Phase 2 Study of ISIS 681257 (AKCEA-APO(a)-LRx) in Participants With Hyperlipoproteinemia(a) and Cardiovascular Disease

A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of ISIS 681257 (AKCEA-APO(a)-LRx) Administered Subcutaneously to Patients With Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)

This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the safety, including tolerability, of ISIS 681257 and to assess the efficacy of different doses and dosing regimens of ISIS 681257 for reduction of plasma Lipoprotein(a) [Lp(a)] levels in participants with hyperlipoproteinemia(a) and established cardiovascular disease (CVD).

Study Overview

• Status: Completed
• Conditions: Cardiovascular Disease; Elevated Lipoprotein(a)
• Intervention / Treatment: Drug: ISIS 681257; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 286
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ottawa, Canada, K1Y4W7
    • Clinical Site
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H7K9
      • Clinical Site
    • Montreal, Quebec, Canada, H1T 1C8
      • Clinical Site
    • Montréal, Quebec, Canada, H3H 2L9
      • Clinical Site
    • Québec, Quebec, Canada, G1V4W2
      • Clinical Site
• Denmark
  • Herlev, Denmark, 2730
    • Clinical Site
  • Viborg, Denmark, 8800
    • Clinical Site
• Germany
  • Berlin, Germany, 13353
    • Clinical Site
  • Cologne, Germany, 50937
    • Clinical Site
• Netherlands
  • Amsterdam, Netherlands, 1105AZ
    • Clinical Site
• United States
  • Arizona
    • Cottonwood, Arizona, United States, 86326
      • Clinical Site
  • California
    • Huntington Beach, California, United States, 92648
      • Clinical Site
    • La Jolla, California, United States, 92103
      • Clinical Site
    • Los Angeles, California, United States, 90048
      • Clinical Site
    • Stanford, California, United States, 94305
      • Clinical Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80909
      • Clinical Site
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Clinical Site
    • Jacksonville, Florida, United States, 32216
      • Clinical Site
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Clinical Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Clinical Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Clinical Site
  • New York
    • Cooperstown, New York, United States, 13326
      • Clinical Site
    • New York, New York, United States, 10016
      • Clinical Site
    • New York, New York, United States, 10029
      • Clinical Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Clinical Site
  • Oregon
    • Portland, Oregon, United States, 97239
      • Clinical Site
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17602
      • Clinical Site
    • Philadelphia, Pennsylvania, United States, 19104
      • Clinical Site
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • Clinical Site
  • Texas
    • Houston, Texas, United States, 77030
      • Clinical Site
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Clinical Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Clinical Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Clinical diagnosis of CVD defined as documented coronary artery disease, stroke, or peripheral artery disease
• Lp(a) plasma level ≥ 60 mg/dL
• Must be on standard-of-care preventative therapy for other than elevated Lp(a) CVD risk factors

Key Exclusion Criteria:

• Within 6 months of Screening: acute coronary syndrome, major cardiac surgery, or stroke/TIA
• Within 3 months of Screening: coronary, carotid, or peripheral arterial revascularization, major non-cardiac surgery, or lipoprotein apheresis
• Heart failure New York Heart Association (NYHA) class IV

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A: ISIS 681257: 20 mg Q4W; Cohort A participants received 20 milligrams (mg) ISIS 681257, subcutaneous (SC) injection, once every 4 weeks (Q4W), for up to 49 weeks and a maximum of 13 doses.	Drug: ISIS 681257; ISIS 681257 solution for SC injection.; Other Names: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen
Experimental: Cohort B: ISIS 681257: 40 mg Q4W; Cohort B participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.	Drug: ISIS 681257; ISIS 681257 solution for SC injection.; Other Names: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen
Experimental: Cohort C: ISIS 681257: 60 mg Q4W; Cohort C participants received 60 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.	Drug: ISIS 681257; ISIS 681257 solution for SC injection.; Other Names: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen
Experimental: Cohort D: ISIS 681257: 20 mg Q2W; Cohort D participants received 20 mg of ISIS 681257, SC injection, once every 2 weeks (Q2W), for up to 51 weeks and a maximum of 26 doses.	Drug: ISIS 681257; ISIS 681257 solution for SC injection.; Other Names: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen
Experimental: Cohort E: ISIS 681257: 20 mg QW; Cohort E participants received 20 mg of ISIS 681257, SC injection, once weekly (QW), for up to 52 weeks and a maximum of 52 doses.	Drug: ISIS 681257; ISIS 681257 solution for SC injection.; Other Names: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen
Placebo Comparator: Placebo; Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).	Drug: Placebo; Sterile normal saline (0.9% NaCl)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point	An ANCOVA model was performed on the log ratio of Lp(a) value at the Primary Analysis Time Point to Lp(a) value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of Lp(a) value at the Primary Analysis Time Point to Lp(a) value at Baseline - 1) × 100.	Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	An adverse event (AE) was defined as any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAEs was defined as any AE with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study.	Up to 16 weeks post treatment period (up to approximately 1.3 years)
Number of Participants With TEAEs by Maximum Severity	An AE was defined as any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAEs was defined as any AE with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study. The severity of TEAEs was assessed based on the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. TEAEs were graded on a 5-point scale where 1 = Mild, 2 = Moderate, 3 = Severe, 4 = Potentially life-threatening and 5 = Death.	Up to 16 weeks post treatment period (up to approximately 1.3 years)
Number of Participants With TEAEs Leading to Study Discontinuation	An AE was defined as any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAE was defined as any AE with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study.	Up to 16 weeks post treatment period (up to approximately 1.3 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C)	An ANCOVA model was performed on the log ratio of LDL-C value at the Primary Analysis Time Point to LDL-C value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of LDL-C value at the Primary Analysis Time Point to LDL-C value at Baseline - 1) × 100.	Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL)	The percentage of participants who achieved ≤ 125 nmol/L or ≤ 50 mg/dL in fasting Lp(a) at the primary analysis time point were compared between each ISIS 681257 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline Lp(a) as a covariate.	Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL	The percentage of participants who achieved ≤ 75 nmol/L or ≤ 30 mg/dL in fasting Lp(a) at the primary analysis time point were compared between each ISIS 681257 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline Lp(a) as a covariate.	Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB)	An ANCOVA model was performed on the log ratio of apoB value at the Primary Analysis Time Point to apoB value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of apoB value at the Primary Analysis Time Point to apoB value at Baseline - 1) × 100.	Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)]	An ANCOVA model was performed on the log ratio of OxPL-apo(a) value at the Primary Analysis Time Point to OxPL-apo(a) value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of OxPL-apo(a) value at the Primary Analysis Time Point to OxPL-apo(a) value at Baseline - 1) × 100.	Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)
Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB)	An ANCOVA model was performed on the log ratio of OxPL-apoB value at the Primary Analysis Time Point to OxPL-apoB value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of OxPL-apoB value at the Primary Analysis Time Point to OxPL-apoB value at Baseline - 1) × 100.	Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Evaluate Plasma Cmax of ISIS 681257 Across Different Doses and Dose Regimens.	Cmax will be calculated for the treatment groups.	6 months
To Evaluate Plasma Tmax of ISIS 681257 Across Different Doses and Dose Regimens.	Tmax will be calculated for the treatment groups.	6 months
To Evaluate Plasma AUC Values of ISIS 681257 Across Different Doses and Dose Regimens.	AUC values will be calculated for the treatment groups.	6 months

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Stiekema LCA, Prange KHM, Hoogeveen RM, Verweij SL, Kroon J, Schnitzler JG, Dzobo KE, Cupido AJ, Tsimikas S, Stroes ESG, de Winther MPJ, Bahjat M. Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a). Eur Heart J. 2020 Jun 21;41(24):2262-2271. doi: 10.1093/eurheartj/ehaa171.
• Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, Baum SJ, Steinhagen-Thiessen E, Shapiro MD, Stroes ES, Moriarty PM, Nordestgaard BG, Xia S, Guerriero J, Viney NJ, O'Dea L, Witztum JL; AKCEA-APO(a)-LRx Study Investigators. Lipoprotein(a) Reduction in Persons with Cardiovascular Disease. N Engl J Med. 2020 Jan 16;382(3):244-255. doi: 10.1056/NEJMoa1905239. Epub 2020 Jan 1.

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2017
• Primary Completion (Actual): July 26, 2018
• Study Completion (Actual): November 13, 2018

Study Registration Dates

• First Submitted: January 31, 2017
• First Submitted That Met QC Criteria: February 28, 2017
• First Posted (Actual): March 6, 2017

Study Record Updates

• Last Update Posted (Actual): October 30, 2020
• Last Update Submitted That Met QC Criteria: October 26, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Dyslipidemia; Lipoprotein(a); Hyperlipidemia; Lipoprotein; Lp(a); Dyslipoproteinemia; Lipoprotein a; IONIS-APO(a)-LRx; AKCEA-APO(a)-LRx; Hyperlipoproteinemia; Hyperlipoproteinemia(a); Hyperlipoproteinemia a; Lp a
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Dyslipidemias; Cardiovascular Diseases; Hyperlipidemias; Hyperlipoproteinemias
• Other Study ID Numbers: ISIS 681257-CS6; 2016-003373-18 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No