Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS-APO(a)Rx in Participants With High Lipoprotein(a)

A Randomized, Double Blind, Placebo-Controlled, Dose Titration, Phase 2 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS 494372 Administered Subcutaneously to Patients With High Lipoprotein(a)

The purpose is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of ISIS-APO(a)Rx given to participants with high lipoprotein(a) for 12 weeks.

Study Overview

• Status: Completed
• Conditions: Elevated Lipoprotein(a)
• Intervention / Treatment: Drug: Placebo; Drug: ISIS-APO(a)Rx

Detailed Description

Lipoprotein(a) [Lp(a)] is a genetic variant of low-density lipoprotein (LDL) in which the apolipoprotein B (apoB) -100 component of LDL is linked by a disulfide bond to apolipoprotein(a) [apo(a)], the distinct protein component of Lp(a) that is mainly responsible for its signature structural and functional properties. Lp(a) is now recognized as an important genetic risk factor for coronary artery disease, stroke and aortic stenosis.

The purpose of this study is to determine if ISIS-APO(a)Rx can reduce the production of apolipoprotein(a), or apo(a). This study will enroll 50 participants with Lipoprotein(a) ≥50 and <175 mg/dL and 10 participants with Lipoprotein(a) ≥175 mg/dL.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G1V4M6
    • Clinique des Maladies Lipidiques de Quebec Inc.
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 5H6
      • Chicoutimi Hospital
• Denmark
  • Herlev, Denmark, 2730
    • Herlev University Hospital
• Germany
  • Berlin, Germany, 13353
    • Charite - University Hospital Berlin - Campus Virchow - Hospital
  • Koln, Germany, 50937
    • Uniklinik Koeln, Zentrum fuer Endokrinologie, Diabetologie und Praeventivmedizin (ZEDP)
  • Magdeburg, Germany, 39120
    • Otto-von Guericke Universitaet, Uniklinik Magdeburg
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • University of Amsterdam - Dept. of Vascular Medicine F4-109
  • Maastricht, Netherlands, 6229 HX
    • Academic Hospital Maastricht
  • Rotterdam, Netherlands, 3045 PM
    • Sint Franciscus Gasthuis
  • Utrecht, Netherlands, 3584 CX
    • University Medical Center Utrecht
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
    • Heart of England NHS Foundation Trust
  • Manchester, United Kingdom, M20 2RN
    • Barlow Medical Centre
  • Newcastle Upon Tyne, United Kingdom, NE1 4LP
    • Newcastle upon Tyne Hospitals

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:

• Males or females aged 18-65 inclusive
• Females must be non-pregnant and non-lactating, and either surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or post-menopausal (defined as 12 months of spontaneous amenorrhea without an alternative medical cause and follicle-stimulating hormone (FSH) levels in the postmenopausal range for the laboratory involved)
• Males must be surgically sterile, abstinent or if engaged in sexual relations with a female of child-bearing potential, the participant must be using an acceptable contraceptive method from the time of signing the informed consent form until at least 16 weeks after the last dose of Study Drug
• Body mass index (BMI) ≤40 kg/m2
• Lipoprotein(a) ≥50 and <175 mg/dL at time of screening (Cohort A)
• Lipoprotein(a) ≥175 mg/dL at time of screening (Cohort B)

Exclusion Criteria:

• Clinically significant abnormalities in medical history (e.g., documented previous myocardial infarction, percutaneous coronary intervention (PCI), or major surgery within 3 months of screening, planned surgery that would occur during the study) or physical examination at screening
• Clinically significant abnormalities in screening laboratory values that would render a participant unsuitable for inclusion
• Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
• Known history or positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B
• Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated
• History of bleeding diathesis or coagulopathy
• Recent history of, or current drug or alcohol abuse
• Participant with Lp(a) ≥50 and <175 mg/dL may not receive concomitant niacin therapy during the period 8 weeks prior to screening through the end of the Post-Treatment Evaluation Period
• Use of statins, ezetimibe or fibrates unless on a stable regimen for at least 8 weeks prior to dosing and will remain on a stable regimen for the duration of the study
• Use of lipid or Lp(a)-specific apheresis within 4 weeks prior to Screening through the end of the Post-Treatment Evaluation Period
• Use of concomitant drugs (including herbal or over-the-counter (OTC) medications other than ibuprofen, Benadryl or topical steroids) unless authorized by the Sponsor Medical Monitor
• Blood donation of 50-499 mL within 30 days of screening or of >499 mL within 8 weeks of screening
• Have any other conditions, which, in the opinion of the Investigator would make the participant unsuitable for inclusion, or could interfere with the participant participating in or completing the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Cohort A: Placebo; Participants will receive placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.	Drug: Placebo; Normal saline as Placebo, subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.
Experimental: Cohort A: ISIS-APO(a)Rx < 2000 mg; Participants will receive ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.	Drug: ISIS-APO(a)Rx; ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.; Other Names: ISIS 494372
Experimental: Cohort A: ISIS-APO(a)Rx >= 2000 mg; Participants will receive ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.	Drug: ISIS-APO(a)Rx; ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.; Other Names: ISIS 494372
Placebo Comparator: Cohort B: Placebo; Participants will receive placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.	Drug: Placebo; Normal saline as Placebo, subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.
Experimental: Cohort B: ISIS-APO(a)Rx < 2000 mg; Participants will receive ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.	Drug: ISIS-APO(a)Rx; ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.; Other Names: ISIS 494372
Experimental: Cohort B: ISIS-APO(a)Rx >= 2000 mg; Participants will receive ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.	Drug: ISIS-APO(a)Rx; ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.; Other Names: ISIS 494372

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Lipoprotein Lp(a) Plasma Concentration at Day 85/Day 99	Data are reported for evaluable participants.	Day 85/Day 99
Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE)	An adverse event is any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product.	Up to approximately 32 weeks

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

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.
• Tragante V, Asselbergs FW, Swerdlow DI, Palmer TM, Moore JH, de Bakker PIW, Keating BJ, Holmes MV. Harnessing publicly available genetic data to prioritize lipid modifying therapeutic targets for prevention of coronary heart disease based on dysglycemic risk. Hum Genet. 2016 May;135(5):453-467. doi: 10.1007/s00439-016-1647-9. Epub 2016 Mar 5.

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: June 5, 2014
• First Submitted That Met QC Criteria: June 9, 2014
• First Posted (Estimate): June 11, 2014

Study Record Updates

• Last Update Posted (Actual): December 20, 2019
• Last Update Submitted That Met QC Criteria: December 17, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: High Lipoprotein(a)
• Other Study ID Numbers: ISIS 494372-CS3