Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS APO(a)-LRx in Healthy Volunteers With Elevated Lipoprotein(a)

Study Overview
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Brief Summary
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The purpose is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of IONIS APO(a)-LRx (ISIS 681257) given to healthy volunteer subjects.

Official Title
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A Blinded, Placebo-Controlled, Dose-Escalation, Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of ISIS 681257 Administered Subcutaneously to Healthy Volunteers With Elevated Lipoprotein(a)

Conditions
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Elevated Lipoprotein(a)

Intervention / Treatment
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* Drug: IONIS-APO(a)-LRx
* Drug: Sterile Normal Saline (0.9% NaCl)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have given written informed consent and be able to comply with all study requirements Healthy males or females aged 18-65 inclusive and weighing ≥ 50 kg at the time of informed consent Females must be non-pregnant and non-lactating, and either surgically sterile or post- menopausal Males must be surgically sterile, abstinent or using an acceptable contraceptive method BMI < 35.0 kg/m2 Subjects must have Lp(a) ≥ 75 nanomoles/liter nmol/L (30 mg/dL) at Screening Exclusion Criteria: Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B Treatment with another Study Drug, biological agent, or device within one-month of screening Regular use of alcohol within 6 months of Screening Use of concomitant drugs unless authorized by the Sponsor Medical Monitor Smoking > 10 cigarettes a day Considered unsuitable for inclusion by the Principal Investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Other
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IONIS-APO(a)-LRx<br>Drug: IONIS-APO(a)-LRx | Drug: IONIS-APO(a)-LRx<br>* Ascending single and multiple doses of IONIS-APO(a)-LRx by subcutaneous (SC) injection<br>|
| Placebo Comparator: Placebo (Normal Saline)<br>Drug: Sterile Normal Saline (0.9% NaCl) | Drug: Sterile Normal Saline (0.9% NaCl)<br>* Calculated volume to match active comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the safety and tolerability of single and multiple doses of IONIS-APO(a)-LRx (incidence, severity, and dose-relationship of adverse effects and changes in the laboratory parameters) | The safety and tolerability of IONIS-APO(a)-LRx will be assessed by determining the incidence, severity, and dose-relationship of adverse effects and changes in the laboratory parameters by dose. Safety results in subjects dosed with IONIS-APO(a)-LRx will be compared with those from subjects dosed with placebo. | Up to 113 days | 
| To evaluate the pharmacokinetics of single and multiple doses of IONIS-APO(a)-LRx (unconjugated and conjugated ASO) | The plasma pharmacokinetics of IONIS-APO(a)-LRx (unconjugated and conjugated ASO) will be assessed following single and multiple-dose SC administration. The amount of ISIS-APO(a)-LRx excreted in urine at selected 24-hour intervals will also be determined. | Up to 113 days | 
| To evaluate the plasma pharmacodynamics of IONIS-APO(a)-LRx (Changes in plasma Lp(a) levels) | Changes in plasma Lp(a) levels compared to baseline. | Up to 113 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx | Effects of IONIS-APO(a)-LRx on changes in levels of oxidized phospholipids associated with apoB-100 compared to baseline. | Up to 113 days | 
| Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx | Effects of IONIS-APO(a)-LRx on changes in levels of oxidized phospholipids associated with apo(a) compared to baseline. | Up to 113 days | 
| Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx | Effects of IONIS-APO(a)-LRx on changes in Lp-PLA2 compared to baseline. | Up to 113 days | 
| Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx | Effects of IONIS-APO(a)-LRx on changes in sPLA2 compared to baseline. | Up to 113 days | 
| Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx | Effects of IONIS-APO(a)-LRx on changes in apo(a) isoform size compared to baseline. | Up to 113 days | 
| Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx | Effects of ISIS-APO(a)-LRx on changes in lipid panel compared to baseline. | Up to 113 days | 
| Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx | Effects of IONIS-APO(a)-LRx on changes in systemic markers of inflammation compared to baseline. | Up to 113 days | 
| Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx | Effects of IONIS-APO(a)-LRx on changes in plasminogen/coagulation compared to baseline. | Up to 113 days |