Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS ANGPTL3-LRx in Healthy Volunteers With Elevated Triglycerides and Participants With Familial Hypercholesterolemia

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 ANGPTL3-LRx (ISIS 703802) given to healthy volunteer subjects with elevated triglycerides and subjects with familial hypercholesterolemia.

Official Title
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A Placebo-Controlled, Dose-Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of ISIS 703802, Targeting ANGPTL3, Administered Subcutaneously to Healthy Volunteers With Elevated Triglycerides and Subjects With Familial Hypercholesterolemia

Conditions
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Hypertriglyceridemia, Familial Hypercholesterolemia

Intervention / Treatment
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* Drug: IONIS ANGPTL3-LRx
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for All Cohorts: Must have given written informed consent and be able to comply with all study requirements Males or females 18 to 65 years, inclusive, at the time of informed consent Body Mass Index (BMI) ≤ 35.0 kg/m2 Females must be non-pregnant and non-lactating, and either surgically sterile or postmenopausal. Males must be surgically sterile, abstinent or using an acceptable contraceptive method Inclusion criteria for Cohorts, A, D, and AA to DD only: Fasting triglycerides (TG) ≥ 150 mg/dL at Screening Fasting low density lipoprotein cholesterol (LDL-C) > 70 mg/dL at Screening Inclusion criteria for Cohorts B and C only: Fasting TG 90 - 150 mg/dL at Screening Fasting LDL-C > 70 mg/dL at Screening Inclusion Criteria for Cohort EE Only: Homozygous FH diagnosis and fasting LDL-C ≥ 190 mg/dL (4.9 mmol/L) Inclusion Criteria for Cohort FF Only: Heterozygous FH diagnosis and fasting LDL-C ≥ 160 mg/dL (4.1 mmol/L) Inclusion Criteria for Cohorts EE and FF Only: Maximally tolerated stable LDL-C lowering agents (stable for at least 12 weeks) On stable low-fat diet Stable weight (± 4 kg) for ≥ 6 weeks prior to screening Exclusion Criteria for All Cohorts: Known history or positive test for Human Immunodeficiency Virus (HIV), Hepatitis C (HCV), or Hepatitis B (HBV) Treatment with another Study Drug, biological agent, or device within one-month or 5-half-lives of screening Regular use of alcohol within 6 months of screening Use of concomitant drugs unless authorized by the Sponsor Medical Monitor Known contraindication and/or allergy to heparin Smoking > 10 cigarettes a day Considered unsuitable for inclusion by the Principal Investigator Exclusion Criteria for Cohorts EE and FF: Myocardial infarction, percutaneous transluminal coronary intervention, or coronary artery bypass graft surgery within 12 weeks prior to screening, or cerebrovascular accident within 24 weeks prior to screening. Participants with adequately treated stable angina, per Investigator assessment, may be included Congestive heart failure defined by NYHA Classes III or IV Type 2 diabetes mellitus (T2DM) with HbA1c > 8.0% Prior treatment with gene therapy Currently receiving apheresis treatments or last apheresis treatment was within 8 weeks of screening

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 |
| --- | --- |
| Placebo Comparator: Cohorts A, D: Placebo<br>Participants received a single-dose of IONIS ANGPTL3-LRx-matching placebo subcutaneously on Day 1. | Drug: Placebo<br>* 0.9%NaCl, water, riboflavin<br>|
| Experimental: Cohorts A, D: IONIS ANGPTL3-LRx 20 mg<br>Participants received a single-dose of IONIS ANGPTL3-LRx 20 milligrams (mg) subcutaneously on Day 1. | Drug: IONIS ANGPTL3-LRx<br> <br> * Other names: ISIS 703802;|
| Experimental: Cohorts A, D: IONIS ANGPTL3-LRx 120 mg<br>Participants received a single-dose of IONIS ANGPTL3-LRx 120 mg subcutaneously on Day 1. | Drug: IONIS ANGPTL3-LRx<br> <br> * Other names: ISIS 703802;|
| Placebo Comparator: Cohorts B, C: Placebo<br>Participants received a single-dose of IONIS ANGPTL3-LRx-matching placebo subcutaneously on Day 1. | Drug: Placebo<br>* 0.9%NaCl, water, riboflavin<br>|
| Experimental: Cohorts B, C: IONIS ANGPTL3-LRx 40 mg<br>Participants received a single-dose of IONIS ANGPTL3-LRx 40 mg subcutaneously on Day 1. | Drug: IONIS ANGPTL3-LRx<br> <br> * Other names: ISIS 703802;|
| Experimental: Cohorts B, C: IONIS ANGPTL3-LRx 80 mg<br>Participants received a single-dose of IONIS ANGPTL3-LRx 80 mg subcutaneously on Day 1. | Drug: IONIS ANGPTL3-LRx<br> <br> * Other names: ISIS 703802;|
| Placebo Comparator: Cohorts AA-DD: Placebo<br>Participants received IONIS ANGPTL3-LRx-matching placebo subcutaneously once per week for 6 weeks. | Drug: Placebo<br>* 0.9%NaCl, water, riboflavin<br>|
| Experimental: Cohorts AA-DD: IONIS ANGPTL3-LRx 10 mg<br>Participants received IONIS ANGPTL3-LRx 10 mg subcutaneously once per week for 6 weeks. | Drug: IONIS ANGPTL3-LRx<br> <br> * Other names: ISIS 703802;|
| Experimental: Cohorts AA-DD: IONIS ANGPTL3-LRx 20 mg<br>Participants received IONIS ANGPTL3-LRx 20 mg subcutaneously once per week for 6 weeks. | Drug: IONIS ANGPTL3-LRx<br> <br> * Other names: ISIS 703802;|
| Experimental: Cohorts AA-DD: IONIS ANGPTL3-LRx 40 mg<br>Participants received IONIS ANGPTL3-LRx 40 mg subcutaneously once per week for 6 weeks. | Drug: IONIS ANGPTL3-LRx<br> <br> * Other names: ISIS 703802;|
| Experimental: Cohorts AA-DD: IONIS ANGPTL3-LRx 60 mg<br>Participants received IONIS ANGPTL3-LRx 60 mg subcutaneously once per week for 6 weeks. | Drug: IONIS ANGPTL3-LRx<br> <br> * Other names: ISIS 703802;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of single and multiple doses of IONIS ANGPTL3-LRx (incidence, severity, and dose-relationship of adverse effects and changes in the laboratory parameters) | The safety and tolerability of IONIS ANGPTL3-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 ANGPTL3-LRx will be compared with those from subjects dosed with placebo. | Up to Day 127 | 
| Pharmacokinetics after single and multiple doses of IONIS ANGPTL3-LRx. | The plasma pharmacokinetics (concentration-time results) of IONIS ANGPTL3-LRx (unconjugated and conjugated ASO) will be assessed following single and multiple-dose SC administration. The amount of IONIS ANGPTL3-LRx excreted in urine at selected 24-hour intervals will also be determined. | Up to Day 127 | 
| Pharmacodynamics of IONIS ANGPTL3-LRx (Changes in serum ANGPTL3 levels) | Changes in serum angiopoietin-like 3 (ANGPTL3) levels compared to baseline. | Up to Day 127 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamic effects of IONIS ANGPTL3-LRx | Effects of IONIS ANGPTL3-LRx on changes in ANGPTL3 plasma protein compared to baseline. | Up to Day 127 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ANGPTL-3