Safety, Tolerability, PK, and Pharmacodynamics(PD) of IONIS APOCIII-LRx in Healthy Volunteers With Elevated Triglycerides

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 APOC-III-LRx given to healthy volunteer subjects.

Official Title
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Placebo-Controlled, Dose-Escalation Study to Assess Safety, Tolerability, PK and PD of a GalNAc3 Conjugated Antisense Oligonucleotide Targeting ApoC-III, Administered Subcutaneously to Healthy Volunteers With Elevated Triglycerides

Conditions
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Elevated Triglycerides (TG)

Intervention / Treatment
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* Drug: APOC-III-L-Rx
* Drug: Placebo Comparator


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 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 Fasting TG ≥ 90 mg/dL or ≥ 200 mg/dL depending on Cohort assignment 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 excessive 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IONIS-APOC-III-LRx<br>Ascending single and multiple doses of IONIS-APOC-III-LRx by subcutaneous (SC) injection | Drug: Placebo Comparator<br>* Sterile Normal Saline (0.9% NaCl) calculated volume to match active comparator<br>|
| Placebo Comparator: Placebo (Normal Saline)<br>Sterile Normal Saline (0.9% NaCl) calculated volume to match active comparator | Drug: APOC-III-L-Rx<br>* Ascending single and multiple doses of IONIS-APOC-III-LRx by subcutaneous (SC) injection<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- APOC-III-LRx - (incidence, severity, and dose-relationship of adverse effects and changes in the laboratory parameters) | The safety and tolerability of IONIS- APOC-III-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 APOC-III-LRx will be compared with those from subjects dosed with placebo. | Up to 183 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the plasma pharmacokinetics of single and multiple doses of IONIS- APOC-III-LRx | The maximum area under the curve (AUC) of IONIS- APOC-III-LRx will be assessed following single and multiple- dose SC administration | Up to 183 days | 
| To evaluate the urine pharmacokinetics of single and multiple doses of IONIS¬-APOC-III-LRx | The amount of IONIS-APOC-III-LRx excreted in urine at selected 24-hour intervals [Ae0-24h] will be determined. | Up to 183 days | 
| To evaluate the plasma pharmacokinetics of single and multiple doses of IONIS- APOC-III-LRx | The maximum plasma concentration (Cmax) of IONIS- APOC-III-LRx will be assessed following single and multiple- dose SC administration | Up to 183 Days | 
| To evaluate the plasma pharmacokinetics of single and multiple doses of IONIS- APOC-III-LRx | The maximum time to Cmax (Tmax) of IONIS- APOC-III-LRx will be assessed following single and multiple-dose SC administration | Up to 183 days |