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

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

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.

Study Overview

• Status: Completed
• Conditions: Hypertriglyceridemia; Familial Hypercholesterolemia
• Intervention / Treatment: Drug: Placebo; Drug: IONIS ANGPTL3-LRx

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M9L 3A2
      • Clinical Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

11

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.
• Collaborators: Akcea Therapeutics

Publications and helpful links

General Publications

• Graham MJ, Lee RG, Brandt TA, Tai LJ, Fu W, Peralta R, Yu R, Hurh E, Paz E, McEvoy BW, Baker BF, Pham NC, Digenio A, Hughes SG, Geary RS, Witztum JL, Crooke RM, Tsimikas S. Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides. N Engl J Med. 2017 Jul 20;377(3):222-232. doi: 10.1056/NEJMoa1701329. Epub 2017 May 24.

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2015
• Primary Completion (Actual): April 12, 2017
• Study Completion (Actual): June 26, 2017

Study Registration Dates

• First Submitted: November 22, 2015
• First Submitted That Met QC Criteria: March 10, 2016
• First Posted (Estimate): March 16, 2016

Study Record Updates

• Last Update Posted (Actual): November 19, 2020
• Last Update Submitted That Met QC Criteria: November 17, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: ANGPTL-3
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hypertriglyceridemia; Hyperlipoproteinemia Type II
• Other Study ID Numbers: ISIS 703802-CS1; 2015-004003-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No