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

Hypertriglyceridemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02709850
• Other study ID #: ISIS 703802-CS1
• Secondary ID: 2015-004003-23
• Status: Completed
• Phase: Phase 1
• Start date: November 30, 2015
• Est. completion date: June 26, 2017

Study information

• Verified date: November 2020
• Source: Ionis Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: June 26, 2017
• Est. primary completion date: April 12, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Familial Hypercholesterolemia
• Hypercholesterolemia
• Hyperlipoproteinemia Type II
• Hypertriglyceridemia

Intervention

Drug:
• IONIS ANGPTL3-LRx

• Placebo
0.9%NaCl, water, riboflavin

Locations

Country	Name	City	State
Canada	Clinical Site	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
Ionis Pharmaceuticals, Inc.	Akcea Therapeutics

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	Pharmacodynamic effects of IONIS ANGPTL3-LRx	Effects of IONIS ANGPTL3-LRx on changes in ANGPTL3 plasma protein compared to baseline.	Up to Day 127