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

NCT02709850 | Completed Phase 1 FDA Drug

• 2 other identifiers: ISIS 703802-CS12015-004003-23
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hypertriglyceridemia; Familial Hypercholesterolemia

Keywords

ANGPTL-3

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (1)

• Pharmacodynamic effects of IONIS ANGPTL3-LRx

  Up to Day 127

Study Arms (11)

Cohorts A, D: Placebo

PLACEBO COMPARATOR

Participants received a single-dose of IONIS ANGPTL3-LRx-matching placebo subcutaneously on Day 1.

Drug: Placebo

Cohorts A, D: IONIS ANGPTL3-LRx 20 mg

EXPERIMENTAL

Participants received a single-dose of IONIS ANGPTL3-LRx 20 milligrams (mg) subcutaneously on Day 1.

Drug: IONIS ANGPTL3-LRx

Cohorts A, D: IONIS ANGPTL3-LRx 120 mg

EXPERIMENTAL

Participants received a single-dose of IONIS ANGPTL3-LRx 120 mg subcutaneously on Day 1.

Drug: IONIS ANGPTL3-LRx

Cohorts B, C: Placebo

PLACEBO COMPARATOR

Participants received a single-dose of IONIS ANGPTL3-LRx-matching placebo subcutaneously on Day 1.

Drug: Placebo

Cohorts B, C: IONIS ANGPTL3-LRx 40 mg

EXPERIMENTAL

Participants received a single-dose of IONIS ANGPTL3-LRx 40 mg subcutaneously on Day 1.

Drug: IONIS ANGPTL3-LRx

Cohorts B, C: IONIS ANGPTL3-LRx 80 mg

EXPERIMENTAL

Participants received a single-dose of IONIS ANGPTL3-LRx 80 mg subcutaneously on Day 1.

Drug: IONIS ANGPTL3-LRx

Cohorts AA-DD: Placebo

PLACEBO COMPARATOR

Participants received IONIS ANGPTL3-LRx-matching placebo subcutaneously once per week for 6 weeks.

Drug: Placebo

Cohorts AA-DD: IONIS ANGPTL3-LRx 10 mg

EXPERIMENTAL

Participants received IONIS ANGPTL3-LRx 10 mg subcutaneously once per week for 6 weeks.

Drug: IONIS ANGPTL3-LRx

Cohorts AA-DD: IONIS ANGPTL3-LRx 20 mg

EXPERIMENTAL

Participants received IONIS ANGPTL3-LRx 20 mg subcutaneously once per week for 6 weeks.

Drug: IONIS ANGPTL3-LRx

Cohorts AA-DD: IONIS ANGPTL3-LRx 40 mg

EXPERIMENTAL

Participants received IONIS ANGPTL3-LRx 40 mg subcutaneously once per week for 6 weeks.

Drug: IONIS ANGPTL3-LRx

Cohorts AA-DD: IONIS ANGPTL3-LRx 60 mg

EXPERIMENTAL

Participants received IONIS ANGPTL3-LRx 60 mg subcutaneously once per week for 6 weeks.

Drug: IONIS ANGPTL3-LRx

Interventions

IONIS ANGPTL3-LRx DRUG

Also known as: ISIS 703802

Cohorts A, D: IONIS ANGPTL3-LRx 120 mg; Cohorts A, D: IONIS ANGPTL3-LRx 20 mg; Cohorts AA-DD: IONIS ANGPTL3-LRx 10 mg; Cohorts AA-DD: IONIS ANGPTL3-LRx 20 mg; Cohorts AA-DD: IONIS ANGPTL3-LRx 40 mg; Cohorts AA-DD: IONIS ANGPTL3-LRx 60 mg; Cohorts B, C: IONIS ANGPTL3-LRx 40 mg; Cohorts B, C: IONIS ANGPTL3-LRx 80 mg

Placebo DRUG

0.9%NaCl, water, riboflavin

Cohorts A, D: Placebo; Cohorts AA-DD: Placebo; Cohorts B, C: Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Fasting triglycerides (TG) ≥ 150 mg/dL at Screening
• Fasting low density lipoprotein cholesterol (LDL-C) \> 70 mg/dL at Screening
• Fasting TG 90 - 150 mg/dL at Screening
• Fasting LDL-C \> 70 mg/dL at Screening
• Homozygous FH diagnosis and fasting LDL-C ≥ 190 mg/dL (4.9 mmol/L)
• Heterozygous FH diagnosis and fasting LDL-C ≥ 160 mg/dL (4.1 mmol/L)
• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Ionis Pharmaceuticals, Inc.: lead
• Akcea Therapeutics: collaborator

Study Sites (1)

Clinical Site

Toronto, Ontario, M9L 3A2, Canada

Location

Related Publications (1)

• 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.

  PMID: 28538111 DERIVED

MeSH Terms

Conditions

Hypertriglyceridemia; Hyperlipoproteinemia Type II

Interventions

IONIS-ANGPTL3-LRx

Condition Hierarchy (Ancestors)

Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hyperlipoproteinemias

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 22, 2015
• First Posted: March 16, 2016
• Study Start: November 30, 2015
• Primary Completion: April 12, 2017
• Study Completion: June 26, 2017
• Last Updated: November 19, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)