Safety, Tolerability, PK and PD of LGT209 in Healthy Volunteers and Patients With Hypercholesterolemia

Study Overview
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Brief Summary
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This study is designed to measure the effects of LGT209 when given intravenously to patients with high cholesterol who are on stable doses of statin medications, and to healthy subjects with elevated cholesterol

Official Title
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A Randomized, Double-blind, Placebo-controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intravenously Administered LGT209 in Healthy Volunteers and Patients With Hypercholesterolemia on Stable Doses of Statin Medications

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: LGT209
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy volunteers: Male and female subjects 18 to 70 years of age, in general good health but with high cholesterol Statin patients: Male and female patients 18 to 70 years of age, with high cholesterol on stable statin therapy for at least 3 months Exclusion Criteria: Healthy volunteers: History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes Women of child-bearing potential unless using highly effective methods of contraception Statin patients: Use of any prescription drugs for lipid lowering other than HMG CO-A reductase inhibitors (statins); use of two concurrent antihypertensive medications is allowed, provided stable dosing has been achieved for the prior 3 months Women of child-bearing potential unless using highly effective methods of contraception Other protocol-defined inclusion/exclusion criteria may apply

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patient: LGT209 0.3 mg/kg<br>0.3 mg/kg LGT209 intravenous administration in patients on stable doses of statins | Drug: LGT209<br>* 150 mg lyophilized powder in glass vial<br>|
| Experimental: Patient: LGT209 1 mg/kg<br>1 mg/kg LGT209 intravenous administration in patients on stable doses of statins | Drug: LGT209<br>* 150 mg lyophilized powder in glass vial<br>|
| Experimental: Patient: LGT209 3 mg/kg<br>3 mg/kg LGT209 intravenous administration in patients on stable doses of statins | Drug: LGT209<br>* 150 mg lyophilized powder in glass vial<br>|
| Experimental: Patient: LGT209 10 mg/kg<br>10 mg/kg LGT209 intravenous administration in patients on stable doses of statins | Drug: LGT209<br>* 150 mg lyophilized powder in glass vial<br>|
| Experimental: Patient: LGT209 20 mg/kg<br>20 mg/kg LGT209 intravenous administration in patients on stable doses of statins | Drug: LGT209<br>* 150 mg lyophilized powder in glass vial<br>|
| Experimental: Healthy Volunteers: LGT209 0.3 mg/kg<br>0.3 mg/kg LGT209 intravenous administration in healthy volunteers | Drug: LGT209<br>* 150 mg lyophilized powder in glass vial<br>|
| Experimental: Healthy Volunteers: LGT209 1 mg/kg<br>1 mg/kg LGT209 intravenous administration in healthy volunteers | Drug: LGT209<br>* 150 mg lyophilized powder in glass vial<br>|
| Experimental: Healthy Volunteers: LGT209 3 mg/kg<br>3 mg/kg LGT209 intravenous administration in healthy volunteers | Drug: LGT209<br>* 150 mg lyophilized powder in glass vial<br>|
| Experimental: Healthy Volunteers: LGT209 10 mg/kg<br>10 mg/kg LGT209 intravenous administration in healthy volunteers | Drug: LGT209<br>* 150 mg lyophilized powder in glass vial<br>|
| Experimental: Healthy Volunteers: 20 mg/kg<br>20 mg/kg LGT209 intravenous administration in healthy volunteers | Drug: LGT209<br>* 150 mg lyophilized powder in glass vial<br>|
| Placebo Comparator: Patient: Placebo<br>Matching intravenous placebo in patients on stable doses of statins | Drug: Placebo<br>* Placebo comparator<br>|
| Placebo Comparator: Healthy Volunteers: Placebo<br>Matching intravenous placebo in healthy volunteers | Drug: Placebo<br>* Placebo comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events, serious adverse events and death |  | from Screening until Day 141 | 
| Change from baseline in low density lipoprotein-cholesterol (LDL-C) concentration in healthy volunteers | Baseline was defined as the arithmetic mean of all the pre-treatment values (i.e. Screening, Day -1 and predose on Day 1) | Baseline, Day 29 | 
| Change from baseline in proprotein convertase subtilisin/kexin type 9 (PCSK9) in healthy volunteers | Baseline was defined as the arithmetic mean of all the pre-treatment values (i.e. Screening, Day -1 and predose on Day 1) | Baseline, Day 29 | 
| Pharmacokinetics of LGT209: : Area under the serum concentration-time curve from time zero to infinity (AUC0-inf) of LGT209 in patients and healthy volunteers following intravenous administration |  | Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2); 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141 | 
| Pharmacokinetics of LGT209: observed maximum serum concentrations (Cmax) of LGT209 in patients and healthy volunteers following intravenous administration |  | Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141 | 
| Pharmacokinetics of LGT209: Area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last) of LGT209 in patients and healthy volunteers following intravenous administration |  | Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141 | 
| Pharmacokinetics of LGT209: Elimination half-life associated with the terminal slope of a semi-logarithmic concentration-time curve (T1/2) of LGT209 in patients and healthy volunteers following intravenous administration |  | Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141 | 
| Number of healthy volunteers with adverse events, serious adverse events and death |  | from Screening until Day 141 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of intravenous LGT209 in relationship to concentrations of PCSK9 and LDL-C in patients and healthy volunteers |  | Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141 | 
| Change from baseline in low density lipoprotein-cholesterol (LDL-C) concentration in patients | Baseline was defined as the arithmetic mean of all the pre-treatment values (i.e. Screening, Day -1 and predose on Day 1) | Baseline, Day 29 | 
| Change from baseline in proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients | Baseline was defined as the arithmetic mean of all the pre-treatment values (i.e. Screening, Day -1 and predose on Day 1) | Baseline, Day 29 | 
| Pharmacokinetics of LGT209: Area under the serum concentration-time curve from time zero to time 't' (AUC0-t) | In AUC 0-t, t is a defined as time point after administration of LGT209 in patients and healthy volunteers following intravenous administration | Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141 | 
| Pharmacokinetics of LGT209: Dose-normalized area under the serum concentration-time curve (AUC/D) of LGT209 in patients and healthy volunteers following intravenous administration |  | Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141 | 
| Pharmacokinetics of LGT209: Dose-normalized maximum serum concentrations (Cmax/D) of LGT209 in patients and healthy volunteers following intravenous administration |  | Day 1 ( 1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141 | 
| Pharmacokinetics of LGT209: Volume of distribution during the terminal elimination phase (Vz) of LGT209 in patients and healthy volunteers following intravenous administration |  | Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141 | 
| Pharmacokinetics of LGT209: Volume of distribution at steady state (Vss) of LGT209 in patients and healthy volunteers following intravenous administration |  | Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141 | 
| Pharmacokinetics of LGT209: Mean residence time (MRT) of LGT209 in patients and healthy volunteers following intravenous administration |  | Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141 | 
| Pharmacokinetics of LGT209: the systemic (or total body) clearance from serum following intravenous administration |  | Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hypercholesterolemia,, LGT209,, PCSK9,, LDL-C