Clinical trial NCT02709850: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS ANGPTL3-LRx in Healthy Volunteers With Elevated Triglycerides and Participants With Familial Hypercholesterolemia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hypertriglyceridemia
Familial Hypercholesterolemia
Keywords: ANGPTL-3
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Akcea Therapeutics
First posted: 2016-03-16
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.


Eligibility criteria: 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

Primary outcomes:
measure: 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)
timeFrame: Up to Day 127
measure: Pharmacokinetics after single and multiple doses of IONIS ANGPTL3-LRx.
timeFrame: Up to Day 127
measure: Pharmacodynamics of IONIS ANGPTL3-LRx (Changes in serum ANGPTL3 levels)
timeFrame: Up to Day 127
Secondary outcomes:
measure: Pharmacodynamic effects of IONIS ANGPTL3-LRx
timeFrame: Up to Day 127
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Clinical Site
state: Ontario
Study officials:
References:
citation: 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.