Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS APO(a)-LRx in Healthy Volunteers With Elevated Lipoprotein(a)

A Blinded, Placebo-Controlled, Dose-Escalation, Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of ISIS 681257 Administered Subcutaneously to Healthy Volunteers With Elevated Lipoprotein(a)

The purpose is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of IONIS APO(a)-LRx (ISIS 681257) given to healthy volunteer subjects.

Study Overview

• Status: Completed
• Conditions: Elevated Lipoprotein(a)
• Intervention / Treatment: Drug: Sterile Normal Saline (0.9% NaCl); Drug: IONIS-APO(a)-LRx

• Study Type: Interventional
• Enrollment (Actual): 60
• 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: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Must have given written informed consent and be able to comply with all study requirements
• Healthy males or females aged 18-65 inclusive and weighing ≥ 50 kg at the time of informed consent
• Females must be non-pregnant and non-lactating, and either surgically sterile or post- menopausal
• Males must be surgically sterile, abstinent or using an acceptable contraceptive method
• BMI < 35.0 kg/m2
• Subjects must have Lp(a) ≥ 75 nanomoles/liter nmol/L (30 mg/dL) at Screening

Exclusion Criteria:

• Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B
• Treatment with another Study Drug, biological agent, or device within one-month of screening
• Regular use of alcohol within 6 months of Screening
• Use of concomitant drugs unless authorized by the Sponsor Medical Monitor
• Smoking > 10 cigarettes a day
• Considered unsuitable for inclusion by the Principal Investigator

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IONIS-APO(a)-LRx; Drug: IONIS-APO(a)-LRx	Drug: IONIS-APO(a)-LRx; Ascending single and multiple doses of IONIS-APO(a)-LRx by subcutaneous (SC) injection
Placebo Comparator: Placebo (Normal Saline); Drug: Sterile Normal Saline (0.9% NaCl)	Drug: Sterile Normal Saline (0.9% NaCl); Calculated volume to match active comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the safety and tolerability of single and multiple doses of IONIS-APO(a)-LRx (incidence, severity, and dose-relationship of adverse effects and changes in the laboratory parameters)	The safety and tolerability of IONIS-APO(a)-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-APO(a)-LRx will be compared with those from subjects dosed with placebo.	Up to 113 days
To evaluate the pharmacokinetics of single and multiple doses of IONIS-APO(a)-LRx (unconjugated and conjugated ASO)	The plasma pharmacokinetics of IONIS-APO(a)-LRx (unconjugated and conjugated ASO) will be assessed following single and multiple-dose SC administration. The amount of ISIS-APO(a)-LRx excreted in urine at selected 24-hour intervals will also be determined.	Up to 113 days
To evaluate the plasma pharmacodynamics of IONIS-APO(a)-LRx (Changes in plasma Lp(a) levels)	Changes in plasma Lp(a) levels compared to baseline.	Up to 113 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx	Effects of IONIS-APO(a)-LRx on changes in levels of oxidized phospholipids associated with apoB-100 compared to baseline.	Up to 113 days
Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx	Effects of IONIS-APO(a)-LRx on changes in levels of oxidized phospholipids associated with apo(a) compared to baseline.	Up to 113 days
Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx	Effects of IONIS-APO(a)-LRx on changes in Lp-PLA2 compared to baseline.	Up to 113 days
Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx	Effects of IONIS-APO(a)-LRx on changes in sPLA2 compared to baseline.	Up to 113 days
Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx	Effects of IONIS-APO(a)-LRx on changes in apo(a) isoform size compared to baseline.	Up to 113 days
Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx	Effects of ISIS-APO(a)-LRx on changes in lipid panel compared to baseline.	Up to 113 days
Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx	Effects of IONIS-APO(a)-LRx on changes in systemic markers of inflammation compared to baseline.	Up to 113 days
Exploratory pharmacodynamic effects of IONIS-APO(a)-LRx	Effects of IONIS-APO(a)-LRx on changes in plasminogen/coagulation compared to baseline.	Up to 113 days

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu RZ, Marcovina SM, Hughes SG, Graham MJ, Crooke RM, Crooke ST, Witztum JL, Stroes ES, Tsimikas S. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet. 2016 Nov 5;388(10057):2239-2253. doi: 10.1016/S0140-6736(16)31009-1. Epub 2016 Sep 21.

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: April 1, 2015
• First Submitted That Met QC Criteria: April 7, 2015
• First Posted (Estimate): April 13, 2015

Study Record Updates

• Last Update Posted (Actual): December 5, 2018
• Last Update Submitted That Met QC Criteria: December 3, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Other Study ID Numbers: IONIS-APO(a)-LRx