derive percent change | 43 days | 
| Percent change in Apolipoprotein B (Apo B) over time | Serum Apo B will be measured at baseline and various time points over 43 days to derive percent change | 43 days | 
| Changes in serum LIB003 concentrations over time | serum LIB003 will be measured at various time points to derive AUC (area under curve) | 43 days | 
| Presence of anti LIB003 antibodies (ADAs) | Measurement of ADAs will be done at baseline and various intervals after LIB003 administration | 43 days |